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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 27 Nov 2020 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: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2020-11-26

Petralia F, Tignor N, Reva B, et al (2020)

Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer.

Cell pii:S0092-8674(20)31451-3 [Epub ahead of print].

We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.

RevDate: 2020-11-26

Rives-Quinto N, Komori H, Ostgaard CM, et al (2020)

Sequential activation of transcriptional repressors promotes progenitor commitment by silencing stem cell identity genes.

eLife, 9: pii:56187 [Epub ahead of print].

Stem cells that indirectly generate differentiated cells through intermediate progenitors drives vertebrate brain evolution. Due to a lack of lineage information, how stem cell functionality, including the competency to generate intermediate progenitors, becomes extinguished during progenitor commitment remains unclear. Type II neuroblasts in fly larval brains divide asymmetrically to generate a neuroblast and a progeny that commits to an intermediate progenitor (INP) identity. We identified Tailless (Tll) as a master regulator of type II neuroblast functional identity, including the competency to generate INPs. Successive expression of transcriptional repressors functions through Hdac3 to silence tll during INP commitment. Reducing repressor activity allows re-activation of Notch in INPs to ectopically induce tll expression driving supernumerary neuroblast formation. Knocking down hdac3 function prevents downregulation of tll during INP commitment. We propose that continual inactivation of stem cell identity genes allows intermediate progenitors to stably commit to generating diverse differentiated cells during indirect neurogenesis.

RevDate: 2020-11-25

Rybak MJ, Le J, Lodise TP, et al (2020)

Questions on Vancomycin dosing.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:6006300 [Epub ahead of print].

RevDate: 2020-11-25

Lin DW, PS Nelson (2020)

Prognostic Genomic Biomarkers in Patients With Localized Prostate Cancer: Is Rising Utilization Justified by Evidence?.

JAMA oncology pii:2773450 [Epub ahead of print].

RevDate: 2020-11-25

Mamolo C, Welch V, Walter RB, et al (2020)

Budget Impact Analysis of Gemtuzumab Ozogamicin for the Treatment of CD33-Positive Acute Myeloid Leukemia.

PharmacoEconomics pii:10.1007/s40273-020-00976-6 [Epub ahead of print].

BACKGROUND: Gemtuzumab ozogamicin (GO) was approved in 2017 in the US for the treatment of adults with newly diagnosed CD33-positive (CD33+) acute myeloid leukemia (AML), and adults and pediatric patients with CD33+ relapsed/refractory (R/R) AML.

OBJECTIVE: The aim of this study was to estimate the budgetary impact of introducing GO to a 1-million-member US health plan over a 5-year period.

METHODS: We developed models to estimate the impact of introducing GO in combination with conventional induction chemotherapy or as monotherapy for newly diagnosed AML, and as monotherapy for R/R AML. Models were built using data on drug costs and treatment-related outcomes obtained from published clinical trials and other publicly available sources. Results were reported on a per member/per year and per member/per month (PMPM) basis.

RESULTS: Base-case results of the newly diagnosed model indicated that the addition of GO in the combination setting reduced the overall budget of a 1-million-member health plan. The estimated net cost (US$) savings ranged from $72,969 ($0.006 PMPM) in year 1 to $745,426 ($0.062 PMPM) in year 5. In the monotherapy setting, GO was associated with increased net costs ranging from $4118 (0.0003 PMPM) in year 1 to $31,885 ($0.003 PMPM) in year 5. Base-case results of the R/R AML model demonstrated increased net costs that ranged from $17,326 ($0.001 PMPM) in year 1 to $46,163 ($0.004 PMPM) in year 5. Scenario analyses in all settings indicated the budget impact was not overly sensitive to the selected input assumptions, with the exception of the scenario considering only the pharmacy budget impact in the combination setting.

CONCLUSIONS: The introduction of GO for newly diagnosed and R/R AML would have a minimal impact on the budget of a US health plan and could result in cost savings in the combination therapy setting for newly diagnosed AML.

RevDate: 2020-11-25

Field MT, Chapple A, Hoeppner C, et al (2020)

Care Coordination in a SARS-CoV-2-infected Child With Newly Diagnosed Medulloblastoma and Fanconi Anemia.

Journal of pediatric hematology/oncology [Epub ahead of print].

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for a global pandemic that can cause severe infections in children, especially those with comorbid conditions. Here, we report a case of a child with a newly diagnosed medulloblastoma, Fanconi Anemia, and SARS-CoV-2 infection. Through multidisciplinary care coordination and meticulous planning, we were able to safely initiate this patient's oncology care and implement a long-term model to address the patient's care. This approach could be replicated with any newly diagnosed pediatric patient that requires monitoring for signs of COVID-19 with concurrent oncology care.

RevDate: 2020-11-24

Gerds AT, Savona MR, Scott BL, et al (2020)

Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis.

Blood advances, 4(22):5825-5835.

PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (-3%, -16%, and -27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.

RevDate: 2020-11-24

Taher H, Mahyari E, Kreklywich C, et al (2020)

In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome.

PLoS pathogens, 16(11):e1008666 pii:PPATHOGENS-D-20-01106 [Epub ahead of print].

Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a representative model for infection of humans with HCMV due to the close evolutionary relationships of both host and virus. However, the only available RhCMV clone that permits genetic modifications is based on the 68-1 strain which has been passaged in fibroblasts for decades resulting in multiple genomic changes due to tissue culture adaptations. As a result, 68-1 displays reduced viremia in RhCMV-naïve animals and limited shedding compared to non-clonal, low passage isolates. To overcome this limitation, we used sequence information from primary RhCMV isolates to construct a full-length (FL) RhCMV by repairing all mutations affecting open reading frames (ORFs) in the 68-1 bacterial artificial chromosome (BAC). Inoculation of adult, immunocompetent, RhCMV-naïve RM with the reconstituted virus resulted in significant viremia in the blood similar to primary isolates of RhCMV and furthermore led to high viral genome copy numbers in many tissues at day 14 post infection. In contrast, viral dissemination was greatly reduced upon deletion of genes also lacking in 68-1. Transcriptome analysis of infected tissues further revealed that chemokine-like genes deleted in 68-1 are among the most highly expressed viral transcripts both in vitro and in vivo consistent with an important immunomodulatory function of the respective proteins. We conclude that FL-RhCMV displays in vitro and in vivo characteristics of a wildtype virus while being amenable to genetic modifications through BAC recombineering techniques.

RevDate: 2020-11-24

Stock W, Martinelli G, Stelljes M, et al (2020)

Efficacy of inotuzumab ozogamicin in patients with Philadelphia chromosome-positive relapsed/refractory acute lymphoblastic leukemia.

Cancer [Epub ahead of print].

BACKGROUND: Patients with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options.

METHODS: The efficacy of inotuzumab ozogamicin (InO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open-label, randomized, phase 3 study 1022 (INO-VATE; NCT01564784). This analysis focused specifically on Ph+ R/R ALL patients. In study 1022, Ph+ patients were randomly assigned 1:1 to InO (n = 22) or standard intensive chemotherapy (SC) (n = 27) and 16 Ph+ patients in study 1010 received InO.

RESULTS: In study 1022, rates of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity (patients achieving CR/CRi) were higher with InO (CR/CRi = 73%; MRD = 81%) versus SC (CR/CRi = 56%; MRD = 33%). The corresponding rates in study 1010 were 56% (CR/CRi) and 100% (MRD). The hematopoietic stem cell transplantation (HSCT) rate in study 1022 was 41% versus 19% for InO versus SC; however, there was no benefit in overall survival (median OS: 8.7 vs 8.4 months; hazard ratio, 1.17 [95% CI, 0.64-2.14]). The probability of being event-free (progression-free survival) at 12 months was greater with InO versus SC (20.1% vs 4.8%).

CONCLUSION: Given the substantial improvement in responses and rates of HSCT, InO is an important treatment option for patients with R/R Ph+ ALL. Future studies need to consider better characterization of disease characteristics, more sensitive MRD measurements, MRD-directed therapy before HSCT, and potentially combination therapies, including tyrosine kinase inhibitors.

RevDate: 2020-11-24

Surendran P, Feofanova EV, Lahrouchi N, et al (2020)

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nature genetics pii:10.1038/s41588-020-00713-x [Epub ahead of print].

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

RevDate: 2020-11-24

S Sheth V, J Gauthier (2020)

Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL.

Bone marrow transplantation pii:10.1038/s41409-020-01134-4 [Epub ahead of print].

Treatment with CD19 or CD22-targeted chimeric antigen receptor-engineered T (CD19/CD22 CAR-T) cells achieve complete responses in 60-90% of adults and children with refractory or relapsed (R/R) acute lymphoblastic leukemia (ALL). This led to the approval of tisagenlecleucel (Kymriah) by the FDA and several European regulatory agencies in ALL patients up to 25 years of age. Although CAR T-cell therapy is likely to transform the ALL therapeutic landscape, its development and wide dissemination have been impacted by the occurrence of significant toxicities; namely, cytokine release syndrome (CRS) and Immune effector cell-Associated Neurotoxicity Syndrome (ICANS) have been reported at higher rates in ALL patients compared to other B cell malignancies, particularly in the adult population. Here, we review recent data suggesting a significant proportion of ALL patients are at risk of developing severe, sometimes life-threatening, CRS, and ICANS after CD19 and CD22 CAR T-cell therapy. After describing the key clinical and laboratory features of severe CRS and ICANS, we explore the disease and treatment-related factors that may predict the severity of these toxicities. Last, we review strategies under investigation in the prophylactic and therapeutic settings to improve the safety of CAR T-cells for ALL.

RevDate: 2020-11-24

Wight DJ, Aimola G, Aswad A, et al (2020)

Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6.

Proceedings of the National Academy of Sciences of the United States of America pii:2011872117 [Epub ahead of print].

Next-generation sequencing technologies allowed sequencing of thousands of genomes. However, there are genomic regions that remain difficult to characterize, including telomeres, centromeres, and other low-complexity regions, as well as transposable elements and endogenous viruses. Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) are closely related viruses that infect most humans and can integrate their genomes into the telomeres of infected cells. Integration also occurs in germ cells, meaning that the virus can be inherited and result in individuals harboring the virus in every cell of their body. The integrated virus can reactivate and cause disease in humans. While it is well established that the virus resides in the telomere region, the integration locus is poorly defined due to the low sequence complexity (TTAGGG)n of telomeres that cannot be easily resolved through sequencing. We therefore employed genome imaging of the integrated HHV-6A and HHV-6B genomes using whole-genome optical site mapping technology. Using this technology, we identified which chromosome arm harbors the virus genome and obtained a high-resolution map of the integration loci of multiple patients. Surprisingly, this revealed long telomere sequences at the virus-subtelomere junction that were previously missed using PCR-based approaches. Contrary to what was previously thought, our technique revealed that the telomere lengths of chromosomes harboring the integrated virus genome were comparable to the other chromosomes. Taken together, our data shed light on the genetic structure of the HHV-6A and HHV-6B integration locus, demonstrating the utility of optical mapping for the analysis of genomic regions that are difficult to sequence.

RevDate: 2020-11-24

Morse CB, Voillet V, Bates BM, et al (2020)

Development of a clinically relevant ovarian cancer model incorporating surgical cytoreduction to evaluate treatment of micro-metastatic disease.

Gynecologic oncology pii:S0090-8258(20)34117-2 [Epub ahead of print].

OBJECTIVES: Mouse models of ovarian cancer commonly transfer large numbers of tumor cells into the peritoneal cavity to establish experimental metastatic disease, which may not adequately model early metastatic spread from a primary tumor site. We hypothesized we could develop an ovarian cancer model that predictably represents micro-metastatic disease.

METHODS: Murine ID8VEGF ovarian cancer cells were transduced to express enhanced luciferase (eLuc) to enable intravital detection of microscopic disease burden and injected beneath the ovarian bursa of C57Bl/6 mice. At 6 or 10 weeks after orthotopic injection, when mice had detectable metastases, hysterectomy and bilateral salpingo-oophorectomy was performed to remove all macroscopic disease, and survival monitored. Immunohistochemistry and gene expression profiling were performed on primary and metastatic tumors.

RESULTS: eLuc-transduced ID8VEGF cells were brighter than cells transduced with standard luciferase, enabling in vivo visualization of microscopic intra-abdominal metastases developing after orthotopic injection. Primary surgical cytoreduction removed the primary tumor mass but left minimal residual disease in all mice. Metastatic sites that developed following orthotopic injection were similar to metastatic human ovarian cancer sites. Gene expression and immune infiltration were similar between primary and metastatic mouse tumors. Surgical cytoreduction prolonged survival compared to no surgery, with earlier cytoreduction more beneficial than delayed, despite micro-metastatic disease in both settings.

CONCLUSIONS: Mice with primary ovarian tumors established through orthotopic injection develop progressively fatal metastatic ovarian cancer, and benefit from surgical cytoreduction to remove bulky disease. This model enables the analysis of therapeutic regimens designed to target and potentially eradicate established minimal residual disease.

RevDate: 2020-11-24

Takadera M, Satomi K, Szulzewsky F, et al (2020)

Phenotypic characterization with somatic genome editing and gene transfer reveals the diverse oncogenicity of ependymoma fusion genes.

Acta neuropathologica communications, 8(1):203 pii:10.1186/s40478-020-01080-8.

Recurrent RELA and YAP1 fusions are intimately associated with tumorigenesis in supratentorial ependymomas. Chromothripsis and focal copy number alterations involving 11q are hallmarks of these tumors. However, it is unknown whether the chromosomal alterations are a direct causal event resulting in fusion transcripts. In addition, the biological significance of the RELA fusion variants and YAP1 fusions is not yet fully characterized. In this study, we generated gene rearrangements on 11q with the CRISPR/Cas9 system and investigated the formation of oncogenic ependymoma fusion genes. Further, we examined the oncogenic potential of RELA fusion variants and YAP1 fusions in a lentiviral gene transfer model. We observed that endogenous RELA fusion events were successfully induced by CRISPR/Cas9-mediated genome rearrangement in cultured cells. In vivo genome editing in mouse brain resulted in the development of ependymoma-like brain tumors that harbored the Rela fusion gene. All RELA fusion variants tested, except a variant lacking the Rel homology domain, were able to induce tumor formation, albeit with different efficacy. Furthermore, expression of YAP1-FAM118B and YAP1-MAMLD1 fusions induced the formation of spindle-cell-like tumors at varying efficacy. Our results indicate that chromosomal rearrangements involving the Rela locus are the causal event for the formation of Rela fusion-driven ependymomas in mice. Furthermore, the type of RELA. fusion might affect the aggressiveness of tumors and that the Rel homology domain is essential for the oncogenic functions of RELA. fusions. The YAP1 fusion genes are also oncogenic when expressed in mice.

RevDate: 2020-11-24

Newman KL, Rogers JH, McCulloch D, et al (2020)

Point-of-care molecular testing and antiviral treatment of influenza in residents of homeless shelters in Seattle, WA: study protocol for a stepped-wedge cluster-randomized controlled trial.

Trials, 21(1):956 pii:10.1186/s13063-020-04871-5.

INTRODUCTION: Influenza is an important public health problem, but data on the impact of influenza among homeless shelter residents are limited. The primary aim of this study is to evaluate whether on-site testing and antiviral treatment of influenza in residents of homeless shelters reduces influenza spread in these settings.

METHODS AND ANALYSIS: This study is a stepped-wedge cluster-randomized trial of on-site testing and antiviral treatment for influenza in nine homeless shelter sites within the Seattle metropolitan area. Participants with acute respiratory illness (ARI), defined as two or more respiratory symptoms or new or worsening cough with onset in the prior 7 days, are eligible to enroll. Approximately 3200 individuals are estimated to participate from October to May across two influenza seasons. All sites will start enrollment in the control arm at the beginning of each season, with routine surveillance for ARI. Sites will be randomized at different timepoints to enter the intervention arm, with implementation of a test-and-treat strategy for individuals with two or fewer days of symptoms. Eligible individuals will be tested on-site with a point-of-care influenza test. If the influenza test is positive and symptom onset is within 48 h, participants will be administered antiviral treatment with baloxavir or oseltamivir depending upon age and comorbidities. Participants will complete a questionnaire on demographics and symptom duration and severity. The primary endpoint is the incidence of influenza in the intervention period compared to the control period, after adjusting for time trends.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04141917 . Registered 28 October 2019. Trial sponsor: University of Washington.

RevDate: 2020-11-24

LaMonte MJ, Larson JC, Manson JE, et al (2020)

Association of Sedentary Time and Incident Heart Failure Hospitalization in Postmenopausal Women.

Circulation. Heart failure [Epub ahead of print].

BACKGROUND: The 2018 US Physical Activity Guidelines recommend reducing sedentary behavior (SB) for cardiovascular health. SB's role in heart failure (HF) is unclear.

METHODS: We studied 80 982 women in the Women's Health Initiative Observational Study, aged 50 to 79 years, who were without known HF and reported ability to walk ≥1 block unassisted at baseline. Mean follow-up was 9 years for physician-adjudicated incident HF hospitalization (1402 cases). SB was assessed repeatedly by questionnaire. Time-varying total SB was categorized according to awake time spent sitting or lying down (≤6.5, 6.6-9.5, >9.5 h/d); sitting time (≤4.5, 4.6-8.5, >8.5 h/d) was also evaluated. Hazard ratios and 95% CI were estimated using Cox regression.

RESULTS: Controlling for age, race/ethnicity, education, income, smoking, alcohol, menopausal hormone therapy, and hysterectomy status, higher HF risk was observed across incremental tertiles of time-varying total SB (hazard ratios [95% CI], 1.00 [referent], 1.15 [1.01-1.31], 1.42 [1.25-1.61], trend P<0.001) and sitting time (1.00 [referent], 1.14 [1.01-1.28], 1.54 [1.34-1.78], trend P<0.001). The inverse trends remained significant after further controlling for comorbidities including time-varying myocardial infarction and coronary revascularization (hazard ratios: SB, 1.00, 1.11, 1.27; sitting, 1.00, 1.09, 1.37, trend P<0.001 each) and for baseline physical activity (hazard ratios: SB 1.00, 1.10, 1.24; sitting 1.00, 1.08, 1.33, trend P<0.001 each). Associations with SB exposures were not different according to categories of baseline age, race/ethnicity, body mass index, physical activity, physical functioning, diabetes, hypertension, or coronary heart disease.

CONCLUSIONS: SB was associated with increased risk of incident HF hospitalization in postmenopausal women. Targeted efforts to reduce SB could enhance HF prevention in later life.

RevDate: 2020-11-23

Noy A, de Vos S, Coleman M, et al (2020)

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis.

Blood advances, 4(22):5773-5784.

Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

RevDate: 2020-11-23

Vanderpool RC, Huang GC, Mollica M, et al (2020)

Cancer Information-seeking in an Age of COVID-19: Findings from the National Cancer Institute's Cancer Information Service.

Health communication [Epub ahead of print].

Seeking cancer information is recognized as an important, life-saving behavior under normal circumstances. However, given the significant impact of COVID-19 on society, the healthcare system, and individuals and their families, it is important to understand how the pandemic has affected cancer information needs in a crisis context and, in turn, how public health agencies have responded to meeting the information needs of various audiences. Using data from the National Cancer Institute's Cancer Information Service (CIS) - a long-standing, multi-channel resource for trusted cancer information in English and Spanish - this descriptive analysis explored differences in cancer information-seeking among cancer survivors, caregivers, tobacco users, and members of the general public during the onset and continuation of the COVID-19 pandemic (February - September 2020), specifically comparing interactions that involved a discussion of COVID-19 to those that did not. During the study period, COVID-19 discussions were more likely to involve survivors or caregivers compared to tobacco users and the general public. Specific patterns emerged across the four user types and their respective discussions of COVID-19 related to language of service, point of CIS access, stage on the cancer continuum, subject of interaction, cancer site discussed, and referrals provided by the CIS. These results provide insights that may help public health agencies deliver, prioritize, and tailor their messaging and response to specific audiences based on heightened health information needs during a crisis.

RevDate: 2020-11-23

Crotty EE, Downey KM, Ferrerosa LM, et al (2020)

Considerations when treating high-grade pediatric glioma patients with immunotherapy.

Expert review of neurotherapeutics [Epub ahead of print].

INTRODUCTION: Children with high-grade gliomas (pHGGs) represent a clinical population in substantial need of new therapeutic options given the inefficacy and toxicity of current standard-of-care modalities. Although immunotherapy has emerged as a promising modality, it has yet to elicit a significant survival benefit for pHGG patients. While preclinical studies address a variety of underlying challenges, translational clinical trial design and management also need to reflect the most updated progress and lessons from the field.

AREAS COVERED: The authors will focus our discussion on the design of clinical trials, the management of potential toxicities, immune monitoring, and novel biomarkers. Clinical trial design should integrate appropriate patient populations, novel and preclinically optimized trial design, and logical treatment combinations, particularly those which synergize with standard of care modalities. However, there are caveats due to the nature of immunotherapy trials, such as patient selection bias, evidenced by the frequent exclusion of patients on high-dose corticosteroids. Robust immune-modulating effects of modern immunotherapy can have toxicities. As such, it is important to understand and manage these, especially in pHGG patients.

EXPERT OPINION: Adequate integration of these considerations should allow us to effectively gain insights on biological activity, safety, and biomarkers associated with benefits for patients.

RevDate: 2020-11-23

Wilson N, Zhao N, Zhan X, et al (2020)

MiRKAT: kernel machine regression-based global association tests for the microbiome.

Bioinformatics (Oxford, England) pii:5952662 [Epub ahead of print].

SUMMARY: Distance-based tests of microbiome beta diversity are an integral part of many microbiome analyses. MiRKAT enables distance-based association testing with a wide variety of outcome types, including continuous, binary, censored time-to-event, multivariate, correlated and high-dimensional outcomes. Omnibus tests allow simultaneous consideration of multiple distance and dissimilarity measures, providing higher power across a range of simulation scenarios. Two measures of effect size, a modified R-squared coefficient and a kernel RV coefficient, are incorporated to allow comparison of effect sizes across multiple kernels.

MiRKAT is available on CRAN as an R package.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RevDate: 2020-11-23

Abrams K, Graves SS, Parker MH, et al (2020)

CD94 Ex Vivo Cultures in a Bone Marrow Transplantation Setting.

Transplantation direct, 6(12):e632.

Background: Complementary, marrow donor-derived peripheral blood T-lymphocyte infusions enable consistent hematopoietic engraftment in lethally irradiated dog leukocyte antigen (DLA)-haploidentical littermate recipients, but at the cost of severe graft versus host disease (GVHD). Here, we explored whether CD94-selected and in vitro-expanded natural killer (NK) cells could be substituted for T-lymphocytes for enhancing marrow engraftment without causing severe GVHD.

Methods: Five dogs were conditioned with 700 cGy total body irradiation followed by infusion of DLA-haploidentical donor marrow and CD94-selected, in vitro-expanded NK cells. NK cells were infused at a median of 140 000 (range 78 000-317 000) cells/kg.

Results: Four dogs rejected their marrow grafts, whereas 1 dog fully engrafted and developed GVHD. We observed an increase in peripheral blood NK cells after infusion of CD94-selected, ex vivo-expanded NK in 2 dogs. Peripheral blood lymphocyte counts peaked at day 7 or 8 posttransplant in the 4 rejecting dogs, whereas in the fully engrafted dog, lymphocyte counts remained stable at suboptimal levels.

Conclusions: Our study indicates NK cells can be expanded in vitro and safely infused into DLA-haploidentical recipients. Within the range of CD94-selected and expanded cells infused we concluded that they failed to both uniformly promote engraftment and avert GVHD.

RevDate: 2020-11-23

Gupta S, Rose CM, Buszkiewicz J, et al (2020)

Characterizing Percent Energy from Ultra-Processed Foods by Participant Demographics, Diet Quality, and Diet Cost Findings from the Seattle Obesity Study SOS III.

The British journal of nutrition pii:S0007114520004705 [Epub ahead of print].

Higher consumption of "ultra-processed"(UP) foods has been linked to adverse health outcomes. The present paper aims to characterize percent energy from UP foods by participant socio-economic status (SES), diet quality measures, self-reported food expenditure, and energy-adjusted diet cost. Participants in the population-based Seattle Obesity Study III (n=755) conducted in WA in 2016-17 completed socio-demographic and food expenditure surveys and the Food Frequency Questionnaire (FFQ). Education and residential property values were measures of SES. Retail prices of FFQ component foods (n=378) were used to estimate individual-level diet cost. Healthy Eating Index (HEI-2015) and Nutrient Rich Food Index (NRF9.3) were measures of diet quality. UP foods were identified following NOVA classification. Multivariable linear regressions were used to test associations between UP foods energy, socio-demographics, two estimates of food spending, and diet quality measures. Higher percent energy from UP foods was associated with higher dietary energy density, and lower HEI-2015 and NRF9.3 scores. The bottom decile of diet cost ($216.4/mo) was associated with 67.5% energy from UP foods; the top decile ($369.9/mo) was associated with only 48.7% energy from UP foods. Percent energy from UP foods was inversely linked to lower food expenditures and diet cost. In multivariate analysis, percent energy from UP foods was predicted by lower food expenditures, diet cost, and education, adjusting for covariates. Percent energy from UP foods was linked to lower food spending and lower SES. Efforts to reduce UP foods consumption, an increasingly common policy measure, need to take affordability, food expenditures and diet costs into account.

RevDate: 2020-11-22

Waqar SN, Redman MW, Arnold SM, et al (2020)

A Phase II Study of Telisotuzumab Vedotin in Patients With c-MET-positive Stage IV or Recurrent Squamous Cell Lung Cancer (LUNG-MAP Sub-study S1400K, NCT03574753).

Clinical lung cancer pii:S1525-7304(20)30293-X [Epub ahead of print].

INTRODUCTION: Lung-MAP S1400K was designed to evaluate the response to telisotuzumab vedotin, an antibody-drug conjugate targeting c-MET, in patients with c-MET-positive squamous cell carcinoma (SCC).

PATIENTS AND METHODS: Patients with previously treated SCC with c-MET-positive tumors (H score ≥ 150, Ventana SP44 assay) were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor-naive) and Cohort 2 (immune checkpoint inhibitor refractory). Telisotuzumab vedotin 2.7 mg/kg was administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival, overall survival, response within cohort, duration of response, and toxicities. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment.

RESULTS: Forty-nine patients (14% of screened patients) were assigned to S1400K, 28 patients enrolled (15 in Cohort 1 and 13 in Cohort 2), and 23 were eligible. S1400K closed on December 21, 2018 owing to lack of efficacy. Two responses (response rate of 9%; 95% confidence interval, 0%-20%) were reported in cohort 1 (1 complete and 1 unconfirmed partial response), whereas 10 patients had stable disease, with a disease control rate of 52%. The median overall and progression-free survival was 5.6 and 2.4 months, respectively. There were 3 grade 5 events (2 pneumonitis, in Cohort 2, and 1 bronchopulmonary hemorrhage, in Cohort 1).

CONCLUSION: Telisotuzumab vedotin failed to meet the pre-specified response needed to justify continuing enrollment to S1400K. Pneumonitis was an unanticipated toxicity observed in patients with SCC.

RevDate: 2020-11-21

Patel JL, Abedi M, Cogle CR, et al (2020)

Real-world diagnostic testing patterns for assessment of ring sideroblasts and SF3B1 mutations in patients with newly diagnosed lower-risk myelodysplastic syndromes.

International journal of laboratory hematology [Epub ahead of print].

INTRODUCTION: The presence of ring sideroblasts (RS) and mutation of the SF3B1 gene are diagnostic of lower-risk (LR) myelodysplastic syndromes (MDS) and are correlated with favorable outcomes. However, information on testing and reporting in community-based clinical settings is scarce. This study from the Connect® MDS/AML Disease Registry aimed to compare the frequency of RS and SF3B1 reporting for patients with LR-MDS, before and after publication of the 2016 World Health Organization (WHO) MDS classification criteria.

METHODS: Ring sideroblasts assessment and molecular testing data were collected from patients with LR-MDS at enrollment in the Registry. Patients enrolled between December 2013 and the data cutoff of March 2020 were included in this analysis.

RESULTS: Among 489 patients with LR-MDS, 434 (88.8%) underwent RS assessment; 190 were assessed prior to the 2016 WHO guidelines (Cohort A), and 244 after (Cohort B). In Cohort A, 87 (45.8%) patients had RS identified; 29 (33.3%) patients had RS < 15%, none of whom underwent molecular testing for SF3B1. In Cohort B, 96 (39.3%) patients had RS identified; 31 (32.3%) patients had < 15% RS, with 13 undergoing molecular testing of which 10 were assessed for SF3B1.

CONCLUSIONS: In the Connect® MDS/AML Registry, only 32% of patients with <15% RS underwent SF3B1 testing after the publication of the WHO 2016 classification criteria. There was no change in RS assessment frequency before and after publication, despite the potential impact on diagnostic subtyping and therapy selection, suggesting an unmet need for education to increase testing rates for SF3B1 mutations.

RevDate: 2020-11-21

Scott SR, O'Daffer AG, Bradford MC, et al (2020)

Adverse childhood experiences (ACEs) and medically traumatic events (TEs) in adolescents and young adults (AYAs) with cancer: a report from the Promoting Resilience in Stress Management (PRISM) randomized controlled trial.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-020-05888-x [Epub ahead of print].

OBJECTIVE: In adolescents and young adults (AYAs) with cancer, we examined (1) the distribution and type of traumatic events (TEs) experienced prior to baseline assessment and (2) how a resilience intervention, Promoting Resilience in Stress Management (PRISM), impacted changes in patient-reported outcomes (PROs) for AYAs with and without TEs.

METHODS: AYAs (12-25 years) within 1-10 weeks of diagnosis of new malignancy or ever diagnosed with advanced cancer were enrolled and randomly assigned to usual care (UC) with or without PRISM. To assess TEs, we screened medical records for traditionally defined adverse childhood experiences (ACEs) and medical traumatic events. Age-validated PROs assessed resilience, benefit-finding, hope, generic health-related quality of life (QoL), cancer-specific QoL, depression, and anxiety at enrollment and 6 months later. We calculated effect sizes (Cohen's d) for PRISM vs. UC effect on PRO score change at 6 months for 1+ TEs and 0 TE groups.

RESULTS: Ninety-two AYAs enrolled and completed baseline surveys (44-UC, 48-PRISM; N = 74 at 6 months, 38-UC, 36-PRISM); 60% experienced 1+ TEs. PROs at baseline were similar across groups. PRISM's effect on score change was greater (Cohen's d ≥ 0.5) for the 1+ TE group on domains of benefit-finding and hope; and similar (d < 0.5) on domains of resilience, depression, anxiety, and both generic and cancer-specific QoL.

CONCLUSIONS: In AYAs with cancer, TEs occurred at similar rates as the general population. PRISM may be particularly helpful for improving benefit-finding and hope for those who have experienced TEs.

RevDate: 2020-11-21

Dibay Moghadam S, Navarro SL, Shojaie A, et al (2020)

Plasma lipidomic profiles after a low and high glycemic load dietary pattern in a randomized controlled crossover feeding study.

Metabolomics : Official journal of the Metabolomic Society, 16(12):121 pii:10.1007/s11306-020-01746-3.

BACKGROUND: Dietary patterns low in glycemic load are associated with reduced risk of cardiometabolic diseases. Improvements in serum lipid concentrations may play a role in these observed associations.

OBJECTIVE: We investigated how dietary patterns differing in glycemic load affect clinical lipid panel measures and plasma lipidomics profiles.

METHODS: In a crossover, controlled feeding study, 80 healthy participants (n = 40 men, n = 40 women), 18-45 y were randomized to receive low-glycemic load (LGL) or high glycemic load (HGL) diets for 28 days each with at least a 28-day washout period between controlled diets. Fasting plasma samples were collected at baseline and end of each diet period. Lipids on a clinical panel including total-, VLDL-, LDL-, and HDL-cholesterol and triglycerides were measured using an auto-analyzer. Lipidomics analysis using mass-spectrometry provided the concentrations of 863 species. Linear mixed models and lipid ontology enrichment analysis were implemented.

RESULTS: Lipids from the clinical panel were not significantly different between diets. Univariate analysis showed that 67 species on the lipidomics panel, predominantly in the triacylglycerol class, were higher after the LGL diet compared to the HGL (FDR < 0.05). Three species with FA 17:0 were lower after LGL diet with enrichment analysis (FDR < 0.05).

CONCLUSION: In the context of controlled eucaloric diets with similar macronutrient distribution, these results suggest that there are relative shifts in lipid species, but the overall pool does not change. Further studies are needed to better understand in which compartment the different lipid species are transported in blood, and how these shifts are related to health outcomes. This trial was registered at clinicaltrials.gov as NCT00622661.

RevDate: 2020-11-21

Kim J, Beidler P, Wang H, et al (2020)

Desmoglein-2 as a prognostic and biomarker in ovarian cancer.

Cancer biology & therapy [Epub ahead of print].

Greater than 80% of all cancer cases are carcinomas, formed by the malignant transformation of epithelial cells. One of the key features of epithelial tumors is the presence of intercellular junctions, which link cells to one another and act as barriers to the penetration of molecules. This study assessed the expression of desmoglein-2, an epithelial junction protein, as a prognostic and diagnostic biomarker for ovarian cancer. Ovarian cancer sections were stained for DSG2 and signal intensity was correlated to cancer type and grade. DSG2 immunohistochemistry signals and mRNA levels were analyzed in chemo-resistant and chemo-sensitive cases. Ovarian cancer patient serum levels of shed DSG2 were correlated to disease-free and overall survival. Primary ovarian cancer cells were used to study DSG2 levels as they changed in response to cisplatin treatment. DSG2 expression was found to be positively correlated with cancer grade. Ovarian cancer patients with high serum levels of shed DSG2 fared significantly worse in both progression-free survival (median survival of 16 months vs. 26 months, p = .0023) and general survival (median survival of 37 months vs. undefined, p < .0001). A subgroup of primary chemotherapy-resistant cases had stronger DSG2 IHC/Western signals and higher DSG2 mRNA levels. Furthermore, our in vitro studies indicate that non-cytotoxic doses of cisplatin can enhance DSG2 expression, which, in turn, can contribute to chemo-resistance. We suggest that DSG2 can be used in stratifying patients, deciding on where to use aggressive treatment strategies, predicting chemoresistance, and as a companion diagnostic for treatments targeting DSG2.

RevDate: 2020-11-20

Carpenter JS, Tisdale JE, Chen CX, et al (2020)

A Menopause Strategies-Finding Lasting Answers for Symptoms and Health (MsFLASH) Investigation of Self-Reported Menopausal Palpitation Distress.

Journal of women's health (2002) [Epub ahead of print].

Background: Study to describe the degree of menopausal palpitation distress and its demographic, clinical, symptom, and quality-of-life (QOL) correlates. Analysis of existing, baseline, data from peri- and postmenopausal women, 42 to 62 years of age, who participated in the Menopause Strategies-Finding Lasting Answers for Symptoms and Health (MsFLASH) clinical trials testing interventions for vasomotor symptoms (n = 759). Up to 46.8% of menopausal women report having palpitations, yet the symptom is relatively understudied. Little is known about palpitation distress or its correlates. Materials and Methods: Degree of distress from "heart racing or pounding" was self-reported over the past two weeks as "not at all," "a little bit," "moderately," "quite a bit," or "extremely." Other measures included self-report forms, clinic-verified body mass index (BMI), vasomotor symptom diaries, and validated symptom and QOL tools. Results: The percentage who reported palpitation distress was 19.6%, 25.2%, and 33.5% in the three trials or 25.0% overall. In multivariate analysis, the odds of reporting palpitation distress was lower in past smokers (odds ratio [OR] = 0.59 [95% confidence interval (CI) 0.38-0.90]) and current smokers (OR = 0.48 [0.27-0.87]) relative to never-smokers and lower with every 5 kg/m2 higher BMI (OR = 0.82 [0.69-0.98]).The odds of reporting palpitation distress was higher with every five point more severe insomnia (OR = 1.28 [1.05-1.54]), five point worse depressive symptoms (OR = 1.47 [1.11-1.95]), five point worse perceived stress (OR = 1.19 [1.01-1.39]), and one point worse menopausal QOL (OR = 1.29 [1.06-1.57]). Conclusions: Menopausal palpitation distress is common and associated with demographic, clinical, symptom, and QOL factors. Findings can be used for screening in clinical practice and to justify additional research on this understudied symptom.

RevDate: 2020-11-20

Choi YG, Hanrahan LP, Norton D, et al (2020)

Simultaneous spatial smoothing and outlier detection using penalized regression, with application to childhood obesity surveillance from electronic health records.

Biometrics [Epub ahead of print].

Electronic health records (EHRs) have become a platform for data-driven granular-level surveillance in recent years. In this paper, we make use of EHRs for early prevention of childhood obesity. The proposed method simultaneously provides smooth disease mapping and outlier information for obesity prevalence, which are useful for raising public awareness and facilitating targeted intervention. More precisely, we consider a penalized multilevel generalized linear model. We decompose regional contribution into smooth and sparse signals, which are automatically identified by a combination of fusion and sparse penalties imposed on the likelihood function. In addition, we weigh the proposed likelihood to account for the missingness and potential non-representativeness arising from the EHR data. We develop a novel alternating minimization algorithm, which is computationally efficient, easy to implement, and guarantees convergence. Simulation studies demonstrate superior performance of the proposed method. Finally, we apply our method to the University of Wisconsin Population Health Information Exchange database. This article is protected by copyright. All rights reserved.

RevDate: 2020-11-19

Krug K, Jaehnig EJ, Satpathy S, et al (2020)

Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.

Cell pii:S0092-8674(20)31400-8 [Epub ahead of print].

The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.

RevDate: 2020-11-19

Müller NF, Wüthrich D, Goldman N, et al (2020)

Characterising the epidemic spread of influenza A/H3N2 within a city through phylogenetics.

PLoS pathogens, 16(11):e1008984 pii:PPATHOGENS-D-20-00910.

Infecting large portions of the global population, seasonal influenza is a major burden on societies around the globe. While the global source sink dynamics of the different seasonal influenza viruses have been studied intensively, its local spread remains less clear. In order to improve our understanding of how influenza is transmitted on a city scale, we collected an extremely densely sampled set of influenza sequences alongside patient metadata. To do so, we sequenced influenza viruses isolated from patients of two different hospitals, as well as private practitioners in Basel, Switzerland during the 2016/2017 influenza season. The genetic sequences reveal that repeated introductions into the city drove the influenza season. We then reconstruct how the effective reproduction number changed over the course of the season. While we did not find that transmission dynamics in Basel correlate with humidity or school closures, we did find some evidence that it may positively correlated with temperature. Alongside the genetic sequence data that allows us to see how individual cases are connected, we gathered patient information, such as the age or household status. Zooming into the local transmission outbreaks suggests that the elderly were to a large extent infected within their own transmission network. In the remaining transmission network, our analyses suggest that school-aged children likely play a more central role than pre-school aged children. These patterns will be valuable to plan interventions combating the spread of respiratory diseases within cities given that similar patterns are observed for other influenza seasons and cities.

RevDate: 2020-11-19

Kates O, Starr K, L Bourassa (2020)

Closing the Brief Case: Nontoxigenic Corynebacterium diphtheriae in a Nonhealing Wound.

Journal of clinical microbiology, 58(12): pii:58/12/e00507-20.

RevDate: 2020-11-19

Kates O, Starr K, L Bourassa (2020)

The Brief Case: Nontoxigenic Corynebacterium diphtheriae in a Nonhealing Wound.

Journal of clinical microbiology, 58(12):.

RevDate: 2020-11-19

Deese J, Philip N, Lind M, et al (2020)

Sexually transmitted infections among women randomised to depot medroxyprogesterone acetate, a copper intrauterine device or a levonorgestrel implant.

Sexually transmitted infections pii:sextrans-2020-054590 [Epub ahead of print].

OBJECTIVES: Reproductive aged women are at risk of pregnancy and sexually transmitted infections (STI). Understanding drivers of STI acquisition, including any association with widely used contraceptives, could help us to reduce STI prevalence and comorbidities. We compared the risk of STI among women randomised to three contraceptive methods.

METHODS: We conducted a secondary analysis to assess the risk of chlamydia and gonorrhoea in a clinical trial evaluating HIV risk among 7829 women aged 16-35 randomised to intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (IUD) or a levonorgestrel (LNG) implant. We estimated chlamydia and gonorrhoea prevalences by contraceptive group and prevalence ratios (PR) using log-binomial regression.

RESULTS: At baseline, chlamydia and gonorrhoea prevalences were 18% and 5%, respectively. Final visit chlamydia prevalence did not differ significantly between DMPA-IM and copper IUD groups or between copper IUD and LNG implant groups. The DMPA-IM group had significantly lower risk of chlamydia compared with the LNG implant group (PR 0.83, 95% CI 0.72 to 0.95). Final visit gonorrhoea prevalence differed significantly only between the DMPA-IM and the copper IUD groups (PR 0.67, 95% CI 0.52 to 0.87).

CONCLUSIONS: The findings suggest that chlamydia and gonorrhoea risk may vary with contraceptive method use. Further investigation is warranted to better understand the mechanisms of chlamydia and gonorrhoea susceptibility in the context of contraceptive use.

RevDate: 2020-11-19

Brown ER, Hendrix CW, van der Straten A, et al (2020)

Greater dapivirine release from the dapivirine vaginal ring is correlated with lower risk of HIV-1 acquisition: a secondary analysis from a randomized, placebo-controlled trial.

Journal of the International AIDS Society, 23(11):e25634.

INTRODUCTION: A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women's risk of sexually acquiring HIV-1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may reflect the extent of product use, permitting estimation of HIV protection in the context of consistent use.

METHODS: We measured the amount of dapivirine in returned rings from a placebo-controlled trial of the dapivirine vaginal ring conducted between August 2012 and June 2015 among 2629 African women. Phase I/II studies established that greater than 4 mg of dapivirine on average is released from the ring when used consistently over 28 days and ≤0.9 mg released suggested non-use. We assessed the relative risk reduction associated with levels of ring use using residual dapivirine in returned rings as a time-dependent covariate for HIV-1 infection in multivariable Cox models, including multiple exploratory analyses designed to estimate upper limits of efficacy given uncertainty in timing of HIV-1 acquisition. All models were adjusted for baseline covariates associated with HIV risk and adherence.

RESULTS: Residual dapivirine levels indicating at least some use (>0.9 mg released over a month) were associated with a 48% relative reduction in HIV-1 acquisition risk (95% confidence interval (CI): 21% to 66%; p = 0.002) compared to the placebo. Exploratory analyses accounting for potential misclassification in timing of HIV-1 acquisition estimated 75% to 91% HIV-1 risk reduction with> 4 mg released when compared to placebo. Results limited to the subgroup of women <25 years of age, who tended to have lower adherence, were generally consistent to those overall.

CONCLUSIONS: Residual dapivirine levels, an objective measure of adherence, were correlated with HIV-1 protection in a secondary analysis of a randomized trial. Periods of ring use were associated with approximately 50% protection, with exploratory analyses suggesting higher protection with more consistent use. The dapivirine vaginal ring is the first method to fulfil the promise of a fully reversible, long-acting, woman-initiated approach for discreet HIV-1 prevention.

RevDate: 2020-11-19

Li S, Simoni Y, Becht E, et al (2020)

Human Tumor-Infiltrating MAIT Cells Display Hallmarks of Bacterial Antigen Recognition in Colorectal Cancer.

Cell reports. Medicine, 1(3):100039.

Growing evidence indicates a role for the gut microbiota in modulating anti-tumor treatment efficacy in human cancer. Here we study mucosa-associated invariant T (MAIT) cells to look for evidence of bacterial antigen recognition in human colon, lung, and kidney carcinomas. Using mass cytometry and single-cell mRNA sequencing, we identify a tumor-infiltrating MAIT cell subset expressing CD4 and Foxp3 and observe high expression of CD39 on MAIT cells from colorectal cancer (CRC) only, which we show in vitro to be expressed specifically after TCR stimulation. We further reveal that these cells are phenotypically and functionally exhausted. Sequencing data show high bacterial infiltration in CRC tumors and highlight an enriched species, Fusobacteria nucleatum, with capability to activate MAIT cells in a TCR-dependent way. Our results provide evidence of a MAIT cell response to microbial antigens in CRC and could pave the way for manipulating MAIT cells or the microbiome for cancer therapy.

RevDate: 2020-11-18

Sari IN, Yang YG, Wijaya YT, et al (2020)

AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth.

Oncogene pii:10.1038/s41388-020-01547-x [Epub ahead of print].

Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaired in the absence of AMD1 in vivo. AMD1 was highly upregulated as chronic myeloid leukemia (CML) progressed from the chronic phase to the blast crisis phase, and was associated with the poor prognosis of CML patients. In addition, the pharmacological inhibition of AMD1 by AO476 treatment resulted in a robust reduction of the progression of leukemic cells both in vitro and in vivo. Mechanistically, AMD1 depletion induced loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS), resulting in the differentiation of LSCs via oxidative stress and aberrant activation of unfolded protein response (UPR) pathway, which was partially rescued by the addition of polyamine. These results indicate that AMD1 is an essential element in the progression of myeloid leukemia and could be an attractive target for the treatment of the disease.

RevDate: 2020-11-18

Labadie JD, Hua X, Harrison TA, et al (2020)

Genetic predictors of severe skin toxicity in stage III colon cancer patients treated with cetuximab: NCCTG N0147 (Alliance).

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-1274 [Epub ahead of print].

BACKGROUND: Cetuximab, an epidermal growth factor receptor inhibitor used to treat multiple cancer types including colon cancer, causes severe skin toxicity in 5-20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity.

METHODS: Our study included 1,209 stage III colon cancer patients randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating ~10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade >3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as p<5x10-8.

RESULTS: Participants were predominantly middle-aged white men; 20% (n=243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity (OR = 3.93, 95% CI 2.47-6.25; p<7.8x10-9). Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions.

CONCLUSIONS: Identified variants could represent a potential target for risk stratification of colon cancer patients receiving cetuximab.

IMPACT: Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.

RevDate: 2020-11-18

Watson NL, Mull KE, JB Bricker (2020)

The association between frequency of e-cigarette use and long-term smoking cessation outcomes among treatment-seeking smokers receiving a behavioral intervention.

Drug and alcohol dependence pii:S0376-8716(20)30559-7 [Epub ahead of print].

INTRODUCTION: A growing body of literature suggests daily, but not non-daily, e-cigarette use is associated with greater odds of quitting combustible cigarettes in the general adult population. However, it is unknown if these findings generalize to treatment-seeking smokers who are receiving a behavioral intervention. Our primary aim was to examine whether frequency of e-cigarette use was associated with subsequent cessation among treatment-seeking smokers who are receiving a behavioral smoking cessation intervention.

METHODS: Participants (N = 2637) enrolled in a RCT of web-based smoking treatments reported their use of e-cigarettes at baseline, 3-, and 6-months. Three groups were created based on e-cigarette use: (1) non-users, (2) intermittent users, and (3) daily users. The primary outcome was complete-case, self-reported 30-day point prevalence abstinence at 12 months.

RESULTS: Compared to non-users, daily e-cigarette users were significantly less likely to be abstinent (21.39 % vs. 29.68 %; p = .006). Quit rates for intermittent users (24.56 %) were not significantly different from non-users (p = .092). Nicotine dependence moderated the results such that among smokers with low nicotine dependence, those who used e-cigarettes (intermittently or daily) were less likely to quit than non-users; these differences were not significant among those with high nicotine dependence. Post hoc analyses indicated that initiating daily e-cigarette use after baseline, but not daily e-cigarette use at baseline, was associated with lower odds of cessation.

CONCLUSIONS: Daily e-cig use may be associated with lower odds of quitting smoking among treatment-seeking smokers, particularly among those with lower nicotine dependence and who initiate daily use after beginning an intervention.

RevDate: 2020-11-17

Kvaskoff M, Mahamat-Saleh Y, Farland LV, et al (2020)

Endometriosis and cancer: a systematic review and meta-analysis.

Human reproduction (Oxford, England) pii:5986656 [Epub ahead of print].

BACKGROUND: Endometriosis is an often chronic, inflammatory gynaecologic condition affecting 190 million women worldwide. Studies have reported an elevated cancer risk among patients with endometriosis. However, prior research has included methodologic issues that impede valid and robust interpretation.

OBJECTIVE AND RATIONALE: We conducted a meta-analysis of studies investigating the association between endometriosis and cancer risk and analysed the results by methodologic characteristics. We discuss the implications of cancer screening in patients and management challenges faced by clinicians.

SEARCH METHODS: We searched PubMed and Embase databases for eligible studies from inception through 24 October 2019. We included cohort and case-control studies examining the association between endometriosis and cancer risk; cross-sectional studies and case reports were excluded. Publications had to present risk/rate/odds estimates with 95% CI. Random effects meta-analysis was used to estimate summary relative risks (SRR) and CIs. Heterogeneity across studies was assessed by the Q test and I2 statistics, and publication bias using Egger's and Begg's tests. Risk of bias and quality of the included studies were assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool.

OUTCOMES: Forty-nine population-based case-control and cohort studies were included. Twenty-six studies were scored as having a 'serious'/'critical' risk of bias, and the remaining 23 'low'/'moderate'. Cancer-specific analyses showed a positive association between endometriosis and ovarian cancer risk (SRR = 1.93, 95% CI = 1.68-2.22; n = 24 studies) that was strongest for clear cell (SRR = 3.44, 95% CI = 2.82-4.42; n = 5 studies) and endometrioid (SRR = 2.33, 95% CI = 1.82-2.98; n = 5 studies) histotypes (Pheterogeneity < 0.0001), although with significant evidence of both heterogeneity across studies and publication bias (Egger's and Begg's P-values < 0.01). A robust association was observed between endometriosis and thyroid cancer (SRR = 1.39, 95% CI =1.24-1.57; n = 5 studies), a very small association with breast cancer (SRR = 1.04, 95% CI =1.00-1.09; n = 20 studies) and no association with colorectal cancer (SRR = 1.00, 95% CI =0.87-1.16; n = 5 studies). The association with endometrial cancer was not statistically significant (SRR = 1.23, 95% CI =0.97-1.57; n = 17 studies) overall and wholly null when restricted to prospective cohort studies (SRR = 0.99, 95% CI =0.72-1.37; n = 5 studies). The association with cutaneous melanoma was also non-significant (SRR = 1.17, 95% CI =0.97-1.41; n = 7 studies) but increased in magnitude and was statistically significant when restricted to studies with low/moderate risk of bias (SRR = 1.71, 95% CI = 1.24-2.36, n = 2 studies). The most robust finding both in terms of statistical significance and magnitude of effect was an inverse association with cervical cancer (SRR = 0.68, 95% CI =0.56-0.82; n = 4 studies); however, this result has a high potential to reflect heightened access to detection of dysplasia for women who reached an endometriosis diagnosis and is thus likely not causal. Several additional cancer types were explored based on <4 studies.

WIDER IMPLICATIONS: Endometriosis was associated with a higher risk of ovarian and thyroid, and minimally (only 4% greater risk) with breast cancer, and with a lower risk of cervical cancer. However, this meta-analysis confirms that: a majority of studies had severe/critical risk of bias; there is impactful heterogeneity across studies-and for ovarian cancer, publication bias; and causal inference requires temporality, which in many studies was not considered. We discuss the implications of these potential associations from the perspectives of patients with endometriosis, clinicians involved in their care, and scientists investigating their long-term health risks.

RevDate: 2020-11-17

Hill JA, Menon MP, Dhanireddy S, et al (2020)

Tocilizumab in hospitalized patients with COVID-19: Clinical outcomes, inflammatory marker kinetics, and safety.

Journal of medical virology [Epub ahead of print].

BACKGROUND: Coronavirus disease 2019 (COVID-19) due to infection with SARS-CoV-2 causes substantial morbidity. Tocilizumab, an interleukin-6 receptor antagonist, might improve outcomes by mitigating inflammation.

METHODS: We conducted a retrospective study of patients admitted to the University of Washington Hospital system with COVID-19 and requiring supplemental oxygen. Outcomes included clinical improvement, defined as a two-point reduction in severity on a 6-point ordinal scale or discharge, and mortality within 28 days. We used Cox proportional-hazards models with propensity score inverse probability weighting to compare outcomes in patients who did and did not receive tocilizumab.

RESULTS: We evaluated 43 patients who received tocilizumab and 45 who did not. Patients receiving tocilizumab were younger with fewer comorbidities but higher baseline oxygen requirements. Tocilizumab treatment was associated with reduced CRP, fibrinogen, and temperature, but there were no meaningful differences in time to clinical improvement (adjusted hazard ratio [aHR], 0.92; 95% CI, 0.38-2.22) or mortality (aHR, 0.57; 95% CI, 0.21-1.52). A numerically higher proportion of tocilizumab-treated patients had subsequent infections, transaminitis, and cytopenias.

CONCLUSIONS: Tocilizumab did not improve outcomes in hospitalized patients with COVID-19. However, this study was not powered to detect small differences, and there remains the possibility for a survival benefit. This article is protected by copyright. All rights reserved.

RevDate: 2020-11-17

Mair F, T Liechti (2020)

Comprehensive phenotyping of human dendritic cells and monocytes.

Cytometry. Part A : the journal of the International Society for Analytical Cytology [Epub ahead of print].

Professional antigen-presenting cells (APCs), which include dendritic cells (DCs) and monocytes are essential for inducing and steering adaptive T cell responses. Recent technological developments in single-cell analysis have significantly advanced our understanding of APC subset heterogeneity. To accurately resolve this functional diversity and to account for tissue-specific adaptation, novel phenotyping markers have been described more recently. While some of these largely overlap with traditionally used markers, more fine-grained phenotyping might be essential during inflammatory settings, where the traditional distinction between monocytes and dendritic cells has become blurred. Within this phenotype report we provide a concise overview of traditional and recently described markers for the phenotyping of DCs and monocytes in the human system. This article is protected by copyright. All rights reserved.

RevDate: 2020-11-17

Lichtenstein AH, Petersen K, Barger K, et al (2020)

Perspective: Design and Conduct of Human Nutrition Randomized Controlled Trials.

Advances in nutrition (Bethesda, Md.) pii:5983119 [Epub ahead of print].

In the field of human nutrition, randomized controlled trials (RCTs) are considered the gold standard for establishing causal relations between exposure to nutrients, foods, or dietary patterns and prespecified outcome measures, such as body composition, biomarkers, or event rates. Evidence-based dietary guidance is frequently derived from systematic reviews and meta-analyses of these RCTs. Each decision made during the design and conduct of human nutrition RCTs will affect the utility and generalizability of the study results. Within the context of limited resources, the goal is to maximize the generalizability of the findings while producing the highest quality data and maintaining the highest levels of ethics and scientific integrity. The aim of this document is to discuss critical aspects of conducting human nutrition RCTs, including considerations for study design (parallel, crossover, factorial, cluster), institutional ethics approval (institutional review boards), recruitment and screening, intervention implementation, adherence and retention assessment, and statistical analyses considerations. Additional topics include distinguishing between efficacy and effectiveness, defining the research question(s), monitoring biomarker and outcome measures, and collecting and archiving data. Addressed are specific aspects of planning and conducting human nutrition RCTs, including types of interventions, inclusion/exclusion criteria, participant burden, randomization and blinding, trial initiation and monitoring, and the analysis plan.

RevDate: 2020-11-17

Gastman B, Agarwal PK, Berger A, et al (2020)

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

Journal for immunotherapy of cancer, 8(2):.

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.

RevDate: 2020-11-17

DeLucia DC, Cardillo TM, Ang LS, et al (2020)

Regulation of CEACAM5 and therapeutic efficacy of an anti-CEACAM5-SN38 antibody-drug conjugate in neuroendocrine prostate cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-3396 [Epub ahead of print].

PURPOSE: Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody-drug conjugate labetuzumab govitecan in prostate cancer.

EXPERIMENTAL DESIGN: The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal mCRPC cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5+ prostate cancer cell lines and patient-derived xenografts models.

RESULTS: CEACAM5 expression was enriched in NEPC compared to other mCRPC subtypes and minimally overlapped with PSMA, PSCA, and Trop2 expression. We focused on a correlation between the expression of the pioneer transcription factor ASCL1 and CEACAM5 to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the CEACAM5 core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5+ prostate cancer cell lines and marked antitumor responses in CEACAM5+ CRPC xenograft models including chemotherapy-resistant NEPC.

CONCLUSIONS: Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.

RevDate: 2020-11-17

Dela Cruz EJ, Fiedler TL, Liu C, et al (2020)

Genetic variation in Toll-like receptor-5 and colonization with flagellated bacterial vaginosis-associated bacteria.

Infection and immunity pii:IAI.00060-20 [Epub ahead of print].

Bacterial vaginosis (BV) is a vaginal dysbiotic condition linked to negative gynecological and reproductive sequelae. Flagellated bacteria have been identified in women with BV, including Mobiluncus spp. and BV-associated bacterium-1 (BVAB1), an uncultivated, putatively flagellated species. The host response to flagellin mediated through toll-like receptor-5 (TLR5) has not been explored in BV. Using independent discovery and validation cohorts, we examined the hypothesis that TLR5 deficiency-defined by a dominant negative stop codon polymorphism rs5744168-is associated with an increased risk for BV and increased colonization with flagellated bacteria associated with BV (BVAB1, Mobiluncus curtisii, Mobiluncus mulieris). TLR5 deficiency was not associated with BV status and TLR5 deficient women had decreased colonization with BVAB1 in both cohorts. We stimulated HEK-hTLR5-overexpressing, NF-kB reporter cells with whole, heat-killed M. mulieris or M. curtisii, and with partially purified flagellin from these species; as BVAB1 is uncultivated, we used cervicovaginal lavage (CVL) supernatant from women colonized with BVAB1 for stimulation. While heat-killed M. mulieris and CVL from women colonized with BVAB1 stimulate a TLR5-mediated response, heat-killed M. curtisii did not. In contrast, partially purified flagellin from both Mobiluncus species stimulated a TLR5-mediated response in vitro. We observed no correlation between vaginal IL-8 and flagellated BVAB concentrations among TLR5 sufficient women. Inter-species variation in accessibility of flagellin recognition domains may be responsible for these observations as reflected in the potentially novel flagellin products encoded by Mobiluncus species versus those encoded by BVAB1.

RevDate: 2020-11-16

Emanuels A, Heimonen J, O'Hanlon J, et al (2020)

Remote Household Observation for Non-influenza Respiratory Viral Illness.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5983780 [Epub ahead of print].

BACKGROUND: Non-influenza respiratory viruses are responsible for a substantial burden of disease in the United States. Household transmission is thought to contribute significantly to subsequent transmission through the broader community. In the context of the COVID-19 pandemic, contactless surveillance methods are of particular importance.

METHODS: From November 2019 to April 2020, 303 households in the Seattle area were remotely monitored in a prospective longitudinal study for symptoms of respiratory viral illness. Enrolled participants reported weekly symptoms and submitted respiratory samples by mail in the event of an acute respiratory illness (ARI). Specimens were tested for fourteen viruses, including SARS-CoV-2, using RT-PCR. Participants completed all study procedures at home without physical contact with research staff.

RESULTS: In total, 1171 unique participants in 303 households were monitored for ARI. Of participating households, 128 (42%) included a child aged <5 years and 202 (67%) included a child aged 5-12 years. Of the 678 swabs collected during the surveillance period, 237 (35%) tested positive for one or more non-influenza respiratory viruses. Rhinovirus, common human coronaviruses, and respiratory syncytial virus were the most common. Four cases of SARS-CoV-2 were detected in three households.

CONCLUSIONS: This study highlights the circulation of respiratory viruses within households during the winter months during the emergence of the SARS-CoV-2 pandemic. Contactless methods of recruitment, enrollment and sample collection were utilized throughout this study, and demonstrate the feasibility of home-based, remote monitoring for respiratory infections.

RevDate: 2020-11-16

Togawa K, Anderson BO, Foerster M, et al (2020)

Geospatial barriers to health care access for breast cancer diagnosis in sub-Saharan African settings: the African Breast Cancer - Disparities in Outcomes (ABC-DO) Cohort Study.

International journal of cancer [Epub ahead of print].

We examined the geospatial dimension of delays to diagnosis of breast cancer in a prospective study of 1541 women newly diagnosed in the African Breast Cancer - Disparities in Outcomes (ABC-DO) Study. Women were recruited at cancer treatment facilities in Namibia, Nigeria, Uganda, and Zambia. The baseline interview included information used to generate the geospatial features: urban/rural residence, travel mode to treatment facility, and straight-line distances from home to first care provider and to diagnostic/treatment facility, categorized into country/ethnicity (population)-specific quartiles. These factors were investigated in relation to delay in diagnosis (≥3 months since first symptom) and late stage at diagnosis (TNM: III, IV) using logistic regression, adjusted for population group and sociodemographic characteristics. The median (interquartile range) distances to first provider and diagnostic and treatment facilities were 5 (1-37), 17 (3-105), and 62 (5-289) kms, respectively. The majority had a delay in diagnosis (74%) and diagnosis at late stage (64%). Distance to first provider was not associated with delay in diagnosis or late stage at diagnosis. Rural residence was associated with delay, but the association did not persist after adjustment for sociodemographic characteristics. Distance to the diagnostic/treatment facility was associated with delay (highest vs lowest quartile: Odds Ratio (OR)=1.56, 95% confidence interval (CI)=1.08-2.27) and late stage (overall: OR=1.47, CI=1.05-2.06; without Nigerian hospitals where mostly local residents were treated: OR=1.73, CI=1.18-2.54). These findings underscore the need of measures addressing the geospatial barriers to early diagnosis in sub-Saharan African settings, including providing transport or travel allowance and decentralizing diagnostic services.

RevDate: 2020-11-16

van Oers NSC, Su DM, Chidgey AP, et al (2020)

Editorial: New Insights Into Thymic Functions During Stress, Aging, and in Disease Settings.

Frontiers in immunology, 11:591936.

RevDate: 2020-11-16

Sun Y, Qi L, Heng F, et al (2020)

A Hybrid Approach for the Stratified Mark-Specific Proportional Hazards Model with Missing Covariates and Missing Marks, with Application to Vaccine Efficacy Trials.

Journal of the Royal Statistical Society. Series C, Applied statistics, 69(4):791-814.

Deployment of the recently licensed CYD-TDV dengue vaccine requires understanding of how the risk of dengue disease in vaccine recipients depends jointly on a host biomarker measured after vaccination (neutralization titer - NAb) and on a "mark" feature of the dengue disease failure event (the amino acid sequence distance of the dengue virus to the dengue sequence represented in the vaccine). The CYD14 phase 3 trial of CYD-TDV measured NAb via case-cohort sampling and the mark in dengue disease failure events, with about a third missing marks. We addressed the question of interest by developing inferential procedures for the stratified mark-specific proportional hazards model with missing covariates and missing marks. Two hybrid approaches are investigated that leverage both augmented inverse probability weighting and nearest neighborhood hot deck multiple imputation. The two approaches differ in how the imputed marks are pooled in estimation. Our investigation shows that NNHD imputation can lead to biased estimation without properly selected neighborhood. Simulations show that the developed hybrid methods perform well with unbiased NNHD imputations from proper neighborhood selection. The new methods applied to CYD14 show that NAb is strongly inversely associated with risk of dengue disease in vaccine recipients, more strongly against dengue viruses with shorter distances.

RevDate: 2020-11-16

Henikoff S, Henikoff JG, Kaya-Okur HS, et al (2020)

Efficient chromatin accessibility mapping in situ by nucleosome-tethered tagmentation.

eLife, 9: pii:63274 [Epub ahead of print].

Chromatin accessibility mapping is a powerful approach to identify potential regulatory elements. A popular example is ATAC-seq, whereby Tn5 transposase inserts sequencing adapters into accessible DNA ('tagmentation'). CUT&Tag is a tagmentation-based epigenomic profiling method in which antibody tethering of Tn5 to a chromatin epitope of interest profiles specific chromatin features in small samples and single cells. Here we show that by simply modifying the tagmentation conditions for histone H3K4me2 or H3K4me3 CUT&Tag, antibody-tethered tagmentation of accessible DNA sites is redirected to produce chromatin accessibility maps that are indistinguishable from the best ATAC-seq maps. Thus, chromatin accessibility maps can be produced in parallel with CUT&Tag maps of other epitopes with all steps from nuclei to amplified sequencing-ready libraries performed in single PCR tubes in the laboratory or on a home workbench. As H3K4 methylation is produced by transcription at promoters and enhancers, our method identifies transcription-coupled accessible regulatory sites.

RevDate: 2020-11-16

Seneviratne HK, Tillotson J, Lade JM, et al (2020)

Metabolism of Long-Acting Rilpivirine Following Intramuscular Injection: HIV Prevention Trials Network Study 076 (HPTN 076).

AIDS research and human retroviruses [Epub ahead of print].

A long-acting injectable formulation of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor, is currently under investigation for use in HIV maintenance therapy. We previously characterized RPV metabolism following oral dosing and identified seven metabolites: four metabolites resulting from mono- or dioxygenation of the 2,6-dimethylphenyl ring itself or either of the two methyl groups located on that ring, one N-linked RPV glucuronide conjugate, and two O-linked RPV glucuronides produced via glucuronidation of mono- and dihydroxymethyl metabolites. However, as is true for most drugs, the metabolism of RPV following injection has yet to be reported. The phase II clinical trial HPTN 076 enrolled 136 HIV-uninfected women and investigated the safety and acceptability of long-acting injectable RPV for use in HIV pre-exposure prophylaxis. Through the analysis of plasma samples from 80 of these participants in the active product arm of the study, we were able to detect two metabolites following intramuscular injection of long-acting RPV, 2-hydroxymethyl-RPV and RPV N-glucuronide. Of the total of 80 individuals, 72 subjects exhibited detectable levels of 2-hydroxymethyl-RPV in plasma samples whereas RPV N-glucuronide was detectable in plasma samples of 78 participants. Additionally, RPV N-glucuronide was detectable in rectal fluid, cervicovaginal fluid, and vaginal tissue. To investigate potential genetic variation in genes encoding enzymes relevant to RPV metabolism, we isolated genomic DNA and performed next-generation sequencing of CYP3A4, CYP3A5, UGT1A1 and UGT1A4. From these analyses, 4 missense variants were detected for CYP3A4 while one missense variant and one frameshift variant were detected for CYP3A5. A total of 8 missense variants of UGT1A4 were detected, whereas 2 variants were detected for UGT1A1; however, these variants did not appear to account for the observed interindividual variability in metabolite levels. These findings provide insight into the metabolism of long-acting RPV and contribute to overall understanding of metabolism following oral dosing versus injection.

RevDate: 2020-11-16

Beasley JM, Rillamas-Sun E, Tinker LF, et al (2020)

Authors Response.

RevDate: 2020-11-15

Bak A, RJ Ho (2020)

Advancing Cell and Gene Therapeutic Products for Health Impact - Progress on Pharmaceutical Research, Development, Manufacturing and Controls.

RevDate: 2020-11-16

Simon S, Voillet V, Vignard V, et al (2020)

PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy.

Journal for immunotherapy of cancer, 8(2):.

BACKGROUND: Clinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated.

METHODS: We isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally after therapy. Using multiparameter flow cytometry and cell sorting, we isolated four subsets of CD8+ T cells, based on PD-1 and TIGIT expression profiles. We performed phenotypic characterization, T cell receptor sequencing, targeted transcriptomic analysis and antitumor reactivity assays to thoroughly characterize each of these subsets.

RESULTS: We documented that the frequency of circulating PD-1+TIGIT+ (DPOS) CD8+ T-cells after 1 month of anti-PD-1 therapy was associated with clinical response and overall survival. This DPOS T-cell population was enriched in highly activated T-cells, tumor-specific and emerging T-cell clonotypes and T lymphocytes overexpressing CXCR5, a key marker of the CD8 cytotoxic follicular T cell population. Additionally, transcriptomic profiling defined a specific gene signature for this population as well as the overexpression of specific pathways associated with the therapeutic response.

CONCLUSIONS: Our results provide a convincing rationale for monitoring this PD-1+TIGIT+ circulating population as an early cellular-based marker of therapeutic response to anti-PD-1 therapy.

RevDate: 2020-11-16

Montaño MA, Alfaro R, Ness T, et al (2020)

Sexual Behavior and Sexually Transmitted Infection Outcomes Among Men Who Have Sex With Men and Transgender Women Participating in a Study of the Timing of Antiretroviral Therapy in Lima, Peru.

Sexually transmitted diseases, 47(12):825-831.

BACKGROUND: We assessed sexual behavior and incidence of sexually transmitted infections (STIs) among men who have sex with men and transgender women participating in Sabes, a study of an expanded treatment as prevention strategy focused on early diagnosis and treatment of HIV infection in Lima, Peru (2013-2017).

METHODS: Sabes participants were tested monthly for HIV to identify acute or early infections, and HIV-positive participants were randomized to receive antiretroviral therapy immediately (immediate arm) or after 24 weeks (deferred arm) during a 48-week follow-up period. Sexual behavior was assessed at randomization (baseline) and every 12 weeks thereafter. Participants were tested for urethral and rectal chlamydia and gonorrhea and for syphilis at baseline, 12, 24, and 48 weeks. We describe patterns of sexual behavior during the 48-week follow-up period and compare sexual behavior and STI incidence between study arms.

RESULTS: After randomization, 207 HIV-positive participants completed questionnaires and STI testing at 2 or more visits. After HIV diagnosis, participants in both arms reported increases in condom use with main and casual partners and decreased drug and alcohol use before or during anal sex. We observed no between-arm differences in sexual behavior. Deferred arm participants had higher incidence of chlamydia (incidence rate ratio, 2.33; 95% confidence interval, 1.14-4.77) but not gonorrhea or syphilis.

CONCLUSIONS: Despite reported increases in condom use, the overall high incidence of STIs reflects some ongoing condomless sex among HIV-positive men who have sex with men and transgender women, highlighting the importance of regular STI screening and counseling to support consistent condom use among HIV-positive individuals at risk for STIs.

RevDate: 2020-11-13

Best CM, Riley DV, Laha TJ, et al (2020)

Vitamin D in human serum and adipose tissue after supplementation.

The American journal of clinical nutrition pii:5979932 [Epub ahead of print].

BACKGROUND: Serum 25-hydroxyvitamin D [25(OH)D] concentration is an indicator of vitamin D exposure, but it is also influenced by clinical characteristics that affect 25(OH)D production and clearance. Vitamin D is the precursor to 25(OH)D but is analytically challenging to measure in biological specimens.

OBJECTIVES: We aimed to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of vitamins D3 and D2 in serum and to explore the potential of circulating vitamin D as a biomarker of exposure in supplementation trials.

METHODS: The method was validated using guideline C62-A from the Clinical and Laboratory Standards Institute and was applied in 2 pilot clinical trials of oral vitamin D3 supplementation. Pilot study 1 included 22 adults randomly assigned to placebo or 2000 IU/d. Blood was collected at baseline, 1, 3, 6, and 12 mo. Pilot study 2 included 15 adults randomly assigned to 2000 or 4000 IU/d. Blood and subcutaneous (SUBQ) adipose tissue were collected at baseline and 3 mo.

RESULTS: In study 1, mean change (baseline to 3 mo) in serum vitamin D3 was -0.1 ng/mL in the placebo group and 6.8 ng/mL in the 2000 IU/d group (absolute difference: 6.9; 95% CI: 4.5, 9.3 ng/mL). In study 2, mean change (baseline to 3 mo) in serum vitamin D3 was 10.4 ng/mL in the 2000 IU/d group and 22.2 ng/mL in the 4000 IU/d group (fold difference: 2.15; 95% CI: 1.40, 3.37). Serum and adipose tissue vitamin D3 concentrations were correlated, and the dose-response of vitamin D3 in adipose mirrored that in serum.

CONCLUSIONS: We validated a sensitive, robust, and high-throughput LC-MS/MS method to quantify vitamins D3 and D2 in serum. Serum and SUBQ adipose tissue vitamin D3 concentrations increased proportionally to dose with 3 mo of daily supplementation.These trials were registered at clinicaltrials.gov as NCT00552409 (pilot study 1) and NCT01477034 (pilot study 2).

RevDate: 2020-11-13

Schmidt KA, Cromer G, Burhans MS, et al (2020)

The impact of diets rich in low-fat or full-fat dairy on glucose tolerance and its determinants: a randomized controlled trial.

The American journal of clinical nutrition pii:5979929 [Epub ahead of print].

BACKGROUND: Dairy foods, particularly yogurt, and plasma biomarkers of dairy fat intake are consistently inversely associated with incident type 2 diabetes. Yet, few trials assessing the impact of dairy on glucose homeostasis include fermented or full-fat dairy foods.

OBJECTIVES: We aimed to compare the effects of diets rich in low-fat or full-fat milk, yogurt, and cheese on glucose tolerance and its determinants, with those of a limited dairy diet.

METHODS: In this parallel-design randomized controlled trial, 72 participants with metabolic syndrome completed a 4-wk wash-in period, limiting dairy intake to ≤3 servings/wk of nonfat milk. Participants were then randomly assigned to either continue the limited dairy diet, or switch to a diet containing 3.3 servings/d of either low-fat or full-fat dairy for 12 wk. Outcome measures included glucose tolerance (area under the curve glucose during an oral-glucose-tolerance test), insulin sensitivity, pancreatic β-cell function, systemic inflammation, liver-fat content, and body weight and composition.

RESULTS: In the per-protocol analysis (n = 67), we observed no intervention effect on glucose tolerance (P = 0.340). Both the low-fat and full-fat dairy diets decreased the Matsuda insulin sensitivity index (ISI) (means ± SDs -0.47 ± 1.07 and -0.25 ± 0.91, respectively) and as compared with the limited dairy group (0.00 ± 0.92) (P = 0.012 overall). Body weight also changed differentially (P = 0.006 overall), increasing on full-fat dairy (+1.0 kg; -0.2, 1.8 kg) compared with the limited dairy diet (-0.4 kg; -2.5, 0.7 kg), whereas the low-fat dairy diet (+0.3 kg; -1.1, 1.9 kg) was not significantly different from the other interventions. Intervention effects on the Matsuda ISI remained after adjusting for changes in adiposity. No intervention effects were detected for liver fat content or systemic inflammation. Findings in intent-to-treat analyses (n = 72) were consistent.

CONCLUSIONS: Contrary to our hypothesis, neither dairy diet improved glucose tolerance in individuals with metabolic syndrome. Both dairy diets decreased insulin sensitivity through mechanisms largely unrelated to changes in key determinants of insulin sensitivity.This trial was registered at clinicaltrials.gov as NCT02663544.

RevDate: 2020-11-13

Estey E (2020)

New treatments for acute myeloid leukemia: how much has changed?.

Leukemia pii:10.1038/s41375-020-01084-2 [Epub ahead of print].

RevDate: 2020-11-16

Cao J, O'Day DR, Pliner HA, et al (2020)

A human cell atlas of fetal gene expression.

Science (New York, N.Y.), 370(6518):.

The gene expression program underlying the specification of human cell types is of fundamental interest. We generated human cell atlases of gene expression and chromatin accessibility in fetal tissues. For gene expression, we applied three-level combinatorial indexing to >110 samples representing 15 organs, ultimately profiling ~4 million single cells. We leveraged the literature and other atlases to identify and annotate hundreds of cell types and subtypes, both within and across tissues. Our analyses focused on organ-specific specializations of broadly distributed cell types (such as blood, endothelial, and epithelial), sites of fetal erythropoiesis (which notably included the adrenal gland), and integration with mouse developmental atlases (such as conserved specification of blood cells). These data represent a rich resource for the exploration of in vivo human gene expression in diverse tissues and cell types.

RevDate: 2020-11-12

Ayeni OA, Norris SA, Joffe M, et al (2020)

Pre-existing morbidity profile of women newly diagnosed with breast cancer in sub-Saharan Africa: African Breast Cancer-Disparities in Outcomes (ABC-DO) study.

International journal of cancer [Epub ahead of print].

The presence of pre-existing morbidities poses a challenge to cancer patient care. There is little information on the profile and prevalence of multi-morbidities in breast cancer patients across middle to lower income countries (MIC and LIC) in Sub-Saharan Africa (SSA). The African Breast Cancer-Disparities in Outcomes breast cancer cohort spans upper MICs South Africa and Namibia, lower MICs Zambia and Nigeria and LIC Uganda. At cancer diagnosis 7 morbidities were assessed: obesity, hypertension, diabetes, asthma/chronic obstructive pulmonary disease, heart disease, tuberculosis and HIV. Logistic regression models were used to assess determinants of morbidities and the influence of morbidities on advanced stage (stage III/IV) breast cancer diagnosis. Among 2189 women, morbidity prevalence was highest for obesity (35%, country-specific range 15-57%), hypertension (32%, 15-51%) and HIV (16%, 2-26%) then for diabetes (7%, 4-10%), asthma (4%, 2-10%), tuberculosis (4%, 0-8%) and heart disease (3%, 1-7%). Obesity and hypertension were more common in upper MICs and in higher socio-economic groups. Overall, 27% of women had at least 2 pre-existing morbidities. Older women were more likely to have obesity (odds ratio: 1.09 per 10 years, 95% CI 1.01-1.18), hypertension (1.98, 1.81-2.17), diabetes (1.51, 1.32-1.74) and heart disease (1.69, 1.37-2.09) and were less likely to be HIV positive (0.64, 0.58-0.71). Multi-morbidity was not associated with stage-at-diagnosis, with the exception of earlier stage in obese and hypertensive women. Breast cancer patients in higher income countries and higher social groups in SSA face the additional burden of pre-existing non-communicable diseases, particularly obesity and hypertension, exacerbated by HIV in Southern/Eastern Africa.

RevDate: 2020-11-12

Shim YA, Weliwitigoda A, Campbell T, et al (2020)

Splenic erythroid progenitors decrease TNFα production by macrophages and reduce systemic inflammation in a mouse model of T cell-induced colitis.

European journal of immunology [Epub ahead of print].

In inflammatory bowel disease [IBD], inflammation can occur beyond the intestine and spread systemically causing complications such as arthritis, cachexia and anemia. Here, we determine the impact of CD45, a pan-leukocyte marker and tyrosine phosphatase, on IBD. Using a mouse model of T cell transfer colitis, normal T cells CD25- CD45RBhigh CD4+ T cells were transferred into Rag1-deficient mice (RAGKO), and CD45 deficient RAGKO mice (CD45RAGKO). Delayed weight loss and systemic wasting syndrome was present in CD45RAGKO mice compared to RAGKO mice, despite equivalent inflammation in the colon. CD45RAGKO mice had reduced serum levels of TNFα, and reduced TNFα production by splenic myeloid cells. CD45RAGKO mice also had increased numbers of erythroid progenitors in the spleen, which had previously been shown to be immunosuppressive. Adoptive transfer of these erythroid progenitors into RAGKO mice reduced their weight loss and TNFα expression by splenic red pulp macrophages. In vitro, erythroid cells suppressed TNFα expression in red pulp macrophages in a phagocytosis-dependent manner. These findings show a novel role for erythroid progenitors in suppressing the pro-inflammatory function of splenic macrophages and cachexia associated with IBD. This article is protected by copyright. All rights reserved.

RevDate: 2020-11-12

Atallah E, Schiffer CA, Radich JP, et al (2020)

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial.

JAMA oncology pii:2772842 [Epub ahead of print].

Importance: Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients.

Objective: To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML.

The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020.

Intervention: Discontinuation of TKIs.

Main Outcomes and Measures: Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR).

Results: Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs.

Conclusions and Relevance: In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies.

Trial Registration: ClinicalTrials.gov Identifier: NCT02269267.

RevDate: 2020-11-12

Fleury ME, Farner AM, JM Unger (2020)

Association of the COVID-19 Outbreak With Patient Willingness to Enroll in Cancer Clinical Trials.

JAMA oncology pii:2772839 [Epub ahead of print].

RevDate: 2020-11-12

Dembitz V, Lalic H, Kodvanj I, et al (2020)

5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts.

BMC cancer, 20(1):1090 pii:10.1186/s12885-020-07533-6.

BACKGROUND: All-trans retinoic acid (ATRA)-based treatment of acute promyelocytic leukemia (APL) is the most successful pharmacological treatment of acute myeloid leukemia (AML). Recent development of inhibitors of mutated isocitrate dehydrogenase and dihydroorotate dehydrogenase (DHODH) has revived interest in differentiation therapy of non-APL AML. Our previous studies demonstrated that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induced differentiation of monocytic cell lines by activating the ATR/Chk1 via pyrimidine depletion. In the present study, the effects of AICAr on the viability and differentiation of primary AML blasts isolated from bone marrow of patients with non-APL AML were tested and compared with the effects of DHODH inhibitor brequinar and ATRA.

METHODS: Bone marrow samples were obtained from 35 patients and leukemia blasts were cultured ex vivo. The cell viability was assessed by MTT assay and AML cell differentiation was determined by flow cytometry and morphological analyses. RNA sequencing and partial data analysis were conducted using ClusterProfiler package. Statistical analysis was performed using GraphPad Prism 6.0.

RESULTS: AICAr is capable of triggering differentiation in samples of bone marrow blasts cultured ex vivo that were resistant to ATRA. AICAr-induced differentiation correlates with proliferation and sensitivity to DHODH inhibition. RNA-seq data obtained in primary AML blasts confirmed that AICAr treatment induced downregulation of pyrimidine metabolism pathways together with an upregulation of gene set involved in hematopoietic cell lineage.

CONCLUSION: AICAr induces differentiation in a subset of primary non-APL AML blasts, and these effects correlate with sensitivity to a well-known, potent DHODH inhibitor.

RevDate: 2020-11-11

Ralph DK, FA Matsen (4th) (2020)

Using B cell receptor lineage structures to predict affinity.

PLoS computational biology, 16(11):e1008391 pii:PCOMPBIOL-D-20-00710 [Epub ahead of print].

COMMENTS: Please post comments or questions on this paper as new issues at https://git.io/Jvxkn.

RevDate: 2020-11-11

Clark SE, Marcum ZA, Radich JP, et al (2020)

Predictors of tyrosine kinase inhibitor adherence trajectories in patients with newly diagnosed chronic myeloid leukemia.

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners [Epub ahead of print].

INTRODUCTION: Although consistent use of tyrosine kinase inhibitors (TKIs) confers significant improvements in long-term survival for individuals with chronic myeloid leukemia (CML), only 70% of CML patients are adherent to TKIs. Understanding the factors that contribute to non-adherence and establishing dynamic adherence patterns in this population are essential aspects of targeted drug monitoring and intervention strategies.

METHODS: Newly diagnosed CML patients were identified in the MarketScan database and relevant covariate values extracted. Proportion of days covered (PDC) per 30-day interval was used to calculate adherence over a 12-month follow-up period. We conducted a latent profile analysis (LPA) on these PDC estimates to identify distinct, dynamic patterns of TKI adherence. Identified trajectories were grouped into four clinically relevant categories and predictors of membership in these categories were determined via multinomial logistic regression.

RESULTS: Four broad adherence categories were identified from the LPA: never adherent, initially non-adherent becoming adherent, initially adherent becoming non-adherent, and stable adherent. Results from the subsequent multinomial logistic regression indicated that younger age, female sex, greater monthly financial burden, fewer comorbidities, fewer concomitant medications, year of diagnosis, higher starting dose, TKI type, and a longer duration from diagnosis to treatment were significantly associated with membership in at least one of the three non-stable adherent groups.

CONCLUSION: Select sociodemographic and clinical characteristics were found to predict membership in clinically meaningful groups of longitudinal TKI adherence. These findings could have major implications for informing personalized monitoring and intervention strategies for individuals who are likely to be non-adherent.

RevDate: 2020-11-11

Horowitz LF, Rodriguez AD, Au-Yeung A, et al (2020)

Microdissected "cuboids" for microfluidic drug testing of intact tissues.

Lab on a chip [Epub ahead of print].

As preclinical animal tests often do not accurately predict drug effects later observed in humans, most drugs under development fail to reach the market. Thus there is a critical need for functional drug testing platforms that use human, intact tissues to complement animal studies. To enable future multiplexed delivery of many drugs to one small biopsy, we have developed a multi-well microfluidic platform that selectively treats cuboidal-shaped microdissected tissues or "cuboids" with well-preserved tissue microenvironments. We create large numbers of uniformly-sized cuboids by semi-automated sectioning of tissue with a commercially available tissue chopper. Here we demonstrate the microdissection method on normal mouse liver, which we characterize with quantitative 3D imaging, and on human glioma xenograft tumors, which we evaluate after time in culture for viability and preservation of the microenvironment. The benefits of size uniformity include lower heterogeneity in future biological assays as well as facilitation of their physical manipulation by automation. Our prototype platform consists of a microfluidic circuit whose hydrodynamic traps immobilize the live cuboids in arrays at the bottom of a multi-well plate. Fluid dynamics simulations enabled the rapid evaluation of design alternatives and operational parameters. We demonstrate the proof-of-concept application of model soluble compounds such as dyes (CellTracker, Hoechst) and the cancer drug cisplatin. Upscaling of the microfluidic platform and microdissection method to larger arrays and numbers of cuboids could lead to direct testing of human tissues at high throughput, and thus could have a significant impact on drug discovery and personalized medicine.

RevDate: 2020-11-11

Wilkins LJ, Tosoian JJ, Sundi D, et al (2020)

Surgical management of high-risk, localized prostate cancer.

Nature reviews. Urology pii:10.1038/s41585-020-00384-7 [Epub ahead of print].

High-risk prostate cancer is a heterogeneous disease that lacks clear consensus on its ideal management. Historically, non-surgical treatment was the preferred strategy, and several studies demonstrated improved survival among men with high-risk disease managed with the combination of radiotherapy and androgen deprivation therapy (ADT) compared with ADT alone. However, practice trends in the past 10-15 years have shown increased use of radical prostatectomy with pelvic lymph node dissection for primary management of high-risk, localized disease. Radical prostatectomy, as a primary monotherapy, offers the potential benefits of avoiding ADT, reducing rates of symptomatic local recurrence, enabling full pathological tumour staging and potentially reducing late adverse effects such as secondary malignancy compared with radiation therapy. Retrospective studies have reported wide variability in short-term (pathological) and long-term (oncological) outcomes of radical prostatectomy. Surgical monotherapy continues to be appropriate for selected patients, whereas in others the best treatment strategy probably involves a multimodal approach. Appropriate risk stratification utilizing clinical, pathological and potentially also genomic risk data is imperative in the initial management of men with prostate cancer. However, data from ongoing and planned prospective trials are needed to identify the optimal management strategy for men with high-risk, localized prostate cancer.

RevDate: 2020-11-11

Feng Z, MS Pepe (2020)

Adding Rigor to Biomarker Evaluations - EDRN Experience.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-0240 [Epub ahead of print].

The cancer early detection biomarker field was, compared to the therapeutic arena, in its infancy when the Early Detection Research Network (EDRN) was initiated in 2000. The EDRN has played a crucial role in changing the culture and the ways people do biomarker studies.The EDRN proposed biomarker developmental guidelines and biomarker pivotal trial study design standards, created biomarker reference sets and functioned as a unbiased broker for the field, implemented the most rigorous blinding policy in biomarker field, developed an array of statistical and computational tools for early detection biomarker evaluations, and developed a multi-disciplinary team-science approach. We reviewed these contributions made by the EDRN and their impacts in bringing the field to more maturity. Challenges and opportunities on the future of cancer early detection biomarker translational research are discussed, particularly in strengthening biomarker discovery pipeline and conducting more efficient biomarker validation studies. EDRN's approach and success changed how the biomarker field does biomarker studies.

RevDate: 2020-11-03

Evins AE, West R, Benowitz NL, et al (2020)

Efficacy and Safety of Pharmacotherapeutic Smoking Cessation Aids in Schizophrenia Spectrum Disorders: Subgroup Analysis of EAGLES.

Psychiatric services (Washington, D.C.) [Epub ahead of print].

OBJECTIVE: This study aimed to evaluate the efficacy and safety of varenicline, bupropion, and nicotine replacement therapy (NRT) among smokers with schizophrenia spectrum disorders in post hoc analyses of Evaluating Adverse Events in a Global Smoking Cessation Study data.

METHODS: Smokers with schizophrenia spectrum disorder (N=390) and without a psychiatric illness (control group, N=4,028) were randomly assigned to receive varenicline, bupropion, NRT patch, or placebo for 12 weeks. Outcomes included abstinence rates during treatment and follow-up, number needed to treat (NNT) for abstinence, incidence of neuropsychiatric adverse events (NPSAEs), and temporal relationship between NPSAEs and abstinence status.

RESULTS: Smokers with schizophrenia smoked more and had greater dependence and fewer prior trials of cessation pharmacotherapy at baseline. At each time point, smokers with schizophrenia assigned to varenicline had significantly greater odds of abstinence compared with their matched placebo group, with NNT comparable to the control group. Bupropion and NRT increased odds of abstinence; confidence intervals (CIs) included 1 for some comparisons, and NNT for smokers with schizophrenia was greater than for the control group. No treatment was associated with significantly more NPSAEs, compared with placebo, in either cohort. The estimated NPSAE rate was 5% (95% CI=3.0-7.7) for smokers with schizophrenia and 1% (95% CI=0.6-2.1) for the control group. Over one-third of NPSAEs occurred during partial or full abstinence, suggesting a multifactorial nature.

CONCLUSIONS: For smokers with schizophrenia, varenicline led to significantly higher abstinence rates, and NNT was comparable to the control group. A significant proportion of NPSAEs occurred during early abstinence. No treatment significantly increased NPSAE prevalence.

RevDate: 2020-11-10

Su Y, Chen D, Yuan D, et al (2020)

Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.

Cell pii:S0092-8674(20)31444-6 [Epub ahead of print].

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention.

RevDate: 2020-11-10

Gupta V, Kennedy JA, Capo-Chichi JM, et al (2020)

Genetic factors rather than blast reduction determine outcomes of allogeneic HCT in BCR-ABL-negative MPN in blast phase.

Blood advances, 4(21):5562-5573.

There is a limited understanding of the clinical and molecular factors associated with outcomes of hematopoietic cell transplantation (HCT) in patients with BCR-ABL-negative myeloproliferative neoplasms in blast phase (MPN-BP). Using the Center for International Blood and Marrow Transplant Research database, we evaluated HCT outcomes in 177 patients with MPN-BP. Ninety-five (54%) had sufficient DNA for targeted next-generation sequencing of 49 genes clinically relevant in hematologic malignancies. At 5 years, overall survival (OS), cumulative incidence of relapse, and nonrelapse mortality of the study cohort was 18%, 61%, and 25%, respectively. In a multivariable model, poor-risk cytogenetics was associated with inferior OS (hazard ratio [HR], 1.71; 95% CI, 1.21-2.41) due to increased relapse (HR, 1.93; 95% CI, 1.32-2.82). Transplants using mobilized peripheral blood (PB) were associated with better OS (HR, 0.60; 95% CI, 0.38-0.96). No difference in outcomes was observed in patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Among the 95 patients with molecular data, mutation of TP53, present in 23%, was the only genetic alteration associated with outcomes. In a multivariate model, TP53-mutant patients had inferior OS (HR, 1.99; 95% CI, 1.14-3.49) and increased incidence of relapse (HR, 2.59; 95% CI, 1.41-4.74). There were no differences in the spectrum of gene mutations, number of mutations, or variant allele frequency between patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Genetic factors, namely cytogenetic alterations and TP53 mutation status, rather than degree of cytoreduction predict outcomes of HCT in MPN-BP. No meaningful benefit of conventional HCT was observed in patients with MPN-BP and mutated TP53.

RevDate: 2020-11-10

Chlebowski RT, Aragaki AK, Anderson GL, et al (2020)

Reply to The Women's Health Initiative; hormone replacement therapy; and surveillance, epidemiology, and end results data.

RevDate: 2020-11-10

Kasinathan B, Colmenares SU, McConnell H, et al (2020)

Innovation of heterochromatin functions drives rapid evolution of essential ZAD-ZNF genes in Drosophila.

eLife, 9: pii:63368.

Contrary to dogma, evolutionarily young and dynamic genes can encode essential functions. We find that evolutionarily dynamic ZAD-ZNF genes, which encode the most abundant class of insect transcription factors, are more likely to encode essential functions in Drosophila melanogaster than ancient, conserved ZAD-ZNF genes. We focus on the Nicknack ZAD-ZNF gene, which is evolutionarily young, poorly retained in Drosophila species, and evolves under strong positive selection. Yet we find that it is necessary for larval development in D. melanogaster. We show that Nicknack encodes a heterochromatin-localizing protein like its paralog Oddjob, also an evolutionarily dynamic yet essential ZAD-ZNF gene. We find that the divergent D. simulans Nicknack protein can still localize to D. melanogaster heterochromatin and rescue viability of female but not male Nicknack-null D. melanogaster. Our findings suggest that innovation for rapidly changing heterochromatin functions might generally explain the essentiality of many evolutionarily dynamic ZAD-ZNF genes in insects.

RevDate: 2020-11-09

Martin AR, Patel EU, Kirby C, et al (2020)

The association of α4β7 expression with HIV acquisition and disease progression in people who inject drugs and men who have sex with men: Case control studies.

EBioMedicine, 62:103102 pii:S2352-3964(20)30478-3 [Epub ahead of print].

BACKGROUND: α4β7 is a gut-homing integrin heterodimer that can act as a non-essential binding molecule for HIV. A previous study in heterosexual African women found that individuals with higher proportions of α4β7 expressing CD4+ T cells were more likely to become infected with HIV, as well as present with faster disease progression. It is unknown if this phenomenon is also observed in men who have sex with men (MSM) or people who inject drugs (PWID).

METHODS: MSM and transgender women who seroconverted as part of the HVTN 505 HIV vaccine trial and PWID who seroconverted during the ALIVE cohort study were selected as cases and matched to HIV-uninfected controls from the same studies (1:1 and 1:3, respectively). Pre-seroconversion PBMC samples from cases and controls in both studies were examined by flow cytometry to measure levels of α4β7 expression on CD4+ T cells. Multivariable conditional logistic regression was used to compare α4β7 expression levels between cases and controls. A Kaplan-Meier curve was used to examine the association of α4β7 expression pre-seroconversion with HIV disease progression.

FINDINGS: In MSM and transgender women (n = 103 cases, 103 controls), there was no statistically significant difference in the levels of α4β7 expression on CD4+ T cells between cases and controls (adjusted odds ratio [adjOR] =1.10, 95% confidence interval [CI]=0.94,1.29; p = 0.246). Interestingly, in PWID (n = 49 cases, 143 controls), cases had significantly lower levels of α4β7 expression compared to their matched controls (adjOR = 0.80, 95% CI = 0.68, 0.93; p = 0.004). Among HIV-positive PWID (n = 47), there was no significant association in HIV disease progression in individuals above or below the median level of α4β7 expression (log-rank p = 0.84).

INTERPRETATION: In contrast to findings in heterosexual women, higher α4β7 expression does not predict HIV acquisition or disease progression in PWID or MSM.

FUNDING: This study was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. The study was also supported by extramural grants from NIAID T32AI102623 (E.U.P.), and UM1AI069470.

RevDate: 2020-11-09

Loh KP, Tsang M, LeBlanc TW, et al (2020)

Decisional involvement and information preferences of patients with hematologic malignancies.

Blood advances, 4(21):5492-5500.

Understanding decisional involvement and information preferences in patients with hematologic malignancies may help to optimize physician-patient communication about treatment decisions and align the decision-making processes with patients' preferences. We described and examined factors associated with preferences of patients with hematologic malignancies for decisional involvement, information sources, and presentation of information. In a multicenter observational study, we recruited 216 patients with hematologic malignancies of any stage from September 2003 to June 2007. Patients were asked about their decisional involvement preferences (Control Preferences Scale), information sources (including most useful source of information), and preferences for their oncologists' presentation of treatment success information. We used multivariate logistic regressions to identify factors associated with decisional involvement preferences and usefulness of information sources (physicians vs nonphysicians). Patient-directed, shared, and physician-directed approaches were preferred in 34%, 38%, and 28% of patients, respectively. Physicians and computer/Internet were the most common information sources; 42% perceived physicians as the most useful source. On multivariate analysis, patients with less than a college education (vs postgraduate education) were less likely to perceive their physician as the most useful source (adjusted odds ratio [AOR], 0.46; 95% confidence interval (CI), 0.21-1.00), whereas patients with acute leukemia (vs other blood cancers) were more likely to perceive their physician as the most useful source (AOR, 2.49; 95% CI, 1.07-5.80). In terms of communicating treatment success rates, 70% preferred ≥1 method(s), and 88% preferred presentation in percentages. Our study suggests that decisional involvement and information preferences vary and should be assessed explicitly as part of each decision-making encounter.

RevDate: 2020-11-09

Moazzam S, Onstad L, O'Leary H, et al (2020)

Gender differences in question-asking at the 2019 American Society of Hematology Annual Meeting.

Blood advances, 4(21):5473-5479.

Attendance at professional conferences is an important component of career development, because conferences are a major forum for presenting new research, interacting with colleagues and networking. An extensive literature documents differences in the professional experiences of women and men, including experiences at professional conferences. We hypothesized that women are less likely than men to ask questions at conferences, thus forgoing opportunities for professional development. To address this issue, we analyzed the question-asking behavior of women and men at the 2019 Annual Meeting and Exposition of the American Society of Hematology. In all, 112 sessions (55% of those eligible) were randomly chosen for coding, yielding data on 577 presentations. Although approximately 50% of moderators and speakers were women, the proportion of questions asked by women was significantly lower compared with the estimated proportion of women attending the conference (23% vs 39%; P < .0001). Women were more likely to ask questions if another woman asked the first question or if the session topic was red cells. These results suggest that although women are represented equally as moderators and speakers, they are less likely to engage in the postpresentation discourse by asking questions. Encouraging women to speak up in professional situations and providing training on question-asking skills can help address this gender gap that potentially contributes to disparities in professional visibility and career advancement for women in hematology.

RevDate: 2020-11-09

Niang MN, Sugimoto JD, Diallo A, et al (2020)

Estimates of inactivated influenza vaccine effectiveness among children in Senegal: results from two consecutive cluster-randomized controlled trials in 2010 and 2011.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5963906 [Epub ahead of print].

BACKGROUND: We report results of Years 2 and 3 of consecutive cluster-randomized controlled trials of trivalent inactivated influenza vaccine (IIV3) in Senegal.

METHODS: We cluster-randomized (1:1) 20 villages to annual vaccination with IIV3 or inactivated poliovirus vaccine (IPV) of age-eligible residents (6 months - 10 years). The primary outcome was total vaccine effectiveness against laboratory-confirmed influenza illness (LCI) among age-eligible children (modified-intention-to-treat population [mITT]). Secondary outcomes were indirect (herd protection) and population (overall community) vaccine effectiveness.

RESULTS: We vaccinated 74% of 12,408 age-eligible children in Year 2 (June 2010-April 11) and 74% of 11,988 age-eligible children in Year 3 (April 2011-December 2011) with study vaccines. Annual cumulative incidence of LCI was 4.7 (Year 2) and 4.2 (Year 3) per 100 mITT child vaccinees of IPV villages. In Year 2, IIV3 matched circulating influenza strains. The total effectiveness was 52.8% (95% CI: 32.3%-67.0%), and the population effectiveness was 36.0% (95% CI: 10.2%-54.4%) against LCI caused by any influenza strain. The indirect effectiveness against LCI by A/H3N2 was 56.4% (95% CI: 39.0%-68.9%). In Year 3, 74% of influenza detections were vaccine-mismatched to circulating B/Yamagata and 24% were vaccine-matched to circulating A/H3N2. The Year 3 total effectiveness against LCI was -14.5% (95% CI: -81.2%-27.6%). Vaccine effectiveness varied by type/subtype of influenza in both years.

CONCLUSION: IIV3 was variably effective against influenza illness in Senegalese children, with total and indirect vaccine effectiveness present during the year when all circulating strains matched the IIV3 formulation.

RevDate: 2020-11-09

Mandal R, Cano R, Davis CD, et al (2020)

Workshop report: Toward the development of a human whole stool reference material for metabolomic and metagenomic gut microbiome measurements.

Metabolomics : Official journal of the Metabolomic Society, 16(11):119 pii:10.1007/s11306-020-01744-5.

INTRODUCTION: To date, there has been little effort to develop standards for metabolome-based gut microbiome measurements despite the significant efforts toward standard development for DNA-based microbiome measurements.

OBJECTIVES: The National Institute of Standards and Technology (NIST), The BioCollective (TBC), and the North America Branch of the International Life Sciences Institute (ILSI North America) are collaborating to extend NIST's efforts to develop a Human Whole Stool Reference Material for the purpose of method harmonization and eventual quality control.

METHODS: The reference material will be rationally designed for adequate quality assurance and quality control (QA/QC) for underlying measurements in the study of the impact of diet and nutrition on functional aspects of the host gut microbiome and relationships of those functions to health. To identify which metabolites deserve priority in their value assignment, NIST, TBC, and ILSI North America jointly conducted a workshop on September 12, 2019 at the NIST campus in Gaithersburg, Maryland. The objective of the workshop was to identify metabolites for which evidence indicates relevance to health and disease and to decide on the appropriate course of action to develop a fit-for-purpose reference material.

RESULTS: This document represents the consensus opinions of workshop participants and co-authors of this manuscript, and provides additional supporting information. In addition to developing general criteria for metabolite selection and a preliminary list of proposed metabolites, this paper describes some of the strengths and limitations of this initiative given the current state of microbiome research.

CONCLUSIONS: Given the rapidly evolving nature of gut microbiome science and the current state of knowledge, an RM (as opposed to a CRM) measured for multiple metabolites is appropriate at this stage. As the science evolves, the RM can evolve to match the needs of the research community. Ultimately, the stool RM may exist in sequential versions. Beneficial to this evolution will be a clear line of communication between NIST and the stakeholder community to ensure alignment with current scientific understanding and community needs.

RevDate: 2020-11-09

Milano F, Emerson RO, Salit R, et al (2020)

Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation.

Frontiers in oncology, 10:583349.

Introduction: Cord blood transplantation (CBT) recipients are at increased risk of mortality due to delayed immune recovery (IR). Prior studies in CBT patients have shown that recovery of absolute lymphocyte count is predictive of survival after transplant. However, there are no data on the association of T-cell receptor (TCR) and clinical outcomes after CBT. Here we retrospectively performed TCR beta chain sequencing on peripheral blood (PB) samples of 34 CBT patients.

Methods: All patients received a total body irradiation based conditioning regimen and cyclosporine and MMF were used for graft versus host disease (GvHD) prophylaxis. PB was collected pretransplant on days 28, 56, 80, 180, and 1-year posttransplant for retrospective analysis of IR utilizing high-throughput sequencing of TCRβ rearrangements from genomic DNA extracted from PB mononuclear cells. To test the association between TCR repertoire diversity and patient outcomes, we conducted a permutation test on median TCR repertoire diversity for patients who died within the first year posttransplant versus those who survived.

Results: Median age was 27 (range 1-58 years) and most of the patients (n = 27) had acute leukemias. There were 15 deaths occurring between 34 to 335 days after transplant. Seven deaths were due to relapse. Rapid turnover of T cell clones was observed at each time point, with TCR repertoires stabilizing by 1-year posttransplant. TCR diversity values at day 100 for patients who died between 100 and 365 days posttransplant were significantly lower than those of the surviving patients (p = 0.01).

Conclusions: Using a fast high-throughput TCR sequencing assay we have demonstrated that high TCR diversity is associated with better patient outcomes following CBT. Importantly, this assay is easily performed on posttransplant PB samples, even as early as day 28 posttransplant, making it an excellent candidate for early identification of patients at high risk of death.

RevDate: 2020-11-09

Yuan S, Liu Y, Till B, et al (2020)

Pretreatment Peripheral B Cells Are Associated With Tumor Response to Anti-PD-1-Based Immunotherapy.

Frontiers in immunology, 11:563653.

Identification of reliable biomarkers to predict efficacy of immune checkpoint inhibitors and to monitor relapse in cancer patients receiving this therapy remains one of the main objectives of cancer immunotherapy research. We found that the pretreatment B cell number in the peripheral blood differed significantly between responders and non-responders to anti-PD-1-based immunotherapy. Patients with various cancer types achieving a clinical response had a significantly lower number of B cells compared with those with progressive disease. Patients who progressed from partial response to progressive disease exhibited a gradually increased number of circulating B cells. Our findings suggest that B cells represent a promising biomarker for anti-PD-1-based immunotherapy responses and inhibit the effect of PD-1 blockade immunotherapy. Thus, preemptive strategies targeting B cells may increase the efficacy of PD-1 blockade immunotherapy in patients with solid tumors.

RevDate: 2020-11-09

Honigberg MC, Zekavat SM, Niroula A, et al (2020)

Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women.

Circulation [Epub ahead of print].

Background: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. Methods: We included postmenopausal women from the UK Biobank (N=11,495) aged 40-70 years with whole exome sequences and from the Women's Health Initiative (WHI, N=8,111) aged 50-79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of (1) any CHIP and (2) CHIP with variant allele frequency (VAF) >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes mellitus, and hormone therapy use. Secondary analyses considered natural vs. surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease (CAD). Results: The sample included 19,606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with vs. without a history of premature menopause was 8.8% vs. 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: OR 1.36, 95% 1.10-1.68, P=0.004; CHIP with VAF >0.1: OR 1.40, 95% CI 1.10-1.79, P=0.007). Associations were larger for natural premature menopause (all CHIP: OR 1.73, 95% CI 1.23-2.44, P=0.001; CHIP with VAF >0.1: OR 1.91, 95% CI 1.30-2.80, P<0.001) but smaller and non-significant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (HR associated with all CHIP: 1.36, 95% CI 1.07-1.73, P=0.012; HR associated with CHIP with VAF >0.1: 1.48, 95% CI 1.13-1.94, P=0.005). Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.

RevDate: 2020-11-08

Diamantopoulos LN, Holt SK, Khaki AR, et al (2020)

Response to Neoadjuvant Chemotherapy and Survival in Micropapillary Urothelial Carcinoma: Data From a Tertiary Referral Center and the Surveillance, Epidemiology, and End Results (SEER) Program.

Clinical genitourinary cancer pii:S1558-7673(20)30229-9 [Epub ahead of print].

BACKGROUND: Micropapillary urothelial carcinoma (MPC) is a rare urothelial carcinoma variant with conflicting data guiding clinical practice. In this study, we explored oncologic outcomes in relation to neoadjuvant chemotherapy (NAC) in a retrospective cohort of patients with MPC, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare.

PATIENTS AND METHODS: We retrospectively identified patients with MPC or conventional urothelial carcinoma (CUC) without any variant histology undergoing radical cystectomy (RC) in our institution (2003-2018). SEER-Medicare was also queried to identify patients diagnosed with MPC (2004-2015). Clinicopathologic data and treatment modalities were extracted. Overall survival (OS) was estimated with the Kaplan-Meier method. Mann-Whitney-Wilcoxon and chi-square tests were used for comparative analysis and Cox regression for identifying clinical covariates associated with OS.

RESULTS: Our institutional database yielded 46 patients with MPC and 457 with CUC. In SEER-Medicare, 183 patients with MPC were identified, and 63 (34%) underwent RC. In the institutional cohort, patients with MPC had significantly higher incidence of cN+ (17% vs. 8%), pN+ stage (30% vs. 17%), carcinoma-in-situ (43% vs. 25%), and lymphovascular invasion (30% vs. 16%) at RC versus those with CUC (all P < .05). Pathologic complete response (ypT0N0) to NAC was 33% for MPC and 35% for CUC (P = .899). Median OS was lower for institutional MPC versus CUC in univariate analysis (43.6 vs. 105.3 months, P = .006); however, MPC was not independently associated with OS in the multivariate model. Median OS was 25 months in the SEER MPC cohort for patients undergoing RC, while NAC was not associated with improved OS in that group.

CONCLUSION: Pathologic response to NAC was not significantly different between MPC and CUC, while MPC histology was not an independent predictor of OS. Further studies are needed to better understand biological mechanisms behind its aggressive features as well as the role of NAC in this histology variant.

RevDate: 2020-11-08

Laher F, Salami T, Hornschuh S, et al (2020)

Willingness to use HIV prevention methods among vaccine efficacy trial participants in Soweto, South Africa: discretion is important.

BMC public health, 20(1):1669 pii:10.1186/s12889-020-09785-0.

BACKGROUND: Despite multiple available HIV prevention methods, the HIV epidemic continues to affect South Africa the most. We sought to understand willingness to use actual and hypothetical HIV prevention methods among participants enrolled in a preventative HIV vaccine efficacy trial in Soweto, South Africa.

METHODS: We conducted a qualitative study with 38 self-reporting HIV-uninfected and consenting 18-35 year olds participating in the HVTN 702 vaccine efficacy trial in Soweto. Using a semi-structured interview guide, five focus group discussions (FGDs) were held, stratified by age, gender and sexual orientation. The FGDs were composed of: (i) 10 heterosexual women aged 18-24 years; (ii) 9 heterosexual and bisexual women aged 25-35 years; (iii & iv) heterosexual men aged 25-35 years with 7 in both groups; and (v) 5 men aged 18-35 years who have sex with men. FGDs were audio-recorded, transcribed verbatim, translated into English and analysed using thematic analysis.

RESULTS: We present five main themes: (i) long-lasting methods are preferable; (ii) condoms are well-known but not preferred for use; (iii) administration route of HIV prevention method is a consideration for the user; (iv) ideal HIV prevention methods should blend into the lifestyle of the user; and the perception that (v) visible prevention methods indicate sexual indiscretion.

CONCLUSIONS: The participants' candour about barriers to condom and daily oral pre-exposure prophylaxis (PrEP) use, and expressed preferences for long-lasting, discreet, lifestyle-friendly methods reveal a gap in the biomedical prevention market aiming to reduce sexually acquired HIV in South Africa. Product developers should consider long-acting injectable formulations, such as vaccines, passive antibodies and chemoprophylaxis, for HIV prevention technologies. Future innovations in HIV prevention products may need to address the desire for the method to blend easily into lifestyles, such as food-medication formulations.

RevDate: 2020-11-07

Imlay H, Dasgupta S, Boeckh M, et al (2020)

Risk Factors for Cytomegalovirus Reactivation and Association with Outcomes in Critically Ill Adults with Sepsis: A Pooled Analysis of Prospective Studies.

The Journal of infectious diseases pii:5959850 [Epub ahead of print].

We performed a multivariable analysis of potential risk factors (including CMV reactivation) for clinical outcomes by day 28 (death or continued hospitalization, ventilator-free days [VFD], ICU-free days [ICUFD], hospital free days [HFD]) from pooled cohorts of two previous prospective studies of CMV seropositive adults with sepsis. CMV reactivation at any level, >100, >1,000 IU/mL, peak viral load, and area under the curve were independently associated with the clinical outcomes. We identified the potential effect size of CMV on outcomes that could be used as endpoints for future interventional trials of CMV prevention using antiviral prophylaxis in ICU patients with sepsis.

RevDate: 2020-11-09

Brandão A, Paulo P, Maia S, et al (2020)

The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Cancers, 12(11): pii:cancers12113254.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

RevDate: 2020-11-06

Itani OA, Zhong X, Tang X, et al (2020)

Coordinate Regulation of Ribosome and tRNA Biogenesis Controls Hypoxic Injury and Translation.

Current biology : CB pii:S0960-9822(20)31505-0 [Epub ahead of print].

The translation machinery is composed of a myriad of proteins and RNAs whose levels must be coordinated to efficiently produce proteins without wasting energy or substrate. However, protein synthesis is clearly not always perfectly tuned to its environment, as disruption of translation machinery components can lengthen lifespan and stress survival. While much has been learned from bacteria and yeast about translational regulation, much less is known in metazoans. In a screen for mutations protecting C. elegans from hypoxic stress, we isolated multiple genes impacting protein synthesis: a ribosomal RNA helicase gene, tRNA biosynthesis genes, and a gene controlling amino acid availability. To define better the mechanisms by which these genes impact protein synthesis, we performed a second screen for suppressors of the conditional developmental arrest phenotype of the RNA helicase mutant and identified genes involved in ribosome biogenesis. Surprisingly, these suppressor mutations restored normal hypoxic sensitivity and protein synthesis to the tRNA biogenesis mutants, but not to the mutant reducing amino acid uptake. Proteomic analysis demonstrated that reduced tRNA biosynthetic activity produces a selective homeostatic reduction in ribosomal subunits, thereby offering a mechanism for the suppression results. Our study uncovers an unrecognized higher-order-translation regulatory mechanism in a metazoan whereby ribosome biogenesis genes communicate with genes controlling tRNA abundance matching the global rate of protein synthesis with available resources.

RevDate: 2020-11-06

Chou EL, Pettinger M, Haring B, et al (2020)

Association of Premature Menopause With Risk of Abdominal Aortic Aneurysm in the Women's Health Initiative.

Annals of surgery [Epub ahead of print].

OBJECTIVE: To determine if premature menopause and early menarche are associated with increased risk of AAA, and to explore potential effect modification by smoking history.

SUMMARY OF BACKGROUND DATA: Despite worse outcomes for women with AAA, no studies have prospectively examined sex-specific risk factors, such as premature menopause and early menarche, with risk of AAA in a large, ethnically diverse cohort of women.

METHODS: This was a post-hoc analysis of Women's Health Initiative participants who were beneficiaries of Medicare Parts A&B fee-for-service. AAA cases and interventions were identified from claims data. Follow-up period included Medicare coverage until death, end of follow-up or end of coverage inclusive of 2017.

RESULTS: Of 101,119 participants included in the analysis, the mean age was 63 years and median follow-up was 11.3 years. Just under 10,000 (9.4%) women experienced premature menopause and 22,240 (22%) experienced early menarche. Women with premature menopause were more likely to be overweight, Black, have ≥20 pack years of smoking, history of cardiovascular disease, hypertension, and early menarche. During 1,091,840 person-years of follow-up, 1125 women were diagnosed with AAA, 134 had premature menopause (11.9%), 93 underwent surgical intervention and 45 (48%) required intervention for ruptured AAA. Premature menopause was associated with increased risk of AAA [hazard ratio 1.37 (1.14, 1.66)], but the association was no longer significant after multivariable adjustment for demographics and cardiovascular disease risk factors. Amongst women with ≥20 pack year smoking history (n = 19,286), 2148 (11.1%) had premature menopause, which was associated with greater risk of AAA in all models [hazard ratio 1.63 (1.24, 2.23)]. Early menarche was not associated with increased risk of AAA.

CONCLUSIONS: This study finds that premature menopause may be an important risk factor for AAA in women with significant smoking history. There was no significant association between premature menopause and risk of AAA amongst women who have never smoked. These results suggest an opportunity to develop strategies for better screening, risk reduction and stratification, and outcome improvement in the comprehensive vascular care of women.

RevDate: 2020-11-06

Schenk JM, Newcomb LF, Zhu K, et al (2020)

Re: African American Race is Not Associated with Risk of Reclassification during Active Surveillance: Results from the Canary Prostate Cancer Active Surveillance Study.

The Journal of urology [Epub ahead of print].

RevDate: 2020-11-06

Granot-Hershkovitz E, Tarraf W, Kurniansyah N, et al (2020)

APOE alleles' association with cognitive function differs across Hispanic/Latino groups and genetic ancestry in the study of Latinos-investigation of neurocognitive aging (HCHS/SOL).

Alzheimer's & dementia : the journal of the Alzheimer's Association [Epub ahead of print].

INTRODUCTION: Apolipoprotein E (APOE) alleles are associated with cognitive decline, mild cognitive impairment (MCI), and Alzheimer's disease in Whites, but have weaker and inconsistent effects reported in Latinos. We hypothesized that this heterogeneity is due to ancestry-specific genetic effects.

METHODS: We investigated the associations of the APOE alleles with significant cognitive decline and MCI in 4183 Latinos, stratified by six Latino backgrounds, and explored whether the proportion of continental genetic ancestry (European, African, and Amerindian) modifies these associations.

RESULTS: APOE ε4 was associated with an increased risk of significant cognitive decline (odds ratio [OR] = 1.15, P-value = 0.03), with the strongest association in Cubans (OR = 1.46, P-value = 0.007). APOE-ε2 was associated with decreased risk of MCI (OR = 0.37, P-value = 0.04) in Puerto Ricans. Amerindian genetic ancestry was found to protect from the risk conferred by APOE ε4 on significant cognitive decline.

DISCUSSION: Results suggest that APOE alleles' effects on cognitive outcomes differ across six Latino backgrounds and are modified by continental genetic ancestry.

RevDate: 2020-11-06

Amundsen SK, Taylor AF, GR Smith (2020)

Chi hotspot control of RecBCD helicase-nuclease by long-range intramolecular signaling.

Scientific reports, 10(1):19415 pii:10.1038/s41598-020-73078-0.

Repair of broken DNA by homologous recombination requires coordinated enzymatic reactions to prepare it for interaction with intact DNA. The multiple activities of enterobacterial RecBCD helicase-nuclease are coordinated by Chi recombination hotspots (5' GCTGGTGG 3') recognized during DNA unwinding. Chi is recognized in a tunnel in RecC but activates the RecB nuclease, > 25 Ǻ away. How the Chi-dependent signal travels this long distance has been unknown. We found a Chi hotspot-deficient mutant in the RecB helicase domain located > 45 Ǻ from both the Chi-recognition site and the nuclease active site. This unexpected observation led us to find additional mutations that reduced or eliminated Chi hotspot activity in each subunit and widely scattered throughout RecBCD. Each mutation alters the intimate contact between one or another pair of subunits in crystal or cryoEM structures of RecBCD bound to DNA. Collectively, these mutations span a path about 185 Ǻ long from the Chi recognition site to the nuclease active site. We discuss these surprising results in the context of an intramolecular signal transduction accounting for many previous observations.

RevDate: 2020-11-05

Horwitz SM, Ansell S, Ai WZ, et al (2020)

NCCN Guidelines Insights: T-Cell Lymphomas, Version 1.2021.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(11):1460-1467 pii:jnccnGLINS1811.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

RevDate: 2020-11-05

Nabors LB, Portnow J, Ahluwalia M, et al (2020)

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(11):1537-1570 pii:jnccnGLS1811.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

RevDate: 2020-11-04

Epplein M, Le Marchand L, Cover TL, et al (2020)

Association of Combined Sero-Positivity to Helicobacter pylori and Streptococcus gallolyticus with Risk of Colorectal Cancer.

Microorganisms, 8(11): pii:microorganisms8111698.

Previously, we found that risk of colorectal cancer (CRC) is increased in individuals with serum antibody response to both Helicobacter pylori (HP) Vacuolating Cytotoxin (VacA) toxin or Streptococcus gallolyticus (SGG) pilus protein Gallo2178. In the present analysis, we tested the hypothesis that combined seropositivity to both antigens is a better indicator of CRC risk than seropositivity to single antigens. We used multiplex serologic assays to analyze pre-diagnostic serum for antibody responses from 4063 incident CRC cases and 4063 matched controls from 10 US cohorts. To examine whether combined SGG Gallo2178 and HP VacA sero-status was associated with CRC risk, we used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to dual sero-negative individuals, there was no increased risk for individuals sero-positive to SGG Gallo2178 only (OR: 0.93; 95% CI: 0.66-1.31) or to HP VacA only (OR: 1.08; 95% CI: 0.98-1.19). However, dual sero-positive individuals had a >50% increased odds of developing CRC (OR: 1.54; 95% CI: 1.16-2.04), suggesting an interaction between antibody responses to these two pathogens and CRC risk (pinteraction = 0.06). In conclusion, this study suggests that dual sero-positivity to HP VacA and SGG Gallo2178 is an indicator of increased risk of CRC.

RevDate: 2020-11-05

Soria F, Black PC, Fairey AS, et al (2020)

Neoadjuvant chemotherapy plus radical cystectomy versus radical cystectomy alone in clinical T2 bladder cancer without hydronephrosis.

BJU international [Epub ahead of print].

OBJECTIVES: To assess the efficacy of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in a retrospective multicenter patient cohort of patients with cT2N0M0 BCa without preoperative hydronephrosis.

MATERIALS AND METHODS: This was a propensity-based analysis of 619 patients. Of these, 316 were treated with NAC followed by RC and 303 with upfront RC. After multiple imputations, inverse probability of treatment weighting (IPTW) was used to account for potential selection bias. Multivariable logistic regression analysis was performed to evaluate the impact of NAC on pathologic complete response and downstaging at RC, while IPTW-adjusted Kaplan-Meier curves and Cox regression models were built to evaluate the impact of NAC on overall survival (OS).

RESULTS: After IPTW-adjusted analysis, standardized differences between groups were less than 15%. A complete response (pT0N0) at final pathology was achieved in 94 (30%) patients receiving NAC and 9 (3%) patients undergoing upfront RC. Downstaging to non-muscle invasive disease (
CONCLUSIONS: In patients with cT2N0 BCa and no preoperative hydronephrosis, NAC increased the rate of pathologic complete response and downstaging.

RevDate: 2020-11-05

Reddy P, Davies S, Majhail N, et al (2020)

In response to "American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults".

Blood advances, 4(21):5431-5432.

RevDate: 2020-11-05

Gralow JR, Asirwa FC, Bhatt AS, et al (2020)

Recommendations from the ASCO Academic Global Oncology Task Force.

JCO global oncology, 6:1666-1673.

In recognition of the rising incidence and mortality of cancer in low- and middle-resource settings, as well as the increasingly international profile of its membership, ASCO has prioritized efforts to enhance its engagement at a global level. Among the recommendations included in the 2016 Global Oncology Leadership Task Force report to the ASCO Board of Directors was that ASCO should promote the recognition of global oncology as an academic field. The report suggested that ASCO could serve a role in transitioning global oncology from an informal field of largely voluntary activities to a more formal discipline with strong research and well-defined training components. As a result of this recommendation, in 2017, ASCO formed the Academic Global Oncology Task Force (AGOTF) to guide ASCO's contributions toward formalizing the field of global oncology. The AGOTF was asked to collect and analyze key issues and barriers toward the recognition of global oncology as an academic discipline, with an emphasis on training, research, and career pathways, and produce a set of recommendations for ASCO action. The outcome of the AGOTF was the development of recommendations designed to advance the status of global oncology as an academic discipline.

RevDate: 2020-11-05

Simon MS, Hastert TA, Barac A, et al (2020)

Cardiometabolic risk factors and survival after cancer in the Women's Health Initiative.

Cancer [Epub ahead of print].

BACKGROUND: Cardiometabolic abnormalities are a leading cause of death among women, including women with cancer.

METHODS: This study examined the association between prediagnosis cardiovascular health and total and cause-specific mortality among 12,076 postmenopausal women who developed local- or regional-stage invasive cancer in the Women's Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity-related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non-Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival.

RESULTS: After a median follow-up of 10.0 years from the date of the cancer diagnosis, there were 3607 total deaths, with 1546 (43%) due to cancer. Most participants (62.9%) had 1 or 2 cardiometabolic risk factors, and 8.1% had 3 or 4. In adjusted models, women with 3 to 4 risk factors (vs none) had a higher risk of all-cause mortality (HR, 1.99; 95% CI, 1.73-2.30), death due to cardiovascular disease (CVD) (HR, 4.01; 95% CI, 2.88-5.57), cancer-specific mortality (HR, 1.37; 95% CI, 1.1-1.72), and other-cause mortality (HR, 2.14; 95% CI, 1.70-2.69). A higher waist circumference was associated with greater all-cause mortality (HR, 1.17; 95% CI, 1.06-1.30) and cancer-specific mortality (HR, 1.22; 95% CI, 1.04-1.42).

CONCLUSIONS: Among postmenopausal women diagnosed with cancer in the WHI, cardiometabolic risk factors before the cancer diagnosis were associated with greater all-cause, CVD, cancer-specific, and other-cause mortality. These results raise hypotheses regarding potential clinical intervention strategies targeting cardiometabolic abnormalities that require future prospective studies for confirmation.

LAY SUMMARY: This study uses information from the Women's Health Initiative (WHI) to find out whether cardiac risk factors are related to a greater risk of dying among older women with cancer. The WHI is the largest study of medical problems faced by older women in this country. The results show that women who have 3 or 4 risk factors are more likely to die of any cause, heart disease, or cancer in comparison with women with no risk factors. It is concluded that interventions to help to lower the burden of cardiac risk factors can have an important impact on survivorship among women with cancer.

RevDate: 2020-11-05

Jensen K, Konnick EQ, Schweizer MT, et al (2020)

Association of Clonal Hematopoiesis in DNA Repair Genes With Prostate Cancer Plasma Cell-free DNA Testing Interference.

JAMA oncology pii:2772786 [Epub ahead of print].

Importance: Cell-free DNA (cfDNA) testing is increasingly used in the treatment of patients with advanced prostate cancer. Clonal hematopoiesis of indeterminate potential (CHIP) can interfere with cfDNA testing and cause incorrect interpretation of results. There is an urgent need to better understand this problem following recent US Food and Drug Administration approval of poly(ADP) ribose polymerase inhibitors (PARPi) for metastatic prostate cancer based on variants in DNA repair genes that can be affected by CHIP.

Objective: To determine the prevalence of clinically relevant CHIP interference in prostate cancer cfDNA testing.

We report a case series of 69 patients with advanced prostate cancer (metastatic disease or with rising PSA following localized therapy) who had cfDNA variant testing with a large panel cancer next generation sequencing assay (UW-OncoPlexCT). To determine the source of variants in plasma, we tested paired cfDNA and whole blood control samples. The study was carried out in an academic medical center system reference laboratory.

Main Outcomes and Measures: Prevalence and gene spectrum of CHIP interference in patients with prostate cancer undergoing cfDNA testing.

Results: We detected CHIP variants at 2% or more variant fraction in cfDNA from 13 of 69 men with prostate cancer (19%; 95% CI, 10%-30%). Seven men (10%; 95% CI, 4%-20%) had CHIP variants in DNA repair genes used to determine PARPi candidacy, including ATM (n = 5), BRCA2 (n = 1), and CHEK2 (n = 1). Overall, CHIP variants accounted for almost half of the somatic DNA repair gene variants detected. Participant CHIP variants were exponentially correlated with older age (R2 = 0.82). CHIP interference variants could be distinguished from prostate cancer variants using a paired whole-blood control.

Conclusions and Relevance: In this case series, approximately 10% of men with advanced prostate cancer had CHIP interference in plasma cfDNA in DNA repair genes that are used for eligibility of PARPi therapy, most frequently in ATM. Clinical cfDNA testing should include a paired whole-blood control to exclude CHIP variants and avoid misdiagnosis.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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