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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 01 Jun 2023 at 01:45 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: ( fhcrc[Affiliation] OR "fred hutchinson"[Affiliation] OR "Fred Hutchinson Cancer Research"[Affiliation] OR "Fred Hutch"[affiliation] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2023-05-31

Phillips NS, Stratton KL, Williams AM, et al (2023)

Late-onset Cognitive Impairment and Modifiable Risk Factors in Adult Childhood Cancer Survivors.

JAMA network open, 6(5):e2316077 pii:2805444.

IMPORTANCE: Long-term survivors of childhood cancer may be at elevated risk for new neurocognitive impairment and decline as they age into adulthood.

OBJECTIVE: To determine whether aging adult childhood cancer survivors report more new-onset neurocognitive impairments compared with their siblings and to identify risk factors associated with such impairments.

Participants of this cohort study included adult survivors of childhood cancer from the Childhood Cancer Survivor Study and their siblings as a control group. The original cohort included survivors who received a diagnosis between January 1, 1970, and December 31, 1986, for whom longitudinal neurocognitive assessment was available. This study examined the prevalence of new-onset neurocognitive impairment between baseline (23.4 years after diagnosis) and follow-up (35.0 years after diagnosis). The analysis was performed from January 2021 to May 2022.

EXPOSURES: Cancer treatment exposures were abstracted from medical records. Chronic health conditions were graded using Common Terminology Criteria for Adverse Events version 4.03.

MAIN OUTCOMES AND MEASURES: The primary outcome was new-onset (present at follow-up, but not present at baseline) neurocognitive impairment (defined as a score in the worst 10% of the sibling cohort). Impairment was assessed using the Childhood Cancer Survivor Study Neurocognitive questionnaire. Relative risks (RRs) and 95% CIs were used to estimate associations of neurocognitive impairment with treatment and health behaviors and conditions using generalized linear models.

RESULTS: The cohort comprised 2375 survivors (mean [SD] age at evaluation, 31.8 [7.5] years; 1298 women [54.6%]) of childhood cancer, including acute lymphoblastic leukemia (ALL; 1316 participants), central nervous system (CNS) tumors (488 participants), and Hodgkin lymphoma (HL; 571 participants). A total of 232 siblings (mean [SD] age at evaluation, 34.2 [8.4] years; 134 women [57.8%]) were included. Compared with siblings, a higher proportion of survivors with no impairment in memory at baseline had new-onset memory impairment at follow-up: siblings proportion, 7.8% (95% CI, 4.3%-11.4%); ALL survivors treated with chemotherapy only, 14.0% (95% CI, 10.7%-17.4%); ALL survivors treated with cranial radiation (CRT), 25.8% (95% CI, 22.6%-29.0%); CNS tumor survivors, 34.7% (95% CI, 30.0%-39.5%); and HL survivors, 16.6% (95% CI, 13.4%-19.8%). New-onset memory impairment was associated with CRT in CNS tumor survivors (RR, 1.97; 95% CI, 1.33-2.90) and alkylator chemotherapy greater than or equal to 8000 mg/m2 in ALL survivors treated without CRT (RR, 2.80; 95% CI, 1.28-6.12). Neurologic conditions mediated the impact of CRT on new-onset memory impairment in CNS survivors. Smoking, low educational attainment, and low physical activity were associated with elevated risk for new-onset memory impairment.

CONCLUSIONS AND RELEVANCE: These findings suggest that adult survivors of childhood cancer are at elevated risk for late-onset memory impairment related to modifiable risk factors identified early in survivorship.

RevDate: 2023-05-31

Fuller H, Iles MM, Moore JB, et al (2023)

Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort.

Frontiers in endocrinology, 14:1157416.

INTRODUCTION: Gestational diabetes mellitus (GDM) is the most common pregnancy complication worldwide and is associated with short- and long-term health implications for both mother and child. Prevalence of GDM varies between ethnicities, with South Asians (SAs) experiencing up to three times the risk compared to white Europeans (WEs). Recent evidence suggests that underlying metabolic difference contribute to this disparity, but an investigation of causality is required.

METHODS: To address this, we paired metabolite and genomic data to evaluate the causal effect of 146 distinct metabolic characteristics on gestational dysglycemia in SAs and WEs. First, we performed 292 GWASs to identify ethnic-specific genetic variants associated with each metabolite (P ≤ 1 x 10-5) in the Born and Bradford cohort (3688 SA and 3354 WE women). Following this, a one-sample Mendelian Randomisation (MR) approach was applied for each metabolite against fasting glucose and 2-hr post glucose at 26-28 weeks gestation. Additional GWAS and MR on 22 composite measures of metabolite classes were also conducted.

RESULTS: This study identified 15 novel genome-wide significant (GWS) SNPs associated with tyrosine in the FOXN and SLC13A2 genes and 1 novel GWS SNP (currently in no known gene) associated with acetate in SAs. Using MR approach, 14 metabolites were found to be associated with postprandial glucose in WEs, while in SAs a distinct panel of 11 metabolites were identified. Interestingly, in WEs, cholesterols were the dominant metabolite class driving with dysglycemia, while in SAs saturated fatty acids and total fatty acids were most commonly associated with dysglycemia.

DISCUSSION: In summary, we confirm and demonstrate the presence of ethnic-specific causal relationships between metabolites and dysglycemia in mid-pregnancy in a UK population of SA and WE pregnant women. Future work will aim to investigate their biological mechanisms on dysglycemia and translating this work towards ethnically tailored GDM prevention strategies.

RevDate: 2023-05-31

VoPham T, Cravero A, Feld LD, et al (2023)

Associations of Race and Ethnicity with Hepatocellular Carcinoma, Decompensation, and Mortality in US Veterans with Cirrhosis.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:727074 [Epub ahead of print].

BACKGROUND: Among patients with cirrhosis, it remains unclear whether there are racial/ethnic differences in cirrhosis complications and mortality. We examined the associations between race/ethnicity and risk for hepatocellular carcinoma (HCC), cirrhosis decompensation, and all-cause mortality overall and by cirrhosis etiology.

METHODS: US Veterans diagnosed with cirrhosis from 2001 to 2014 (n = 120,992), due to hepatitis C virus (HCV; n = 55,814), alcohol-associated liver disease (ALD; n = 36,323), hepatitis B virus (HBV; n = 1,972), nonalcoholic fatty liver disease (NAFLD; n = 17,789), or other (n = 9,094), were followed through 2020 for incident HCC (n = 10,242), cirrhosis decompensation (n = 27,887), and mortality (n = 81,441). Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI).

RESULTS: Compared with non-Hispanic White patients, Hispanic patients had higher risk for HCC overall (aHR, 1.32; 95% CI, 1.24-1.41) and by cirrhosis etiology, particularly for ALD- (aHR, 1.63; 95% CI, 1.42-1.87) and NAFLD-cirrhosis (aHR, 1.76; 95% CI, 1.41-2.20), whereas non-Hispanic Black patients had lower HCC risk in ALD- (aHR, 0.79; 95% CI, 0.63-0.98) and NAFLD-cirrhosis (aHR, 0.54; 95% CI, 0.33-0.89). Asian patients had higher HCC risk (aHR, 1.70; 95% CI, 1.29-2.23), driven by HCV- and HBV-cirrhosis. Non-Hispanic Black patients had lower risk for cirrhosis decompensation overall (aHR, 0.71; 95% CI, 0.68-0.74) and by cirrhosis etiology. There was lower risk for mortality among all other racial/ethnic groups compared with non-Hispanic White patients.

CONCLUSIONS: Race/ethnicity is an important predictor for risk of developing HCC, decompensation, and mortality.

IMPACT: Future research should examine factors underlying these racial/ethnic differences to inform prevention, screening, and treatment for patients with cirrhosis.

RevDate: 2023-05-30

Yarborough S, Fitzpatrick A, Schwartz SM, et al (2023)

Author Correction: Evaluation of cognitive function in the Dog Aging Project: associations with baseline canine characteristics.

Scientific reports, 13(1):8753 pii:10.1038/s41598-023-34875-5.

RevDate: 2023-05-30

Cai CR, Cornelius S, Demedis J, et al (2023)

Experiences of adult survivors of childhood cancer in a randomized cardiovascular health promotion trial: a qualitative report from the Childhood Cancer Survivor Study.

Journal of cancer survivorship : research and practice [Epub ahead of print].

PURPOSE: To better understand preferences and attitudes that adult-aged survivors of childhood cancer have toward survivorship care plans (SCP) and related SCP-based counseling.

METHODS: Semi-structured qualitative interviews were conducted with 20 survivors participating in the Childhood Cancer Survivor Study who were at increased risk for cardiovascular disease secondary to their original cancer treatment. All participants were part of a larger randomized clinical trial (NCT03104543) testing the efficacy of an SCP-based counseling intervention with goal-setting designed to improve control of cardiovascular risk factors (i.e., hypertension, dyslipidemia, diabetes). A primarily deductive thematic analysis methodology guided interpretation; coded interview segments were grouped into primary themes of facilitators, barriers, suggestions, and positive sentiments.

RESULTS: Participants described benefits of the intervention including facilitation of accountability, goal-setting, and increased knowledge of their health. Many participants also noted improved knowledge of their cancer treatment and subsequent risks, and they were interested in sharing this information with their primary care provider. However, several participants were disappointed when they did not achieve their goals or felt that they had low motivation. Participants generally wanted increased flexibility in the intervention, whether in the duration, frequency, or method of delivery.

CONCLUSIONS: The SCP-based intervention was generally well-received by those interviewed and appears promising for promoting goal-setting and accountability as part of an SCP-based intervention to improve control of cardiovascular risk factors.

Many survivors are at risk for cardiovascular disease or other potentially modifiable effects of their treatment. SCP-based interventions may facilitate improved control of these late effects.

RevDate: 2023-05-30

Glunk V, Laber S, Sinnott-Armstrong N, et al (2023)

A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes.

Nature metabolism, 5(5):861-879.

Recent large-scale genomic association studies found evidence for a genetic link between increased risk of type 2 diabetes and decreased risk for adiposity-related traits, reminiscent of metabolically obese normal weight (MONW) association signatures. However, the target genes and cellular mechanisms driving such MONW associations remain to be identified. Here, we systematically identify the cellular programmes of one of the top-scoring MONW risk loci, the 2q24.3 risk locus, in subcutaneous adipocytes. We identify a causal genetic variant, rs6712203, an intronic single-nucleotide polymorphism in the COBLL1 gene, which changes the conserved transcription factor motif of POU domain, class 2, transcription factor 2, and leads to differential COBLL1 gene expression by altering the enhancer activity at the locus in subcutaneous adipocytes. We then establish the cellular programme under the genetic control of the 2q24.3 MONW risk locus and the effector gene COBLL1, which is characterized by impaired actin cytoskeleton remodelling in differentiating subcutaneous adipocytes and subsequent failure of these cells to accumulate lipids and develop into metabolically active and insulin-sensitive adipocytes. Finally, we show that perturbations of the effector gene Cobll1 in a mouse model result in organismal phenotypes matching the MONW association signature, including decreased subcutaneous body fat mass and body weight along with impaired glucose tolerance. Taken together, our results provide a mechanistic link between the genetic risk for insulin resistance and low adiposity, providing a potential therapeutic hypothesis and a framework for future identification of causal relationships between genome associations and cellular programmes in other disorders.

RevDate: 2023-05-30

Feofanova EV, Brown MR, Alkis T, et al (2023)

Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations.

Nature communications, 14(1):3111.

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

RevDate: 2023-05-30

Guenthoer J, Lilly M, Starr TN, et al (2023)

Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection.

Proceedings of the National Academy of Sciences of the United States of America, 120(23):e2220948120.

The antiviral benefit of antibodies can be compromised by viral escape especially for rapidly evolving viruses. Therefore, durable, effective antibodies must be both broad and potent to counter newly emerging, diverse strains. Discovery of such antibodies is critically important for SARS-CoV-2 as the global emergence of new variants of concern (VOC) has compromised the efficacy of therapeutic antibodies and vaccines. We describe a collection of broad and potent neutralizing monoclonal antibodies (mAbs) isolated from an individual who experienced a breakthrough infection with the Delta VOC. Four mAbs potently neutralize the Wuhan-Hu-1 vaccine strain, the Delta VOC, and also retain potency against the Omicron VOCs through BA.4/BA.5 in both pseudovirus-based and authentic virus assays. Three mAbs also retain potency to recently circulating VOCs XBB.1.5 and BQ.1.1 and one also potently neutralizes SARS-CoV-1. The potency of these mAbs was greater against Omicron VOCs than all but one of the mAbs that had been approved for therapeutic applications. The mAbs target distinct epitopes on the spike glycoprotein, three in the receptor-binding domain (RBD) and one in an invariant region downstream of the RBD in subdomain 1 (SD1). The escape pathways we defined at single amino acid resolution with deep mutational scanning show they target conserved, functionally constrained regions of the glycoprotein, suggesting escape could incur a fitness cost. Overall, these mAbs are unique in their breadth across VOCs, their epitope specificity, and include a highly potent mAb targeting a rare epitope outside of the RBD in SD1.

RevDate: 2023-05-30

Wang CY, Z Feng (2023)

A Flexible Method for Diagnostic Accuracy with Biomarker Measurement Error.

Mathematics (Basel, Switzerland), 11(3):.

Diagnostic biomarkers are often measured with errors due to imperfect lab conditions or analytic variability of the assay. The ability of a diagnostic biomarker to discriminate between cases and controls is often measured by the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, among others. Ignoring measurement error can cause biased estimation of a diagnostic accuracy measure, which results in misleading interpretation of the efficacy of a diagnostic biomarker. Existing assays available are either research grade or clinical grade. Research assays are cost effective, often multiplex, but they may be associated with moderate measurement errors leading to poorer diagnostic performance. In comparison, clinical assays may provide better diagnostic ability, but with higher cost since they are usually developed by industry. Correction for attenuation methods are often valid when biomarkers are from a normal distribution, but may be biased with skewed biomarkers. In this paper, we develop a flexible method based on skew-normal biomarker distributions to correct for bias in estimating diagnostic performance measures including AUC, sensitivity, and specificity. Finite sample performance of the proposed method is examined via extensive simulation studies. The methods are applied to a pancreatic cancer biomarker study.

RevDate: 2023-05-30

Higano CS, George DJ, Shore ND, et al (2023)

Clinical outcomes and treatment patterns in REASSURE: planned interim analysis of a real-world observational study of radium-223 in metastatic castration-resistant prostate cancer.

EClinicalMedicine, 60:101993.

BACKGROUND: Radium-223, a targeted alpha therapy, is approved to treat bone-dominant metastatic castration-resistant prostate cancer (mCRPC), based on significantly prolonged overall survival versus placebo and a favourable safety profile in the phase 3 ALSYMPCA study. ALSYMPCA was conducted when few other treatment options were available, and prospectively collected data are limited on the use of radium-223 in the current mCRPC treatment landscape. We sought to understand long-term safety and treatment patterns in men who received radium-223 in real-world clinical practice.

METHODS: REASSURE (NCT02141438) is a global, prospective, observational study of radium-223 in men with mCRPC. Primary outcomes are adverse events (AEs), including treatment-emergent serious AEs (SAEs) and drug-related AEs during and ≤30 days after radium-223 completion, grade 3/4 haematological toxicities ≤6 months after last radium-223 dose, drug-related SAEs after radium-223 therapy completion, and second primary malignancies.

FINDINGS: Data collection commenced on Aug 20, 2014, and the data cutoff date for this prespecified interim analysis was Mar 20, 2019 (median follow-up 11.5 months [interquartile range 6.0-18.6]), 1465 patients were evaluable. For second primary malignancies, 1470 patients were evaluable, 21 (1%) of whom had a total of 23 events. During radium-223 therapy, 311 (21%) of 1465 patients had treatment-emergent SAEs, and 510 (35%) had drug-related AEs. In the 6 months after completion of radium-223 therapy, 214 (15%) patients had grade 3/4 haematological toxicities. Eighty patients (5%) had post-treatment drug-related SAEs. Median overall survival was 15.6 months (95% confidence interval 14.6-16.5) from radium-223 initiation. Patient-reported pain scores declined or stabilised. Seventy (5%) patients had fractures.

INTERPRETATION: REASSURE offers insight into radium-223 use in global real-world clinical practice with currently available therapies. At this interim analysis, with a median follow-up of almost 1 year, 1% of patients had second primary malignancies, and safety and overall survival findings were consistent with clinical trial experience. Final analysis of REASSURE is due in 2024.

FUNDING: Bayer HealthCare.

RevDate: 2023-05-30

Sorey W, Krantz EM, Morris J, et al (2023)

Antiviral Prescribing Among Patients at an Ambulatory Cancer Center With Laboratory-Confirmed Influenza.

Open forum infectious diseases, 10(5):ofad254.

Among 133 cancer outpatients diagnosed with influenza between 2016 and 2018, 110 (83%) were prescribed oseltamivir. Among 109 with a known symptom onset date, 53% presented for care and 31% were prescribed oseltamivir within 48 hours. Patient/provider education and rapid diagnostics are needed to improve early oseltamivir use among cancer patients with influenza.

RevDate: 2023-05-30

Aglago EK, Kim AE, Lin Y, et al (2023)

A genetic locus within the FMN1/GREM1 gene region interacts with body mass index in colorectal cancer risk.

Cancer research pii:727007 [Epub ahead of print].

Colorectal cancer (CRC) risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment (G×E) interactions can provide biological insights into the effects of obesity on CRC risk. Here, we assessed potential genome-wide G×E interactions between body mass index (BMI) and common single nucleotide polymorphisms (SNPs) for CRC risk using data from 36,415 CRC cases and 48,451 controls from three international CRC consortia (CCFR, CORECT, and GECCO). The G×E tests included the conventional logistic regression using multiplicative terms (one-degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G×E interactions under specific conditions. BMI was associated with higher CRC risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher CRC risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with CRC risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and CRC.

RevDate: 2023-05-30

Sprague BL, Coley RY, Lowry KP, et al (2023)

Digital Breast Tomosynthesis versus Digital Mammography Screening Performance on Successive Screening Rounds from the Breast Cancer Surveillance Consortium.

Radiology, 307(5):e223142.

Background Prior cross-sectional studies have observed that breast cancer screening with digital breast tomosynthesis (DBT) has a lower recall rate and higher cancer detection rate compared with digital mammography (DM). Purpose To evaluate breast cancer screening outcomes with DBT versus DM on successive screening rounds. Materials and Methods In this retrospective cohort study, data from 58 breast imaging facilities in the Breast Cancer Surveillance Consortium were collected. Analysis included women aged 40-79 years undergoing DBT or DM screening from 2011 to 2020. Absolute differences in screening outcomes by modality and screening round were estimated during the study period by using generalized estimating equations with marginal standardization to adjust for differences in women's risk characteristics across modality and round. Results A total of 523 485 DBT examinations (mean age of women, 58.7 years ± 9.7 [SD]) and 1 008 123 DM examinations (mean age, 58.4 years ± 9.8) among 504 863 women were evaluated. DBT and DM recall rates decreased with successive screening round, but absolute recall rates in each round were significantly lower with DBT versus DM (round 1 difference, -3.3% [95% CI: -4.6, -2.1] [P < .001]; round 2 difference, -1.8% [95% CI: -2.9, -0.7] [P = .003]; round 3 or above difference, -1.2% [95% CI: -2.4, -0.1] [P = .03]). DBT had significantly higher cancer detection (difference, 0.6 per 1000 examinations [95% CI: 0.2, 1.1]; P = .009) compared with DM only for round 3 and above. There were no significant differences in interval cancer rate (round 1 difference, 0.00 per 1000 examinations [95% CI: -0.24, 0.30] [P = .96]; round 2 or above difference, 0.04 [95% CI: -0.19, 0.31] [P = .76]) or total advanced cancer rate (round 1 difference, 0.00 per 1000 examinations [95% CI: -0.15, 0.19] [P = .94]; round 2 or above difference, -0.06 [95% CI: -0.18, 0.11] [P = .43]). Conclusion DBT had lower recall rates and could help detect more cancers than DM across three screening rounds, with no difference in interval or advanced cancer rates. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Skaane in this issue.

RevDate: 2023-05-29

Prater KE, Green KJ, Mamde S, et al (2023)

Human microglia show unique transcriptional changes in Alzheimer's disease.

Nature aging [Epub ahead of print].

Microglia, the innate immune cells of the brain, influence Alzheimer's disease (AD) progression and are potential therapeutic targets. However, microglia exhibit diverse functions, the regulation of which is not fully understood, complicating therapeutics development. To better define the transcriptomic phenotypes and gene regulatory networks associated with AD, we enriched for microglia nuclei from 12 AD and 10 control human dorsolateral prefrontal cortices (7 males and 15 females, all aged >60 years) before single-nucleus RNA sequencing. Here we describe both established and previously unrecognized microglial molecular phenotypes, the inferred gene networks driving observed transcriptomic change, and apply trajectory analysis to reveal the putative relationships between microglial phenotypes. We identify microglial phenotypes more prevalent in AD cases compared with controls. Further, we describe the heterogeneity in microglia subclusters expressing homeostatic markers. Our study demonstrates that deep profiling of microglia in human AD brain can provide insight into microglial transcriptional changes associated with AD.

RevDate: 2023-05-29

Banerjee R, Williams L, JR Mikhael (2023)

Should I stay or should I go (to transplant)? Managing insufficient responses to induction in multiple myeloma.

Blood cancer journal, 13(1):89.

RevDate: 2023-05-28

Prentice RL, Vasan S, Tinker LF, et al (2023)

Metabolomics-Based Biomarker for Dietary Fat and Associations with Chronic Disease Risk in Postmenopausal Women[1].

The Journal of nutrition pii:S0022-3166(23)70114-4 [Epub ahead of print].

BACKGROUND: The Women's Health Initiative (WHI) randomized, controlled Dietary Modification (DM) trial of a low-fat dietary pattern suggested intervention benefits related to breast cancer, coronary heart disease (CHD), and diabetes. Here we use WHI observational data for the further insight into the chronic disease implications of adopting this type of low-fat dietary pattern.

OBJECTIVES: We aim to use our earlier work on metabolomics-based biomarkers of carbohydrate and protein to develop a fat intake biomarker by subtraction; to use the resulting biomarker to develop calibration equations that adjusts self-reported fat intake for measurement error; and to study associations of biomarker-calibrated fat intake with chronic disease risk in WHI cohorts. Corresponding studies for specific fatty acids will follow separately.

METHODS: Prospective disease association results are presented using WHI cohorts of postmenopausal women, aged 50-79 when enrolled at 40 U.S. clinical centers. Biomarker equations were developed using an embedded human feeding study (n=153). Calibration equations were developed using a WHI nutritional biomarker study (n=436). Calibrated intakes were associated with cancer, cardiovascular diseases, and diabetes incidence in WHI cohorts (n=81,954) over an approximate 20-year follow-up period.

RESULTS: A biomarker for fat density was developed by subtracting protein, carbohydrate, and alcohol densities from one. A calibration equation was developed for fat density. Hazard ratios (95% confidence intervals) for 20% higher fat density were 1.16 (1.06, 1.27) for breast cancer, 1.13 (1.02, 1.26) for CHD, and 1.19 (1.13, 1.26) for diabetes, in substantial agreement with findings from the DM trial. With control for additional dietary variables, especially fiber, fat density was no longer associated with CHD, with HR (95% confidence interval) of 1.00 (0.88, 1.13), while that for breast cancer was 1.11 (1.00, 1.24).

CONCLUSIONS: WlHI observational data support prior DM trial findings of low-fat dietary pattern benefits in this population of postmenopausal U.S. women. This study is registered with clinicaltrials.gov identifier: NCT00000611.

RevDate: 2023-05-27

Zafar A, Huang CY, Lo M, et al (2023)

Intensity of cyclophosphamide-based bridging therapy before CAR-T therapy in myeloma.

Transplantation and cellular therapy pii:S2666-6367(23)01299-X [Epub ahead of print].

INTRODUCTION: Patients receiving autologous chimeric antigen receptor T-cell (CAR-T) therapies for multiple myeloma (MM) may require bridging therapy (BT) before CAR-T infusion to maintain some level of disease control. Alkylators such as cyclophosphamide (Cy) are often used as parts of BT regimens, either in high-intensity regimens such as modified hyperCVAD or once-weekly regimens such as KCd. However, there is no consensus around the optimal BT alkylator dose intensity in MM.

METHODS: We performed a single-center analysis of all instances of BT before planned autologous CAR-T for MM during a 5-year period ending April 2022. We classified bridging regimens into three cohorts: (1) hyperfractionated Cy (HyperCy) with inpatient Cy every 12-24 hours or as continuous intravenous infusions, (2) less intensive Cy dosing (WeeklyCy) such as KPd or KCd, and (3) NonCy, where no alkylators were used in BT. Demographic, disease-related, and treatment-related characteristics were collected for all patients. The three BT cohorts were compared using Fisher's exact tests, Kruskal-Wallis tests, and log-rank tests where appropriate.

RESULTS: We identified 70 discrete BT instances among 64 unique patients: 29 (41%) with HyperCy, 23 (33%) with WeeklyCy, and 18 (26%) with NonCy. Median total levels of Cy dosing during BT were 2100 mg/m[2], 615 mg/m[2], and 0 mg/m[2] respectively. Age, number of prior lines, triple-class refractory status, presence of high-risk cytogenetics, extramedullary disease, bone marrow plasma cell burden, involved free light chain (iFLC) kinetics before collection, and other measures of disease aggressiveness were comparable between cohorts. iFLC levels rose ≥25% and ≥100 mg/L during BT (approximating progressive disease) in comparable proportions (p=0.25) between cohorts: 52% HyperCy, 39% WeeklyCy, and 28% NonCy. All BT instances without subsequent CAR-T were due to manufacturing failures. Among 61 instances of bridging followed by CAR-T, vein-to-vein times were slightly longer (p = 0.03) with HyperCy (45 days) vs WeeklyCy (39 days) and NonCy (46.5 days). Neutrophil recovery timeframes were similar between cohorts, but platelet recovery took longer with HyperCy (64 days) vs WeeklyCy (42 days) and NonCy (12 days). PFS was comparable between cohorts, but median OS was not: 15.3 months with HyperCy versus 30.0 months with WeeklyCy and not reached with NonCy.

DISCUSSION: In our retrospective analysis of BT before CAR-T therapy in MM, HyperCy did not result in superior disease control than WeeklyCy despite a threefold higher dose of Cy. In contrast, HyperCy was associated with longer post-CAR-T platelet recovery and worsened OS despite comparable measurements of disease aggressiveness and tumor burden. Study limitations include our small sample size as well as confounding from gestalt markers of MM aggressiveness that might have led both to poorer outcomes as well as physicians' decisions to prescribe HyperCy. Given the rarity of objective disease responses to chemotherapy in relapsed/refractory MM, our analysis suggests that hyperfractionated Cy regimens do not outperform once-weekly Cy regimens for most patients who require BT before CAR-T therapy.

RevDate: 2023-05-27

D H Gates E, Hippe DS, Vesselle HJ, et al (2023)

Independent Association of Metabolic Tumor Response on FDG-PET with Pulmonary Toxicity Following Risk-Adaptive Chemoradiation for Unresectable Non-Small Cell Lung Cancer: Inherent Radiosensitivity or Immune Response?.

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology pii:S0167-8140(23)00258-X [Epub ahead of print].

BACKGROUND: In the context of a phase II trial of risk-adaptive chemoradiation, we evaluated whether tumor metabolic response could serve as a correlate of treatment sensitivity and toxicity.

METHODS: Forty-five patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on the FLARE-RT phase II trial (NCT02773238). [18F]fluorodeoxyglucose (FDG) PET-CT images were acquired prior to treatment and after 24 Gy during week 3. Patients with unfavorable on-treatment tumor response received concomitant boosts to 74 Gy total over 30 fractions rather than standard 60 Gy. Metabolic tumor volume and mean standardized uptake value (SUVmean) were calculated semi-automatically. Risk factors of pulmonary toxicity included concurrent chemotherapy regimen, adjuvant anti-PDL1 immunotherapy, and lung dosimetry. Incidence of CTCAE v4 grade 2+ pneumonitis was analyzed using the Fine-Gray method with competing risks of metastasis or death. Peripheral germline DNA microarray sequencing measured predefined candidate genes from distinct pathways: 96 DNA repair, 53 immunology, 38 oncology, 27 lung biology.

RESULTS: Twenty-four patients received proton therapy, 23 received ICI, 26 received carboplatin-paclitaxel, and 17 pneumonitis events were observed. Pneumonitis risk was significantly higher for patients with COPD (HR 3.78 [1.48,9.60], p=0.005), those treated with immunotherapy (HR 2.82 [1.03,7.71], p=0.043) but not with carboplatin-paclitaxel (HR 1.98 [0.71,5.54], p=0.19). Pneumonitis rates were similar among selected patients receiving 74 Gy radiation vs 60 Gy (p=0.33), proton therapy vs photon (p=0.60), or with higher lung dosimetric V20 (p=0.30). Patients in the upper quartile decrease in SUVmean (>39.7%) were at greater risk for pneumonitis (HR 4.00 [1.54,10.44], p=0.005) and remained significant in multivariable analysis (HR 3.34 [1.12,9.10], p=0.018). Germline DNA gene alterations in immunology pathways were most frequently associated with pneumonitis.

CONCLUSION: Tumor metabolic response as measured by mean SUV is associated with increased pneumonitis risk in a clinical trial cohort of NSCLC patients independent of treatment factors. This may be partially attributed to patient-specific differences in immunogenicity.

RevDate: 2023-05-27

Watanabe R, Miura N, Kurata M, et al (2023)

Spatial Gene Expression Analysis Reveals Characteristic Gene Expression Patterns of De Novo Neuroendocrine Prostate Cancer Coexisting with Androgen Receptor Pathway Prostate Cancer.

International journal of molecular sciences, 24(10): pii:ijms24108955.

Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.

RevDate: 2023-05-27

Clavero E, Sanchez-Maldonado JM, Macauda A, et al (2023)

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

International journal of molecular sciences, 24(10): pii:ijms24108500.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10[-9]) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10[-4]-5.79 × 10[-14]). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10[-4]), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24[+]CD38[+] B cells (p = 4.8 × 10[-4]) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10[-4]). We also found that the CD46rs1142469 SNP correlated with numbers of CD19[+] B cells, CD19[+]CD3[-] B cells, CD5[+]IgD[-] cells, IgM[-] cells, IgD[-]IgM[-] cells, and CD4[-]CD8[-] PBMCs (p = 4.9 × 10[-4]-8.6 × 10[-4]) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4[+]EMCD45RO[+]CD27[-] cells (p = 9.3 × 10[-4]). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3[-], MCP-2[-], and IL20-dependent pathways.

RevDate: 2023-05-26

Wang Z, Peters BA, Bryant M, et al (2023)

Gut microbiota, circulating inflammatory markers and metabolites, and carotid artery atherosclerosis in HIV infection.

Microbiome, 11(1):119.

BACKGROUND: Alterations in gut microbiota have been implicated in HIV infection and cardiovascular disease. However, how gut microbial alterations relate to host inflammation and metabolite profiles, and their relationships with atherosclerosis, have not been well-studied, especially in the context of HIV infection. Here, we examined associations of gut microbial species and functional components measured by shotgun metagenomics with carotid artery plaque assessed by B-mode carotid artery ultrasound in 320 women with or at high risk of HIV (65% HIV +) from the Women's Interagency HIV Study. We further integrated plaque-associated microbial features with serum proteomics (74 inflammatory markers measured by the proximity extension assay) and plasma metabolomics (378 metabolites measured by liquid chromatography tandem mass spectrometry) in relation to carotid artery plaque in up to 433 women.

RESULTS: Fusobacterium nucleatum, a potentially pathogenic bacteria, was positively associated with carotid artery plaque, while five microbial species (Roseburia hominis, Roseburia inulinivorans, Johnsonella ignava, Odoribacter splanchnicus, Clostridium saccharolyticum) were inversely associated with plaque. Results were consistent between women with and without HIV. Fusobacterium nucleatum was positively associated with several serum proteomic inflammatory markers (e.g., CXCL9), and the other plaque-related species were inversely associated with proteomic inflammatory markers (e.g., CX3CL1). These microbial-associated proteomic inflammatory markers were also positively associated with plaque. Associations between bacterial species (especially Fusobacterium nucleatum) and plaque were attenuated after further adjustment for proteomic inflammatory markers. Plaque-associated species were correlated with several plasma metabolites, including the microbial metabolite imidazole-propionate (ImP), which was positively associated with plaque and several pro-inflammatory markers. Further analysis identified additional bacterial species and bacterial hutH gene (encoding enzyme histidine ammonia-lyase in ImP production) associated with plasma ImP levels. A gut microbiota score based on these ImP-associated species was positively associated with plaque and several pro-inflammatory markers.

CONCLUSION: Among women living with or at risk of HIV, we identified several gut bacterial species and a microbial metabolite ImP associated with carotid artery atherosclerosis, which might be related to host immune activation and inflammation. Video Abstract.

RevDate: 2023-05-26

Graham SE, Clarke SL, Wu KH, et al (2023)

Author Correction: The power of genetic diversity in genome-wide association studies of lipids.

RevDate: 2023-05-26

Shi J, Shiraishi K, Choi J, et al (2023)

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Nature communications, 14(1):3043.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

RevDate: 2023-05-26

Rashidi A, Ebadi M, Rehman TU, et al (2023)

Randomized Double-Blind Phase II Trial of Fecal Microbiota Transplantation Versus Placebo in Allogeneic Hematopoietic Cell Transplantation and AML.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Gut microbiota injury in allogeneic hematopoietic cell transplantation (HCT) recipients and patients with AML has been associated with adverse clinical outcomes. Previous studies in these patients have shown improvements in various microbiome indices after fecal microbiota transplantation (FMT). However, whether microbiome improvements translate into improved clinical outcomes remains unclear. We examined this question in a randomized, double-blind, placebo-controlled phase II trial.

METHODS: Two independent cohorts of allogeneic HCT recipients and patients with AML receiving induction chemotherapy were randomly assigned in a 2:1 ratio to receive standardized oral encapsulated FMT versus placebo upon neutrophil recovery. After each course of antibacterial antibiotics, patients received a study treatment. Up to three treatments were administered within 3 months. The primary end point was 4-month all-cause infection rate. Patients were followed for 9 months.

RESULTS: In the HCT cohort (74 patients), 4-month infection density was 0.74 and 0.91 events per 100 patient-days in FMT and placebo arms, respectively (infection rate ratio, 0.83; 95% CI, 0.48 to 1.42; P = .49). In the AML cohort (26 patients), 4-month infection density was 0.93 in the FMT arm and 1.25 in the placebo arm, with an infection rate ratio of 0.74 (95% CI, 0.32 to 1.71; P = .48). Unique donor bacterial sequences comprised 25%-30% of the fecal microbiota after FMT. FMT improved postantibiotic recovery of microbiota diversity, restored several depleted obligate anaerobic commensals, and reduced the abundance of expanded genera Enterococcus, Streptococcus, Veillonella, and Dialister.

CONCLUSION: In allogeneic HCT recipients and patients with AML, third-party FMT was safe and ameliorated intestinal dysbiosis, but did not decrease infections. Novel findings from this trial will inform future development of FMT trials.

RevDate: 2023-05-26

Gadgeel SM, Miao J, Riess JW, et al (2023)

Phase II study of docetaxel and trametinib in patients with KRAS mutation positive recurrent non-small cell lung cancer (NSCLC) (SWOG S1507, NCT-02642042).

Clinical cancer research : an official journal of the American Association for Cancer Research pii:727002 [Epub ahead of print].

PURPOSE: Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and co-mutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC.

PATIENTS AND METHODS: S1507 is a single arm phase II assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients with at least 25 with G12C mutation. The design was 2-stage design to rule out a 17% RR, within the overall population at the 1-sided 3% level and within the G12C subset at the 5% level.

RESULTS: Between July 18, 2016 and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% (95%CI- 22-48) overall and 28% (95%CI- 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR:2.85, 95%CI 1.16-7.01) and RR (0% vs. 56%, p = 0.004) were worse in patients with TP53 mutated versus wild type cancers.

CONCLUSIONS: RRs were significantly improved in the overall population. Contrary to pre-clinical studies, the combination showed no improvement in efficacy in G12C patients. Co-mutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation.

RevDate: 2023-05-25

Lustberg MB, Kuderer NM, Desai A, et al (2023)

Mitigating long-term and delayed adverse events associated with cancer treatment: implications for survivorship.

Nature reviews. Clinical oncology [Epub ahead of print].

Despite the importance of chemotherapy-associated adverse events in oncology practice and the broad range of interventions available to mitigate them, limited systematic efforts have been made to identify, critically appraise and summarize the totality of evidence on the effectiveness of these interventions. Herein, we review the most common long-term (continued beyond treatment) and late or delayed (following treatment) adverse events associated with chemotherapy and other anticancer treatments that pose major threats in terms of survival, quality of life and continuation of optimal therapy. These adverse effects often emerge during and continue beyond the course of therapy or arise among survivors in the months and years following treatment. For each of these adverse effects, we discuss and critically evaluate their underlying biological mechanisms, the most commonly used pharmacological and non-pharmacological treatment strategies, and evidence-based clinical practice guidelines for their appropriate management. Furthermore, we discuss risk factors and validated risk-assessment tools for identifying patients most likely to be harmed by chemotherapy and potentially benefit from effective interventions. Finally, we highlight promising emerging supportive-care opportunities for the ever-increasing number of cancer survivors at continuing risk of adverse treatment effects.

RevDate: 2023-05-25

Little P, Liu S, Zhabotynsky V, et al (2023)

A computational method for cell type-specific expression quantitative trait loci mapping using bulk RNA-seq data.

Nature communications, 14(1):3030.

Mapping cell type-specific gene expression quantitative trait loci (ct-eQTLs) is a powerful way to investigate the genetic basis of complex traits. A popular method for ct-eQTL mapping is to assess the interaction between the genotype of a genetic locus and the abundance of a specific cell type using a linear model. However, this approach requires transforming RNA-seq count data, which distorts the relation between gene expression and cell type proportions and results in reduced power and/or inflated type I error. To address this issue, we have developed a statistical method called CSeQTL that allows for ct-eQTL mapping using bulk RNA-seq count data while taking advantage of allele-specific expression. We validated the results of CSeQTL through simulations and real data analysis, comparing CSeQTL results to those obtained from purified bulk RNA-seq data or single cell RNA-seq data. Using our ct-eQTL findings, we were able to identify cell types relevant to 21 categories of human traits.

RevDate: 2023-05-25

Parks CG, Pettinger M, de Roos AJ, et al (2023)

Life events, caregiving, and risk of autoimmune rheumatic diseases in the Women's Health Initiative Observational Study.

Arthritis care & research [Epub ahead of print].

BACKGROUND: Growing evidence suggests psychosocial stressors may increase risk of developing autoimmune disease. We examined stressful life events and caregiving in relation to incident Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) in the Women's Health Initiative Observational Study cohort.

METHODS: The sample of post-menopausal women included 211 incident RA or SLE cases reported within 3 years after enrollment, confirmed by use of disease modifying anti-rheumatic drugs (i.e., Probable RA/SLE), and 76,648 non-cases. Baseline questionnaires asked about life events in the past year, caregiving, and social support. We used Cox regression models to calculate Hazard Ratios (HR) and 95% Confidence Intervals (CI), adjusting for age, race/ethnicity, occupational class, education, pack-years smoking and BMI.

RESULTS: Incident RA/SLE was associated with having 3 or more life events (e.g., age-adjusted HR 1.70; 95%CI 1.14, 2.53; ptrend =0.0026). Elevated HRs were noted for physical (2.48; 1.02, 6.04) and verbal (1.34; 0.89, 2.02) abuse (ptrend =0.0614), 2 or more interpersonal events (1.23, 95%CI 0.87, 1.73; ptrend =0.2403), financial stress (1.22; 95%CI 0.90, 1.64), and caregiving 3 or more days per week (1.25; 95%CI 0.87, 1.81; ptrend =0.2571). Results were similar excluding women with baseline symptoms of depression or moderate to severe joint pain in the absence of diagnosed arthritis.

DISCUSSION: Our findings support the idea that diverse stressors may increase risk of developing probable RA or SLE in post-menopausal women, supporting the need for further studies in autoimmune rheumatic diseases including childhood adverse events, life event trajectories, and modifying psychosocial and socioeconomic factors. This article is protected by copyright. All rights reserved.

RevDate: 2023-05-25

Neuhouser ML, Pettinger M, Tinker LF, et al (2022)

Associations of Biomarker-Calibrated Healthy Eating Index-2010 Scores with Chronic Disease Risk and Their Dependency on Energy Intake and Body Mass Index in Postmenopausal Women.

The Journal of nutrition, 152(12):2808-2817.

BACKGROUND: Prior studies examined associations between the Healthy Eating Index (HEI) and chronic disease risk based on self-reported diet without measurement error correction.

OBJECTIVE: Our objective was to test associations between biomarker calibration of the food-frequency questionnaire (FFQ)-derived HEI-2010 with incident cardiovascular disease (CVD), cancer, and type 2 diabetes (T2D) among Women's Health Initiative (WHI) participants.

METHODS: Data were derived from WHI postmenopausal women (n = 100,374) aged 50-79 y at enrollment (1993-1998) at 40 US clinical centers, linked to nutritional biomarker substudies and outcomes over subsequent decades of follow-up. Baseline or year 1 FFQ-derived HEI-2010 scores were calibrated with nutritional biomarkers and participant characteristics (e.g., BMI) for systematic measurement error correction. Calibrated data were then used in HR models examining associations with incidence of CVD (total, subtypes, mortality), cancer (total, subtypes, mortality), and T2D in WHI participants with approximately 2 decades of follow-up. Models were multivariable-adjusted with further adjustment for BMI and doubly labeled water (DLW)-calibrated energy.

RESULTS: Multivariable-adjusted HRs modeled a 20% increment in HEI-2010 score in relation to outcomes. HRs were modest using uncalibrated HEI-2010 scores (HRs = 0.91-1.09). Using biomarker-calibrated HEI-2010, 20% increments in scores yielded multivariable-adjusted HRs (95% CIs) of 0.75 (0.60, 0.93) for coronary heart disease; 0.75 (0.61, 0.91) for myocardial infarction; 0.96 (0.92, 1.01) for stroke; 0.88 (0.75, 1.02) for CVD mortality; 0.81 (0.70, 0.94) for colorectal cancer; 0.81 (0.74, 0.88) for breast cancer; 0.79 (0.73, 0.87) for cancer mortality; and 0.45 (0.36-0.55) for T2D. Except for cancer mortality and T2D incidence, results became null when adjusted for DLW-calibrated energy intake and BMI.

CONCLUSIONS: Biomarker calibration of FFQ-derived HEI-2010 was associated with lower CVD and cancer incidence and mortality and lower T2D incidence in postmenopausal women. Attenuation after adjustment with BMI and DLW-calibrated energy suggests that energy intake and/or obesity are strong drivers of diet-related chronic disease risk in postmenopausal women. The Women's Health Initiative is registered at clinicaltrials.gov at NCT00000611.

RevDate: 2023-05-25

Praiss AM, Miller A, Smith J, et al (2023)

Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.

Gynecologic oncology, 174:213-223 pii:S0090-8258(23)00252-4 [Epub ahead of print].

OBJECTIVE: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl).

METHODS: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event.

RESULTS: AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively.

CONCLUSION: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.

RevDate: 2023-05-25

Itell HL, Humes D, J Overbaugh (2023)

Several cell-intrinsic effectors drive type I interferon-mediated restriction of HIV-1 in primary CD4[+] T cells.

Cell reports, 42(6):112556 pii:S2211-1247(23)00567-3 [Epub ahead of print].

Type I interferon (IFN) upregulates proteins that inhibit HIV within infected cells. Prior studies have identified IFN-stimulated genes (ISGs) that impede lab-adapted HIV in cell lines, yet the ISG(s) that mediate IFN restriction in HIV target cells, primary CD4[+] T cells, are unknown. Here, we interrogate ISG restriction of primary HIV in CD4[+] T cells by performing CRISPR-knockout screens with a custom library that specifically targets ISGs expressed in CD4[+] T cells. Our investigation identifies previously undescribed HIV-restricting ISGs (HM13, IGFBP2, LAP3) and finds that two factors characterized in other HIV infection models (IFI16 and UBE2L6) mediate IFN restriction in T cells. Inactivation of these five ISGs in combination further diminishes IFN's protective effect against diverse HIV strains. This work demonstrates that IFN restriction of HIV is multifaceted, resulting from several effectors functioning collectively, and establishes a primary cell ISG screening model to identify both single and combinations of HIV-restricting ISGs.

RevDate: 2023-05-25

Russell ML, Simon N, Bradley P, et al (2023)

Statistical inference reveals the role of length, GC content, and local sequence in V(D)J nucleotide trimming.

eLife, 12: pii:85145.

To appropriately defend against a wide array of pathogens, humans somatically generate highly diverse repertoires of B cell and T cell receptors (BCRs and TCRs) through a random process called V(D)J recombination. Receptor diversity is achieved during this process through both the combinatorial assembly of V(D)J-genes and the junctional deletion and insertion of nucleotides. While the Artemis protein is often regarded as the main nuclease involved in V(D)J recombination, the exact mechanism of nucleotide trimming is not understood. Using a previously published TCRβ repertoire sequencing data set, we have designed a flexible probabilistic model of nucleotide trimming that allows us to explore various mechanistically interpretable sequence-level features. We show that local sequence context, length, and GC nucleotide content in both directions of the wider sequence, together, can most accurately predict the trimming probabilities of a given V-gene sequence. Because GC nucleotide content is predictive of sequence-breathing, this model provides quantitative statistical evidence regarding the extent to which double-stranded DNA may need to be able to breathe for trimming to occur. We also see evidence of a sequence motif that appears to get preferentially trimmed, independent of GC-content-related effects. Further, we find that the inferred coefficients from this model provide accurate prediction for V- and J-gene sequences from other adaptive immune receptor loci. These results refine our understanding of how the Artemis nuclease may function to trim nucleotides during V(D)J recombination and provide another step toward understanding how V(D)J recombination generates diverse receptors and supports a powerful, unique immune response in healthy humans.

RevDate: 2023-05-25

Im A, Pusic I, Onstad L, et al (2023)

Patient-reported treatment response in chronic graft-versus-host disease.

Haematologica [Epub ahead of print].

Chronic graft vs. host disease (GVHD) treatment response is assessed using NIH Consensus criteria in clinical trials, and by clinician assessment in routine practice. Patient-reported treatment response is central to the experience of chronic GVHD manifestations as well as treatment benefit and toxicity, but how they correlate with clinician- or NIH-responses has not been well studied. We aimed to characterize 6-month patient-reported response, determine associated chronic GVHD baseline organ features and changes, and evaluate which patientreported quality of life and chronic GVHD symptom burden measures correlated with patientreported response. From two nationally representative Chronic GVHD Consortium prospective observational studies, 382 subjects were included in this analysis. Patient and clinician responses were categorized as improved (completely gone, very much better, moderately better, a little better) vs. not improved (about the same, a little worse, moderately worse, very much worse). At 6 months, 270 (71%) patients perceived chronic GVHD improvement, while 112 (29%) perceived no improvement. Patient-reported response had limited correlation with either clinician-reported (kappa 0.37) or NIH chronic GVHD response criteria (kappa 0.18). Notably, patient-reported response at 6 months was significantly associated with subsequent failure-free survival. In multivariate analysis, NIH responses in eye, mouth, and lung had significant association with 6-month patient-reported response, as well as a change in Short Form 36 general health and role physical domains and Lee Symptom Score skin and eye changes. Based on these findings, patient-reported responses should be considered as an important complementary endpoint in chronic GVHD clinical trials and drug development.

RevDate: 2023-05-25

Heath J, Chour W, Choi J, et al (2022)

Large libraries of single-chain trimer peptide-MHCs enable rapid antigen-specific CD8+ T cell discovery and analysis.

Research square.

CD8 + cytotoxic T cell responses against viral infection represent a major element of the adaptive immune response. We describe the development of a peptide antigen - major histompatibility complex (pMHC) library representing the full SARS-CoV-2 viral proteome, and comprised of 634 pMHC multimers representing the A*02.01, A*24.02, and B*07.02 HLA alleles, as well as specific antigens associated with the cytomegalovirus (CMV). These libraries were used to capture non-expanded CD8 + T cells from blood samples collected from 64 infected individuals, and then analyzed using single cell RNA-seq. The discovery and characterization of antigen-specific CD8 [+] T cell clonotypes typically involves the labor-intensive synthesis and construction of peptide-MHC tetramers. We adapted single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation, showing that hundreds can be rapidly prepared across multiple Class I HLA alleles. We used this platform to explore the impact of peptide and SCT template mutations on protein expression yield, thermal stability, and functionality. SCT libraries were an efficient tool for identifying T cells recognizing commonly reported viral epitopes. We then constructed SCT libraries designed to capture SARS-CoV-2 specific CD8 [+] T cells from COVID-19 participants and healthy donors. The immunogenicity of these epitopes was validated by functional assays of T cells with cloned TCRs captured using SCT libraries. These technologies should enable the rapid analyses of peptide-based T cell responses across several contexts, including autoimmunity, cancer, or infectious disease.

RevDate: 2023-05-24

Lawson MB, ET Oluyemi (2023)

Leveraging Area Deprivation to Improve Breast Cancer Outcomes.

Journal of the American College of Radiology : JACR pii:S1546-1440(23)00343-5 [Epub ahead of print].

RevDate: 2023-05-24

Savage T, Sun Q, Bell-Brown A, et al (2023)

Association between patient, clinic, and geographical-level factors and 1-year surveillance colonoscopy adherence.

Clinical and translational gastroenterology pii:01720094-990000000-00157 [Epub ahead of print].

INTRODUCTION: Surveillance colonoscopy 1-year after surgical resection for patients with stages I-III colorectal cancer (CRC) is suboptimal and data on factors associated with lack of adherence are limited. Using surveillance colonoscopy data from Washington state, we aimed to determine the patient, clinic, and geographical factors associated with adherence.

METHODS: Using administrative insurance claims linked to Washington (WA) cancer registry data we conducted a retrospective cohort study of adult patients diagnosed with stage I-III CRC between 2011 and 2018 with continuous insurance for at least 18 months after diagnosis. We determined the adherence rate to 1-year surveillance colonoscopy and conducted logistic regression analysis to identify factors associated with completion.

RESULTS: Of 4,481 stage I-III CRC patients identified, 55.8% completed a 1-year surveillance colonoscopy. The median time to colonoscopy completion was 370 days. On multivariate analysis, older age, higher stage CRC, Medicare insurance or multiple insurance carriers, higher Charlson Comorbidity Index score and living without a partner were significantly associated with decreased adherence to 1-year surveillance colonoscopy. Among 29 eligible clinics, 51% (n=15) reported lower than expected surveillance colonoscopy rates based on patient mix.

CONCLUSION: Surveillance colonoscopy 1-year after surgical resection is sub-optimal in WA state. Patient and clinic factors, but not geographic factors (Area Deprivation Index), were significantly associated with surveillance colonoscopy completion. This data will inform the development of patient and clinic level interventions to address an important quality of care issue across Washington.

RevDate: 2023-05-24

Cohen KW, De Rosa SC, Fulp WJ, et al (2023)

A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses.

Science translational medicine, 15(697):eadf3309.

The engineered outer domain germline targeting version 8 (eOD-GT8) 60-mer nanoparticle was designed to prime VRC01-class HIV-specific B cells that would need to be matured, through additional heterologous immunizations, into B cells that are able to produce broadly neutralizing antibodies. CD4 T cell help will be critical for the development of such high-affinity neutralizing antibody responses. Thus, we assessed the induction and epitope specificities of the vaccine-specific T cells from the IAVI G001 phase 1 clinical trial that tested immunization with eOD-GT8 60-mer adjuvanted with AS01B. Robust polyfunctional CD4 T cells specific for eOD-GT8 and the lumazine synthase (LumSyn) component of eOD-GT8 60-mer were induced after two vaccinations with either the 20- or 100-microgram dose. Antigen-specific CD4 T helper responses to eOD-GT8 and LumSyn were observed in 84 and 93% of vaccine recipients, respectively. CD4 helper T cell epitope "hotspots" preferentially targeted across participants were identified within both the eOD-GT8 and LumSyn proteins. CD4 T cell responses specific to one of these three LumSyn epitope hotspots were observed in 85% of vaccine recipients. Last, we found that induction of vaccine-specific peripheral CD4 T cells correlated with expansion of eOD-GT8-specific memory B cells. Our findings demonstrate strong human CD4 T cell responses to an HIV vaccine candidate priming immunogen and identify immunodominant CD4 T cell epitopes that might improve human immune responses either to heterologous boost immunogens after this prime vaccination or to other human vaccine immunogens.

RevDate: 2023-05-24

Dwyer ER, Holt SK, Wolff EM, et al (2023)

Patient-centered outcomes of telehealth for the care of rural-residing patients with urologic cancer.

Cancer [Epub ahead of print].

BACKGROUND: Patients residing in rural areas with urologic cancers confront significant obstacles in obtaining oncologic care. In the Pacific Northwest, a sizeable portion of the population lives in a rural county. Telehealth offers a potential access solution.

METHODS: Patients receiving urologic care through telehealth or an in-person appointment at the Fred Hutchinson Cancer Center in Seattle, Washington, were surveyed to assess appointment-related satisfaction and travel costs. Patients' residences were classified as rural or urban based on their self-reported ZIP code. Median patient satisfaction scores and appointment-related travel costs were compared by rural versus urban residence within telehealth and in-person appointment groups using Wilcoxon signed-rank or χ[2] testing.

RESULTS: A total of 1091 patients seen for urologic cancer care between June 2019 and April 2022 were included, 28.7% of which resided in a rural county. Patients were mostly non-Hispanic White (75%) and covered by Medicare (58%). Among rural-residing patients, telehealth and in-person appointment groups had the same median satisfaction score (61; interquartile ratio, 58, 63). More rural-residing than urban-residing patients in the telehealth appointment groups strongly agreed that "Considering the cost and time commitment of my appointment, I would choose to meet with my provider in this setting in the future" (67% vs. 58%, p = .03). Rural-residing patients with in-person appointments carried a higher financial burden than those with telehealth appointments (medians, $80 vs. $0; p <.001).

CONCLUSIONS: Appointment-related costs are high among rural-residing patients traveling for urologic oncologic care. Telehealth provides an affordable solution that does not compromise patient satisfaction.

RevDate: 2023-05-24

Srinivasan J, Vasudev A, Shasha C, et al (2023)

The initial age-associated decline in early T-cell progenitors reflects fewer pre-thymic progenitors and altered signals in the bone marrow and thymus microenvironments.

Aging cell [Epub ahead of print].

Age-related thymus involution results in decreased T-cell production, contributing to increased susceptibility to pathogens and reduced vaccine responsiveness. Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circulating bone marrow (BM)-derived thymus seeding progenitors (TSPs) that differentiate into early T-cell progenitors (ETPs). We find that ETP cellularity declines as early as 3 months (3MO) of age in mice. This initial ETP reduction could reflect changes in thymic stromal niches and/or pre-thymic progenitors. Using a multicongenic progenitor transfer approach, we demonstrate that the number of functional TSP/ETP niches does not diminish with age. Instead, the number of pre-thymic lymphoid progenitors in the BM and blood is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM lymphoid progenitors and in ETPs diminishes by 3MO, suggesting reduced niche quality in the BM and thymus contribute to the early decline in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to an initial reduction in ETPs in young adulthood, setting the stage for progressive age-associated thymus involution.

RevDate: 2023-05-23

Reed-Perino DE, Lai M, Yu EY, et al (2023)

Re-sensitization to pembrolizumab following PSMA-CD3 T-cell redirection therapy with JNJ-081 in a patient with mismatch repair-deficient metastatic castration-resistant prostate cancer: a case report.

Journal for immunotherapy of cancer, 11(5):.

While checkpoint inhibitor therapy has revolutionized the treatment landscape of some solid tumors, it has shown limited efficacy in metastatic castration-resistant prostate cancers (mCRPC). A small (~3-5%) but clinically distinct subset of mCRPC tumors have a DNA mismatch repair deficiency (dMMR) and develop a hypermutation phenotype with elevated tumor mutational burden and high microsatellite instability (MSI-H). Retrospective analyses have shown dMMR/MSI-H status to be a predictive biomarker for response to pembrolizumab in prostate tumors. Here, in this report, we present a case of a patient with mCRPC harboring a somatic dMMR who had progressed on pembrolizumab after an initial response. He enrolled on a clinical trial with JNJ-081, a prostate-specific membrane antigen-CD3 bispecific T-cell engager antibody and experienced a partial response with course complicated by cytokine release syndrome. On progression, he was reinitiated on pembrolizumab and experienced an exceptional second response, with his prostate-specific antigen falling from a high of 20.01 to undetectable after 6 weeks and remaining undetectable for >11 months. To our knowledge, this represents the first reported case of bispecific T-cell engager-mediated re-sensitization to checkpoint inhibitor therapy in any cancer.

RevDate: 2023-05-23

Gersekowski K, Ibiebele TI, Doherty JA, et al (2023)

Folate intake and ovarian cancer risk among women with endometriosis: a case-control study from the Ovarian Cancer Association Consortium.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:726908 [Epub ahead of print].

Background While folate intake has not been associated with an increased risk of ovarian cancer overall, studies of other cancer types have suggested that high folate intake may promote carcinogenesis in pre-cancerous lesions. Women with endometriosis (a potential pre-cancerous lesion) have an increased risk of developing ovarian cancer; however, whether high folate intake increases risk in this group is unknown. Methods We conducted a pooled analysis of six case-control studies from the Ovarian Cancer Association Consortium to investigate the association between folate intake and risk of ovarian cancer among women with and without self-reported endometriosis. We included 570 cases/558 controls with and 5,171/7,559 without endometriosis. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals for the association between folate intake (dietary, supplemental, total) and ovarian cancer risk. Finally, we used Mendelian randomization (MR) to evaluate our results using genetic markers as a proxy for folate status. Results Higher dietary folate intake was associated with an increased risk of ovarian cancer for women with endometriosis (OR 1.37[1.01-1.86]) but not for women without endometriosis. There was no association between supplemental folate intake and ovarian cancer risk for women with or without endometriosis. A similar pattern was seen using MR. Conclusions High dietary folate intake may be associated with an increased risk of ovarian cancer among women with endometriosis. Impact Women with endometriosis with high folate diets may be at increased risk of ovarian cancer. Further research is needed on the potential cancer-promoting effects of folate in this group.

RevDate: 2023-05-23

Sharma A, Logan B, Estrada-Merly N, et al (2023)

Impact of Public Reporting of Center-Specific Survival Analysis Scores on Patient Volumes at Hematopoietic Cell Transplant Centers.

Transplantation and cellular therapy pii:S2666-6367(23)01296-4 [Epub ahead of print].

BACKGROUND: The Center for International Blood and Marrow Transplant Research (CIBMTR) reports the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) at United States transplant centers (TC) annually through its Center-Specific Survival Analysis (CSA). The CSA compares the actual 1-year overall survival (OS) and predicted 1-year OS rate after alloHCT at each TC, which is then reported as 0 (OS as expected), -1 (OS worse than expected), or +1 (OS better than expected).

OBJECTIVE: We evaluated the impact of public reporting of TC performance on their alloHCT patient volumes.

STUDY DESIGN: Ninety-one TCs that serve adult or combined adult and pediatric populations and had CSA scores reported for 2012-2018 were included. We analyzed prior-calendar year TC volume, prior-calendar year CSA score, whether the CSA score had changed in the prior year from two years earlier, calendar year, TC type (adult only vs. combined adult and pediatric), and years of alloHCT experience for their impact on patient volumes.

RESULTS: A CSA score of -1, as compared with 0 or +1, was associated with an 8%-9% reduction in the mean TC volume (P < 0.001) in the subsequent year, adjusting for the prior year center volume. Additionally, being a TC neighboring an index TC with a -1 CSA score, was associated with a 3.5% increase in mean TC volume (P = 0.04).

CONCLUSION: Our data show that public reporting of CSA scores is associated with changes in alloHCT volumes at TCs. Additional investigation into the causes of this shift in patient volume and the impact on outcomes is ongoing.

RevDate: 2023-05-23

Song H, Sontz RA, Vance MJ, et al (2023)

High-fat diet plus HNF1A variant promotes polyps by activating β-catenin in early onset colorectal cancer.

JCI insight pii:167163 [Epub ahead of print].

The incidence of early onset colorectal cancer (EO-CRC) is rising and is poorly understood. Lifestyle factors and altered genetic background possibly contribute. Here we performed targeted exon sequencing of archived leukocyte DNA from 158 EO-CRC participants, which identified a missense mutation at p.A98V within the proximal DNA binding domain of Hepatic Nuclear Factor 1 alpha (HNF1AA98V, Rs1800574). The HNF1AA98V exhibited reduced DNA binding. To test function, the HNF1A variant was introduced into the mouse genome by CRISPR/Cas9 and the mice were placed on either a high fat (HFD) or high sugar diet (HSD). Only 1% of the HNF1A mutant mice developed polyps on normal chow; however,19% and 3% developed polyps on the HFD and HSD, respectively. RNA-Seq revealed an increase in metabolic, immune, lipid biogenesis genes and Wnt/β-catenin signaling components in the HNF1A mutant relative to the wildtype mice. Mouse polyps and colon cancers from subjects carrying the HNF1AA98V variant exhibited reduced CDX2 and elevated β-catenin proteins. We further demonstrated decreased occupancy of HNF1AA98V at the Cdx2 locus and reduced Cdx2 promoter activity compared to wildtype HNF1A. Collectively, our study shows that the HNF1AA98V variant plus HFD promotes the formation of colonic polyps by activating β-catenin via decreasing Cdx2 expression.

RevDate: 2023-05-23

Moore SM, Quirk JD, Lassiter AW, et al (2023)

Co-Clinical Imaging Metadata Information (CIMI) for Cancer Research to Promote Open Science, Standardization, and Reproducibility in Preclinical Imaging.

Tomography (Ann Arbor, Mich.), 9(3):995-1009 pii:tomography9030081.

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an enabling technology for translational imaging research. Unlike clinical imaging, where equipment manufacturers strive to meet standards in practice at clinical sites, standards are neither fully developed nor implemented in preclinical imaging. This fundamentally limits the collection and reporting of metadata to qualify preclinical imaging studies, thereby hindering open science and impacting the reproducibility of co-clinical imaging research. To begin to address these issues, the NCI co-clinical imaging research program (CIRP) conducted a survey to identify metadata requirements for reproducible quantitative co-clinical imaging. The enclosed consensus-based report summarizes co-clinical imaging metadata information (CIMI) to support quantitative co-clinical imaging research with broad implications for capturing co-clinical data, enabling interoperability and data sharing, as well as potentially leading to updates to the preclinical Digital Imaging and Communications in Medicine (DICOM) standard.

RevDate: 2023-05-23

Kaku CI, Starr TN, Zhou P, et al (2022)

Evolution of antibody immunity following Omicron BA.1 breakthrough infection.

bioRxiv : the preprint server for biology.

Understanding the evolution of antibody immunity following heterologous SAR-CoV-2 breakthrough infection will inform the development of next-generation vaccines. Here, we tracked SARS-CoV-2 receptor binding domain (RBD)-specific antibody responses up to six months following Omicron BA.1 breakthrough infection in mRNA-vaccinated individuals. Cross-reactive serum neutralizing antibody and memory B cell (MBC) responses declined by two- to four-fold through the study period. Breakthrough infection elicited minimal de novo Omicron-specific B cell responses but drove affinity maturation of pre-existing cross-reactive MBCs toward BA.1. Public clones dominated the neutralizing antibody response at both early and late time points, and their escape mutation profiles predicted newly emergent Omicron sublineages. The results demonstrate that heterologous SARS-CoV-2 variant exposure drives the evolution of B cell memory and suggest that convergent neutralizing antibody responses continue to shape viral evolution.

RevDate: 2023-05-22

Esbenshade AJ, Lu L, Friedman DL, et al (2023)

Accumulation of Chronic Disease Among Survivors of Childhood Cancer Predicts Early Mortality.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Cancer survivors develop cancer and treatment-related morbidities at younger than normal ages and are at risk for early mortality, suggestive of an aging phenotype. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) is specifically designed to describe the accumulation of comorbidities over time with estimates of severity such as total score (TS) which is a sum of possible conditions weighted by severity. These severity scores can then be used to predict future mortality.

METHODS: CIRS-G scores were calculated in cancer survivors and their siblings from Childhood Cancer Survivor Study cohort members from two time points 19 years apart and members of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. CIRS-G metrics were analyzed using Cox proportional hazards regression to determine subsequent mortality risk.

RESULTS: In total, 14,355 survivors with a median age of 24 (IQR, 18-30) years and 4,022 siblings with a median age of 26 (IQR, 19-33) years provided baseline data; 6,138 survivors and 1,801 siblings provided follow-up data. Cancer survivors had higher median baseline TS than siblings at baseline (5.75 v 3.44) and follow-up (7.76 v 4.79), all P < .01. The mean increase in TS from baseline to follow-up was significantly steeper in cancer survivors (2.89 males and 3.18 females) vs. siblings (1.79 males and 1.69 females) and NHANES population (2.0 males and 1.94 females), all P < .01. Every point increase in baseline TS increased hazard for death by 9% (95% CI, 8 to 10) among survivors.

CONCLUSION: Application of a geriatric rating scale to characterize disease supports the hypothesis that morbidity accumulation is accelerated in young adult survivors of childhood cancer when compared with siblings and the general population.

RevDate: 2023-05-22

Yaffe ZA, Ding S, Sung K, et al (2023)

Reconstruction of a polyclonal ADCC antibody repertoire from an HIV-1 non-transmitting mother.

iScience, 26(5):106762 pii:S2589-0042(23)00839-8.

Human natural history and vaccine studies support a protective role of antibody dependent cellular cytotoxicity (ADCC) activity against many infectious diseases. One setting where this has consistently been observed is in HIV-1 vertical transmission, where passively acquired ADCC activity in HIV-exposed infants has correlated with reduced acquisition risk and reduced pathogenesis in HIV+ infants. However, the characteristics of HIV-specific antibodies comprising a maternal plasma ADCC response are not well understood. Here, we reconstructed monoclonal antibodies (mAbs) from memory B cells from late pregnancy in mother MG540, who did not transmit HIV to her infant despite several high-risk factors. Twenty mAbs representing 14 clonal families were reconstructed, which mediated ADCC and recognized multiple HIV Envelope epitopes. In experiments using Fc-defective variants, only combinations of several mAbs accounted for the majority of plasma ADCC of MG540 and her infant. We present these mAbs as evidence of a polyclonal repertoire with potent HIV-directed ADCC activity.

RevDate: 2023-05-22

Beresford SA, Rillamas-Sun E, Rudd K, et al (2023)

Development of an Assessment Tool to Measure Healthy Eating in Navajo Children and Their Families.

Current developments in nutrition, 7(5):100074 pii:S2475-2991(23)19947-1.

BACKGROUND: To estimate the efficacy of interventions to improve healthy eating, valid measures are essential. Although simple dietary intake tools have been developed with other populations, few have been culturally tailored and assessed for validity and reliability among Navajo.

OBJECTIVES: This study aimed to develop a simple dietary intake tool tailored to Navajo culture, derive healthy eating indices, and assess their validity and reliability in Navajo children and adults and to describe the process used to develop this tool.

METHODS: A picture-sort tool using typically consumed foods was developed. Elementary school children and family members provided qualitative feedback in focus groups, used to refine the tool. Next, school-aged children and adults completed assessments at baseline and follow-up. Baseline behavior measures including child self-efficacy for fruits and vegetables (F&V) were examined for internal consistency. Healthy eating indices were derived from intake frequencies from picture sorting. The convergent validity of the indices and behavior measures for children and adults were examined. The reliability of the indices at the 2 time points was derived using Bland-Altman plots.

RESULTS: The picture-sort was refined from feedback provided by the focus groups. Baseline measures from 25 children and 18 adults were obtained. In children, a modified Alternative Healthy Eating Index (AHEI) and 2 other indices from the picture-sort were correlated with self-efficacy for eating F&V and had good reliability. In adults, the modified AHEI and 3 other indices from the picture-sort had significant correlations with adult abbreviated food frequency of F&V or obesogenic dietary index and had good reliability.

CONCLUSIONS: The Navajo foods picture-sort tool developed for Navajo children and adults is proven to be acceptable and feasible to implement. Indices derived from the tool has good convergent validity and repeatability, supporting use in evaluating dietary change interventions in Navajo, with the potential for broader use of the approach in other underserved populations.

RevDate: 2023-05-22

Mao Z, JK Lee (2023)

Expanding the landscape of TCR gene therapy targeting MAGE.

Molecular therapy oncolytics, 29:59-60 pii:S2372-7705(23)00029-3.

RevDate: 2023-05-22

Sarvari P, Rubio K, Dobersch S, et al (2023)

Editorial: Therapeutic targeting of splicing variants in cancer.

Frontiers in pharmacology, 14:1206342 pii:1206342.

RevDate: 2023-05-22

Crandall CJ, Larson JC, Schousboe JT, et al (2023)

Race and Ethnicity and Fracture Prediction Among Younger Postmenopausal Women in the Women's Health Initiative Study.

JAMA internal medicine pii:2804684 [Epub ahead of print].

IMPORTANCE: The best approach to identify younger postmenopausal women for osteoporosis screening is uncertain. The Fracture Risk Assessment Tool (FRAX), which includes self-identified racial and ethnic information, and the Osteoporosis Self-assessment Tool (OST), which does not, are risk assessment tools recommended by US Preventive Services Task Force guidelines to identify candidates for bone mineral density (BMD) testing in this age group.

OBJECTIVE: To compare the ability of FRAX vs OST to discriminate between younger postmenopausal women who do and do not experience incident fracture during a 10-year follow-up in the 4 racial and ethnic groups specified by FRAX.

This cohort study of Women's Health Initiative participants included 67 169 women (baseline age range, 50-64 years) with 10 years of follow-up for major osteoporotic fracture (MOF; including hip, clinical spine, forearm, and shoulder fracture) at 40 US clinical centers. Data were collected from October 1993 to December 2008 and analyzed between May 11, 2022, and February 23, 2023.

MAIN OUTCOMES AND MEASURES: Incident MOF and BMD (in a subset of 4607 women) were assessed. The area under the receiver operating characteristic curve (AUC) for FRAX (without BMD information) and OST was calculated within each racial and ethnic category.

RESULTS: Among the 67 169 participants, mean (SD) age at baseline was 57.8 (4.1) years. A total of 1486 (2.2%) self-identified as Asian, 5927 (8.8%) as Black, 2545 (3.8%) as Hispanic, and 57 211 (85.2%) as White. During follow-up, 5594 women experienced MOF. For discrimination of MOF, AUC values for FRAX were 0.65 (95% CI, 0.58-0.71) for Asian, 0.55 (95% CI, 0.52-0.59) for Black, 0.61 (95% CI, 0.56-0.65) for Hispanic, and 0.59 (95% CI, 0.58-0.59) for White women. The AUC values for OST were 0.62 (95% CI, 0.56-0.69) for Asian, 0.53 (95% CI, 0.50-0.57) for Black, 0.58 (95% CI, 0.54-0.62) for Hispanic, and 0.55 (95% CI, 0.54-0.56) for White women. For discrimination of femoral neck osteoporosis, AUC values were excellent for OST (range, 0.79 [95% CI, 0.65-0.93] to 0.85 [95% CI, 0.74-0.96]), higher for OST than FRAX (range, 0.72 [95% CI, 0.68-0.75] to 0.74 [95% CI, 0.60-0.88]), and similar in each of the 4 racial and ethnic groups.

CONCLUSIONS AND RELEVANCE: These findings suggest that within each racial and ethnic category, the US FRAX and OST have suboptimal performance in discrimination of MOF in younger postmenopausal women. In contrast, for identifying osteoporosis, OST was excellent. The US version of FRAX should not be routinely used to make screening decisions in younger postmenopausal women. Future investigations should improve existing tools or create new approaches to osteoporosis risk assessment for this age group.

RevDate: 2023-05-20

Schmeusser BN, Midenberg E, Palacios AR, et al (2023)

Low Skeletal Muscle as a Risk Factor for Worse Survival in Nonmetastatic Renal Cell Carcinoma with Venous Tumor Thrombus.

Clinical genitourinary cancer pii:S1558-7673(23)00092-7 [Epub ahead of print].

BACKGROUND: Renal cell carcinoma (RCC) with tumor thrombosis often requires nephrectomy and tumor thrombectomy. As an extensive and potentially morbid operation, patient preoperative functional reserve and body composition is an important consideration. Sarcopenia is a risk factor for increased postoperative complications, systemic therapy toxicity, and death solid organ tumors, including RCC. The influence of sarcopenia in RCC patients with tumor thrombus is not well defined. This study evaluates the prognostic ability of sarcopenia regarding surgical outcomes and complications in patients undergoing surgery for RCC with tumor thrombus.

METHODS: We retrospectively analyzed patients with nonmetastatic RCC and tumor thrombus undergoing radical nephrectomy and tumor thrombectomy. Skeletal muscle index (SMI; cm[2]/m[2]) was measured on preoperative CT/MRI. Sarcopenia was defined using body mass index- and sex-stratified thresholds optimally fit via a receiver-operating characteristic analysis for survival. Associations between preoperative sarcopenia and overall (OS), cancer-specific survival (CSS), and 90-day major complications were determined using multivariable analysis.

RESULTS: 115 patients were analyzed, with median (IQR) age and body mass index of 69 (56-72) and 28.6 kg/m[2] (23.6-32.9), respectively. 96 (83.4%) of the cohort had ccRCC. Sarcopenia was associated with shorter median OS (P = .0017) and CSS (P = .0019) in Kaplan-Meier analysis. In multivariable analysis, preoperative sarcopenia was prognostic of shorter OS (HR = 3.38, 95% confidence interval [CI] 1.61-7.09) and CSS (HR = 5.15, 95% CI 1.46-18.18). Notably, 1 unit increases in SMI were associated with improved OS (HR = 0.97, 95% CI 0.94-0.999) but not CSS (HR = 0.95, 95% CI 0.90-1.01). No significant relationship between preoperative sarcopenia and 90-day major surgical complications was observed in this cohort (HR = 2.04, 95% CI 0.65-6.42).

CONCLUSION: Preoperative sarcopenia was associated with decreased OS and CSS in patients surgically managed for nonmetastatic RCC and VTT, however, was not predictive of 90-day major postoperative complications. Body composition analysis has prognostic utility for patients with nonmetastatic RCC and venous tumor thrombus undergoing surgery.

RevDate: 2023-05-20

Koutros S, Kiemeney LA, Pal Choudhury P, et al (2023)

Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.

European urology pii:S0302-2838(23)02780-X [Epub ahead of print].

BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology.

OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data.

Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis.

Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking.

RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10[-8]) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [pM-I] = 0.004), 8q21.13 (PAG1; pM-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; pM-I = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers.

CONCLUSIONS: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer.

PATIENT SUMMARY: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer.

RevDate: 2023-05-20

Blosser CD, Portuguese AJ, Santana C, et al (2023)

Transplant Onconephrology: An Update.

Seminars in nephrology, 42(6):151348 pii:S0270-9295(23)00058-X [Epub ahead of print].

Transplant onconephrology is a growing specialty focused on the health care of kidney transplant recipients with cancer. Given the complexities associated with the care of transplant patients, along with the advent of novel cancer therapies such as immune checkpoint inhibitors and chimeric antigen-receptor T cells, there is a dire need for the subspecialty of transplant onconephrology. The management of cancer in the setting of kidney transplantation is best accomplished by a multidisciplinary team, including transplant nephrologists, oncologists, and patients. This review addresses the current state and future opportunities for transplant onconephrology, including the roles of the multidisciplinary team, and related scientific and clinical knowledge.

RevDate: 2023-05-19

Baek GT, Huang IJ, AK Gopal (2023)

Safety of loncastuximab tesirine-lpyl in diffuse large B-cell lymphoma with severe hepatic dysfunction.

Cancer [Epub ahead of print].

Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma with a high rate of disease relapse despite the achievement of clinical responses to frontline chemoimmunotherapy treatments. Loncastuximab tesirine-lpyl is a novel anti-CD19 antibody conjugated to an alkylating pyrrolobenzodiazepine agent (SG3199), and it has been approved for relapsed/refractory (r/r) DLBCL. Baseline moderate to severe hepatic impairment has an unclear impact on the safety of loncastuximab tesirine-lpyl, and there is a lack of clear guidance on dose adjustment from the manufacturer. The authors present two cases of r/r DLBCL safely treated with full-dose loncastuximab tesirine-lpyl in the setting of severe hepatic dysfunction.

RevDate: 2023-05-19

Stoyanova G, Jabeen S, Landazuri Vinueza J, et al (2023)

Zika virus triggers autophagy to exploit host lipid metabolism and drive viral replication.

Cell communication and signaling : CCS, 21(1):114.

BACKGROUND: Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain-Barré syndrome in adults. Like other flaviviruses, ZIKV depends on cholesterol to facilitate its replication; thus, cholesterol has been proposed as a therapeutic target to treat the infection using FDA-approved statins. Cholesterol is stored in intracellular lipid droplets (LD) in the form of cholesterol esters and can be regulated by autophagy. We hypothesize that the virus hijacks autophagy machinery as an early step to increase the formation of LD and viral replication, and that interference with this pathway will limit reproduction of virus.

METHODS: We pretreated MDCK cells with atorvastatin or other inhibitors of autophagy prior to infection with ZIKV. We measured viral expression by qPCR for NS1 RNA and immunofluorescence for Zika E protein.

RESULTS: Autophagy increases in virus-infected cells as early as 6 h post infection (hpi). In the presence of atorvastatin, LD are decreased, and cholesterol is reduced, targeting key steps in viral replication, resulting in suppression of replication of ZIKV is suppressed. Other both early- and late-acting autophagy inhibitors decrease both the number of LD and viral replication. Bafilomycin renders cholesterol is inaccessible to ZIKV. We also confirm previous reports of a bystander effect, in which neighboring uninfected cells have higher LD counts compared to infected cells.

CONCLUSIONS: We conclude that atorvastatin and inhibitors of autophagy lead to lower availability of LD, decreasing viral replication. We conclude that bafilomycin A1 inhibits viral expression by blocking cholesterol esterification to form LD. Video Abstract.

RevDate: 2023-05-19

Beauchamp G, Donnell D, Hosek S, et al (2023)

Trust in the provider and accurate self-reported PrEP adherence among adolescent girls and young women in South Africa and Zimbabwe: HPTN 082 study.

BMC women's health, 23(1):276.

BACKGROUND: Trust is an important cornerstone of patient-provider communication. Accurate reporting of pre-exposure prophylaxis (PrEP) adherence is vital for providers to determine who needs adherence support, especially adolescent girls and young women (AGYW) disproportionately affected by newly diagnosed HIV.

METHODS: This is a secondary analysis of the HPTN 082 open-label PrEP demonstration trial. From 2016-2018, 451 AGYW aged 16-25 years were enrolled in South Africa (Cape Town and Johannesburg) and Zimbabwe (Harare). PrEP was initiated by 427, and 354 (83%) had month three patient-reported adherence responses and intracellular tenofovir diphosphate (TFV-DP) measurements. The patient-reported adherence response to 'In the past month, how often did you take the tablet?' was dichotomized as 'high' if the response was every day or most days, and 'low' if some days or not many days or never. The biomarker marker evidence of adherence in dried blood spots was defined as 'high' if TFV-DP ≥ 700, and 'low' if < 350 fmol/punch. We used multinomial logistic regression to examine if trust in the PrEP provider was associated with concordance between patient-reported adherence and intracellular tenofovir-diphosphate (TFV-DP).

RESULTS: AGYW who reported trust in their providers were almost four-fold (aOR 3.72, 95% CI 1.20-11.51) more likely to have concordant adherence (high self-reported adherence and high TFV-DP concentrations) compared to discordant non-adherence (high self-reported adherence and low TFV-DP concentrations).

CONCLUSION: Education and training of providers to build trusting relationships with AGYW may lead to more accurate reporting of PrEP adherence. With accurate reporting, adequate support can be provided to bolster adherence.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02732730.

RevDate: 2023-05-19

Sabo MC, Lokken EM, Srinivasan S, et al (2023)

Changes in vaginal bacteria and inflammatory mediators from periconception through early-postpartum in a cohort of HIV-negative Kenyan women.

The Journal of infectious diseases pii:7174003 [Epub ahead of print].

BACKGROUND: Women's increased risk of HIV acquisition during pregnancy and postpartum may be mediated by changes in vaginal microbiota and/or cytokines.

METHODS: A cohort of 80 HIV-1-seronegative Kenyan women contributed 409 vaginal samples at six pregnancy timepoints: periconception, positive pregnancy test, first trimester, second trimester, third trimester, and postpartum. Concentrations of vaginal bacteria linked with HIV risk and Lactobacillus species were measured using quantitative polymerase chain reaction. Cytokines were measured by immunoassay.

RESULTS: Using Tobit regression, later pregnancy timepoints were associated with lower concentrations of Sneathia spp. (p = 0.01), Eggerthella sp. Type 1 (p = 0.002) and Parvimonas sp. Type 2 (p = 0.02), and higher concentrations of L iners (p < 0.001), L. crispatus (p=<0.001), L. vaginalis (p < 0.001), IL-6 (p < 0.001), TNF (p = 0.004), CXCL10 (p < 0.001), CCL3 (p = 0.009), CCL4 (p < 0.001), CCL5 (p = 0.002), IL-1β (p = 0.02), and IL-8 (p = 0.002). Most cervicovaginal cytokines and vaginal bacteria clustered separately in principal components analysis, except for CXCL10, which did not group with either cytokines or bacteria. The shift toward a Lactobacillus dominated microbiota during pregnancy mediated the relationship between pregnancy timepoint and CXCL10.

CONCLUSIONS: Increases in proinflammatory cytokines, but not vaginal bacterial taxa linked with higher HIV risk, could provide an explanation for increased HIV susceptibility during pregnancy and postpartum.

RevDate: 2023-05-19

Herberts C, Wyatt AW, Nguyen PL, et al (2023)

Genetic and Genomic Testing for Prostate Cancer: Beyond DNA Repair.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 43:e390384.

Significant progress has been made in genetic and genomic testing for prostate cancer across the disease spectrum. Molecular profiling is increasingly relevant for routine clinical management, fueled in part by advancements in testing technology and integration of biomarkers into clinical trials. In metastatic prostate cancer, defects in DNA damage response genes are now established predictors of benefit to US Food and Drug Administration-approved poly (ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors, and trials are actively investigating these and other targeted treatment strategies in earlier disease states. Excitingly, opportunities for molecularly informed management beyond DNA damage response genes are also maturing. Germline genetic variants (eg, BRCA2 or MSH2/6) and polygenic germline risk scores are being investigated to inform cancer screening and active surveillance in at-risk carriers. RNA expression tests have recently gained traction in localized prostate cancer, enabling patient risk stratification and tailored treatment intensification via radiotherapy and/or androgen deprivation therapy for localized or salvage treatment. Finally, emerging minimally invasive circulating tumor DNA technology promises to enhance biomarker testing in advanced disease pending additional methodological and clinical validation. Collectively, genetic and genomic tests are rapidly becoming indispensable tools for informing the optimal clinical management of prostate cancer.

RevDate: 2023-05-19

Savonen C, Wright C, Hoffman AM, et al (2023)

Open-source Tools for Training Resources - OTTR.

Journal of statistics and data science education : an official journal of the of the American Statistical Association, 31(1):57-65.

Data science and informatics tools are developing at a blistering rate, but their users often lack the educational background or resources to efficiently apply the methods to their research. Training resources and vignettes that accompany these tools often deprecate because their maintenance is not prioritized by funding, giving teams little time to devote to such endeavors. Our group has developed Open-source Tools for Training Resources (OTTR) to offer greater efficiency and flexibility for creating and maintaining these training resources. OTTR empowers creators to customize their work and allows for a simple workflow to publish using multiple platforms. OTTR allows content creators to publish training material to multiple massive online learner communities using familiar rendering mechanics. OTTR allows the incorporation of pedagogical practices like formative and summative assessments in the form of multiple choice questions and fill in the blank problems that are automatically graded. No local installation of any software is required to begin creating content with OTTR. Thus far, 15 training courses have been created with OTTR repository template. By using the OTTR system, the maintenance workload for updating these courses across platforms has been drastically reduced. For more information about OTTR and how to get started, go to ottrproject.org.

RevDate: 2023-05-19

Dross S, Venkataraman R, Patel S, et al (2023)

Efficient ex vivo expansion of conserved element vaccine-specific CD8+ T-cells from SHIV-infected, ART-suppressed nonhuman primates.

Frontiers in immunology, 14:1188018.

HIV-specific T cells are necessary for control of HIV-1 replication but are largely insufficient for viral clearance. This is due in part to these cells' recognition of immunodominant but variable regions of the virus, which facilitates viral escape via mutations that do not incur viral fitness costs. HIV-specific T cells targeting conserved viral elements are associated with viral control but are relatively infrequent in people living with HIV (PLWH). The goal of this study was to increase the number of these cells via an ex vivo cell manufacturing approach derived from our clinically-validated HIV-specific expanded T-cell (HXTC) process. Using a nonhuman primate (NHP) model of HIV infection, we sought to determine i) the feasibility of manufacturing ex vivo-expanded virus-specific T cells targeting viral conserved elements (CE, CE-XTCs), ii) the in vivo safety of these products, and iii) the impact of simian/human immunodeficiency virus (SHIV) challenge on their expansion, activity, and function. NHP CE-XTCs expanded up to 10-fold following co-culture with the combination of primary dendritic cells (DCs), PHA blasts pulsed with CE peptides, irradiated GM-K562 feeder cells, and autologous T cells from CE-vaccinated NHP. The resulting CE-XTC products contained high frequencies of CE-specific, polyfunctional T cells. However, consistent with prior studies with human HXTC and these cells' predominant CD8[+] effector phenotype, we did not observe significant differences in CE-XTC persistence or SHIV acquisition in two CE-XTC-infused NHP compared to two control NHP. These data support the safety and feasibility of our approach and underscore the need for continued development of CE-XTC and similar cell-based strategies to redirect and increase the potency of cellular virus-specific adaptive immune responses.

RevDate: 2023-05-19

Finton KAK, Rupert PB, Friend DJ, et al (2023)

Effects of HLA single chain trimer design on peptide presentation and stability.

Frontiers in immunology, 14:1170462.

MHC class I "single-chain trimer" molecules, coupling MHC heavy chain, β2-microglobulin, and a specific peptide into a single polypeptide chain, are widely used in research. To more fully understand caveats associated with this design that may affect its use for basic and translational studies, we evaluated a set of engineered single-chain trimers with combinations of stabilizing mutations across eight different classical and non-classical human class I alleles with 44 different peptides, including a novel human/murine chimeric design. While, overall, single-chain trimers accurately recapitulate native molecules, care was needed in selecting designs for studying peptides longer or shorter than 9-mers, as single-chain trimer design could affect peptide conformation. In the process, we observed that predictions of peptide binding were often discordant with experiment and that yields and stabilities varied widely with construct design. We also developed novel reagents to improve the crystallizability of these proteins and confirmed novel modes of peptide presentation.

RevDate: 2023-05-19

Torabi A, Fromm JR, KN Naresh (2023)

MEF2B is the ideal immunohistochemical marker to highlight neoplastic LP cells in nodular lymphocyte-predominant Hodgkin lymphoma.

EJHaem, 4(2):517-519 pii:JHA2690.

RevDate: 2023-05-19

Jamali H, Wu D, Soma L, et al (2023)

Ibrutinib response in a patient with refractory mixed essential cryoglobulinemia.

EJHaem, 4(2):499-500 pii:JHA2686.

RevDate: 2023-05-19

Han CJ, Reding KW, Kalady MF, et al (2023)

Factors associated with long-term gastrointestinal symptoms in colorectal cancer survivors in the women's health initiatives (WHI study).

PloS one, 18(5):e0286058 pii:PONE-D-23-03069.

PURPOSE: Colorectal cancer (CRC) survivors often experience long-term symptoms after cancer treatments. But gastrointestinal (GI) symptom experiences are under-investigated in CRC survivors. We described persistent GI symptoms after cancer treatments in female CRC survivors and assessed GI symptoms' risk and life-impact factors.

METHODS: A cross-sectional study utilized data from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study that recruited postmenopausal women. Correlation analyses and multivariable linear regression models were used.

RESULTS: CRC survivors after cancer treatments were included (N = 413, mean age 71.2 years old, mean time since diagnosis = 8.1 years). 81% of CRC survivors experienced persistent GI symptoms. Bloating/gas was the most prevalent (54.2%± 0.88) and severe GI symptom, followed by constipation (44.1%±1.06), diarrhea (33.4%±0.76), and abdominal/pelvic pain (28.6%±0.62). Significant risk factors for GI symptoms include time since cancer diagnosis (<5 years), advanced cancer stage, high psychological distress, poor dietary habits, and low physical activity. Fatigue and sleep disturbance were the most significant risk factors for long-term GI symptoms (β = 0.21, t = 3.557; β = 0.20, t = 3.336, respectively, Ps < .001). High severity of GI symptoms was positively associated with poor quality of life (QOL), increased daily life interferences (social and physical functions), and low body image satisfaction (Ps < .001).

CONCLUSIONS: Women CRC survivors experience a high GI symptom burden, highlighting the need to inform policy and improve the QOL of cancer survivors. Our findings will aid in identifying those more vulnerable to symptoms, and inform future survivorship care interventions (i.e., community-based cancer symptom management) by considering multiple risk factors (e.g., psychological distress).

RevDate: 2023-05-19

Lin J, Ehinger E, Hanna DB, et al (2023)

HIV infection and cardiovascular disease have both shared and distinct monocyte gene expression features: Women's Interagency HIV study.

PloS one, 18(5):e0285926 pii:PONE-D-23-02143.

Persistent inflammation contributes to the development of cardiovascular disease (CVD) as an HIV-associated comorbidity. Innate immune cells such as monocytes are major drivers of inflammation in men and women with HIV. The study objectives are to examine the contribution of circulating non-classical monocytes (NCM, CD14dimCD16+) and intermediate monocytes (IM, CD14+CD16+) to the host response to long-term HIV infection and HIV-associated CVD. Women with and without chronic HIV infection (H) were studied. Subclinical CVD (C) was detected as plaques imaged by B-mode carotid artery ultrasound. The study included H-C-, H+C-, H-C+, and H+C+ participants (23 of each, matched on race/ethnicity, age and smoking status), selected from among enrollees in the Women's Interagency HIV Study. We assessed transcriptomic features associated with HIV or CVD alone or comorbid HIV/CVD comparing to healthy (H-C-) participants in IM and NCM isolated from peripheral blood mononuclear cells. IM gene expression was little affected by HIV alone or CVD alone. In IM, coexisting HIV and CVD produced a measurable gene transcription signature, which was abolished by lipid-lowering treatment. In NCM, versus non-HIV controls, women with HIV had altered gene expression, irrespective of whether or not they had comorbid CVD. The largest set of differentially expressed genes was found in NCM among women with both HIV and CVD. Genes upregulated in association with HIV included several potential targets of drug therapies, including LAG3 (CD223). In conclusion, circulating monocytes from patients with well controlled HIV infection demonstrate an extensive gene expression signature which may be consistent with the ability of these cells to serve as potential viral reservoirs. Gene transcriptional changes in HIV patients were further magnified in the presence of subclinical CVD.

RevDate: 2023-05-19

Whiteaker JR, Zhao L, Schoenherr RM, et al (2023)

A multiplexed assay for quantifying immunomodulatory proteins supports correlative studies in immunotherapy clinical trials.

Frontiers in oncology, 13:1168710.

INTRODUCTION: Immunotherapy is an effective treatment for a subset of cancer patients, and expanding the benefits of immunotherapy to all cancer patients will require predictive biomarkers of response and immune-related adverse events (irAEs). To support correlative studies in immunotherapy clinical trials, we are developing highly validated assays for quantifying immunomodulatory proteins in human biospecimens.

METHODS: Here, we developed a panel of novel monoclonal antibodies and incorporated them into a novel, multiplexed, immuno-multiple reaction monitoring mass spectrometry (MRM-MS)-based proteomic assay targeting 49 proteotypic peptides representing 43 immunomodulatory proteins.

RESULTS AND DISCUSSION: The multiplex assay was validated in human tissue and plasma matrices, where the linearity of quantification was >3 orders of magnitude with median interday CVs of 8.7% (tissue) and 10.1% (plasma). Proof-of-principle demonstration of the assay was conducted in plasma samples collected in clinical trials from lymphoma patients receiving an immune checkpoint inhibitor. We provide the assays and novel monoclonal antibodies as a publicly available resource for the biomedical community.

RevDate: 2023-05-18

Mehta RS, Ali H, Dai Y, et al (2023)

A prospective phase 2 clinical trial of a C5a complement inhibitor for acute GVHD with lower GI tract involvement.

Bone marrow transplantation [Epub ahead of print].

Involvement of lower gastrointestinal tract (LGI) occurs in 60% of patients with graft-versus-host-disease (GVHD). Complement components C3 and C5 are involved in GVHD pathogenesis. In this phase 2a study, we evaluated the safety and efficacy of ALXN1007, a monoclonal antibody against C5a, in patients with newly diagnosed LGI acute GVHD receiving concomitant corticosteroid. Twenty-five patients were enrolled; one was excluded from the efficacy analysis based upon negative biopsy. Most patients (16/25, 64%) had acute leukemia; 52% (13/25) had an HLA-matched unrelated donor; and 68% (17/25) received myeloablative conditioning. Half the patients (12/24) had a high biomarker profile, Ann Arbor score 3; 42% (10/24) had high-risk GVHD per Minnesota classification. Day-28 overall response was 58% (13/24 complete response, 1/24 partial response), and 63% by Day-56 (all complete responses). Day-28 overall response was 50% (5/10) in Minnesota high-risk and 42% (5/12) in high-risk Ann Arbor patients, increasing to 58% (7/12) by Day-56. Non-relapse mortality at 6-months was 24% (95% CI 11-53). The most common treatment-related adverse event was infection (6/25, 24%). Neither baseline complement levels (except for C5), activity, nor inhibition of C5a with ALXN1007 correlated with GVHD severity or responses. Further studies are needed to evaluate the role of complement inhibition in GVHD treatment.

RevDate: 2023-05-18

Gray HJ, Chatterjee P, Rosati R, et al (2023)

Extraordinary clinical response to ibrutinib in low-grade ovarian cancer guided by organoid drug testing.

NPJ precision oncology, 7(1):45.

Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient's tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient's tumor identified several therapeutic choices, including Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient's CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient's CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments.

RevDate: 2023-05-18

Chiang SS, Senador L, Altamirano E, et al (2023)

Adolescent, caregiver and provider perspectives on tuberculosis treatment adherence: a qualitative study from Lima, Peru.

BMJ open, 13(5):e069938 pii:bmjopen-2022-069938.

OBJECTIVES: To understand the perspectives of adolescents (10-19 years old), their caregivers and healthcare providers regarding factors that impact adherence to tuberculosis (TB) treatment among adolescents.

DESIGN: We conducted in-depth interviews using semistructured interview guides based on the World Health Organization (WHO)'s Five Dimensions of Adherence framework, which conceptualises adherence as being related to the health system, socioeconomic factors, patient, treatment and condition. We applied framework thematic analysis.

SETTING: Between August 2018 and May 2019, at 32 public health centres operated by the Ministry of Health in Lima, Peru.

PARTICIPANTS: We interviewed 34 adolescents who completed or were lost to follow-up from treatment for drug-susceptible pulmonary TB disease in the preceding 12 months; their primary caregiver during treatment; and 15 nurses or nurse technicians who had ≥6 months' experience supervising TB treatment.

RESULTS: Participants reported numerous treatment barriers, the most common of which were the inconvenience of health facility-based directly observed therapy (DOT), long treatment duration, adverse treatment events and symptom resolution. The support of adult caregivers was critical for helping adolescents overcome these barriers and carry out the behavioural skills (eg, coping with the large pill burden, managing adverse treatment events and incorporating treatment into daily routines) needed to adhere to treatment.

CONCLUSION: Our findings support a three-pronged approach to improve TB treatment adherence among adolescents: (1) reduce barriers to adherence (eg, home-based or community-based DOT in lieu of facility-based DOT, reducing pill burden and treatment duration when appropriate), (2) teach adolescents the behavioural skills required for treatment adherence and (3) strengthen caregivers' ability to support adolescents.

RevDate: 2023-05-18

Burnett AL, Nyame YA, E Mitchell (2023)

Disparities in prostate cancer.

Journal of the National Medical Association, 115(2S):S38-S45.

Despite substantial advances in early detection/prevention and treatments, and improved outcomes in recent decades, prostate cancer continues to disproportionately affect Black men and is the secondleading cause of cancer death in this subgroup. Black men are substantially more likely to develop prostate cancer and are twice as likely to die from the disease compared with White men. In addition, Black men are younger at diagnosis and face a higher risk of aggressive disease relative to White men. Striking racial disparities endure along the continuum of prostate cancer care, including screening, genomic testing, diagnostic procedures, and treatment modalities. The underlying causes of these inequalities are complex and multifactorial and involve biological factors, structural determinants of equity (i.e., public policy, structural and systemic racism, economic policy), social determinants of health (including income, education, and insurance status, neighborhood/physical environment, community/social context, and geography), and health care factors. The objective of this article is to review the sources of racial disparities in prostate cancer and to propose actionable recommendations to help address these inequities and narrow the racial gap.

RevDate: 2023-05-18

Jehangir M, Hippe DS, Huang G, et al (2023)

LIMITED AXIAL INTERPRETATION OF CORONARY CT ANGIOGRAPHY IN THE EMERGENCY DEPARTMENT SETTING.

Journal of the American College of Radiology : JACR pii:S1546-1440(23)00337-X [Epub ahead of print].

BACKGROUND: Incorporating coronary CT angiography (CCTA) into Emergency Department (ED) workflows has been limited by the need for 24/7 real-time post-processing.

PURPOSE: This study studied whether interpretation of trans-axial CCTA images alone (LI) is noninferior to interpretation of combined trans-axial and multiplanar reformation images (FI) in assessing acute chest pain patients in the ED.

MATERIALS AND METHODS: CCTA exams of 74 patients were evaluated by two radiologists, one without dedicated CCTA training and one with basic CCTA experience. Each exam was evaluated three times in separate sessions, once by LI and twice by FI, in random order. Nineteen coronary artery segments were rated as having significant stenosis (≥ 50%) or not. Inter-reader agreement was assessed using Cohen's kappa. The primary analysis was whether the accuracy of LI for detecting significant stenosis was noninferior to FI at the patient-level (margin =-10%). Secondary analyses included similar analyses of sensitivity and specificity, at both the patient- and vessel-level.

RESULTS: Inter-reader agreement for significant stenosis was good for both LI and FI (kappa:0.72vs.0.70, P =.74). Average accuracy for significant stenosis at the patient-level was 90.5% for LI and 91.9% for FI, with a difference of -1.4%. The accuracy of LI was noninferior to FI as the CI did not include the noninferiority margin. Noninferiority was also found for patient-level sensitivity, and for accuracy, sensitivity, and specificity at the vessel-level.

CONCLUSION: Limited interpretation of the coronary arteries using trans-axial CCTA images may be sufficient for the detection of significant CAD in the ED setting.

RevDate: 2023-05-18

Bao T, Greenlee H, Lopez AM, et al (2023)

How to Make Evidence-Based Integrative Medicine a Part of Everyday Oncology Practice.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 43:e389830.

Integrativety oncology (IO) is a "patient-centered, evidence-informed field of comprehensive cancer care that utilizes mind-body practices, natural products, and lifestyle modifications from different traditions alongside conventional cancer treatments." There is an urgent need to educate oncology health care providers on the fundamentals of evidence-based IO to meet the needs of people with cancer. In this chapter, we aim to provide oncology professionals with actionable guidance on the basis of the Society for Integrative Oncology (SIO)-American Society of Clinical Oncology (ASCO) guidelines on integrative medicine use during oncology visits to help alleviate symptoms and side effects in people with cancer during and after treatment.

RevDate: 2023-05-18

Hesko C, Liu W, Srivastava DK, et al (2023)

Neurocognitive outcomes in adult survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

Cancer [Epub ahead of print].

BACKGROUND: Despite survival improvements, there is a paucity of data on neurocognitive outcomes in neuroblastoma survivors. This study addresses this literature gap.

METHODS: Neurocognitive impairments in survivors were compared to sibling controls from the Childhood Cancer Survivor Study (CCSS) using the CCSS Neurocognitive Questionnaire. Impaired emotional regulation, organization, task efficiency, and memory defined as scores ≥90th percentile of sibling norms. Modified Poisson regression models evaluated associations with treatment exposures, era of diagnosis, and chronic conditions. Analyses were stratified by age at diagnosis (≤1 and >1 year) as proxy for lower versus higher risk disease.

RESULTS: Survivors (N = 837; median [range] age, 25 [17-58] years, age diagnosed, 1 [0-21] years) were compared to sibling controls (N = 728; age, 32 [16-43] years). Survivors had higher risk of impaired task efficiency (≤1 year relative risk [RR], 1.48; 95% confidence interval [CI], 1.08-2.03; >1 year RR, 1.58; 95% CI, 1.22-2.06) and emotional regulation (≤1 year RR, 1.51; 95% CI, 1.07-2.12; >1 year RR, 1.44; 95% CI, 1.06-1.95). Impaired task efficiency associated with platinum exposure (≤1 year RR, 1.74; 95% CI, 1.01-2.97), hearing loss (≤1 year RR, 1.95; 95% CI, 1.26-3.00; >1 year RR, 1.56; 95% CI, 1.09-2.24), cardiovascular (≤1 year RR, 1.83; 95% CI, 1.15-2.89; >1 year RR, 1.74; 95% CI, 1.12-2.69), neurologic (≤1 year RR, 2.00; 95% CI, 1.32-3.03; >1 year RR, 2.29; 95% CI, 1.64-3.21), and respiratory (>1 year RR, 2.35; 95% CI, 1.60-3.45) conditions. Survivors ≤1 year; female sex (RR, 1.54; 95% CI, 1.02-2.33), cardiovascular (RR, 1.71; 95% CI, 1.08-2.70) and respiratory (RR, 1.99; 95% CI, 1.14-3.49) conditions associated impaired emotional regulation. Survivors were less likely to be employed full-time (p < .0001), graduate college (p = .035), and live independently (p < .0001).

CONCLUSIONS: Neuroblastoma survivors report neurocognitive impairment impacting adult milestones. Identified health conditions and treatment exposures can be targeted to improve outcomes.

PLAIN LANGUAGE SUMMARY: Survival rates continue to improve in patients with neuroblastoma. There is a lack of information regarding neurocognitive outcomes in neuroblastoma survivors; most studies examined survivors of leukemia or brain tumors. In this study, 837 adult survivors of childhood neuroblastoma were compared to siblings from the Childhood Cancer Survivorship Study. Survivors had a 50% higher risk of impairment with attention/processing speed (task efficiency) and emotional reactivity/frustration tolerance (emotional regulation). Survivors were less likely to reach adult milestones such as living independently. Survivors with chronic health conditions are at a higher risk of impairment. Early identification and aggressive management of chronic conditions may help mitigate the level of impairment.

RevDate: 2023-05-18

Colón-Thillet R, Stone D, Loprieno MA, et al (2023)

Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies.

Microbiology spectrum [Epub ahead of print].

Hepatitis B virus (HBV) is a pathogen of major public health importance that is largely incurable once a chronic infection is established. Only humans and great apes are fully permissive to HBV infection, and this species restriction has impacted HBV research by limiting the utility of small animal models. To combat HBV species restrictions and enable more in vivo studies, liver-humanized mouse models have been developed that are permissive to HBV infection and replication. Unfortunately, these models can be difficult to establish and are expensive commercially, which has limited their academic use. As an alternative mouse model to study HBV, we evaluated liver-humanized NSG-PiZ mice and showed that they are fully permissive to HBV. HBV selectively replicates in human hepatocytes within chimeric livers, and HBV-positive (HBV[+]) mice secrete infectious virions and hepatitis B surface antigen (HBsAg) into blood while also harboring covalently closed circular DNA (cccDNA). HBV[+] mice develop chronic infections lasting at least 169 days, which should enable the study of new curative therapies targeting chronic HBV, and respond to entecavir therapy. Furthermore, HBV[+] human hepatocytes in NSG-PiZ mice can be transduced by AAV3b and AAV.LK03 vectors, which should enable the study of gene therapies that target HBV. In summary, our data demonstrate that liver-humanized NSG-PiZ mice can be used as a robust and cost-effective alternative to existing chronic hepatitis B (CHB) models and may enable more academic research labs to study HBV disease pathogenesis and antiviral therapy. IMPORTANCE Liver-humanized mouse models have become the gold standard for the in vivo study of hepatitis B virus (HBV), yet their complexity and cost have prohibited widespread use of existing models in research. Here, we show that the NSG-PiZ liver-humanized mouse model, which is relatively inexpensive and simple to establish, can support chronic HBV infection. Infected mice are fully permissive to hepatitis B, supporting both active replication and spread, and can be used to study novel antiviral therapies. This model is a viable and cost-effective alternative to other liver-humanized mouse models that are used to study HBV.

RevDate: 2023-05-18

Luo K, Wang Z, Peters BA, et al (2023)

Tryptophan metabolism, gut microbiota, and carotid artery plaque in women with and without HIV infection.

AIDS (London, England) pii:00002030-990000000-00261 [Epub ahead of print].

OBJECTIVE: The perturbation of tryptophan (TRP) metabolism has been linked with HIV infection and cardiovascular disease (CVD), but the interrelationship among TRP metabolites, gut microbiota, and atherosclerosis remain unclear in the context of HIV infection.

METHODS: We included 361 women (241 HIV+, 120 HIV-) with carotid artery plaque assessments from the Women's Interagency HIV Study, measured ten plasma TRP metabolites and profiled fecal gut microbiome. TRP metabolites-related gut bacteria were selected through the Analysis of Compositions of Microbiomes with Bias Correction method. Associations of TRP metabolites and related microbial features with plaque were examined using multivariable logistic regression.

RESULTS: While plasma kynurenic acid (KYNA) (odds ratio [OR] = 1.93, 95% confidence interval [CI]:1.12, 3.32 per one SD increase; P = 0.02) and KYNA/TRP (OR = 1.83 [95%CI:1.08, 3.09], P = 0.02) were positively associated with plaque, indole-3-propionate (IPA) (OR = 0.62 [95%CI:0.40, 0.98], P = 0.03) and IPA/KYNA (OR = 0.51[95%CI:0.33, 0.80], P < 0.01) were inversely associated with plaque. Five gut bacterial genera and many affiliated species were positively associated with IPA (FDR-q < 0.25), including Roseburia sp., Eubacterium sp., Lachnospira sp., and Coprobacter sp.; but no bacterial genera were found to be associated with KYNA. Furthermore, an IPA-associated-bacteria score was inversely associated with plaque (OR = 0.47[95%CI:0.28, 0.79], P < 0.01). But no significant effect modification by HIV serostatus was observed in these associations.

CONCLUSIONS: In a cohort of women living with and without HIV infection, plasma IPA levels and related gut bacteria were inversely associated with carotid artery plaque, suggesting a potential beneficial role of IPA and its gut bacterial producers in atherosclerosis and CVD.

RevDate: 2023-05-17

Chen Y, Li H, Janowczyk A, et al (2023)

Computational pathology improves risk stratification of a multi-gene assay for early stage ER+ breast cancer.

NPJ breast cancer, 9(1):40.

Prognostic markers currently utilized in clinical practice for estrogen receptor-positive (ER+) and lymph node-negative (LN-) invasive breast cancer (IBC) patients include the Nottingham grading system and Oncotype Dx (ODx). However, these biomarkers are not always optimal and remain subject to inter-/intra-observer variability and high cost. In this study, we evaluated the association between computationally derived image features from H&E images and disease-free survival (DFS) in ER+ and LN- IBC. H&E images from a total of n = 321 patients with ER+ and LN- IBC from three cohorts were employed for this study (Training set: D1 (n = 116), Validation sets: D2 (n = 121) and D3 (n = 84)). A total of 343 features relating to nuclear morphology, mitotic activity, and tubule formation were computationally extracted from each slide image. A Cox regression model (IbRiS) was trained to identify significant predictors of DFS and predict a high/low-risk category using D1 and was validated on independent testing sets D2 and D3 as well as within each ODx risk category. IbRiS was significantly prognostic of DFS with a hazard ratio (HR) of 2.33 (95% confidence interval (95% CI) = 1.02-5.32, p = 0.045) on D2 and a HR of 2.94 (95% CI = 1.18-7.35, p = 0.0208) on D3. In addition, IbRiS yielded significant risk stratification within high ODx risk categories (D1 + D2: HR = 10.35, 95% CI = 1.20-89.18, p = 0.0106; D1: p = 0.0238; D2: p = 0.0389), potentially providing more granular risk stratification than offered by ODx alone.

RevDate: 2023-05-17

Martin GM, Fernández-Quintero ML, Lee WH, et al (2023)

Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9.

Nature communications, 14(1):2815.

A primary objective in malaria vaccine design is the generation of high-quality antibody responses against the circumsporozoite protein of the malaria parasite, Plasmodium falciparum (PfCSP). To enable rational antigen design, we solved a cryo-EM structure of the highly potent anti-PfCSP antibody L9 in complex with recombinant PfCSP. We found that L9 Fab binds multivalently to the minor (NPNV) repeat domain, which is stabilized by a unique set of affinity-matured homotypic, antibody-antibody contacts. Molecular dynamics simulations revealed a critical role of the L9 light chain in integrity of the homotypic interface, which likely impacts PfCSP affinity and protective efficacy. These findings reveal the molecular mechanism of the unique NPNV selectivity of L9 and emphasize the importance of anti-homotypic affinity maturation in protective immunity against P. falciparum.

RevDate: 2023-05-17

Zhen DB, Safyan RA, Konick EQ, et al (2023)

The role of molecular testing in pancreatic cancer.

Therapeutic advances in gastroenterology, 16:17562848231171456 pii:10.1177_17562848231171456.

Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. Germline testing for hereditary genetic abnormalities is recommended for all patients with PDA and somatic molecular testing is recommended for all patients with locally advanced or metastatic disease. KRAS mutations are present in 90% of PDA, while 10% are KRAS wild type and are potentially targetable with epidermal growth factor receptor blockade. KRAS[G12C] inhibitors have shown activity in G12C-mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. DNA damage repair abnormalities, germline or somatic, occur in 5-10% of patients and are likely to benefit from DNA damaging agents and maintenance therapy with poly-ADP ribose polymerase inhibitors. Fewer than 1% of PDA harbor microsatellite instability high status and are susceptible to immune checkpoint blockade. Albeit very rare, occurring in <1% of patients with KRAS wild-type PDAs, BRAF V600E mutations, RET and NTRK fusions are targetable with cancer agnostic Food and Drug Administration-approved therapies. Genetic, epigenetic, and tumor microenvironment targets continue to be identified at an unprecedented pace, enabling PDA patients to be matched to targeted and immune therapeutics, including antibody-drug conjugates, and genetically engineered chimeric antigen receptor or T-cell receptor - T-cell therapies. In this review, we highlight clinically relevant molecular alterations and focus on targeted strategies that can improve patient outcomes through precision medicine.

RevDate: 2023-05-17

Peak T, Spiess PE, Li R, et al (2023)

Comparative Genomic Landscape of Urothelial Carcinoma of the Bladder Among Patients of East and South Asian Genomic Ancestry.

The oncologist pii:7169380 [Epub ahead of print].

BACKGROUND: Despite the low rate of urothelial carcinoma of the bladder (UCB) in patients of South Asian (SAS) and East Asian (EAS) descent, they make up a significant portion of the cases worldwide. Nevertheless, these patients are largely under-represented in clinical trials. We queried whether UCB arising in patients with SAS and EAS ancestry would have unique genomic features compared to the global cohort.

METHODS: Formalin-fixed, paraffin-embedded tissue was obtained for 8728 patients with advanced UCB. DNA was extracted and comprehensive genomic profiling was performed. Ancestry was classified using a proprietary calculation algorithm. Genomic alterations (GAs) were determined using a 324-gene hybrid-capture-based method which also calculates tumor mutational burden (TMB) and determines microsatellite status (MSI).

RESULTS: Of the cohort, 7447 (85.3%) were EUR, 541 (6.2%) were AFR, 461 (5.3%) were of AMR, 74 (0.85%) were SAS, and 205 (2.3%) were EAS. When compared with EUR, TERT GAs were less frequent in SAS (58.1% vs. 73.6%; P = .06). When compared with non-SAS, SAS had less frequent GAs in FGFR3 (9.5% vs. 18.5%, P = .25). TERT promoter mutations were significantly less frequent in EAS compared to non-EAS (54.1% vs. 72.9%; P < .001). When compared with the non-EAS, PIK3CA alterations were significantly less common in EAS (12.7% vs. 22.1%, P = .005). The mean TMB was significantly lower in EAS vs. non-EAS (8.53 vs. 10.02; P = .05).

CONCLUSIONS: The results from this comprehensive genomic analysis of UCB provide important insight into the possible differences in the genomic landscape in a population level. These hypothesis-generating findings require external validation and should support the inclusion of more diverse patient populations in clinical trials.

RevDate: 2023-05-17

Oyong DA, Duffy FJ, Neal ML, et al (2023)

Distinct immune responses associated with vaccination status and protection outcomes after malaria challenge.

PLoS pathogens, 19(5):e1011051 pii:PPATHOGENS-D-22-02126 [Epub ahead of print].

Understanding immune mechanisms that mediate malaria protection is critical for improving vaccine development. Vaccination with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) induces high level of sterilizing immunity against malaria and serves as a valuable tool for the study of protective mechanisms. To identify vaccine-induced and protection-associated responses during malarial infection, we performed transcriptome profiling of whole blood and in-depth cellular profiling of PBMCs from volunteers who received either PfRAS or noninfectious mosquito bites, followed by controlled human malaria infection (CHMI) challenge. In-depth single-cell profiling of cell subsets that respond to CHMI in mock-vaccinated individuals showed a predominantly inflammatory transcriptome response. Whole blood transcriptome analysis revealed that gene sets associated with type I and II interferon and NK cell responses were increased in prior to CHMI while T and B cell signatures were decreased as early as one day following CHMI in protected vaccinees. In contrast, non-protected vaccinees and mock-vaccinated individuals exhibited shared transcriptome changes after CHMI characterized by decreased innate cell signatures and inflammatory responses. Additionally, immunophenotyping data showed different induction profiles of vδ2+ γδ T cells, CD56+ CD8+ T effector memory (Tem) cells, and non-classical monocytes between protected vaccinees and individuals developing blood-stage parasitemia, following treatment and resolution of infection. Our data provide key insights in understanding immune mechanistic pathways of PfRAS-induced protection and infective CHMI. We demonstrate that vaccine-induced immune response is heterogenous between protected and non-protected vaccinees and that inducted-malaria protection by PfRAS is associated with early and rapid changes in interferon, NK cell and adaptive immune responses. Trial Registration: ClinicalTrials.gov NCT01994525.

RevDate: 2023-05-17

Fair D, Maese L, Chi YY, et al (2023)

TP53 germline pathogenic variant frequency in anaplastic rhabdomyosarcoma: A Children's Oncology Group report.

Pediatric blood & cancer [Epub ahead of print].

Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with anRMS.

RevDate: 2023-05-17

Close A, Burns K, Bjornard K, et al (2023)

Fertility preservation in pediatric leukemia and lymphoma: A report from the Children's Oncology Group.

Pediatric blood & cancer [Epub ahead of print].

Certain chemotherapy agents, radiation, and surgery can all negatively impact future fertility. Consults regarding treatment-related risk for infertility and gonadal late effects of these agents should occur at the time of diagnosis as well as during survivorship. Counseling on fertility risk has traditionally varied significantly across providers and institutions. We aim to provide a guide to standardize the assignment of gonadotoxic risk, which can be used in counseling patients both at the time of diagnosis and in survivorship. Gonadotoxic therapies were abstracted from 26 frontline Children's Oncology Group (COG) phase III protocols for leukemia/lymphoma, in use from 2000-2022. A stratification system based on gonadotoxic therapies, sex, and pubertal status was used to assign treatments into minimal, significant, and high level of increased risk for gonadal dysfunction/infertility. Risk levels were assigned to protocols and different treatment arms to aid oncologists and survivor care providers in counseling patients regarding treatment-related gonadotoxicity. Males were most commonly at high risk, with at least one high-risk arm in 14/26 protocols (54%), followed by pubertal females (23% of protocols) and prepubertal females (15% of protocols). All patients who received direct gonadal radiation or hematopoietic stem cell transplant (HSCT) were considered at high risk. Partnering with patients and their oncology/survivorship team is imperative for effective fertility counseling both prior to and post treatment, and this comprehensive guide can be used as a tool to standardize and improve reproductive health counseling in patients undergoing COG-based leukemia/lymphoma care.

RevDate: 2023-05-17

Cieniewicz B, Bhatta A, Torabi D, et al (2023)

Chimeric TIM-4 receptor-modified T cells targeting phosphatidylserine mediates both cytotoxic anti-tumor responses and phagocytic uptake of tumor-associated antigen for T cell cross presentation.

Molecular therapy : the journal of the American Society of Gene Therapy pii:S1525-0016(23)00264-2 [Epub ahead of print].

To leverage complementary mechanisms for cancer cell removal, we developed a novel cell engineering and therapeutic strategy co-opting phagocytic clearance and antigen presentation activity into T cells. We engineered a chimeric engulfment receptor, (CER)-1236, that combines the extracellular domain of TIM-4, a phagocytic receptor recognizing the 'eat me' signal phosphatidylserine, with intracellular signaling domains (TLR2/TIR, CD28, and CD3ζ) to enhance both TIM-4-mediated phagocytosis and T-cell cytotoxic function. CER-1236 T cells demonstrate target-dependent phagocytic function and induce transcriptional signatures of key regulators responsible for phagocytic recognition and uptake, along with cytotoxic mediators. Pre-clinical models of mantle cell lymphoma (MCL) and EGFR-mutation positive non-small cell lung cancer (NSCLC) demonstrate collaborative innate-adaptive anti-tumor immune responses both in vitro and in vivo. Treatment with BTK (MCL) and EGFR (NSCLC) inhibitors increased target ligand, conditionally driving CER-1236 function to augment anti-tumor responses. We also show that activated CER-1236 T cells exhibit superior cross-presentation ability compared to conventional T cells, triggering E7-specific TCR-T responses in an HLA class I and TLR-2 dependent manner, thereby overcoming the limited antigen presentation capacity of conventional T cells. Therefore, CER-1236 T cells have the potential to achieve tumor control by eliciting both direct cytotoxic effects and indirect-mediated cross-priming.

RevDate: 2023-05-16

Chour W, Choi J, Xie J, et al (2023)

Large libraries of single-chain trimer peptide-MHCs enable antigen-specific CD8+ T cell discovery and analysis.

Communications biology, 6(1):528.

The discovery and characterization of antigen-specific CD8[+] T cell clonotypes typically involves the labor-intensive synthesis and construction of peptide-MHC tetramers. We adapt single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation, showing that hundreds can be rapidly prepared across multiple Class I HLA alleles. We use this platform to explore the impact of peptide and SCT template mutations on protein expression yield, thermal stability, and functionality. SCT libraries were an efficient tool for identifying T cells recognizing commonly reported viral epitopes. We then construct SCT libraries to capture SARS-CoV-2 specific CD8[+] T cells from COVID-19 participants and healthy donors. The immunogenicity of these epitopes is validated by functional assays of T cells with cloned TCRs captured using SCT libraries. These technologies should enable the rapid analyses of peptide-based T cell responses across several contexts, including autoimmunity, cancer, or infectious disease.

RevDate: 2023-05-16

Zheng J, Dong X, Newton CC, et al (2023)

A Generalized Integration Approach to Association Analysis with Multi-category Outcome: An Application to a Tumor Sequencing Study of Colorectal Cancer and Smoking.

Journal of the American Statistical Association, 118(541):29-42.

Cancer is a heterogeneous disease, and rapid progress in sequencing and -omics technologies has enabled researchers to characterize tumors comprehensively. This has stimulated an intensive interest in studying how risk factors are associated with various tumor heterogeneous features. The Cancer Prevention Study-II (CPS-II) cohort is one of the largest prospective studies, particularly valuable for elucidating associations between cancer and risk factors. In this paper, we investigate the association of smoking with novel colorectal tumor markers obtained from targeted sequencing. However, due to cost and logistic difficulties, only a limited number of tumors can be assayed, which limits our capability for studying these associations. Meanwhile, there are extensive studies for assessing the association of smoking with overall cancer risk and established colorectal tumor markers. Importantly, such summary information is readily available from the literature. By linking this summary information to parameters of interest with proper constraints, we develop a generalized integration approach for polytomous logistic regression model with outcome characterized by tumor features. The proposed approach gains the efficiency through maximizing the joint likelihood of individual-level tumor data and external summary information under the constraints that narrow the parameter searching space. We apply the proposed method to the CPS-II data and identify the association of smoking with colorectal cancer risk differing by the mutational status of APC and RNF43 genes, neither of which is identified by the conventional analysis of CPS-II individual data only. These results help better understand the role of smoking in the etiology of colorectal cancer.

RevDate: 2023-05-16

Wang ML, Jurczak W, Zinzani PL, et al (2023)

Pirtobrutinib in Covalent BTK-Inhibitor Pre-treated Mantle Cell Lymphoma.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent (c) BTKi pre-treated mantle cell lymphoma (MCL), a population with poor prognosis.

PATIENTS AND METHODS: Patients with cBTKi pre-treated relapsed/refractory MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 trial (BRUIN, NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR) and safety.

RESULTS: Median patient age was 70 years (range, 46-87), median prior lines of therapy 3 (range, 1-8), 82.2% had discontinued a prior cBTKi due to disease progression, and 77.8% had intermediate or high risk sMIPI score. The ORR was 57.8% (95% CI, 46.9-68.1), including 20.0% complete responses (n=18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5-not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n=164), the most common treatment-emergent adverse events (TEAE) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAE of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib due to a treatment-related AE.

CONCLUSION: Pirtobrutinib is a first-in-class novel non-covalent (reversible) BTKi, and the first BTKi of any kind to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated relapsed/refractory MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation due to toxicity.

RevDate: 2023-05-16

Byrd DA, Fan W, Greathouse KL, et al (2023)

The intratumor microbiome is associated with microsatellite instability.

Journal of the National Cancer Institute pii:7165232 [Epub ahead of print].

Intratumoral microbes may have multifunctional roles in carcinogenesis. Microsatellite instability (MSI) is associated with higher tumor immunity and mutational burden. Using whole transcriptome and whole genome sequencing microbial abundance data, we investigated associations of intratumoral microbes with MSI, survival, and MSI-relevant tumor molecular characteristics across multiple cancer types including colorectal cancer (CRC), stomach adenocarcinoma, and endometrial carcinoma. Among CRC patients (N = 451), our key finding was strong associations of multiple CRC-associated genera, including Dialister, and Casatella, with MSI. Dialister and Casatella abundance was associated with improved overall survival (HRsMortality [95% CIs]=0.56 [0.34-0.92] and 0.44 [0.27-0.72], respectively, comparing higher relative to lower quantiles). Multiple intratumor microbes were associated with immune genes and tumor mutational burden. Diversity of oral cavity-originating microbes was also associated with MSI among CRC and stomach adenocarcinoma patients. Overall, our findings suggest the intratumor microbiota may differ by MSI status and play a role in influencing the tumor microenvironment.

RevDate: 2023-05-15

Gatbonton-Schwager T, Yagishita Y, Joshi T, et al (2023)

A Point Mutation at C151 of Keap1 of Mice Abrogates NRF2 Signaling, Cytoprotection In Vitro and Hepatoprotection In Vivo by Bardoxolone Methyl (CDDO-Me).

Molecular pharmacology pii:molpharm.123.000671 [Epub ahead of print].

Bardoxolone methyl (CDDO-Me) is an oleanane triterpenoid in late-stage clinical development for the treatment of patients with diabetic kidney disease. Preclinical studies in rodents demonstrate the efficacy of triterpenoids against carcinogenesis and other diseases including renal ischemia-reperfusion injury, hyperoxia-induced acute lung injury and immune hepatitis. Genetic disruption of NRF2 abrogates protection by triterpenoids, suggesting that induction of the NRF2 pathway may drive this protection. Herein, we examined the effect of a point mutation (C151S) in KEAP1, a repressor of NRF2 signaling, at cysteine 151 in mouse embryo fibroblasts and mouse liver. Induction of target gene transcripts and enzyme activity by CDDO-Me was lost in C151S mutant fibroblasts compared to wild-type. Protection against menadione toxicity was also nullified in the mutant fibroblasts. In mouse liver, CDDO-Me evoked the nuclear translocation of NRF2 followed by increased transcript and activity levels of a prototypic target gene Nqo1 in wild-type, but not C151S mutant mice. To test the role of KEAP1 Cys151 in governing the broader pharmacodynamic action of CDDO-Me, wild-type and C151S mutant mice were challenged with concanavalin A to induce immune hepatitis. Strong protection was seen in wild-type but not C151S mutant mice. RNA-seq analysis of mouse liver from wild-type, C151S mutant and Nrf2-knockout mice revealed a vigorous response of the Nrf2 transcriptome in wild-type, but in neither C151S mutant nor Nrf2-knockout mice. Activation of "off-target" pathways by CDDO were not observed. These data highlight the singular importance of the KEAP1 cysteine 151 sensor for activation of NRF2 signaling by CDDO-Me. Significance Statement Keap1 serves as a key sensor for induction of the cytoprotective signaling pathway driven by the transcription factor NRF2. Mutation of a single cysteine (C151) in KEAP1 abrogates the induction of NRF2 signaling and its downstream cytoprotective actions in vitro and in vivo by bardoxolone methyl (CDDO-Me), a drug in late-stage clinical development. Further, at these bioeffective concentrations/doses, activation of "off-target" pathways by CDDO-Me are not observed, highlighting the singular importance of NRF2 in its mode of action.

RevDate: 2023-05-15

Rahman M, Leroux BG, McKinney CM, et al (2023)

Observations by Caregivers Using the Infant with Clefts Observation Outcomes Instrument (iCOO): A Comparison of Three Versus Seven-day Daily Diaries.

The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association [Epub ahead of print].

OBJECTIVE: Our goal was to compare data collected from 3- and 7-day Infant with Clefts Observation Outcomes (iCOO) diaries.

DESIGN: Secondary data analysis of an observational longitudinal cohort study. Caregivers completed the daily iCOO for 7 days before cleft lip surgery (T0) and for 7 days after cleft lip repair (T1). We compared 3- and 7-day diaries collected at T0 and 3- and 7-day diaries collected at T1.

SETTING: United States.

PARTICIPANTS: Primary caregivers of infants with cleft lip with and without cleft palate (N  =  131) planning lip repair and enrolled in original iCOO study.

MAIN OUTCOMES MEASURE(S): Mean differences and Pearson correlation coefficients.

RESULTS: Correlation coefficients were high for global impressions (>0.90) and scaled scores (0.80-0.98). Mean differences were small across iCOO domains at T0. T1 comparisons reflected the same pattern.

CONCLUSIONS: Three-day diary data is comparable to 7-day diaries for measuring caregiver observations using iCOO across T0 and T1.

RevDate: 2023-05-15

VoPham T, Cravero A, Feld LD, et al (2023)

Associations of race and ethnicity with hepatocellular carcinoma, decompensation, and mortality in US Veterans with cirrhosis.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:726395 [Epub ahead of print].

BACKGROUND: Among cirrhosis patients, it remains unclear whether there are racial/ethnic differences in cirrhosis complications and mortality. We examined the associations between race/ethnicity and risk for hepatocellular carcinoma (HCC), cirrhosis decompensation, and all-cause mortality overall and by cirrhosis etiology.

METHODS: US Veterans diagnosed with cirrhosis from 2001-2014 (n=120,992), due to hepatitis C virus (HCV) (n=55,814), alcohol-associated liver disease (ALD) (n=36,323), hepatitis B virus (HBV) (n=1,972), nonalcoholic fatty liver disease (NAFLD) (n=17,789), or other (n=9,094), were followed through 2020 for incident HCC (n=10,242), cirrhosis decompensation (n=27,887), and mortality (n=81,441). Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).

RESULTS: Compared to non-Hispanic White patients, Hispanic patients had higher risk for HCC overall (aHR 1.32, 95% CI 1.24-1.41) and by cirrhosis etiology, particularly for ALD- (aHR 1.63, 95% CI 1.42-1.87) and NAFLD-cirrhosis (aHR 1.76, 95% CI 1.41-2.20), while non-Hispanic Black patients had lower HCC risk in ALD- (aHR 0.79, 95% CI 0.63-0.98) and NAFLD-cirrhosis (aHR 0.54, 95% CI 0.33-0.89). Asian patients had higher HCC risk (aHR 1.70, 95% CI 1.29-2.23), driven by HCV- and HBV-cirrhosis. Non-Hispanic Black patients had lower risk for cirrhosis decompensation overall (aHR 0.71, 95% CI 0.68-0.74) and by cirrhosis etiology. There was lower risk for mortality among all other racial/ethnic groups compared to non-Hispanic White patients.

CONCLUSIONS: Race/ethnicity is an important predictor for risk of developing HCC, decompensation, and mortality.

IMPACT: Future research should examine factors underlying these racial/ethnic differences to inform prevention, screening, and treatment for cirrhosis patients.

RevDate: 2023-05-15

Bloudek L, Wright P, McKay C, et al (2023)

Systematic Literature Review (SLR) and Network Meta-Analysis (NMA) of First-Line Therapies (1L) for Locally Advanced/Metastatic Urothelial Carcinoma (la/mUC).

Current oncology (Toronto, Ont.), 30(4):3637-3647 pii:curroncol30040277.

To compare efficacy outcomes for all approved and investigational first-line (1L) treatment regimens for locally advanced or metastatic urothelial carcinoma (la/mUC) with standard of care (SOC), a network meta-analysis (NMA) was conducted. A systematic literature review (SLR) identified phase 2 and 3 randomized trials investigating 1L treatment regimens in la/mUC published January 2001-September 2021. Three networks were formed based on cisplatin (cis) eligibility: cis-eligible/mixed (cis-eligible patients and mixed populations of cis-eligible/ineligible patients), cis-ineligible (strict; exclusively cis-ineligible patients), and cis-ineligible (wide; including studies with investigator's choice of carbo). Analyses examined comparative efficacy by hazard ratio (HR) for overall survival (OS), and progression-free survival (PFS), and odds ratio (OR) for overall response rate (ORR), with 1L regimens vs. SOC. SOC was gemcitabine + cis (GemCis) or carboplatin (GemCarbo), cis-eligible/mixed network, and GemCarbo cis-ineligible networks. Of 1906 SLR identified citations, 55 trials were selected for data extraction. The NMA comprised 11, 6, and 8 studies in the cis-eligible/mixed, cis-ineligible (strict), cis-ineligible (wide) networks, respectively. In a meta-analysis of SOC control arms, median (95% CI) overall survival (OS) in months varied by network: 13.19 (12.43, 13.95) cis-eligible/mixed, 11.96 (10.43, 13.48) cis-ineligible (wide), and 9.74 (6.71, 12.76) cis-ineligible (strict). Most differences in OS, PFS, and ORR with treatment regimens across treatment networks were not statistically significant compared with SOC. Outcomes with current 1L regimens remain poor, and few significant improvements over SOC have been made, despite inclusion of recent clinical trial data, highlighting an unmet need in the la/mUC patient population.

RevDate: 2023-05-14

Dieffenbach BV, Murphy AJ, Liu Q, et al (2023)

Cumulative burden of late, major surgical intervention in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS) cohort.

The Lancet. Oncology pii:S1470-2045(23)00154-7 [Epub ahead of print].

BACKGROUND: Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions.

METHODS: We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in the USA, with a comparison group of nearest-age siblings of survivors selected by simple random sampling. The primary outcome was any self-reported late, major surgical intervention (defined as any anaesthesia-requiring operation) occurring 5 years or more after the primary cancer diagnosis. The cumulative burden was assessed with mean cumulative counts (MCC) of late, major surgical interventions. Piecewise exponential regression models with calculation of adjusted rate ratios (RRs) evaluated associations between treatment exposures and late, major surgical interventions.

FINDINGS: Between Jan 1, 1970, and Dec 31, 1999, 25 656 survivors were diagnosed (13 721 male, 11 935 female; median follow-up 21·8 years [IQR 16·5-28·4]; median age at diagnosis 6·1 years [3·0-12·4]); 5045 nearest-age siblings were also included as a comparison group. Survivors underwent 28 202 late, major surgical interventions and siblings underwent 4110 late, major surgical interventions. The 35-year MCC of a late, major surgical intervention was 206·7 per 100 survivors (95% CI 202·7-210·8) and 128·9 per 100 siblings (123·0-134·7). The likelihood of a late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1·8, 95% CI 1·7-1·9) and in female versus male survivors (1·4; 1·4-1·5). Survivors diagnosed in the 1990s (adjusted RR 1·4, 95% CI 1·3-1·5) had an increased likelihood of late surgery compared with those diagnosed in the 1970s. Survivors received late interventions more frequently than siblings in most anatomical regions or organ systems, including CNS (adjusted RR 16·9, 95% CI 9·4-30·4), endocrine (6·7, 5·2-8·7), cardiovascular (6·6, 5·2-8·3), respiratory (5·3, 3·4-8·2), spine (2·4, 1·8-3·2), breast (2·1, 1·7-2·6), renal or urinary (2·0, 1·5-2·6), musculoskeletal (1·5, 1·4-1·7), gastrointestinal (1·4, 1·3-1·6), and head and neck (1·2, 1·1-1·4) interventions. Survivors of Hodgkin lymphoma (35-year MCC 333·3 [95% CI 320·1-346·6] per 100 survivors), Ewing sarcoma (322·9 [294·5-351·3] per 100 survivors), and osteosarcoma (269·6 [250·1-289·2] per 100 survivors) had the highest cumulative burdens of late, major surgical interventions. Locoregional surgery or radiotherapy cancer treatment were associated with undergoing late surgical intervention in the same body region or organ system.

INTERPRETATION: Childhood cancer survivors have a significant burden of late, major surgical interventions, a late effect that has previously been poorly quantified. Survivors would benefit from regular health-care evaluations aiming to anticipate impending surgical issues and to intervene early in the disease course when feasible.

FUNDING: US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital.

RevDate: 2023-05-14

Dominguez-Valentin M, Haupt S, Seppälä TT, et al (2023)

Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.

EClinicalMedicine, 58:101909 pii:S2589-5370(23)00086-X.

BACKGROUND: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.

METHODS: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.

FINDINGS: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.

INTERPRETATION: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome.

FUNDING: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

RevDate: 2023-05-14

Grassberger C, King G, S Apisarnthanarax (2023)

Combining immunotherapy and radiotherapy in hepatocellular carcinoma: the importance of irradiated tumor burden and the possible role of a low dose radiotherapy induction strategy.

Translational cancer research, 12(4):701-704.

RevDate: 2023-05-13

Prentice RL, Vasan S, Tinker LF, et al (2023)

Metabolomics Biomarkers for Fatty Acid Intake and Biomarker-Calibrated Fatty Acid Associations with Chronic Disease Risk in Postmenopausal Women[1].

The Journal of nutrition pii:S0022-3166(23)37596-5 [Epub ahead of print].

BACKGROUND: A substantial observational literature relating specific fatty acid classes to chronic disease risk may be limited by its reliance on self-reported dietary data.

OBJECTIVES: We aimed to develop biomarkers for saturated (SFA), monounsaturated (MFA) and polyunsaturated (PFA) fatty acid densities, and to study their associations with cardiovascular disease (CVD), cancer, and type 2 diabetes (T2D) in Women's Health Initiative (WHI) cohorts.

METHODS: Biomarker equations were based primarily on serum and urine metabolomics profiles from an embedded WHI human feeding study (n=153). Calibration equations were based on biomarker values in a WHI nutritional biomarker study (n=436). Calibrated intakes were assessed in relation to disease incidence in larger WHI cohorts (n=81,894). Participants were postmenopausal women, aged 50-79 when enrolled at 40 U.S. Clinical Centers (1993-1998), with a follow-up period of about 20 years.

RESULTS: Biomarker equations meeting criteria were developed for SFA, MFA, and PFA densities. That for SFA density depended somewhat weakly on metabolite profiles. Based on our metabolomics platforms, biomarkers were insensitive to trans fatty acid (TFA) intake. Calibration equations meeting criteria were developed for SFA and PFA density, but not for MFA density. With or without biomarker calibration SFA density was associated positively with the risk of CVD, cancer and T2D, but with small hazard ratios, and CVD associations were not statistically significant after controlling for other dietary variables, including TFA and fiber intake. Following this same control PFA density was not significantly associated with CVD risk, but there were positive associations for some cancers and T2D, with or without biomarker calibration.

CONCLUSIONS: Higher SFA and PFA diets were associated with null or somewhat higher risk for clinical outcomes considered in this population of postmenopausal U.S. women. Further research is needed to develop even stronger biomarkers for these fatty acid densities and their major components. This study is registered with clinicaltrials.gov identifier: NCT00000611.

RevDate: 2023-05-13

Bui N, Dietz H, Farag S, et al (2023)

A Retrospective Multi-Institutional Cohort Analysis of Clinical Characteristics and Outcomes in Dedifferentiated Chondrosarcoma.

Cancers, 15(9): pii:cancers15092617.

BACKGROUND: Dedifferentiated chondrosarcoma (DDCS) is a rare subset of chondrosarcoma. It is an aggressive neoplasm characterized by a high rate of recurrent and metastatic disease with overall poor outcomes. Systemic therapy is often used to treat DDCS; however, the optimal regimen and timing are not well defined, with current guidelines recommending following osteosarcoma protocols.

METHODS: We conducted a multi-institutional retrospective analysis of clinical characteristics and outcomes of patients with DDCS. Between 1 January 2004 and 1 January 2022, the databases from five academic sarcoma centers were reviewed. Patient and tumor factors, including age, sex, tumor size, site, location, the treatments rendered, and survival outcomes, were collected.

RESULTS: Seventy-four patients were identified and included in the analysis. Most patients presented with localized disease. Surgical resection was the mainstay of therapy. Chemotherapy was used predominantly in the metastatic setting. Partial responses were low (n = 4; 9%) and occurred upon treatment with doxorubicin with cisplatin or ifosfamide and single-agent pembrolizumab. For all other regimens, stable disease was the best response. Prolonged stable disease occurred with the use of pazopanib and immune checkpoint inhibitors.

CONCLUSIONS: DDCS has poor outcomes and conventional chemotherapy has limited benefit. Future studies should focus on defining the possible role of molecularly targeted therapies and immunotherapy in the treatment of DDCS.

RevDate: 2023-05-13

Eljilany I, Noor A, Paravathaneni M, et al (2023)

Granulomatous and Sarcoid-like Immune-Related Adverse Events following CTLA4 and PD1 Blockade Adjuvant Therapy of Melanoma: A Combined Analysis of ECOG-ACRIN E1609 and SWOG S1404 Phase III Trials and a Literature Review.

Cancers, 15(9): pii:cancers15092561.

BACKGROUND: Treatment with immune checkpoint inhibitors (ICIs) has been linked to granulomatous and sarcoid-like lesions (GSLs) affecting different organs. This study sought to evaluate GSL incidence in patients with high-risk melanoma treated with cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 (PD1) blockade adjuvant therapy in two clinical trials: ECOG-ACRIN E1609 and SWOG S1404. Descriptions and GSL severity ratings were recorded.

METHODS: Data were collected from ECOG-ACRIN E1609 and SWOG S1404. Descriptive statistics along with GSL severity grades were reported. Additionally, a literature review for such cases was summarized.

RESULTS: A total of 11 GSL cases were reported among 2878 patients treated with either ICI or with High-Dose Interferon Alfa-2b (HDI) in ECOG-ACRIN E1609 and SWOG S1404 trials. Cases were numerically more commonly reported with ipi10, followed by pembrolizumab, ipi3, and HDI, respectively. Most of the cases were grade III. Further, organs involved included lung, mediastinal lymph nodes, skin and subcutaneous tissue, and eye. Furthermore, a summary of 62 reports in the literature was described.

CONCLUSIONS: GSLs following anti-CTLA4 and anti-PD1 antibody therapy in patients with melanoma were reported unusually. Reported cases ranged in grade from I to III and appeared manageable. Careful attention to these events and their reporting will be essential to better guide practice and management guidelines.

RevDate: 2023-05-12

Kaku CI, Starr TN, Zhou P, et al (2023)

Evolution of antibody immunity following Omicron BA.1 breakthrough infection.

Nature communications, 14(1):2751.

Understanding the longitudinal dynamics of antibody immunity following heterologous SAR-CoV-2 breakthrough infection will inform the development of next-generation vaccines. Here, we track SARS-CoV-2 receptor binding domain (RBD)-specific antibody responses up to six months following Omicron BA.1 breakthrough infection in six mRNA-vaccinated individuals. Cross-reactive serum neutralizing antibody and memory B cell (MBC) responses decline by two- to four-fold through the study period. Breakthrough infection elicits minimal de novo Omicron BA.1-specific B cell responses but drives affinity maturation of pre-existing cross-reactive MBCs toward BA.1, which translates into enhanced breadth of activity across other variants. Public clones dominate the neutralizing antibody response at both early and late time points following breakthough infection, and their escape mutation profiles predict newly emergent Omicron sublineages, suggesting that convergent antibody responses continue to shape SARS-CoV-2 evolution. While the study is limited by our relatively small cohort size, these results suggest that heterologous SARS-CoV-2 variant exposure drives the evolution of B cell memory, supporting the continued development of next-generation variant-based vaccines.

RevDate: 2023-05-12

Zayac AS, Landsburg DJ, Hughes ME, et al (2023)

High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study.

Blood advances pii:495790 [Epub ahead of print].

In this multi-institutional retrospective study, we examined characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS). This rare lymphoma category is defined by high-grade morphologic features, most commonly Burkitt-like, and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements (so-called double-hit). Our results show that HGBL-NOS tumors are heterogeneous: 83% had a germinal center B-cell immunophenotype, 37% a dual expressor immunophenotype (MYC and BCL2 expression), 28% (single-hit) MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage 4 disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included DA-EPOCH-R (43%), R-CHOP (33%), or other intensive chemotherapy programs (11%). We found no significant differences in the rates of complete response (CR, P=0.32), progression-free (PFS, P=0.82), or overall survival (OS, P=0.60) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% (95%CI, 46.9-62.7), and OS was 68.1% (95%CI, 59.7-75.0). In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3x upper limit of normal, and a dual expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS (13% at 2 years). Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R versus R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

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ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

Biographies

Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )