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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 09 Apr 2020 at 01:41 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®)

RevDate: 2020-04-08

Burroughs L, Petrovic A, Brazauskas R, et al (2020)

Excellent Outcomes Following Hematopoietic Cell Transplantation for Wiskott-Aldrich Syndrome: A PIDTC Report.

Blood pii:454301 [Epub ahead of print].

Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. Here we report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers between 2005 and 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs. ≥5 years old at the time of HCT (94% vs. 66%, overall p=0.0008). OS was excellent regardless of donor type even in cord blood recipients (90%). Conditioning intensity did not impact OS, but was associated with donor T-cell and myeloid engraftment post-HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early post-HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) versus low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005 compared to prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution following either myeloablative or busulfan-containing reduced intensity conditioning. (www.clinicaltrials.gov NCT02064933.).

RevDate: 2020-04-08

Dolina JS, Lee J, Griswold RQ, et al (2020)

TLR9 Sensing of Self-DNA Controls Cell-Mediated Immunity to Listeria Infection via Rapid Conversion of Conventional CD4+ T Cells to Treg.

Cell reports, 31(1):107249.

CD4+ T lymphocytes are crucial for controlling a range of innate and adaptive immune effectors. For CD8+ cytotoxic T lymphocyte (CTL) responses, CD4+ T cells can function as helpers (TH) to amplify magnitude and functionality or as regulatory cells (Treg) capable of profound inhibition. It is unclear what determines differentiation to these phenotypes and whether pathogens provoke alternate programs. We find that, depending on the size of initial dose, Listeria infection drives CD4+ T cells to act as TH or induces rapid polyclonal conversion to immunosuppressive Treg. Conversion to Treg depends on the TLR9 and IL-12 pathways elicited by CD8α+ dendritic cell (DC) sensing of danger-associated neutrophil self-DNA. These findings resolve long-standing questions regarding the conditional requirement for TH amongst pathogens and reveal a remarkable degree of plasticity in the function of CD4+ T cells, which can be quickly converted to Tregin vivo by infection-mediated immune modulation.

RevDate: 2020-04-08

Mair F, Erickson JR, Voillet V, et al (2020)

A Targeted Multi-omic Analysis Approach Measures Protein Expression and Low-Abundance Transcripts on the Single-Cell Level.

Cell reports, 31(1):107499.

High-throughput single-cell RNA sequencing (scRNA-seq) has become a frequently used tool to assess immune cell heterogeneity. Recently, the combined measurement of RNA and protein expression was developed, commonly known as cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). Acquisition of protein expression data along with transcriptome data resolves some of the limitations inherent to only assessing transcripts but also nearly doubles the sequencing read depth required per single cell. Furthermore, there is still a paucity of analysis tools to visualize combined transcript-protein datasets. Here, we describe a targeted transcriptomics approach that combines an analysis of over 400 genes with simultaneous measurement of over 40 proteins on 2 × 104 cells in a single experiment. This targeted approach requires only about one-tenth of the read depth compared to a whole-transcriptome approach while retaining high sensitivity for low abundance transcripts. To analyze these multi-omic datasets, we adapted one-dimensional soli expression by nonlinear stochastic embedding (One-SENSE) for intuitive visualization of protein-transcript relationships on a single-cell level.

RevDate: 2020-04-08

Verneris MR, Miller JS, Hsu KC, et al (2020)

Investigation of donor KIR content and matching in children undergoing hematopoietic cell transplantation for acute leukemia.

Blood advances, 4(7):1350-1356.

Multiple models of donor killer immunoglobulin receptor (KIR) alloreactivity or KIR genotype have been reported to be protective against leukemia relapse after allogeneic transplantation. However, few studies have addressed this topic in the pediatric population. Here, we assessed the outcomes of allogeneic transplantation in children with acute lymphoblastic leukemia (ALL; n = 372) or acute myeloid leukemia (AML; n = 344) who received unrelated donor (URD) transplantation and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2005 to 2016. As expected in this pediatric population, most patients underwent myeloablative conditioning while in remission and with bone marrow as a stem cell source. We tested KIR ligand mismatch, KIR gene content (centromeric [Cen] B), KIR2DS1 mismatching, and Cen B/telomeric A using Cox regression models and found that none were significantly associated with either relapse or disease-free survival when considering the entire cohort of patients (ALL and AML), AML, or ALL separately. Moreover, there was no significant association with outcomes in the in vivo T-cell-depleted (ie, serotherapy) cohort. This study, which is the largest analysis of donor KIR in the pediatric acute leukemia population, does not support the use of KIR in the selection of URDs for children undergoing T-replete transplantation.

RevDate: 2020-04-08

Cortes JE, Jiang Q, Wang J, et al (2020)

Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study.

Leukemia pii:10.1038/s41375-020-0805-1 [Epub ahead of print].

Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.

RevDate: 2020-04-08

Tettamanti Boshier FA, Srinivasan S, Lopez A, et al (2020)

Complementing 16S rRNA Gene Amplicon Sequencing with Total Bacterial Load To Infer Absolute Species Concentrations in the Vaginal Microbiome.

mSystems, 5(2): pii:5/2/e00777-19.

Whereas 16S rRNA gene amplicon sequencing quantifies relative abundances of bacterial taxa, variation in total bacterial load between samples restricts its ability to reflect absolute concentrations of individual bacterial species. Quantitative PCR (qPCR) can quantify individual species, but it is not practical to develop a suite of qPCR assays for every bacterium present in a diverse sample. We sought to determine the accuracy of an inferred measure of bacterial concentration using total bacterial load and relative abundance. We analyzed 1,320 samples from 20 women with a history of frequent bacterial vaginosis who self-collected vaginal swabs daily over 60 days. We inferred bacterial concentrations by taking the product of species relative abundance (assessed by 16S rRNA gene amplicon sequencing) and bacterial load (measured by broad-range 16S rRNA gene qPCR). Log10-converted inferred concentrations correlated with targeted qPCR (r = 0. 935, P < 2.2e-16) for seven key bacterial species. The mean inferred concentration error varied across bacteria, with rarer bacteria associated with larger errors. A total of 92% of the >0.5-log10 errors occurred when the relative abundance was <10%. Many errors occurred during early bacterial expansion from or late contraction to low abundance. When the relative abundance of a species is >10%, inferred concentrations are reliable proxies for targeted qPCR in the vaginal microbiome. However, targeted qPCR is required to capture bacteria at low relative abundance and is preferable for characterizing growth and decay kinetics of single species.IMPORTANCE Microbiome studies primarily use 16S rRNA gene amplicon sequencing to assess the relative abundance of bacterial taxa in a community. However, these measurements do not accurately reflect absolute taxon concentrations. We sought to determine whether the product of species' relative abundance and total bacterial load measured by broad-range qPCR is an accurate proxy for individual species' concentrations, as measured by taxon-specific qPCR assays. Overall, the inferred bacterial concentrations were a reasonable proxy of species-specific qPCR values, particularly when bacteria are present at a higher relative abundance. This approach offers an opportunity to assess the concentrations of bacterial species and how they change in a community over time without developing individual qPCR assays for each taxon.

RevDate: 2020-04-08

Richardson D, Crossnohere NL, Seo J, et al (2020)

Age at Diagnosis and Patient Preferences for Treatment Outcomes in AML: A Discrete Choice Experiment to Explore Meaningful Benefits.

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-19-1277 [Epub ahead of print].

BACKGROUND: The recent expansion of treatment options in acute myeloid leukemia (AML) has necessitated a greater understanding of patient preferences for treatment benefits about which little is known.

METHODS: We sought to quantify and assess heterogeneity of the preferences of AML patients for treatment outcomes. An AML-specific discrete choice experiment (DCE) was developed involving multiple stakeholders. Attributes included in the DCE were event-free survival (EFS), complete remission (CR), time in the hospital, short-term side effects, and long-term side effects. Continuously coded conditional, stratified, and latent-class logistic regressions were used to model preferences of 294 patients with AML.

RESULTS: Most patients were white (89.4%) and in remission (95.0%). A 10% improvement in the chance of CR was the most meaningful offered benefit (P < 0.001). Patients were willing to trade up to 22 months of EFS or endure 8.7 months in the hospital or a two-step increase in long-term side effects to gain a 10% increase in chance of CR. Patients diagnosed at 60 years or older (21.6%) more strongly preferred to avoid short-term side effects (P = 0.03). Latent class analysis showed significant differences of preferences across gender and insurance status.

CONCLUSIONS: In this national sample of mostly AML survivors, patients preferred treatments that maximized chance at remission; however, significant preference heterogeneity for outcomes was identified. Age and gender may affect patients' preferences.

IMPACT: Survivor preferences for outcomes can inform patient-focused drug development and shared decision-making. Further studies are necessary to investigate the use of DCEs to guide treatment for individual patients.

RevDate: 2020-04-08

Figlin RA, Tannir NM, Uzzo RG, et al (2020)

Results of the ADAPT Trial; a Randomized Phase III Study of Rocapuldencel-T an Autologous Dendritic Cell-Based Vaccine, in Combination with Sunitinib as First-line Therapy in Patients with Groups Metastatic Clear-Cell Renal Cell Carcinoma.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-2427 [Epub ahead of print].

PURPOSE: Rocapuldencel-T is an autologous immunotherapy prepared from mature monocyte-derived dendritic cells (DC), coelectroporated with amplified tumor RNA plus CD40L RNA. This pivotal phase III trial was initiated to investigate the safety and efficacy of a combination therapy dosing regimen of Rocapuldencel-T plus sunitinib in patients with metastatic renal cell carcinoma (mRCC).

PATIENTS AND METHODS: Patients received either Rocapuldencel-T plus standard of care (SOC) or SOC treatment alone. The primary objective compared overall survival (OS) between groups. Secondary objectives included safety assessments, progression-free survival (PFS), and tumor responses based on RECIST 1.1 criteria. Exploratory analyses included immunologic assessments and correlates with OS.

RESULTS: Between 2013 and 2016, 462 patients were randomized 2:1, 307 to the combination group and 155 to the SOC group. Median OS in the combination group was 27.7 months [95% confidence interval (CI) 23.0-35.9] and 32.4 months (95% CI, 22.5-) in the SOC group HR of 1.10 (95% CI, 0.83-1.40). PFS was 6.0 months and 7.83 months for the combination and SOC groups, respectively [HR = 1.15 (95% CI, 0.92-1.44)]. The ORR was 42.7% (95% CI, 37.1-48.4) for the combination group and 39.4% (95% CI, 31.6-47.5) for the SOC group. Median follow up was 29 months (0.4-47.7 months). On the basis of the lack of clinical efficacy, the ADAPT trial was terminated on February 17, 2017. Immune responses were detected in 70% of patients treated with Rocapuldencel-T, and the magnitude of the immune response positively correlated with OS. In addition, we report the survival-predictive value of measuring IL-12 produced by the DC vaccine and the observation that high baseline numbers of T regulatory cells are associated with improved outcomes in DC-treated patients, but are associated with poor outcomes in patients receiving SOC treatment. No serious adverse events attributed to the study medication have been reported to date.

CONCLUSIONS: Rocapuldencel-T did not improve OS in patients treated with combination therapy, although the induced immune response correlated with OS. Moreover, we identified two potential survival-predictive biomarkers for patients receiving DC based immunotherapy, IL-12 produced by the DC vaccine and higher numbers of T regulatory cells present in the peripheral blood of patients with advanced RCC.

RevDate: 2020-04-07

Vetter C, VoPham T, Wright KP, et al (2020)

Response to Martín-Olalla.

Current biology : CB, 30(7):R300-R301.

Vetter et al. respond to Martín-Olalla's comment about their study linking motor vehicle fatalities to the transition to Daylight Saving Time.

RevDate: 2020-04-07

Pergam SA (2020)

Before the Flood.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5816959 [Epub ahead of print].

RevDate: 2020-04-04

Zhao LP, Papadopoulos GK, Kwok WW, et al (2020)

Motifs of Three HLA-DQ Amino Acid Residues (α44, β57, β135) Capture Full Association with the Risk of Type 1 Diabetes in DQ2 and DQ8 Children.

Diabetes pii:db20-0075 [Epub ahead of print].

HLA-DQA1 and -DQB1 are strongly associated with type 1 diabetes (T1D), and DQ8.1 and DQ2.5 are major risk haplotypes. Next generation targeted sequencing of HLA-DQA1 and -DQB1 in Swedish newly diagnosed 1-18 year-old patients (n=962) and controls (n=636) was used to construct abbreviated DQ haplotypes, converted into amino acid (AA) residues, and assessed for their associations with T1D. A hierarchically-organized haplotype (HOH) association analysis, allowed 45 unique DQ haplotypes to be categorized into seven clusters. The DQ8/9 cluster included two DQ8.1 risk and the DQ9 resistant haplotypes, and the DQ2 cluster, included the DQ2.5 risk and DQ2.2 resistant haplotypes. Within each cluster, HOH found residues α44Q (OR 3.29, p=2.38*10-85) and β57A (OR 3.44, p=3.80*10-84) to be associated with T1D in the DQ8/9 cluster representing all ten residues (α22, α23, α44, α49, α51, α53, α54, α73, α184, β57) due to complete linkage-disequilibrium (LD) of α44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found α44C and β135D to share the risk for T1D (OR 2.10, p=1.96*10-20). The motif "QAD" of α44, β57, and β135 captured the T1D risk association of DQ8.1 (OR 3.44, p=3.80*10-84), the corresponding motif "CAD" captured the risk association of DQ2.5 (OR 2.10, p=1.96*10-20). Two risk associations were related to GADA and IA-2A, but in opposite directions. "CAD" was positively associated with GADA (OR 1.56; p=6.35*10-8) but negatively with IA-2A (OR 0.59, p= 6.55*10-11). "QAD" was negatively associated with GADA (OR 0.88; p= 3.70*10-3) but positively with IA-2A (OR 1.64; p= 2.40*10-14), despite a single difference at α44. The residues are found in and around anchor pockets 1 and 9, as potential TCR contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AA (α44, β57, β135) conferring T1D risk should sharpen functional and translational studies.

RevDate: 2020-04-06

Daugherty SE, Wright JL, Black A, et al (2020)

Self-reported Prostate Cancer Progression Status Is Accurate: A Validation Study.

Epidemiology (Cambridge, Mass.), 31(3):441-447.

BACKGROUND: Studies of prostate cancer progression are important for discovering risk factors that may increase the risk of prostate cancer-specific death; however, little is known about the validity of self-reported prostate cancer progression.

METHODS: We conducted a validation study of self-reported prostate cancer progression in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and in a prostate cancer cohort enrolled in a Fred Hutchinson Cancer Research Center (FHCRC)-based study. We calculated measures of validity for self-reported progression, including sensitivity, specificity, positive predictive value, and negative predictive value using medical records as the gold standard.

RESULTS: Our results suggest that ascertaining prostate cancer progression-related events (i.e., prostate-specific antigen elevation, recurrence, metastasis, and use of secondary treatment) through self-report may be a viable option for identifying men whose disease has progressed after diagnosis or initial therapy, particularly when multiple questions related to progression are included in the assessment (aggregate cluster of questions: sensitivity = 0.76 [PLCO]; 0.93 [FHCRC], specificity = 0.80 [PLCO]; 0.97 [FHCRC]). With an aggregate positive predictive value of 0.50 (PLCO), however, our PLCO results suggest that additional medical record verification of self-reported progression events may be necessary to rule out false positives. Most individuals reporting no evidence of progression-related events, however, were true negatives (aggregate negative predictive value = 0.92 [PLCO]; 0.98 [FHCRC]). Thus, there may be limited utility to investing resources in chart review to confirm self-reported nonevents.

CONCLUSION: Ascertaining prostate cancer progression through self-report provides an efficient and valid approach to enhancing existing cancer cohorts with updated data on progression status. See video abstract at, http://links.lww.com/EDE/B658.

RevDate: 2020-04-06

Reding KW, Aragaki AK, Cheng RK, et al (2020)

Cardiovascular Outcomes in Relation to Antihypertensive Medication Use in Women with and Without Cancer: Results from the Women's Health Initiative.

The oncologist [Epub ahead of print].

BACKGROUND: Recent clinical trials have evaluated angiotensin-converting enzyme (ACE) inhibitors (ACEis), angiotensin receptor blockers (ARBs), and beta blockers (BBs) in relation to cardiotoxicity in patients with cancer, typically defined by ejection fraction declines. However, these trials have not examined long-term, hard clinical endpoints. Within a prospective study, we examined the risk of heart failure (HF) and coronary heart disease (CHD) events in relation to use of commonly used antihypertensive medications, including ACEis/ARBs, BBs, calcium channel blockers (CCB), and diuretics, comparing women with and without cancer.

MATERIALS AND METHODS: In a cohort of 56,997 Women's Health Initiative study participants free of cardiovascular disease who received antihypertensive treatment, we used multivariable-adjusted Cox regression models to calculate the hazard ratios (HRs) of developing CHD, HF, and a composite outcome of cardiac events (combining CHD and HF) in relation to use of ACEis/ARBs, CCBs, or diuretics versus BBs, separately in women with and without cancer.

RESULTS: Whereas there was no difference in risk of cardiac events comparing ACEi/ARB with BB use among cancer-free women (HR = 0.99 [0.88-1.12]), among cancer survivors ACEi/ARB users were at a 2.24-fold risk of total cardiac events (1.18-4.24); p-interaction = .06). When investigated in relation to CHD only, an increased risk was similarly observed in ACEi/ARB versus BB use for cancer survivors (HR = 1.87 [0.88-3.95]) but not in cancer-free women (HR = 0.91 [0.79-1.06]; p-interaction = .04). A similar pattern was also seen in relation to HF but did not reach statistical significance (p-interaction = .23).

CONCLUSION: These results from this observational study suggest differing risks of cardiac events in relation to antihypertensive medications depending on history of cancer. Although these results require replication before becoming actionable in a clinical setting, they suggest the need for more rigorous examination of the effect of antihypertensive choice on long-term cardiac outcomes in cancer survivors.

IMPLICATIONS FOR PRACTICE: Although additional research is needed to replicate these findings, these data from a large, nationally representative sample of postmenopausal women indicate that beta blockers are favorable to angiotensin-converting enzyme inhibitors in reducing the risk of cardiac events among cancer survivors. This differs from the patterns observed in a noncancer cohort, which largely mirrors what is found in the randomized clinical trials in the general population.

RevDate: 2020-04-06

Lyman GH, Nguyen A, Snyder S, et al (2020)

Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma.

JAMA network open, 3(4):e202072 pii:2763968.

Importance: Chimeric antigen receptor (CAR) T-cell therapies are currently administered at a limited number of cancer centers and are primarily delivered in an inpatient setting. However, variations in total costs associated with these therapies remain unknown.

Objective: To estimate the economic differences in the administration of CAR T-cell therapy by the site of care and the incidence of key adverse events.

A decision-tree model was designed to capture clinical outcomes and associated costs during a predefined period (from lymphodepletion to 30 days after the receipt of CAR T-cell infusion) to account for the potential incidence of acute adverse events and to evaluate variations in total costs for the administration of CAR T-cell therapy by site of care. Cost estimates were from the health care practitioner perspective and were based on data obtained from the literature and publicly available databases, including the Healthcare Cost and Utilization Project National Inpatient Sample, the Medicare Hospital Outpatient Prospective Payment System, the Medicare physician fee schedule, the Centers for Medicare and Medicaid Services Healthcare Common Procedure Coding System, and the IBM Micromedex RED BOOK. The model evaluated an average adult patient with relapsed or refractory large B-cell lymphoma who received CAR T-cell therapy in an academic inpatient hospital or nonacademic specialty oncology network.

Intervention: The administration of CAR T-cell therapy.

Main Outcomes and Measures: Total cost of the administration of CAR T-cell therapy by site of care. The costs associated with lymphodepletion, acquisition and infusion of CAR T cells, and management of acute adverse events were also examined.

Results: The estimated total cost of care associated with the administration of CAR T-cell therapy was $454 611 (95% CI, $452 466-$458 267) in the academic hospital inpatient setting compared with $421 624 (95% CI, $417 204-$422 325) in the nonacademic specialty oncology network setting, for a difference of $32 987. After excluding the CAR T-cell acquisition cost, hospitalization and office visit costs were $53 360 (65.3% of the total cost) in academic inpatient hospitals and $23 526 (48.4% of the total cost) in nonacademic specialty oncology networks. The administration of CAR T-cell therapy in nonacademic specialty oncology networks was associated with a $29 834 (55.9%) decrease in hospitalization and office visit costs and a $3154 (20.1%) decrease in procedure costs.

Conclusions and Relevance: The potential availability of CAR T-cell therapies that are associated with a lower incidence of adverse events and are suitable for outpatient administration may reduce the total costs of care by enabling the use of these therapies in nonacademic specialty oncology networks.

RevDate: 2020-04-06

Walter RB, EH Estey (2020)

Selection of initial therapy for newly-diagnosed adult acute myeloid leukemia: Limitations of predictive models.

Blood reviews pii:S0268-960X(20)30029-1 [Epub ahead of print].

Acute myeloid leukemia (AML) remains difficult to treat: despite multiagent chemotherapy, allogeneic hematopoietic cell transplantation, and several newly approved agents, many patients will not be alive and in remission 3 years after diagnosis. However, with more agents available there are more options and a corresponding need to choose among them. Doing so is complicated by the molecular diversity of AML and the older age of many patients, predisposing them to both treatment-related mortality and, more commonly, resistance to treatment. There is no shortage of scoring systems to identify patients at high risk of early death or treatment resistance after conventional AML induction chemotherapy. As we point out here, their accuracy is limited. Furthermore, without periodic recalibration to account for new therapies and changes in supportive care, the accuracy of any prediction model will decrease over time. The limitations we describe here are important for clinicians to be aware of.

RevDate: 2020-04-06

Hansen RN, Zhang Y, Seal B, et al (2020)

Long-term survival trends in patients with unresectable stage III non-small cell lung cancer receiving chemotherapy and radiation therapy: a SEER cancer registry analysis.

BMC cancer, 20(1):276 pii:10.1186/s12885-020-06734-3.

BACKGROUND: To evaluate the value of new therapies for non-small cell lung cancer (NSCLC), it is necessary to understand overall survival (OS) rates associated with previous standard therapies and how these rates have evolved over time.

METHODS: We retrospectively analyzed data from patients enrolled in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Adults with unresectable, stage III NSCLC treated with chemoradiotherapy were grouped by diagnosis year (2000-2002; 2003-2005; 2006-2008; 2009-2011; 2012-2013). The primary endpoint was OS (data cut-off, December 31, 2014), estimated using the Kaplan-Meier estimator. Temporal survival-trend significance was tested using a two-sided log-rank trend test.

RESULTS: Of 12,865 eligible patients, 59.1% were male, 59.9% had stage IIIB disease, and 62.7% had non-squamous histology. Median age at diagnosis was 67 years. Overall, 10,899 (84.7%) patients died and 1966 (15.3%) were censored/lost to follow-up. Median follow-up (95% confidence interval [CI]) was 80 (77-82) months; median OS (95% CI) was 15 (15-16) months; 1- and 3-year survival probabilities (95% CI) were 57.7% (56.9-58.6) and 24.1% (23.3-24.8), respectively. Stratification by diagnosis year showed consistent improvements in survival over time (p < 0.0001 for trend). Median OS was 12, 14, 15, 18, and 19 months in successive cohorts.

CONCLUSIONS: OS in patients diagnosed with unresectable, stage III NSCLC between 2003 and 2013 was consistent with that from clinical studies of sequential/concurrent chemoradiotherapy. Despite improvement over time, median OS was < 2 years and mortality remained high during the first year post-diagnosis.

RevDate: 2020-04-05

Zhang J, Litvinova M, Wang W, et al (2020)

Evolving epidemiology and transmission dynamics of coronavirus disease 2019 outside Hubei province, China: a descriptive and modelling study.

The Lancet. Infectious diseases pii:S1473-3099(20)30230-9 [Epub ahead of print].

BACKGROUND: The coronavirus disease 2019 (COVID-19) epidemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began in Wuhan city, Hubei province, in December, 2019, and has spread throughout China. Understanding the evolving epidemiology and transmission dynamics of the outbreak beyond Hubei would provide timely information to guide intervention policy.

METHODS: We collected individual information from official public sources on laboratory-confirmed cases reported outside Hubei in mainland China for the period of Jan 19 to Feb 17, 2020. We used the date of the fourth revision of the case definition (Jan 27) to divide the epidemic into two time periods (Dec 24 to Jan 27, and Jan 28 to Feb 17) as the date of symptom onset. We estimated trends in the demographic characteristics of cases and key time-to-event intervals. We used a Bayesian approach to estimate the dynamics of the net reproduction number (Rt) at the provincial level.

FINDINGS: We collected data on 8579 cases from 30 provinces. The median age of cases was 44 years (33-56), with an increasing proportion of cases in younger age groups and in elderly people (ie, aged >64 years) as the epidemic progressed. The mean time from symptom onset to hospital admission decreased from 4·4 days (95% CI 0·0-14·0) for the period of Dec 24 to Jan 27, to 2·6 days (0·0-9·0) for the period of Jan 28 to Feb 17. The mean incubation period for the entire period was estimated at 5·2 days (1·8-12·4) and the mean serial interval at 5·1 days (1·3-11·6). The epidemic dynamics in provinces outside Hubei were highly variable but consistently included a mixture of case importations and local transmission. We estimated that the epidemic was self-sustained for less than 3 weeks, with mean Rt reaching peaks between 1·08 (95% CI 0·74-1·54) in Shenzhen city of Guangdong province and 1·71 (1·32-2·17) in Shandong province. In all the locations for which we had sufficient data coverage of Rt, Rt was estimated to be below the epidemic threshold (ie, <1) after Jan 30.

INTERPRETATION: Our estimates of the incubation period and serial interval were similar, suggesting an early peak of infectiousness, with possible transmission before the onset of symptoms. Our results also indicate that, as the epidemic progressed, infectious individuals were isolated more quickly, thus shortening the window of transmission in the community. Overall, our findings indicate that strict containment measures, movement restrictions, and increased awareness of the population might have contributed to interrupt local transmission of SARS-CoV-2 outside Hubei province.

FUNDING: National Science Fund for Distinguished Young Scholars, National Institute of General Medical Sciences, and European Commission Horizon 2020.

RevDate: 2020-04-03

Chow VA, Rajendran JG, Fisher DR, et al (2020)

A Phase II Trial Evaluating The Efficacy of High-Dose Radioiodinated Tositumomab (Anti-CD20) Antibody, Etoposide and Cyclophosphamide followed by Autologous Transplantation, for High-Risk Relapsed or Refractory Non-Hodgkin's Lymphoma.

American journal of hematology [Epub ahead of print].

Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤ 25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. 107 patients were treated including aggressive lymphoma (N=29), indolent lymphoma (N=45), and MCL (N=33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared. This article is protected by copyright. All rights reserved.

RevDate: 2020-04-03

Yen HJ, Eissa H, Bhatt NS, et al (2020)

Patient-Reported Outcomes in Survivors of Childhood Hematologic Malignancies with Hematopoietic Stem Cell Transplant.

Blood pii:454260 [Epub ahead of print].

Patient-reported outcomes among survivors of pediatric hematopoietic stem cell transplant (HSCT) are understudied. We compared symptom prevalence, health-related quality of life (HRQOL), and risk factors in adult survivors of childhood hematologic malignancies treated with HSCT to those treated with conventional therapy and non-cancer controls. Survivors of childhood hematologic malignancies (HSCT N=112 [70% allogeneic, 30% autologous]; conventionally-treated N=1,106) and non-cancer controls (N=242) from the St. Jude Lifetime Cohort Study completed surveys assessing 10 symptom domains, and SF-36 HRQOL summary scores. Chronic health conditions (CHCs) were validated by clinical assessment. Multivariable logistic regression reveals that compared to non-cancer controls, HSCT survivors endorsed a significantly higher symptom prevalence in sensation (OR=4.7, 95% CI=2.6-8.4), motor/movement (OR=4.3, 95% CI=1.6-11.0), pulmonary (OR=4.6, 95% CI=1.8-11.8) and memory domains (OR=4.8, 95% CI=2.5-9.2), and poorer physical HRQOL (OR=6.9, 95% CI=2.8-17.0). HSCT and conventionally-treated survivors had a similar prevalence of all symptom domains and HRQOL (P's>0.05); however, HSCT survivors had a significantly higher cumulative prevalence for specific symptoms: double vision (P=0.04), very dry eyes (P<0.0001), and trouble seeing when wearing glasses (P<0.0001). Occurrence of organ-specific CHCs, instead of transplant receipt, was significantly associated with a higher prevalence of all symptom domains (P's<0.05) in adult survivors of childhood cancer, except for pain and anxiety domains. This study found that patient-reported outcomes were equally impaired between HSCT and conventionally-treated survivors, but poorer in both groups compared to non-cancer controls. Poor patient-reported outcomes in all survivors of childhood hematologic malignancies correlated with the presence of CHCs, whether treated with conventional therapy or HSCT.

RevDate: 2020-04-03

Gobillot TA, Kikawa C, Lehman DA, et al (2020)

Zika Virus Circulates at Low Levels in Western and Coastal Kenya.

The Journal of infectious diseases pii:5815394 [Epub ahead of print].

Zika virus (ZIKV) was discovered over 70 years ago in East Africa but little is known about its circulation and pathogenesis there. We screened 327 plasma samples collected 2-12 months after febrile illness in Western and coastal Kenya (1993-2016) for binding and neutralizing antibodies to distinguish ZIKV and Dengue virus (DENV) responses, which we found were common in coastal Kenya. Two cases had durable ZIKV-specific antibodies and two cases had ZIKV antibodies at similar levels as DENV antibodies. This suggests low-level ZIKV circulation in Kenya over two decades and sets a baseline for future surveillance efforts in East Africa.

RevDate: 2020-04-03

Dean NE, Gsell PS, Brookmeyer R, et al (2020)

Creating a Framework for Conducting Randomized Clinical Trials during Disease Outbreaks.

The New England journal of medicine, 382(14):1366-1369.

RevDate: 2020-04-03

Jaeger-Ruckstuhl CA, Hinterbrandner M, Höpner S, et al (2020)

TNIK signaling imprints CD8+ T cell memory formation early after priming.

Nature communications, 11(1):1632 pii:10.1038/s41467-020-15413-7.

Co-stimulatory signals, cytokines and transcription factors regulate the balance between effector and memory cell differentiation during T cell activation. Here, we analyse the role of the TRAF2-/NCK-interacting kinase (TNIK), a signaling molecule downstream of the tumor necrosis factor superfamily receptors such as CD27, in the regulation of CD8+ T cell fate during acute infection with lymphocytic choriomeningitis virus. Priming of CD8+ T cells induces a TNIK-dependent nuclear translocation of β-catenin with consecutive Wnt pathway activation. TNIK-deficiency during T cell activation results in enhanced differentiation towards effector cells, glycolysis and apoptosis. TNIK signaling enriches for memory precursors by favouring symmetric over asymmetric cell division. This enlarges the pool of memory CD8+ T cells and increases their capacity to expand after re-infection in serial re-transplantation experiments. These findings reveal that TNIK is an important regulator of effector and memory T cell differentiation and induces a population of stem cell-like memory T cells.

RevDate: 2020-03-31

Du Y, Wang W, Washburn DJ, et al (2020)

Violence against healthcare workers and other serious responses to medical disputes in China: surveys of patients at 12 public hospitals.

BMC health services research, 20(1):253.

BACKGROUND: Workplace violence against healthcare workers is a global issue that is on the rise, with Chinese healthcare workers facing growing challenges with hospital violence. Attacks on medical staff have increased in recent years with no clear resolution. Prior research focused on policies to improve the doctor-patient relationship and better protect clinicians, but few studies addressed the patient perspective. This paper examines patients' choices when facing a medical dispute and identifies groups who are more likely to respond to conflict with violence or other serious actions.

METHODS: Patient survey responses were collected in 12 leading public hospitals in five Chinese provinces with 5556 participants. The survey asked sociodemographic information, patients' attitudes (e.g., general optimism, trust in their physicians, perceived healthcare quality), and their primary response to a medical dispute. From least to most severe, the options range from "complaining within the family" to "violence." We used t-tests and Chi-square tests to explore the relationships between reactions and patient characteristics. We also performed multivariable logistic regressions to determine the impact of sociodemographics and provider trust on the seriousness of responses.

RESULTS: The primary response of a third of respondents was complaining to hospital or health department officials (32.5%). Seeking legal help (26.3%) and direct negotiation with doctors (19.6%) were other frequent responses. More serious responses included 83 stating violence (1.5%), 9.7% expressing a desire to expose the issue to the news media, and 7.4% resorting to seeking third-party assistance. Patients who were more likely to report "violence" were male (OR = 1.81, p < .05), high-income earners (OR = 3.71, p < .05), or reported lower life satisfaction (OR = 1.40, p < .05). Higher trust scores were associated with a lower likelihood of a serious response, including violence (OR = 0.80, p < .01).

CONCLUSION: Most respondents reported mild reactions when facing a medical dispute. Among those who reported the intent of serious reactions, some sociodemographic characteristics and the trust of physicians could be predictive. To prevent future hospital violence, this work helps identify the characteristics of patients who are more likely to seek severe approaches to medical dispute resolution, including resorting to violence. From these results, hospitals will be better able to target specific groups for interventions that build patient-provider trust and improve general patient satisfaction.

RevDate: 2020-04-02

Babic A, Sasamoto N, Rosner BA, et al (2020)

Association Between Breastfeeding and Ovarian Cancer Risk.

JAMA oncology pii:2763398 [Epub ahead of print].

Importance: Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent.

Objective: To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype.

A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019.

Exposures: Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies.

Main Outcomes and Measures: Diagnosis of epithelial ovarian cancer.

Results: A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02).

Conclusions and Relevance: Breastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.

RevDate: 2020-04-02

Cannioto RA, Hutson A, Dighe S, et al (2020)

Physical activity before, during and after chemotherapy for high-risk breast cancer: relationships with survival.

Journal of the National Cancer Institute pii:5814214 [Epub ahead of print].

BACKGROUND: Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based upon data collected at one occasion. We examined how pre- and post-diagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients.

METHODS: Included were 1,340 patients enrolled in the DELCaP Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at one-and two-year intervals after enrollment were collected. Patients were categorized according to the Physical Activity Guidelines as meeting the minimum Guidelines (yes/no) and incrementally as inactive, low-active, moderately active (meeting the Guidelines), or high-active.

RESULTS: In joint-exposure analyses, patients meeting the Guidelines before and one-year after diagnosis experienced statistically significant reductions in hazards of recurrence (HR=0.59, 95% CI: 0.42-0.82) and mortality (HR=0.51, 95% CI: 0.34-0.77); associations were stronger at two-year follow-up for recurrence (HR=0.45, 95% CI: 0.31-0.65) and mortality (HR=0.32, 95% CI: 0.19-0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI: 0.24-0.68), moderate- (HR = 0.42, 95% CI: 0.23-0.76), and high-active patients (HR=0.31, 95% CI: 0.18-0.53).

CONCLUSIONS: Meeting the minimum Guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the Guidelines.

RevDate: 2020-04-02

Krchlíková V, Fábryová H, Hron T, et al (2020)

Antiviral Activity and Adaptive Evolution of Avian Tetherins.

Journal of virology pii:JVI.00416-20 [Epub ahead of print].

Tetherin/BST-2 is an antiviral protein that blocks the release of enveloped viral particles by linking them to the membrane of producing cells. At first, BST-2 genes were described only in humans and other mammals. Recent work identified BST-2 orthologs in non-mammalian vertebrates, including birds. Here, we identify the BST-2 sequence in domestic chicken (Gallus gallus) for the first time and demonstrate its activity against Avian sarcoma and leukosis virus (ASLV). We generated BST-2 knockout in chicken cells and showed that BST-2 is a major determinant of an interferon-induced block of ASLV release. Ectopic expression of chicken BST-2 blocks the release of ASLV in chicken cells and of Human immunodeficiency virus type 1 (HIV-1) in human cells. Using metabolic labeling and pulse-chase analysis of HIV-1 Gag proteins, we verified that chicken BST-2 blocks the virus at the release stage. Further, we describe BST-2 orthologs in multiple avian species from 12 avian orders. Previously, some of these species were reported to lack BST-2, highlighting the difficulty of identifying sequences of this extremely variable gene. We analyzed BST-2 genes in the avian orders Galliformes and Passeriformes and showed that they evolve under positive selection. This indicates that avian BST-2 is involved in host-virus evolutionary arms races and suggests that BST-2 antagonists exist in some avian viruses. In summary, we show that chicken BST-2 has the potential to act as a restriction factor against ASLV. Characterizing the interaction of avian BST-2 with avian viruses is important in understanding innate antiviral defenses in birds.IMPORTANCE Birds are important hosts of viruses that have the potential to cause zoonotic infections in humans. However, only a few antiviral genes (called viral restriction factors) have been described in birds, mostly because birds lack counterparts of highly studied mammalian restriction factors. Tetherin/BST-2 is a restriction factor, originally described in humans, that blocks the release of newly formed virus particles from infected cells. Recent work identified BST-2 in non-mammalian vertebrate species, including birds. Here, we report the BST-2 sequence in domestic chicken and describe its antiviral activity against a prototypical avian retrovirus, ASLV. We also identify BST-2 genes in multiple avian species and show that they evolve rapidly in birds, which is an important indication of their relevance for antiviral defense. Analysis of avian BST-2 genes will shed light on defense mechanisms against avian viral pathogens.

RevDate: 2020-04-02

Andrews K, Hamers AAJ, Sun X, et al (2020)

Expansion and CD2/CD3/CD28 stimulation enhance Th2 cytokine secretion of human invariant NKT cells with retained anti-tumor cytotoxicity.

Cytotherapy pii:S1465-3249(20)30015-3 [Epub ahead of print].

BACKGROUND AIMS: Key obstacles in human iNKT cell translational research and immunotherapy include the lack of robust protocols for dependable expansion of human iNKT cells and the paucity of data on phenotypes in post-expanded cells.

METHODS: We delineate expansion methods using interleukin (IL)-2, IL-7 and allogeneic feeder cells and anti-CD2/CD3/CD28 stimulation by which to dependably augment Th2 polarization and direct cytotoxicity of human peripheral blood CD3+Vα24+Vβ11+ iNKT cells.

RESULTS: Gene and protein expression profiling demonstrated augmented Th2 cytokine secretion (IL-4, IL-5, IL-13) in expanded iNKT cells stimulated with anti-CD2/CD3/CD28 antibodies. Cytotoxic effector molecules including granzyme B were increased in expanded iNKT cells after CD2/CD3/CD28 stimulation. Direct cytotoxicity assays using unstimulated expanded iNKT cell effectors revealed α-galactosyl ceramide (α-GalCer)-dependent killing of the T-ALL cell line Jurkat. Moreover, CD2/CD3/CD28 stimulation of expanded iNKT cells augmented their (α-GalCer-independent) killing of Jurkat cells. Co-culture of expanded iNKT cells with stimulated responder cells confirmed contact-dependent inhibition of activated CD4+ and CD8+ responder T cells.

DISCUSSION: These data establish a robust protocol to expand and novel pathways to enhance Th2 cytokine secretion and direct cytotoxicity in human iNKT cells, findings with direct implications for autoimmunity, vaccine augmentation and anti-infective immunity, cancer immunotherapy and transplantation.

RevDate: 2020-04-02

Issaka RB, Rachocki C, Huynh MP, et al (2020)

Standardized Workflows Improve Colonoscopy Follow-Up After Abnormal Fecal Immunochemical Tests in a Safety-Net System.

Digestive diseases and sciences pii:10.1007/s10620-020-06228-z [Epub ahead of print].

BACKGROUND: How clinical teams function varies across sites and may affect follow-up of abnormal fecal immunochemical test (FIT) results.

AIMS: This study aimed to identify the characteristics of clinical practices associated with higher diagnostic colonoscopy completion after an abnormal FIT result in a multi-site integrated safety-net system.

METHODS: We distributed survey questionnaires about tracking and follow-up of abnormal FIT results to primary care team members across 11 safety-net clinics from January 2017 to April 2017. Surveys were distributed at all-staff clinic meetings and electronic surveys sent to those not in attendance. Participants received up to three reminders to complete the survey.

RESULTS: Of the 501 primary care team members identified, 343 (68.5%) completed the survey. In the four highest-performing clinics, nurse managers identified at least two team members who were responsible for communicating abnormal FIT results to patients. Additionally, team members used a clinic-based registry to track patients with abnormal FIT results until colonoscopy completion. Compared to higher-performing clinics, lower-performing clinics more frequently cited competing health issues (56% vs. 40%, p = 0.03) and lack of patient priority (59% vs. 37%, p < 0.01) as barriers and were also more likely to discuss abnormal results at a clinic visit (83% vs. 61%, p < 0.01).

CONCLUSIONS: Our findings suggest organized and dedicated efforts to communicate abnormal FIT results and track patients until colonoscopy completion through registries is associated with improved follow-up. Increased utilization of electronic health record platforms to coordinate communication and navigation may improve diagnostic colonoscopy rates in patients with abnormal FIT results.

RevDate: 2020-04-02

Chesarino NM, M Emerman (2020)

Polymorphisms in Human APOBEC3H Differentially Regulate Ubiquitination and Antiviral Activity.

Viruses, 12(4): pii:v12040378.

The APOBEC3 family of cytidine deaminases are an important part of the host innate immune defense against endogenous retroelements and retroviruses like Human Immunodeficiency Virus (HIV). APOBEC3H (A3H) is the most polymorphic of the human APOBEC3 genes, with four major haplotypes circulating in the population. Haplotype II is the only antivirally-active variant of A3H, while the majority of the population possess independently destabilizing polymorphisms present in haplotype I (R105G) and haplotypes III and IV (N15del). In this paper, we show that instability introduced by either polymorphism is positively correlated with degradative ubiquitination, while haplotype II is protected from this modification. Inhibiting ubiquitination by mutating all of the A3H lysines increased the expression of haplotypes III and IV, but these stabilized forms of haplotype III and IV had a strict nuclear localization, and did not incorporate into virions, nor exhibit antiviral activity. Fusion chimeras with haplotype II allowed for stabilization, cytoplasmic retention, and packaging of the N15del-containing haplotype III, but the haplotype III component of these chimeras was unable to restrict HIV-1 on its own. Thus, the evolutionary loss of A3H activity in many humans involves functional deficiencies independent of protein stability.

RevDate: 2020-04-02

Hammer KJ, Copeland VC, Loggers ET, et al (2020)

Doxorubicin and Olaratumab Versus Doxorubicin, Ifosfamide, and Mesna for Treatment of Advanced Soft Tissue Sarcomas.

American journal of clinical oncology [Epub ahead of print].

OBJECTIVE: We compared the outcomes in soft tissue sarcoma (STS) treated with olaratumab and doxorubicin (OD) versus doxorubicin, ifosfamide, and mesna (AIM) to assess whether OD could supersede AIM in STS therapy.

METHODS: A single-institution, retrospective study of STS treated for advanced disease with OD or AIM in 2013 to 2017 was conducted. Demographic and clinical parameters were compared by Fisher's exact test. Kaplan-Meier and Cox analyses examined progression-free survival (PFS) and overall survival (OS). Adverse events were compared.

RESULTS: Thirty patients (13 OD, 17 AIM) were included. OD was administered more commonly after first-line therapy (54% OD vs. 6% AIM, P=0.0005). The 2 groups did not differ in other parameters. Median OS [OD: 14.2 mo, 95% confidence interval (CI): 7.1-not reached; AIM 19.9 mo, 95% CI 9.5-35.5; hazard ratio: 0.99, 95% CI: 0.38-2.59, P=0.99] and PFS (OD: 2.6 mo, 95% CI: 1.3-7; AIM 6.4 mo, 95% CI: 1.5-14.5; hazard ratio: 0.57, 95% CI: 0.26-1.24, P=0.16) were not statistically different, although median values favored AIM. Grade 3 to 4 neutropenia, but not febrile neutropenia, was more frequent with OD.

CONCLUSIONS: OD and AIM did not differ with respect to either OS or PFS. Although this study's size initially appeared the most likely explanation, lack of significant activity of olaratumab was subsequently reported in the phase III trial of OD. Our results suggest that future conditional oncology drug approvals should be accompanied by mandated registries to monitor outcomes of patients treated after conditional approval, but before full approval.

RevDate: 2020-04-02

Sokolova AO, Yu EY, HH Cheng (2020)

Honing in on PARPi response in Prostate Cancer: from HR pathway- to gene-by-gene granularity.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-0707 [Epub ahead of print].

Poly-ADP-ribose-polymerase inhibitors (PARPi) are promising in BRCA2-altered prostate cancer. Data were presented on PARPi efficacy in prostate cancers with alterations in other DNA damage repair genes which suggest low response rates in ATM-, CHEK2-, CDK12-altered tumors and promising results in PALB2-, RAD51B-, FANCA-, and BRIP1-altered tumors.

RevDate: 2020-04-02

Kim RD, McDonough S, El-Khoueiry AB, et al (2020)

Randomised phase II trial (SWOG S1310) of single agent MEK inhibitor trametinib Versus 5-fluorouracil or capecitabine in refractory advanced biliary cancer.

European journal of cancer (Oxford, England : 1990), 130:219-227 pii:S0959-8049(20)30065-4 [Epub ahead of print].

BACKGROUND: The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC.

METHODS: Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm.

RESULTS: The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%-19%) in arm 1 versus 10% (95% CI 0%-23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2.

CONCLUSIONS: This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.

RevDate: 2020-04-02

Mallhi KK, Srikanthan MA, Baker KK, et al (2020)

HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Non-Malignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30176-2 [Epub ahead of print].

Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with non-malignant diseases; however, many patients do not have a human leukocyte antigen (HLA)-matched donor. Historically, poor survival was seen following HLA-haploidentical HCT due to poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T-cell replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various non-malignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n=17) or G-CSF mobilized peripheral blood stem cell (n=6) grafts following conditioning with cyclophosphamide (CY) 50 mg/kg, fludarabine 150 mg/m2, and 2 Gy or 4 Gy total body irradiation (TBI). Post-grafting immunosuppression consisted of CY, mycophenolate mofetil, tacrolimus, ± sirolimus. The median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/GVHD. The estimated probabilities of grades II-IV and III-IV acute GVHD at day 100 and 2-year NIH-consensus chronic GVHD were 78%, 26% and 42%, respectively. With a median follow-up of 2.5 years, the 2-year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease specific lineage engraftment with low TRM in patients with non-malignant diseases using nonmyeloablative conditioning followed by T-replete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention in order to make this a viable treatment approach for patients with non-malignant diseases.

RevDate: 2020-04-01

Georganaki M, Ramachandran M, Tuit S, et al (2020)

Tumor endothelial cell up-regulation of IDO1 is an immunosuppressive feed-back mechanism that reduces the response to CD40-stimulating immunotherapy.

Oncoimmunology, 9(1):1730538 pii:1730538.

CD40-stimulating immunotherapy can elicit potent anti-tumor responses by activating dendritic cells and enhancing T-cell priming. Tumor vessels orchestrate T-cell recruitment during immune response, but the effect of CD40-stimulating immunotherapy on tumor endothelial cells has not been evaluated. Here, we have investigated how tumor endothelial cells transcriptionally respond to CD40-stimulating immunotherapy by isolating tumor endothelial cells from agonistic CD40 mAb- or isotype-treated mice bearing B16-F10 melanoma, and performing RNA-sequencing. Gene set enrichment analysis revealed that agonistic CD40 mAb therapy increased interferon (IFN)-related responses in tumor endothelial cells, including up-regulation of the immunosuppressive enzyme Indoleamine 2, 3-Dioxygenase 1 (IDO1). IDO1 was predominantly expressed in endothelial cells within the tumor microenvironment, and its expression in tumor endothelium was positively correlated to T-cell infiltration and to increased intratumoral expression of IFNγ. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth in B16-F10 melanoma, associated with increased activation of tumor-infiltrating T-cells. Hereby, we show that the tumor endothelial cells up-regulate IDO1 upon CD40-stimulating immunotherapy in response to increased IFNγ-secretion by T-cells, revealing a novel immunosuppressive feedback mechanism whereby tumor vessels limit T-cell activation.

RevDate: 2020-04-01

Hosgood HD, Slavkovich V, Hua S, et al (2020)

Urinary Arsenic Species are Detectable in Urban Underserved Hispanic/Latino Populations: A Pilot Study from the Study of Latinos: Nutrition & Physical Activity Assessment Study (SOLNAS).

International journal of environmental research and public health, 17(7): pii:ijerph17072247.

BACKGROUND: Hispanics/Latinos represent >15% of the United States (US) population and experience a high burden of cardiovascular disease (CVD) and diabetes. Dietary exposure, particularly to arsenic (As), may be associated with CVD and diabetes in Hispanics/Latinos. Rural populations in the US exposed to As in drinking water have increased risk of diabetes and CVD; however, little is known about the risk among urban populations with low As in water who are mostly exposed to As through food.

METHODS: To explore the levels of inorganic arsenic exposure (the sum of inorganic and methylated arsenic species in urine, ∑As, corrected by a residual-based method) in persons of Hispanic/Latino origin, we conducted a pilot study quantifying urinary arsenic levels among 45 participants in the Study of Latinos: Nutrition & Physical Activity Assessment Study (SOLNAS).

RESULTS: The median (interquartile range) of the urinary arsenic species (µg/L) were as follows: inorganic As 0.6 (0.4, 1.0), monomethylarsonic acid 1.2 (0.7, 1.9), dimethylarsinic acid 7.2 (4.3, 15.3), and ∑As 6.0 (4.3, 10.5).

CONCLUSIONS: This study adds to the existing evidence that harmful forms of arsenic are present in this group of Hispanics/Latinos.

RevDate: 2020-04-01

Cunningham JA, Thomson RM, Murphy SC, et al (2020)

WHO malaria nucleic acid amplification test external quality assessment scheme: results of distribution programmes one to three.

Malaria journal, 19(1):129 pii:10.1186/s12936-020-03200-0.

BACKGROUND: The World Health Organization (WHO) recommends parasite-based diagnosis of malaria. In recent years, there has been surge in the use of various kinds of nucleic-acid amplification based tests (NAATs) for detection and identification of Plasmodium spp. to support clinical care in high-resource settings and clinical and epidemiological research worldwide. However, these tests are not without challenges, including lack (or limited use) of standards and lack of reproducibility, due in part to variation in protocols amongst laboratories. Therefore, there is a need for rigorous quality control, including a robust external quality assessment (EQA) scheme targeted towards malaria NAATs. To this effect, the WHO Global Malaria Programme worked with the UK National External Quality Assessment Scheme (UK NEQAS) Parasitology and with technical experts to launch a global NAAT EQA scheme in January 2017.

METHODS: Panels of NAAT EQA specimens containing five major species of human-infecting Plasmodium at various parasite concentrations and negative samples were created in lyophilized blood (LB) and dried blood spot (DBS) formats. Two distributions per year were sent, containing five LB and five DBS specimens. Samples were tested and validated by six expert referee laboratories prior to distribution. Between 37 and 45 laboratories participated in each distribution and submitted results using the online submission portal of UK NEQAS. Participants were scored based on their laboratory's stated capacity to identify Plasmodium species, and individual laboratory reports were sent which included performance comparison with anonymized peers.

RESULTS: Analysis of the first three distributions revealed that the factors that most significantly affected performance were sample format (DBS vs LB), species and parasite density, while laboratory location and the reported methodology used (type of nucleic acid extraction, amplification, or DNA vs RNA target) did not significantly affect performance. Referee laboratories performed better than non-referee laboratories.

CONCLUSIONS: Globally, malaria NAAT assays now inform a range of clinical, epidemiological and research investigations. EQA schemes offer a way for laboratories to assess and improve their performance, which is critical to safeguarding the reliability of data and diagnoses especially in situations where various NAAT methodologies and protocols are in use.

RevDate: 2020-03-31

Bhatraju PK, Ghassemieh BJ, Nichols M, et al (2020)

Covid-19 in Critically Ill Patients in the Seattle Region - Case Series.

The New England journal of medicine [Epub ahead of print].

BACKGROUND: Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020.

METHODS: We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up.

RESULTS: We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63% were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58% had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU.

CONCLUSIONS: During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.).

RevDate: 2020-03-31

Karlson CW, Alberts NM, Liu W, et al (2020)

Longitudinal pain and pain interference in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Cancer [Epub ahead of print].

BACKGROUND: The objective of this study was to characterize the prevalence and risk of pain, pain interference, and recurrent pain in adult survivors of childhood cancer in comparison with siblings.

METHODS: This study analyzed longitudinal data from survivors (n = 10,012; 48.7% female; median age, 31 years [range, 17-57 years]; median time since diagnosis, 23 years) and siblings (n = 3173) from the Childhood Cancer Survivor Study. Survivors were diagnosed between 1970 and 1986 at 1 of 26 participating sites. Associations between risk factors (demographics, cancer-related factors, and psychological symptoms) and pain, pain interference, and recurrent pain (5 years apart) were assessed with multinomial logistic regression. Path analyses examined cross-sectional associations between risk factors and pain outcomes.

RESULTS: Twenty-nine percent of survivors reported moderate to severe pain, 20% reported moderate to extreme pain interference, and 9% reported moderate to severe recurrent pain. Female sex, a sarcoma/bone tumor diagnosis, and severe/life-threatening chronic medical conditions were associated with recurrent pain. Depression and anxiety were associated with increased risk for all pain outcomes. Poor vitality mediated the effects of anxiety on high pain and pain interference (root mean square error of approximation, 0.002).

CONCLUSIONS: A large proportion of adult survivors report moderate to severe pain and pain interference more than 20 years after their diagnosis. Increased screening and early intervention for pain interference and recurrent pain are warranted.

RevDate: 2020-03-31

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

Executive Summary: Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

Pharmacotherapy [Epub ahead of print].

BACKGROUND: Recent vancomycin PK/PD and toxicodynamic studies enable a reassessment of the current dosing and monitoring guideline in an attempt to further optimize the efficacy and safety of vancomycin therapy. The area-under-the-curve to minimum inhibitory concentration (AUC/MIC) has been identified as the most appropriate pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin. The 2009 vancomycin consenus guidelines recommended specific trough concentrations as a surrogate marker for AUC/MIC. However, more recent toxicodynamic studies have reported an increase in nephrotoxicity associated with trough monitoring.

METHODS AND RESULTS: This is the executive summary of the new vancomycin consensus guidelines for dosing and monitoring vancomycin therapy and was developed by the American Society of Health-Systems Pharmacists, Infectious Diseases Society of America, Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee.

CONCLUSIONS: The recommendations provided in this document are intended to assist the clinician in optimizing vancomycin for the treatment of invasive MRSA infections in adult and pediatric patients. An AUC/MIC by broth microdilution (BMD) ratio of 400 to 600 (assuming MICBMD of 1 mg/L) should be advocated as the target to achieve clinical efficacy while improving patient safety for patients with serious MRSA infections. In such cases, AUC-guided dosing and monitoring is the most accurate and optimal way to manage vancomycin therapy.

RevDate: 2020-03-31

Foord AM, Cushing-Haugen KL, Boeckh MJ, et al (2020)

Late infectious complications in hematopoietic cell transplantation survivors: a population-based study.

Blood advances, 4(7):1232-1241.

Few studies have compared the incidence of infections occurring ≥2 years after hematopoietic cell transplant (HCT) with other cancer patients and the general population. In this study, ≥2-year HCT survivors who were Washington residents treated from 1992 through 2009 (n = 1792; median age, 46 years; 52% allogeneic; 90% hematologic malignancies) were matched to individuals from the state cancer registry (n = 5455, non-HCT) and driver's license files (n = 16 340; Department of Licensing [DOL]). Based on hospital and death registry codes, incidence rate ratios (IRRs; 95% confidence interval [CI]) of infections by organism type and organ system were estimated using Poisson regression. With 7-year median follow-up, the incidence rate (per 1000 person-years) of all infections was 65.4 for HCT survivors vs 39.6 for the non-HCT group (IRR, 1.6; 95% CI, 1.3-1.9) and 7.2 for DOL (IRR, 10.0; 95% CI, 8.3-12.1). Bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRR, 1.7; P < .01), whereas the risk for viral infection was lower (IRR, 1.4; P = .07). Among potentially vaccine-preventable organisms, the IRR was 3.0 (95% CI, 2.1-4.3) vs the non-HCT group. Although the incidences of all infections decreased with time, the relative risk in almost all categories remained significantly increased in ≥5-year HCT survivors vs other groups. Risk factors for late infection included history of relapse and for some infections, history of chronic graft-versus-host disease. Providers caring for HCT survivors should maintain vigilance for infections and ensure adherence to antimicrobial prophylaxis and vaccination guidelines.

RevDate: 2020-03-31

Srikanthan MA, Humbert O, Haworth KG, et al (2020)

Effective Multi-lineage Engraftment in a Mouse Model of Fanconi Anemia Using Non-genotoxic Antibody-Based Conditioning.

Molecular therapy. Methods & clinical development, 17:455-464 pii:S2329-0501(20)30026-7.

Conditioning chemotherapy is used to deplete hematopoietic stem cells in the recipient's marrow, facilitating donor cell engraftment. Although effective, a major issue with chemotherapy is the systemic genotoxicity that increases the risk for secondary malignancies. Antibody conjugates targeting hematopoietic cells are an emerging non-genotoxic method of opening the marrow niche and promoting engraftment of transplanted cells while maintaining intact marrow cellularity. Specifically, this platform would be useful in diseases associated with DNA damage or cancer predisposition, such as dyskeratosis congenita, Schwachman-Diamond syndrome, and Fanconi anemia (FA). Our approach utilizes antibody-drug conjugates (ADC) as an alternative conditioning regimen in an FA mouse model of autologous transplantation. Antibodies targeting either CD45 or CD117 were conjugated to saporin (SAP), a ribosomal toxin. FANCA knockout mice were conditioned with either CD45-SAP or CD117-SAP prior to receiving whole marrow from a heterozygous healthy donor. Bone marrow and peripheral blood analysis revealed equivalent levels of donor engraftment, with minimal toxicity in ADC-treated groups as compared with cyclophosphamide-treated controls. Our findings suggest ADCs may be an effective conditioning strategy in stem cell transplantation not only for diseases where traditional chemotherapy is not tolerated, but also more broadly for the field of blood and marrow transplantation.

RevDate: 2020-03-31

Hu Y, Graff M, Haessler J, et al (2020)

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

PLoS genetics, 16(3):e1008684 pii:PGENETICS-D-19-00861 [Epub ahead of print].

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

RevDate: 2020-03-31

Choi R, Hulverson MA, Huang W, et al (2020)

Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned.

International journal for parasitology pii:S0020-7519(20)30056-4 [Epub ahead of print].

Bumped Kinase Inhibitors (BKIs), targeting Calcium-dependent Protein Kinase 1 (CDPK1) in apicomplexan parasites with a glycine gatekeeper, are promising new therapeutics for apicomplexan diseases. Here we will review advances, as well as challenges and lessons learned regarding efficacy, safety, and pharmacology, that have shaped our selection of pre-clinical candidates.

RevDate: 2020-03-31

Jamil S, Mark N, Carlos G, et al (2020)

Diagnosis and Management of COVID-19 Disease.

American journal of respiratory and critical care medicine [Epub ahead of print].

RevDate: 2020-03-30

Liu Y, Yang W, VoPham T, et al (2020)

Plant-based and animal-based low-carbohydrate diets and risk of hepatocellular carcinoma among US men and women.

Hepatology (Baltimore, Md.) [Epub ahead of print].

Little is known about the role of low-carbohydrate diets (LCDs) in the development of hepatocellular carcinoma (HCC). We prospectively evaluated the associations between plant-based and animal-based LCDs and risk of HCC in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Dietary intake was assessed every 4 years using validated food frequency questionnaires. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). HRs are shown for a 1-standard deviation (SD) increment with variable modelled as continuous. During 3,664,769 person years of follow-up, there were 156 incident HCC cases. Although there were no associations between overall or animal-based LCD score and risk of HCC, plant-based LCD score was inversely associated with HCC risk (HR: 0.83; 95% CI: 0.70-0.98; Ptrend =0.03). Carbohydrate intake, especially from refined grains (HR: 1.18; 95% CI: 1.00-1.39; Ptrend =0.04) was positively, while plant fat (HR: 0.78; 95% CI: 0.65-0.95; Ptrend =0.01) was inversely associated with HCC risk. Substituting 5% of energy from plant fat and protein for carbohydrate (HR: 0.74; 95% CI: 0.58-0.93; Ptrend =0.01) or refined grains (HR: 0.70; 95% CI: 0.55-0.90; Ptrend =0.006) was associated with lower HCC risk. In conclusion, a plant-based LCD and dietary restriction of carbohydrate from refined grains were associated with a lower risk of HCC. Substituting plant fat and protein for carbohydrate, particularly refined grains, may decrease HCC incidence. Our findings support a potential benefit in emphasizing plant sources of fat and protein in the diet for HCC primary prevention. Additional studies that carefully consider hepatitis B and C virus infections and chronic liver diseases are needed to confirm our findings.

RevDate: 2020-03-28

Tabachnick-Cherny S, Pulliam T, Church C, et al (2020)

Polyomavirus-driven Merkel cell carcinoma: Prospects for therapeutic vaccine development.

Molecular carcinogenesis [Epub ahead of print].

Great strides have been made in cancer immunotherapy including the breakthrough successes of anti-PD-(L)1 checkpoint inhibitors. In Merkel cell carcinoma (MCC), a rare and aggressive skin cancer, PD-(L)1 blockade is highly effective. Yet, ~50% of patients either do not respond to therapy or develop PD-(L)1 refractory disease and, thus, do not experience long-term benefit. For these patients, additional or combination therapies are needed to augment immune responses that target and eliminate cancer cells. Therapeutic vaccines targeting tumor-associated antigens, mutated self-antigens, or immunogenic viral oncoproteins are currently being developed to augment T-cell responses. Approximately 80% of MCC cases in the United States are driven by the ongoing expression of viral T-antigen (T-Ag) oncoproteins from genomically integrated Merkel cell polyomavirus (MCPyV). Since T-Ag elicits specific B- and T-cell immune responses in most persons with virus-positive MCC (VP-MCC), and ongoing T-Ag expression is required to drive VP-MCC cell proliferation, therapeutic vaccination with T-Ag is a rational potential component of immunotherapy. Failure of the endogenous T-cell response to clear VP-MCC (allowing clinically evident tumors to arise) implies that therapeutic vaccination will need to be potent anśd synergize with other mechanisms to enhance T-cell activity against tumor cells. Here, we review the relevant underlying biology of VP-MCC, potentially applicable therapeutic vaccine platforms, and antigen delivery formats. We also describe early successes in the field of therapeutic cancer vaccines and address several clinical scenarios in which VP-MCC patients could potentially benefit from a therapeutic vaccine.

RevDate: 2020-03-28

Michelson AP, McDonough S, Willman CL, et al (2020)

Association of immunophenotype with expression of topoisomerase II α and β in adult acute myeloid leukemia.

Scientific reports, 10(1):5486 pii:10.1038/s41598-020-62345-9.

Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P < 0.0001). In contrast to topo IIα, topo IIβ was significantly associated with blast percentage in marrow or blood (P = 0.0001), CD7 (P = 0.01), CD14 (P < 0.0001) and CD54 (P < 0.0001). Event free survival was worse for CD56-negative compared to CD56-high (HR = 1.9, 95% CI [1.0-3.5], p = 0.04), and overall survival was worse for CD-15 low as compared to CD15-high (HR = 2.2, 95% CI [1.1-4.2], p = 0.02). Ingenuity pathway analysis indicated topo IIβ and immunophenotype markers in a network associated with cell-to-cell signaling, hematological system development/function and inflammatory response. Topo IIβ expression reflects disease biology of highly proliferative disease and distinct IP but does not appear to be an independent variable influencing outcome in adult AML patients treated with anthracycline-based therapy.

RevDate: 2020-03-27

Disis MLN (2020)

JAMA Oncology-The Year in Review, 2019.

JAMA oncology pii:2763305 [Epub ahead of print].

RevDate: 2020-03-27

Jones SMW, Shulman LJ, Richards JE, et al (2020)

Mechanisms for the testing effect on patient-reported outcomes.

Contemporary clinical trials communications, 18:100554 pii:100554.

The testing effect is when patient-reported outcomes (PRO) improve with repeated administration without intervention. The testing effect can confound interpretation of clinical trials using PROs as endpoints. This study investigated potential mechanisms. The parent study (n = 302) investigated a self-management intervention for depression. We qualitatively analyzed exit interview feedback from the 89 control group participants completing the last assessment. Participants reported several perceived benefits from control group participation including novel mechanisms (study participation was meaningful, emotional support, appreciating outreach), a possible negative testing effect and mechanisms previously identified (behavioral change).

RevDate: 2020-03-26

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

Forty-year trends in menopausal hormone therapy use and breast cancer incidence among postmenopausal black and white women.

Cancer [Epub ahead of print].

After reports from the Women's Health Initiative randomized trial evaluating estrogen plus progestin, there was a sudden, substantial, and sustained decrease in all categories of menopausal hormone therapy, and the first reduction in age-adjusted breast cancer incidence in more than 20 years was seen in 2003-2004 among US women 50 years of age or older. Subsequent trends in breast cancer incidence have been described, but most reports have not focused on the postmenopausal age group or fully engaged the potential influence of reduced hormone therapy on breast cancer incidence trends by race/ethnicity. To address this gap, this commentary examines trends for annual age-adjusted breast cancer incidence over a 40-year period from 1975 to 2015 for white and black women on the basis of findings from the Surveillance, Epidemiology, and End Results 9 registries. Overall, the sharp decline in breast cancer incidence seen in 2003-2004 was followed in the subsequent decade by a continued low breast cancer incidence plateau in white women that has largely persisted. In contrast, a new discordance between breast cancer incidence trends in black and white women has emerged. In the 2005-2015 decade, a sustained increase in breast cancer incidence in black women has resulted in annual incidence rates comparable, for the first time, to those in white women. This commentary explores the hypothesis that the over-decade-long and discordant changes in breast cancer incidence rates in postmenopausal black and white women are, to a large extent, associated with changes in hormone therapy use in these 2 groups.

RevDate: 2020-03-26

Ueda M, Stefan T, Stetson L, et al (2020)

Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia.

Frontiers in oncology, 10:327.

Glycogen synthase kinase-3 (GSK3) inhibitors induce differentiation and growth inhibition of acute myeloid leukemia (AML) cells. Our pre-clinical studies showed GSK3 inhibition leads to sensitization of AML cells to tretinoin-mediated differentiation. We conducted a phase I trial of lithium, a GSK3 inhibitor, plus tretinoin for relapsed, refractory non-promyelocytic AML. Nine patients with median (range) age 65 (42-82) years were enrolled. All subjects had relapsed leukemia after prior therapy, with a median (range) of 3 (1-3) prior therapies. Oral lithium carbonate 300 mg was given 2-3 times daily and adjusted to meet target serum concentration (0.6 to 1.0 mmol/L); tretinoin 22.5 or 45 mg/m2/day (two equally divided doses) was administered orally on days 1-7 and 15-21 of a 28-day cycle. Four patients attained disease stability with no increase in circulating blasts for ≥4 weeks. Median (range) survival was 106 days (60-502). Target serum lithium concentration was achieved in all patients and correlated with GSK3 inhibition in leukemic cells. Immunophenotypic changes associated with myeloid differentiation were observed in five patients. The combination treatment led to a reduction in the CD34+ CD38- AML stem cell population both in vivo and in vitro. The combination of lithium and tretinoin is well-tolerated, induces differentiation of leukemic cells, and may target AML stem cells, but has limited clinical activity in the absence of other antileukemic agents. The results of this clinical trial suggest GSK3 inhibition can result in AML cell differentiation and may be a novel therapeutic strategy in this disease, particularly in combination with other antileukemic agents. Lithium is a weak GSK3 inhibitor and future strategies in AML treatment will probably require more potent agents targeting this pathway or combinations with other antileukemic agents. This trial is registered at ClinicalTrials.gov NCT01820624.

RevDate: 2020-03-26

Kaluza J, Harris HR, Håkansson N, et al (2020)

Adherence to the WCRF/AICR 2018 recommendations for cancer prevention and risk of cancer: prospective cohort studies of men and women.

British journal of cancer pii:10.1038/s41416-020-0806-x [Epub ahead of print].

BACKGROUND: In 2018, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) issued revised recommendations for cancer prevention. We examined the relation between adherence to these recommendations and risk of total cancer in two population-based Swedish prospective cohorts (29,451 men and 25,349 women).

METHODS: Standardized-WCRF/AICR 2018 and simplified-WCRF/AICR 2018 adherence scores were constructed based on the WCRF/AICR recommendations for body weight, physical activity, diet, alcohol consumption and dietary supplement use. Data were collected using a self-administered questionnaire.

RESULTS: During the 15.4 years of follow-up, 12,693 incident cancers were ascertained. The multivariable HR between extreme categories of the Standardized-WCRF/AICR 2018 score (4.1-7 vs. 0-2) was 0.88 (95% CI = 0.82-0.95) and for the Simplified score (5-8 vs. 0-2) was 0.85 (95% CI = 0.80-0.90); each 1-score increment in recommendation adherence was associated with 3% (95% CI = 1-5%) and 4% (95% CI = 2-5%) decreased risk, respectively. Based on the Simplified scoring, most participants (>90%) did not meet WCRF/AICR 2018 recommendations regarding consumption of plant foods, limited consumption of red/processed meat and 'fast food'/processed food, and <50% of participants met the weight and physical activity recommendations.

CONCLUSIONS: Adherence to the 2018WCRF/AICR recommendations substantially reduced the risk of total cancer. Given that many people do not meet the recommendations, there is a great potential for cancer prevention.

RevDate: 2020-03-25

Bellissimo DC, Chen CH, Zhu Q, et al (2020)

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling.

Blood advances, 4(6):1145-1158.

RUNX1 is frequently mutated in myeloid and lymphoid malignancies. It has been shown to negatively regulate Toll-like receptor 4 (TLR4) signaling through nuclear factor κB (NF-κB) in lung epithelial cells. Here we show that RUNX1 regulates TLR1/2 and TLR4 signaling and inflammatory cytokine production by neutrophils. Hematopoietic-specific RUNX1 loss increased the production of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), by bone marrow neutrophils in response to TLR1/2 and TLR4 agonists. Hematopoietic RUNX1 loss also resulted in profound damage to the lung parenchyma following inhalation of the TLR4 ligand lipopolysaccharide (LPS). However, neutrophils with neutrophil-specific RUNX1 loss lacked the inflammatory phenotype caused by pan-hematopoietic RUNX1 loss, indicating that dysregulated TLR4 signaling is not due to loss of RUNX1 in neutrophils per se. Rather, single-cell RNA sequencing indicates the dysregulation originates in a neutrophil precursor. Enhanced inflammatory cytokine production by neutrophils following pan-hematopoietic RUNX1 loss correlated with increased degradation of the inhibitor of NF-κB signaling, and RUNX1-deficient neutrophils displayed broad transcriptional upregulation of many of the core components of the TLR4 signaling pathway. Hence, early, pan-hematopoietic RUNX1 loss de-represses an innate immune signaling transcriptional program that is maintained in terminally differentiated neutrophils, resulting in their hyperinflammatory state. We hypothesize that inflammatory cytokine production by neutrophils may contribute to leukemia associated with inherited RUNX1 mutations.

RevDate: 2020-03-25

Shore ND, Morrow MP, McMullan T, et al (2020)

CD8+ T Cells Impact Rising PSA in Biochemically Relapsed Cancer Patients Using Immunotherapy Targeting Tumor-Associated Antigens.

Molecular therapy : the journal of the American Society of Gene Therapy pii:S1525-0016(20)30134-9 [Epub ahead of print].

The management of men with prostate cancer (PCa) with biochemical recurrence following local definitive therapy remains controversial. Early use of androgen deprivation therapy (ADT) leads to significant side effects. Developing an alternative, clinically effective, and well-tolerated therapy remains an unmet clinical need. INO-5150 is a synthetic DNA therapy that includes plasmids encoding for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA), and INO-9012 is a synthetic DNA plasmid encoding for interleukin-12 (IL-12). This phase 1/2, open-label, multi-center study enrolled men with PCa with rising PSA after surgery and/or radiation therapy. Patients were enrolled into one of four treatment arms: arm A, 2 mg of INO-5150; arm B, 8.5 mg of INO-5150; arm C, 2 mg of INO-5150 + 1 mg of INO-9012; and arm D, 8.5 mg of INO-5150 + 1 mg of INO-9012. Patients received study drug with electroporation on day 0 and on weeks 3, 12, and 24, and they were followed for up to 72 weeks. Sixty-two patients were enrolled. Treatment was well tolerated. 81% (50/62) of patients completed all visits. 85% (53/62) remained progression-free at 72 weeks. PSA doubling time (PSADT) was increased when assessed in patients with day 0 PSADT ≤12 months. Immunogenicity was observed in 76% (47/62) of patients by multiple assessments. Analysis indicated that CD38 and perforin co-positive CD8 T cell frequency correlated with attenuated PSA rise (p = 0.05, n = 50).

RevDate: 2020-03-24

Comstock CE, Gatsonis C, Newstead GM, et al (2020)

Comparison of Abbreviated Breast MRI vs Digital Breast Tomosynthesis for Breast Cancer Detection Among Women With Dense Breasts Undergoing Screening.

JAMA, 323(8):746-756.

Importance: Improved screening methods for women with dense breasts are needed because of their increased risk of breast cancer and of failed early diagnosis by screening mammography.

Objective: To compare the screening performance of abbreviated breast magnetic resonance imaging (MRI) and digital breast tomosynthesis (DBT) in women with dense breasts.

Cross-sectional study with longitudinal follow-up at 48 academic, community hospital, and private practice sites in the United States and Germany, conducted between December 2016 and November 2017 among average-risk women aged 40 to 75 years with heterogeneously dense or extremely dense breasts undergoing routine screening. Follow-up ascertainment of cancer diagnoses was complete through September 12, 2019.

Exposures: All women underwent screening by both DBT and abbreviated breast MRI, performed in randomized order and read independently to avoid interpretation bias.

Main Outcomes and Measures: The primary end point was the invasive cancer detection rate. Secondary outcomes included sensitivity, specificity, additional imaging recommendation rate, and positive predictive value (PPV) of biopsy, using invasive cancer and ductal carcinoma in situ (DCIS) to define a positive reference standard. All outcomes are reported at the participant level. Pathology of core or surgical biopsy was the reference standard for cancer detection rate and PPV; interval cancers reported until the next annual screen were included in the reference standard for sensitivity and specificity.

Results: Among 1516 enrolled women, 1444 (median age, 54 [range, 40-75] years) completed both examinations and were included in the analysis. The reference standard was positive for invasive cancer with or without DCIS in 17 women and for DCIS alone in another 6. No interval cancers were observed during follow-up. Abbreviated breast MRI detected all 17 women with invasive cancer and 5 of 6 women with DCIS. Digital breast tomosynthesis detected 7 of 17 women with invasive cancer and 2 of 6 women with DCIS. The invasive cancer detection rate was 11.8 (95% CI, 7.4-18.8) per 1000 women for abbreviated breast MRI vs 4.8 (95% CI, 2.4-10.0) per 1000 women for DBT, a difference of 7 (95% CI, 2.2-11.6) per 1000 women (exact McNemar P = .002). For detection of invasive cancer and DCIS, sensitivity was 95.7% (95% CI, 79.0%-99.2%) with abbreviated breast MRI vs 39.1% (95% CI, 22.2%-59.2%) with DBT (P = .001) and specificity was 86.7% (95% CI, 84.8%-88.4%) vs 97.4% (95% CI, 96.5%-98.1%), respectively (P < .001). The additional imaging recommendation rate was 7.5% (95% CI, 6.2%-9.0%) with abbreviated breast MRI vs 10.1% (95% CI, 8.7%-11.8%) with DBT (P = .02) and the PPV was 19.6% (95% CI, 13.2%-28.2%) vs 31.0% (95% CI, 17.0%-49.7%), respectively (P = .15).

Conclusions and Relevance: Among women with dense breasts undergoing screening, abbreviated breast MRI, compared with DBT, was associated with a significantly higher rate of invasive breast cancer detection. Further research is needed to better understand the relationship between screening methods and clinical outcome.

Trial Registration: ClinicalTrials.gov Identifier: NCT02933489.

RevDate: 2020-03-24

Hall ET, Fernandez-Lopez E, Silk AW, et al (2020)

Immunologic Characteristics of Nonmelanoma Skin Cancers: Implications for Immunotherapy.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 40:1-10.

In this review, we summarize the immunology of nonmelanoma skin cancers (NMSCs) and the clinical data with immunotherapy in this heterogeneous group of cancers that include basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (CSCC), and Merkel cell carcinoma (MCC). NMSCs are exceedingly common, and their treatment consumes substantial health care resources. Annual global mortality from NMSCs is comparable to that from malignant melanoma. Although the majority of NMSCs are localized at diagnosis and are treated effectively with surgery, metastases (nodal and distant) can sometimes arise and require systemic therapy. Given the success of immunotherapy in treating cutaneous melanoma, there has been an increasing interest in studying the immunology of NMSCs. Immunocompromised patients have a substantially higher risk of developing NMSCs (particularly CSCC and MCC), suggesting a role of the immune system in the pathogenesis of these cancers. Similar to cutaneous melanoma, the pathogenesis of BCC, CSCC, and virus-negative MCC is related to DNA damage from ultraviolet radiation exposure, and these cancers have a very high tumor mutational burden, which likely results in higher levels of tumor neoantigens that may be targets for the immune system. Viral antigens in virus-positive MCC are also strongly immunogenic. Emerging data from clinical trials of immune checkpoint inhibitors in NMSCs look very promising and are rapidly changing the treatment landscape of these cancers. Specifically, pembrolizumab and avelumab are U.S. Food and Drug Administration-approved for treatment of metastatic MCC and cemiplimab for metastatic CSCC. Several ongoing trials are investigating novel immunotherapies (monotherapies as well as combination) for treatment of NMSCs.

RevDate: 2020-03-24

Xia Z, Su YR, Petersen P, et al (2020)

Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk.

Cancer medicine [Epub ahead of print].

BACKGROUND: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.

METHODS: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.

RESULTS: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5), PSMC5 (P = 4.51 × 10-4) and CD33 (P = 2.71 × 10-4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5) and SCN1B (P = 2.76 × 10-4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5).

CONCLUSIONS: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

RevDate: 2020-03-24

Sheng IY, Diaz-Montero CM, Rayman P, et al (2020)

Blood Myeloid-Derived Suppressor Cells Correlate with Neutrophil-to-Lymphocyte Ratio and Overall Survival in Metastatic Urothelial Carcinoma.

Targeted oncology pii:10.1007/s11523-020-00707-z [Epub ahead of print].

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) were linked to pathologic stage in bladder urothelial carcinoma (UC). Neutrophil lymphocyte ratio (NLR) is an inflammatory biomarker with a prognostic role in metastatic (m)UC.

OBJECTIVE: We hypothesized that MDSC levels correlate with NLR and overall survival (OS) in mUC.

PATIENTS AND METHODS: MDSCs were measured in blood samples from patients with mUC in fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC) by flow cytometry and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UNC-MDSC: CD15-/CD14-). MDSC populations were presented as a percentage of live nucleated blood cells. Spearman's rank correlation assessed correlations between MDSC and NLR. Kaplan-Meier curves and log-rank test estimated OS from the time of MDSC collection to last follow-up or date of death.

RESULTS: Of the 76 patients, 78% were men and 43% were never smokers with a median age of 69 years (range 31-83); 72% had pure UC and 76% had lower tract UC. Prior therapies included intravesical therapy (22%), neoadjuvant chemotherapy (30%), cystectomy or nephroureterectomy (55%). Median follow-up for all patients was 12 months (0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p ≤ 0.001). Both WB UNC-MDSC/PMN-MDSC ratios (rho = - 0.27, p = 0.03) and PBMC UNC-MDSC/PMN-MDSC (rho = - 0.28, p = 0.02) were negatively correlated with NLR. Median OS was 17.7 months (95% CI: 11.0-NE). Overall 1-year and 3-year survival rates were 0.60 (95% CI 0.49-0.73) and 0.15 (95% CI 0.03-0.67), respectively. Higher WB UNC-MDSC levels (HR 3.78, p = 0.0022) and higher NLR (HR 2.6, p = 0.0179) were associated with shorter OS.

CONCLUSIONS: Specific MDSC subsets correlate with NLR. Higher WB UNC-MDSC levels and higher NLR were negative prognostic factors. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow-up are warranted.

RevDate: 2020-03-24

Lee EJ, Hanchate NK, Kondoh K, et al (2020)

A psychological stressor conveyed by appetite-linked neurons.

Science advances, 6(12):eaay5366 pii:aay5366.

Mammals exhibit instinctive reactions to danger critical to survival, including surges in blood stress hormones. Hypothalamic corticotropin-releasing hormone neurons (CRHNs) control stress hormones but how diverse stressors converge on CRHNs is poorly understood. We used sRNA profiling to define CRHN receptors for neurotransmitters and neuromodulators and then viral tracing to localize subsets of upstream neurons expressing cognate receptor ligands. Unexpectedly, one subset comprised POMC (proopiomelanocortin)-expressing neurons in the arcuate nucleus, which are linked to appetite suppression. The POMC neurons were activated by one psychological stressor, physical restraint, but not another, a predator odor. Chemogenetic activation of POMC neurons induced a stress hormone response, mimicking a stressor. Moreover, their silencing markedly reduced the stress hormone response to physical restraint, but not predator odor. These findings indicate that POMC neurons involved in appetite suppression also play a major role in the stress hormone response to a specific type of psychological stressor.

RevDate: 2020-03-24

Kang JH, VoPham T, Laden F, et al (2020)

Cohort Study of Non-melanoma Skin Cancer and the Risk of Exfoliation Glaucoma.

Journal of glaucoma [Epub ahead of print].

PRECIS: In a cohort study of 120,307 participants with 25+ years of follow-up, a history of non-melanoma skin cancer was associated with a 40% higher exfoliation glaucoma risk.

PURPOSE: To evaluate the relationship between non-melanoma skin cancer (a marker of ultraviolet radiation exposure) and exfoliation glaucoma (XFG).

METHODS: We performed a cohort study of US women (n=79,102; 1980-2014) and men (n=41,205; 1986-2014), aged 40+ years and at risk for glaucoma who reported eye exams. From 1984 (women)/1988 (men), we asked about basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) history separately; in prior years, we asked about any non-melanoma skin cancer history in a single question. SCC was confirmed with histopathology reports while BCC and any early (<1984/<1988) non-melanoma skin cancer history was self-reported. Incident XFG cases (362 women and 83 men) were confirmed with medical records. Using pooled data, we estimated multivariable-adjusted relative risks (MVRR; 95% confidence intervals [CIs]) with Cox proportional hazards models that were stratified by age (in months), 2-year time period at risk and average lifetime residential latitude.

RESULTS: In multivariable-adjusted analyses, we observed a 40% higher XFG risk with any non-melanoma skin cancer history (MVRR=1.40; 95% CI=1.08,1.82); the association was observed even with 4 and 8 year lags in non-melanoma skin cancer history. Also, the non-melanoma skin cancer association was stronger in younger (<65▒y; MVRR=2.56; 95% CI=1.62,4.05) versus older participants (≥65▒y; MVRR=1.25; 95% CI=0.94,1.66; p for interaction=0.01) and those living in northern latitudes (≥42° north; MVRR=1.92; 95% CI=1.28,2.88) versus more southern latitudes (<42° north; MVRR=1.19; 95% CI=0.86,1.66; p for interaction=0.04).

CONCLUSIONS: Non-melanoma skin cancer was associated with higher XFG risk, particularly among younger participants and those living in Northern US.

RevDate: 2020-03-24

Buckee CO, Balsari S, Chan J, et al (2020)

Aggregated mobility data could help fight COVID-19.

RevDate: 2020-03-24

Wei AH, Roberts AW, Spencer A, et al (2020)

Targeting MCL-1 in hematologic malignancies: Rationale and progress.

Blood reviews pii:S0268-960X(20)30022-9 [Epub ahead of print].

Myeloid cell leukemia sequence 1 (MCL-1) is an antiapoptotic protein that plays a key role in promoting cell survival in multiple myeloma (MM), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL). Overexpression of MCL-1 is associated with treatment resistance and poor prognosis; thus, MCL-1 inhibitors are rational therapeutic options for malignancies depending on MCL-1. Several MCL-1 inhibitors have entered clinical trials, including AZD5991, S64315, AMG 176, and AMG 397. A key area of investigation is whether MCL-1 inhibitors will complement the activity of BCL-2 inhibitors, such as venetoclax, and synergistically enhance anti-tumor efficacy when given in combination with other anti-cancer drugs. Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway.

RevDate: 2020-03-24

Dayan GH, Langevin E, Gilbert PB, et al (2020)

Assessment of the long-term efficacy of a dengue vaccine against symptomatic, virologically-confirmed dengue disease by baseline dengue serostatus.

Vaccine pii:S0264-410X(20)30384-4 [Epub ahead of print].

CYD-TDV is a live, attenuated, tetravalent dengue vaccine licensed in 21 countries. We undertook a post-hoc analysis of the long-term efficacy of CYD-TDV during the surveillance expansion phase (SEP) of two Phase III studies (CYD14 in the Asia-Pacific region; CYD15 in Latin America). The SEP included approximately Year 5 and the entire Year 6 of follow-up after the first study injection. Vaccine efficacy against symptomatic virologically-confirmed dengue (VCD) was assessed by participant age (any age, ≥9, <9, 2-5, and 6-8 years at the time of the first injection) and baseline dengue serostatus using a case-cohort framework. Baseline dengue serostatus was estimated by several methods including logistic regression-based multiple imputation (MI) to predict PRNT50 with key predictor being Month 13 (M13) anti-non-structural protein (NS1) titers; superlearner-based imputation by targeted minimum loss based estimation (TMLE); and M13 anti-NS1 titer threshold 9 EU/mL (NS1 M13). There were 436 symptomatic VCD cases (CYD14: n = 360; CYD15: n = 76) during the SEP. Vaccine efficacy in seropositive participants aged ≥9 years was assessed by MI (47.9% [95% CI 19.4; 66.3]), TMLE (53.0% [95% CI 23; 71]), and NS1 M13 (52.4% [95% CI 30.8; 67.3]). Vaccine efficacy estimates were lower in seropositive individuals aged <9 years compared with individuals ≥9 years. Among seropositive individuals aged 2-5 and 6-8 years, vaccine efficacy across the different approaches for assessing serostatus ranged from between -25.7 to 36.9% and 44.4 to 64.7% during the SEP, respectively. In the pooled CYD14/15 data of seronegatives, vaccine efficacy was null to modest. In conclusion, CYD-TDV was shown to maintain efficacy against symptomatic VCD in seropositive participants aged ≥9 years up to six years after the first dose. Persistence of efficacy was also observed in seropositive participants aged 6-8 years.

RevDate: 2020-03-23

Navarro-Costa PA, Molaro A, Misra CS, et al (2020)

Sex and suicide: The curious case of Toll-like receptors.

PLoS biology, 18(3):e3000663 pii:PBIOLOGY-D-20-00025 [Epub ahead of print].

During in vitro fertilisation (IVF), pharmacological activation of the murine X chromosome-encoded receptor proteins Toll-like receptor (TLR) 7 and TLR8 reportedly results in male-biased litters by selectively disrupting the motility of X-bearing sperm cells. Thus-in the context of agonist treatment during IVF-these receptors act as 'suicidal' segregation distorters that impair their own transmission to the next generation. Such behaviour would, from an evolutionary perspective, be strongly selected against if present during natural fertilisation. Consequently, TLR7/8 biology in vivo must differ significantly from this in vitro situation to allow these genes to persist in the genome. Here, we use our current understanding of male germ cell biology and TLR function as a starting point to explore the mechanistic and evolutionary aspects of this apparent paradox.

RevDate: 2020-03-23

Correnti CE, Hallinan JP, Doyle LA, et al (2020)

Engineering and functionalization of large circular tandem repeat protein nanoparticles.

Nature structural & molecular biology pii:10.1038/s41594-020-0397-5 [Epub ahead of print].

Protein engineering has enabled the design of molecular scaffolds that display a wide variety of sizes, shapes, symmetries and subunit compositions. Symmetric protein-based nanoparticles that display multiple protein domains can exhibit enhanced functional properties due to increased avidity and improved solution behavior and stability. Here we describe the creation and characterization of a computationally designed circular tandem repeat protein (cTRP) composed of 24 identical repeated motifs, which can display a variety of functional protein domains (cargo) at defined positions around its periphery. We demonstrate that cTRP nanoparticles can self-assemble from smaller individual subunits, can be produced from prokaryotic and human expression platforms, can employ a variety of cargo attachment strategies and can be used for applications (such as T-cell culture and expansion) requiring high-avidity molecular interactions on the cell surface.

RevDate: 2020-03-23

Izzo F, Lee SC, Poran A, et al (2020)

DNA methylation disruption reshapes the hematopoietic differentiation landscape.

Nature genetics pii:10.1038/s41588-020-0595-4 [Epub ahead of print].

Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies1-3 and clonal hematopoiesis4,5. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.

RevDate: 2020-03-23

Einsele H, Ljungman PT, MJ Boeckh (2020)

How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation.

Blood pii:452747 [Epub ahead of print].

CMV reactivation remains one of the most common and life-threatening infectious complications following allogeneic hematopoietic stem cell transplantation (allo-HCT) in spite of novel diagnostic technologies, several novel prophylactic agents and further improvement in preemptive therapy and treatment for established CMV disease. Today treatment decisions for CMV reactivation are becoming increasingly difficult and have to consider whether the patient has received antiviral prophylaxis, the patient`s individual risk profile for CMV disease, CMV-specific T cell reconstitution as well as both the CMV viral load and the potential drug-resistance detected at the time of initiation of antiviral therapy. Thus, we increasingly use personalized treatment strategies for the recipient of an allograft with CMV reactivation based on prior use of anti-CMV prophylaxis, viral load, the assessment of CMV-specific T cell immunity, and the molecular assessment of resistance to antiviral drugs.

RevDate: 2020-03-23

Martin PJ (2020)

How I treat steroid-refractory acute graft-versus-host disease.

Blood pii:452748 [Epub ahead of print].

Steroid-resistant or refractory acute GVHD (SR-aGVHD) poses one of the most vexing challenges faced by providers who care for patients after allogeneic hematopoietic cell transplantation. For the past 4 decades, research in the field been driven by the premise that persistent GVHD results from inadequate immunosuppression. Accordingly, most efforts to solve this problem have relied on retrospective or prospective studies testing agents that have direct or indirect immunosuppressive effects. Retrospective studies far outnumber prospective studies, and no controlled prospective trial has shown superior results for any agent over others. Truth be told, we do not know how to treat SR-aGVHD. Preclinical work during the past decade has provided fresh insights into the pathogenesis of acute GVHD, and translation of these insights toward development of more effective treatments for patients with SR-aGVHD has at last begun. Given the limited state of current knowledge, this "How I Treat" review highlights the overriding imperative to avoid harm in caring for patients with SR-aGVHD. Prospective trials that are widely available are urgently needed to advance the field.

RevDate: 2020-03-23

Looker KJ, Johnston C, Welton NJ, et al (2020)

The global and regional burden of genital ulcer disease due to herpes simplex virus: a natural history modelling study.

BMJ global health, 5(3):e001875 pii:bmjgh-2019-001875.

Introduction: Herpes simplex virus (HSV) infection can cause painful, recurrent genital ulcer disease (GUD), which can have a substantial impact on sexual and reproductive health. HSV-related GUD is most often due to HSV type 2 (HSV-2), but may also be due to genital HSV type 1 (HSV-1), which has less frequent recurrent episodes than HSV-2. The global burden of GUD has never been quantified. Here we present the first global and regional estimates of GUD due to HSV-1 and HSV-2 among women and men aged 15-49 years old.

Methods: We developed a natural history model reflecting the clinical course of GUD following HSV-2 and genital HSV-1 infection, informed by a literature search for data on model parameters. We considered both diagnosed and undiagnosed symptomatic infection. This model was then applied to existing infection estimates and population sizes for 2016. A sensitivity analysis was carried out varying the assumptions made.

Results: We estimated that 187 million people aged 15-49 years had at least one episode of HSV-related GUD globally in 2016: 5.0% of the world's population. Of these, 178 million (95% of those with HSV-related GUD) had HSV-2 compared with 9 million (5%) with HSV-1. GUD burden was highest in Africa, and approximately double in women compared with men. Altogether there were an estimated 8 billion person-days spent with HSV-related GUD globally in 2016, with 99% of days due to HSV-2. Taking into account parameter uncertainty, the percentage with at least one episode of HSV-related GUD ranged from 3.2% to 7.9% (120-296 million). However, the estimates were sensitive to the model assumptions.

Conclusion: Our study represents a first attempt to quantify the global burden of HSV-related GUD, which is large. New interventions such as HSV vaccines, antivirals or microbicides have the potential to improve the quality of life of millions of people worldwide.

RevDate: 2020-03-22

Muhsen IN, Bar M, Savani BN, et al (2020)

Follow-up issues in survivors of hematologic malignancies - Current stance and future perspectives.

Blood reviews pii:S0268-960X(20)30024-2 [Epub ahead of print].

Cancer care advances have led to increased numbers of cancer survivors and to improved understanding of late effects of cancers and their therapies and survivorship issues. Long-term follow-up of cancer patients is crucial in preventing and managing many of the late effects of cancers and their therapies. However, the literature has highlighted the high rates of loss to follow-up (loss to FU) after cancer treatment, particularly in patients with hematologic malignancies. In this review, we performed a systematic search of published literature on issues pertaining to loss to FU in survivors of hematologic malignancies, highlighting the predictors of increased or decreased rates of loss to FU. We found that the literature on survivors of adulthood cancers is very limited, in contrast to articles discussing young adult survivors of childhood cancers. Predictors and barriers of loss to FU were found to be variable in different studies; however, they shared some common themes, including disease-related, logistic, financial and educational factors. Furthermore, we discuss the potential interventions to mitigate the loss to FU, along with discussing research priorities in this area.

RevDate: 2020-03-21

Mato AR, Roeker LE, Jacobs R, et al (2020)

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK inhibition as an Effective Strategy.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-3815 [Epub ahead of print].

PURPOSE: Venetoclax-based therapy is a standard of care option in front-line and relapsed/refractory CLL. Patient management following venetoclax discontinuation remains non-standard and poorly understood.

EXPERIMENTAL DESIGN: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Co-primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post-venetoclax treatments stratified by treatment type (BTKi, PI3Ki, and cellular therapies).

RESULTS: We identified CLL patients who discontinued venetoclax in the front-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n=130), and 81% were idelalisib naïve (n=263). ORR to BTKi was 84% (n=44) in BTKi-naïve patients vs. 54% (n=30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

CONCLUSIONS: For BTKi naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.

RevDate: 2020-03-21

Necchi A, Gallina A, Dyrskjøt L, et al (2020)

Converging Roads to Early Bladder Cancer.

RevDate: 2020-03-21

Chow EJ, Ness KK, Armstrong GT, et al (2020)

Current and coming challenges in the management of the survivorship population.

Seminars in oncology pii:S0093-7754(20)30007-5 [Epub ahead of print].

With the widespread adoption of multimodality treatment, 5-year survival of children diagnosed with cancer has improved dramatically in the past several decades from approximately 60% in 1970 to greater than 85% currently. As a result, there are an estimated nearly half a million long-term survivors of childhood cancer living in the United States today. However, survivors have, on average, significantly greater serious medical and psychosocial late effects compared with the general population. In this review, we will discuss the current epidemiology of childhood cancer survivorship, including new methods to estimate the burden of late effects and genetic susceptibility toward late effects. We will also review the development of surveillance guidelines for childhood cancer survivors and early toxicity signals from novel agents now being tested and used increasingly to treat pediatric and adult cancers. We conclude with an overview of current models of survivorship care and areas for future research.

RevDate: 2020-03-20

Ueda M, Martins R, Hendrie PC, et al (2020)

Managing Cancer Care During the COVID-19 Pandemic: Agility and Collaboration Toward a Common Goal.

Journal of the National Comprehensive Cancer Network : JNCCN pii:jnccn1804COVID [Epub ahead of print].

The first confirmed case of coronavirus disease 2019 (COVID-19) in the United States was reported on January 20, 2020, in Snohomish County, Washington. At the epicenter of COVID-19 in the United States, the Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, and University of Washington are at the forefront of delivering care to patients with cancer during this public health crisis. This Special Feature highlights the unique circumstances and challenges of cancer treatment amidst this global pandemic, and the importance of organizational structure, preparation, agility, and a shared vision for continuing to provide cancer treatment to patients in the face of uncertainty and rapid change.

RevDate: 2020-03-20

Qu X, Yeung C, Coleman I, et al (2020)

Comparison of four next generation sequencing platforms for fusion detection: Oncomine by ThermoFisher, AmpliSeq by illumina, FusionPlex by ArcherDX, and QIAseq by QIAGEN.

Cancer genetics, 243:11-18 pii:S2210-7762(20)30147-2 [Epub ahead of print].

As fusion detection NGS techniques are adopted by clinical labs, assay performance comparison is urgently needed. We compared four fusion-detection assay platforms on a pilot cohort of 24 prostate cancer samples: (1) Oncomine Comprehensive panel v3; (2) AmpliSeq comprehensive panel v3; (3) The solid tumor panel of FusionPlex; and (4) The human oncology panel of QIAseq. The assays were compared for the detection of different types of fusion based on whether the partner gene or the breakpoints are known. All assays detected fusion with known gene partners and known breakpoint, represented by TMPRSS2-ERG. A fusion with known partners but unknown breakpoint, TMPRSS2-ETV4, was reported by OCAv3 and FusionPlex, but not by AICv3 because the specific breakpoint was not in the manifest, nor by QIAseq since the panel did not target the exact exons involved. For fusion with unknown partners, FusionPlex identified the largest number of ETV1 fusions because it had the highest exon coverage for ETV1. Among these, SNRPN-ETV1 and MALAT1-ETV1, were novel findings. To determine reportability of low-level calls of highly prevalent fusions, such as TMPRSS2-ERG, we propose the use of percent fusion reads over total number of reads per sample instead of the fusion read count.

RevDate: 2020-03-20

Blain M, Walter K, Sibulesky L, et al (2019)

New skin lesions in a liver transplant recipient.

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 19(10):2955-2957.

RevDate: 2020-03-20

Stevens EA, Jenkins IC, Beppu LW, et al (2020)

Targeted Sequencing Improves DIPSS-Plus Prognostic Scoring in Myelofibrosis Patients Undergoing Allogeneic Transplant.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30144-0 [Epub ahead of print].

Primary myelofibrosis (MF) and secondary MF developing after polycythemia vera or essential thrombocythemia are clonal disorders of hematopoiesis. Currently the only therapy offering the potential of cure is hematopoietic cell transplantation (HCT). Several risk classification systems including clinical, hematological and mutational parameters have been proposed. We analyzed the mutational landscape in addition to the Dynamic International Prognostic Scoring System (DIPSS)-plus in 55 MF patients to determine the combined impact on post-HCT outcome. Mutations, analyzed in 75 genes, were most common in JAK2, CALR, ASXL1, TET2, GATA2, EZH2, U2AF1, and ETV6. Patients with three or more mutations in addition to JAK2 or CALR mutations had a higher post-transplant relapse rate and non-relapse mortality than patients with fewer mutations, independent of DIPSS-plus risk. The presence of higher numbers of mutations identified patients at the highest risk of relapse within the highest overall risk group as determined by DIPSS-plus. These findings are consistent with molecular risk classifications for non-transplanted patients and support the proposed transplant risk classification incorporating mutational information.

RevDate: 2020-03-20

Haanen J, Ernstoff MS, Wang Y, et al (2020)

Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy.

Annals of oncology : official journal of the European Society for Medical Oncology pii:S0923-7534(20)36364-X [Epub ahead of print].

Patients with cancer and with preexisting active autoimmune diseases (ADs) have been excluded from immunotherapy clinical trials because of concerns for high susceptibility to development of severe adverse events resulting from exacerbation of their preexisting ADs. However, a growing body of evidence indicates that immune-checkpoint inhibitors (ICIs) may be safe and effective in this patient population. However, baseline corticosteroids (CS) and other nonselective immunosuppressants appear to negatively impact drug efficacy, whereas retrospective and case report data suggest that use of specific immunosuppressants may not have the same consequences. Therefore, we propose here a two-step strategy. First, to lower the risk of compromising ICI efficacy before their initiation, nonselective immunosuppressant drugs (nSIs) could be replaced by specific selective immunosuppressant drugs (SI) following a short rotation phase. Subsequently, combining ICI with the selective immunosuppressant could prevent exacerbation of the AD. For the most common active ADs encountered in the context of cancer, we propose specific algorithms to optimize ICI therapy. These preventive strategies go beyond current practices and recommendations, and should be practiced in ICI-specialized clinics, as these require multidisciplinary teams with extensive knowledge in the field of clinical immunology and oncology. In addition, we challenge the exclusion from ICI therapy for patients with cancer and active ADs and propose the implementation of an international registry to study such novel strategies in a prospective fashion.

RevDate: 2020-03-19

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

Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists pii:5810200 [Epub ahead of print].

RevDate: 2020-03-19

Antar AAR, Jenike KM, Jang S, et al (2020)

Longitudinal study reveals HIV-1-infected CD4+ T cell dynamics during long-term antiretroviral therapy.

The Journal of clinical investigation pii:135953 [Epub ahead of print].

Proliferation of CD4+ T cells harboring HIV-1 proviruses is a major contributor to viral persistence in people on antiretroviral therapy (ART). To determine whether differential rates of clonal proliferation or HIV-1-specific CTL pressure shape the provirus landscape, we performed the intact proviral DNA assay (IPDA) and obtained 661 near-full length provirus sequences from eight individuals with suppressed viral loads on ART at time points seven years apart. We observed slow decay of intact proviruses but no changes in the proportions of various types of defective proviruses. The proportion of intact proviruses in expanded clones was similar to that of defective proviruses in clones. Intact proviruses observed in clones did not have more escaped CTL epitopes than intact proviruses observed as singlets. Concordantly, total proviruses at later timepoints or observed in clones were not enriched in escaped or unrecognized epitopes. Three individuals with natural control of HIV-1 infection (controllers) on ART, included because controllers have strong HIV-1-specific CTL responses, had a smaller proportion of intact proviruses but a similar distribution of defective provirus types and escaped or unrecognized epitopes as the other individuals. This work suggests that CTL selection does not significantly check clonal proliferation of infected cells or greatly alter the provirus landscape in people on ART.

RevDate: 2020-03-19

Liu Z, Yoshimi A, Wang J, et al (2020)

Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization.

Cancer discovery pii:2159-8290.CD-19-1330 [Epub ahead of print].

Although mutations in the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here we characterize 98 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3' splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common SF3B1 mutation activates MYC via effects conserved across human and mouse cells. SF3B1 mutations promote decay of transcripts encoding the PP2A phosphatase subunit PPP2R5A, increasing c-MYC S62 and BCL2 S70 phosphorylation which, in turn, promote MYC protein stability and impair apoptosis, respectively. Genetic PPP2R5A restoration or pharmacologic PP2A activation impaired SF3B1-mutant tumorigenesis elucidating a therapeutic approach to aberrant splicing by mutant SF3B1.

RevDate: 2020-03-19

Poramba-Liyanage DW, Korthout T, Cucinotta CE, et al (2020)

Inhibition of transcription leads to rewiring of locus-specific chromatin proteomes.

Genome research pii:gr.256255.119 [Epub ahead of print].

Transcription of a chromatin template involves the concerted interaction of many different proteins and protein complexes. Analyses of specific factors showed that these interactions change during stress and upon developmental switches. However, how the binding of multiple factors at any given locus is coordinated has been technically challenging to investigate. Here we employed Epi-Decoder in yeast to systematically decode, at one transcribed locus, the chromatin binding changes of hundreds of proteins in parallel upon perturbation of transcription. Taking advantage of improved Epi-Decoder libraries, we observed broad rewiring of local chromatin proteomes following chemical inhibition of RNA polymerase. Rapid reduction of RNA polymerase II binding was accompanied by reduced binding of many other core transcription proteins and gain of chromatin remodelers. In quiescent cells, where strong transcriptional repression is induced by physiological signals, eviction of the core transcriptional machinery was accompanied by the appearance of quiescent-cell specific repressors and rewiring of the interactions of protein-folding factors and metabolic enzymes. These results show that Epi-Decoder provides a powerful strategy for capturing the temporal binding dynamics of multiple chromatin proteins under varying conditions and cell states. The systematic and comprehensive delineation of dynamic local chromatin proteomes will greatly aid in uncovering protein-protein relationships and protein functions at the chromatin template.

RevDate: 2020-03-19

Neumeyer S, Butterbach K, Banbury BL, et al (2020)

Genetic predictors of circulating 25-hydroxyvitamin D and prognosis after colorectal cancer.

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-19-1409 [Epub ahead of print].

BACKGROUND: Low serum 25-hydroxyvitamin D (25(OH)D) concentrations in colorectal cancer (CRC) patients have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence CRC mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and CRC-specific survival.

METHODS: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. Based on data from the International Survival Analysis in Colorectal Cancer Consortium (ISACC) the individual genetic variants and a weighted genetic risk score were tested for association with overall and CRC-specific survival using Cox proportional hazards models in 7 657 stage I-IV CRC patients of which 2 438 died from any cause and 1 648 died from CRC.

RESULTS: The 25(OH)D decreasing allele of single nucleotide polymorphism (SNP) rs2282679 (GC) was associated with poorer CRC-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed non-significant associations with increased overall (HR=1.54, 95% CI:0.86-2.78) and CRC-specific mortality (HR=1.76, 95% CI:0.86-3.58). A significant increased risk of overall mortality was observed in women (HR=3.26, 95% CI:1.45-7.33, p-value for heterogeneity=0.01) and normal-weight individuals (HR=4.14, 95% CI:1.50-11.43, p-value for heterogeneity=0.02).

CONCLUSIONS: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or CRC-specific survival, although power might have been an issue.

IMPACT: Further studies are warranted to investigate the association in specific subgroups.

RevDate: 2020-03-18

Tarlock K, Alonzo T, Wang YC, et al (2020)

Prognostic Impact of CSF3R Mutations in Favorable Risk Childhood Acute Myeloid Leukemia.

Blood pii:452717 [Epub ahead of print].

RevDate: 2020-03-18

Song MJ, Potter B, Doyle JJ, et al (2020)

Gene Balance Predicts Transcriptional Responses Immediately Following Ploidy Change in Arabidopsis thaliana.

The Plant cell pii:tpc.19.00832 [Epub ahead of print].

The Gene Balance Hypothesis postulates that there is selection on gene copy number (gene dosage) to preserve stoichiometric balance among interacting proteins. This presupposes that gene product abundance is governed by gene dosage, and that gene dosage responses are consistent for interacting genes in a dosage balance-sensitive network or complex. Gene dosage responses, however, have rarely been quantified and the available data suggest that they are highly variable. We sequenced the transcriptomes of two synthetic autopolyploid accessions of Arabidopsis thaliana and their diploid progenitors, as well as one natural tetraploid and its synthetic diploid produced via haploid induction, to estimate transcriptome size and dosage responses immediately following ploidy change. Similar to what has been observed in previous studies, overall transcriptome size does not exhibit a simple doubling in response to genome doubling, and individual gene dosage responses are highly variable in all three accessions, indicating that expression is not strictly coupled with gene dosage. Nonetheless, putatively dosage balance-sensitive gene groups (GO terms, metabolic networks, gene families, and predicted interacting proteins) exhibit smaller and more coordinated dosage responses than do putatively dosage-insensitive gene groups, suggesting that constraints on dosage balance operate immediately following whole genome duplication, and that duplicate gene retention patterns are shaped by selection to preserve dosage balance.

RevDate: 2020-03-18

Raghunandan R, Mayer BT, Flores-Garcia Y, et al (2020)

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein.

Malaria journal, 19(1):113 pii:10.1186/s12936-020-03181-0.

BACKGROUND: New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models.

METHODS: Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity.

RESULTS: Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs.

CONCLUSION: The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.

RevDate: 2020-03-18

Gorfine M, Schlesinger M, L Hsu (2020)

K-sample omnibus non-proportional hazards tests based on right-censored data.

Statistical methods in medical research [Epub ahead of print].

RevDate: 2020-03-17

McDermott CL, Engelberg RA, Sibley J, et al (2020)

The Association between Chronic Conditions, End-of-Life Health Care Use, and Documentation of Advance Care Planning among Patients with Cancer.

Journal of palliative medicine [Epub ahead of print].

Background: Multiple chronic conditions (MCCs) are associated with increased intensity of end-of-life (EOL) care, but their effect is not well explored in patients with cancer. Objective: We examined EOL health care intensity and advance care planning (ACP) documentation to better understand the association between MCCs and these outcomes. Design: Retrospective cohort study. Setting/Subjects: Patients aged 18+ years at UW Medicine who died during 2010-2017 with poor prognosis cancer, with or without chronic liver disease, chronic pulmonary disease, coronary artery disease, dementia, diabetes with end-stage organ damage, end-stage renal disease, heart failure, or peripheral vascular disease. Measurements: ACP documentation 30+ days before death, in-hospital death, and inpatient or intensive care unit (ICU) admission in the last 30 days. We performed logistic regression for outcomes. Results: Of 15,092 patients with cancer, 10,596 (70%) had 1+ MCCs (range 1-8). Patients with cancer and heart failure had highest odds of hospitalization (odds ratio [OR] 1.67, 95% confidence interval [CI] 1.46-1.91), ICU admission (OR 2.06, 95% CI 1.76-2.41), or in-hospital death (OR 1.62, 95% CI 1.43-1.84) versus patients with cancer and other conditions. Patients with ACP 30+ days before death had lower odds of in-hospital death (OR 0.65, 95% CI 0.60-0.71), hospitalization (OR 0.67, 95% CI 0.61-0.74), or ICU admission (OR 0.71, 95% CI 0.64-0.80). Conclusions: Patients with ACP 30+ days before death had lower odds of high-intensity EOL care. Further research needs to explore how to best use ACP to ensure patients receive care aligned with patient and family goals for care.

RevDate: 2020-03-17

Jing L, Ott M, Church CD, et al (2020)

Prevalent and diverse intratumoral oncoprotein-specific CD8+ T cells within polyoma virus-driven Merkel cell carcinomas.

Cancer immunology research pii:2326-6066.CIR-19-0647 [Epub ahead of print].

Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AAs). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. Strategies to increase CD8+ T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TILs) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DCs). TILs from 9 of 12 (75%) subjects contained CD8+ T cells recognizing 1-8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8+ TIL epitopes and prior TIL data indicated that 97% of MCPyV+ MCC patients had HLA alleles with the genetic potential that restrict CD8+ T-cell responses to MCPyV T-Ag. The LT AA 70-110 region was epitope-rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag-expressing DCs was documented. Recovery of MCPyV oncoprotein-specific CD8+ TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicate that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity.

RevDate: 2020-03-17

Diamantopoulos LN, Khaki AR, Sonpavde GP, et al (2019)

Central Nervous System Metastasis in Patients With Urothelial Carcinoma: Institutional Experience and a Comprehensive Review of the Literature.

Clinical genitourinary cancer pii:S1558-7673(19)30359-3 [Epub ahead of print].

INTRODUCTION: Central nervous system (CNS) metastasis in patients with urothelial carcinoma (UC) is uncommon and poorly understood. We aimed to explore the clinical behavior and outcomes of this unique patient population.

MATERIALS AND METHODS: We performed a retrospective analysis of patients with UC and CNS metastasis, treated in our institution (2006-2018), along with an exploratory patient-point meta-analysis of a similar patient population derived from a comprehensive literature review. Data regarding diagnosis, management, and outcomes were extracted. Overall survival, time to CNS metastasis (TTCM), and residual survival (RS) from CNS involvement to death were calculated (Kaplan-Meier method). Cox regression was used for testing key clinicopathologic associations.

RESULTS: We identified 20 "institutional" and 154 "literature" patients with adequate data granularity for analysis. Median TTCM was 17.7 (institutional cohort) and 10 (literature cohort) months. Most patients who developed CNS metastases had previous non-CNS metastasis (15/20 [75%] and 103/154 [67%], respectively). CNS lesions without previous history of metastasis were identified in 5/20 (25%) and 33/154 (21%) cases and those patients had a shorter TTCM. CNS lesions in the absence of known UC history were also documented in 18/154 (12%) literature cases. Multifocal CNS disease was associated with shorter RS in both cohorts in univariate, but not multivariate, analysis.

CONCLUSION: We observed a variability in disease presentation and course, with a subset of patients showing an early predilection for CNS insult, potentially reflecting a diverse underlying biology. Genomic profiling studies, elucidating the molecular landscape, and driving future treatments should be considered in this setting.

RevDate: 2020-03-17

Pescatello LS, Buchner DM, Jakicic JM, et al (2020)

Response.

Medicine and science in sports and exercise, 52(4):1003-1004.

RevDate: 2020-03-16

Ording AG, Christensen LB, Bjørge T, et al (2020)

Birthweight and all-cause mortality after childhood and adolescent leukemia: a cohort of children with leukemia from Denmark, Norway, Sweden, and Washington State.

Acta oncologica (Stockholm, Sweden) [Epub ahead of print].

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia.Material and methods: In a cohort of childhood and adolescent leukemia (0-19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967-2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down's syndrome or other malformations, and type of leukemia.Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (<2500 g) and 19% were high (≥4000 g) birthweight. Compared with average weight, hazard ratios (HRs) of death associated with low birthweight varied by age at leukemia diagnosis: 1.5 (95% confidence interval (CI): 0.7, 3.2) for patients 0-1 year old, 1.6 (95% CI: 1.0, 2.6) for >1-2 years old; 1.0 (95% CI: 0.6, 1.5) for 3-8 years old; 1.0 (95% CI: 0.6, 1.8) for 9-13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14-19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37-41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8).Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

RevDate: 2020-03-19

Hodonsky CJ, Baldassari AR, Bien SA, et al (2020)

Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics.

BMC genomics, 21(1):228.

BACKGROUND: Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population.

RESULTS: We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p < 5E-9), with lead SNPs at nine loci significantly associated with three or more RBC traits. A majority of the lead SNPs were common (MAF > 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP.

CONCLUSION: This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.

RevDate: 2020-03-20

Iovino L, M Shadman (2020)

Novel Therapies in Chronic Lymphocytic Leukemia: A Rapidly Changing Landscape.

Current treatment options in oncology, 21(4):24.

OPINION STATEMENT: Treatment landscape of chronic lymphocytic leukemia (CLL) has changed since 2014 after the introduction of inhibitors of B-cell receptor signaling pathway (ibrutinib, acalabrutinib, idelalisib and duvelisib) and the inhibitor of the anti-apoptotic protein BCL-2 (venetoclax). In 2019, novel agents were upgraded from being a "great treatment option" to the "preferred choice" for all lines of treatment after number of randomized clinical trials proved their superiority compared to conventional chemoimmunotherapy (CIT) regimens. A growing number of next-generation molecules are in clinical trials with a promise of improved efficacy and less toxicity. This includes agents with expected better safety profile (zanubrutinib, umbralisib, etc.) or more importantly with a potential to overcome the resistance mechanism to early generation agents (ARQ-531, LOXO-305, or vecabrutinib). Early intervention has once again become an active topic of research and, if proven to provide an overall survival benefit, will eliminate the "watch and wait" strategy for asymptomatic CLL patients. Until then, treatment should only be offered to patients who meet the standard treatment indication in standard practice. With our upgraded therapeutic toolbox, there are and will be many unanswered questions. CLL field will need to define the optimal treatment sequence and most effective combinations with a goal of having a time-limited and chemotherapy-free regimen that provides longest remissions and potentially cure. Cellular immunotherapy with chimeric antigen receptor T-cell (CAR-T) may become available for high-risk CLL along with allogeneic stem cell transplant (allo-SCT). Financial toxicity of novel agents especially when used in combination will need to be an important aspect of research in coming years to avoid unnecessary overtreatment of patients. As current prognostic models (CLL-IPI, etc.) were developed and validated in the CIT era, there is ongoing effort to develop new models using clinical and molecular characteristics to accurately define high-risk CLL in the era of novel agents. We all need to keep in mind that access to the novel agents is currently limited to certain developed countries and every effort should be made to make sure patients around the world also benefit from these outstanding drugs.

RevDate: 2020-03-14

Parsons HA, Rhoades J, Reed SC, et al (2020)

Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-3005 [Epub ahead of print].

PURPOSE: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1000-fold lower error rate than conventional sequencing.

EXPERIMENTAL DESIGN: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within six months following metastatic diagnosis and 142 patients with stage 0-III breast cancer who received curative-intent treatment with most sampled at surgery and one year post-op. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.

RESULTS: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median 57, range 2-346). Clinical sensitivity was 81% (n=13/16) in newly diagnosed MBC, 23% (n=7/30) at post-op and 19% (n=6/32) at one year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at one year was strongly associated with distant recurrence (HR=20.8 [95%CI: 7.3-58.9]). Median lead time from first positive sample to recurrence was 18.9 months (range: 3.4-39.2 months).

CONCLUSIONS: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.

RevDate: 2020-03-14

Heck AM, Russo J, Wilusz J, et al (2020)

YTHDF2 destabilizes m6A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells.

RNA (New York, N.Y.) pii:rna.073502.119 [Epub ahead of print].

N6-methyladenosine (m6A) is an abundant post-transcriptional modification that can impact RNA fate via interactions with m6A-specific RNA binding proteins. Despite accumulating evidence that m6A plays an important role in modulating pluripotency, the influence of m6A reader proteins in pluripotency is less clear. Here, we report that YTHDF2, an m6A reader associated with mRNA degradation, is highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation. Through RNA sequencing, we identified a group of m6A-modified transcripts associated with neural development that are directly regulated by YTDHF2. Depletion of YTHDF2 in iPSCs leads to stabilization of these transcripts, loss of pluripotency and induction of neural-specific gene expression. Collectively, our results suggest YTHDF2 functions to restrain expression of neural-specific mRNAs in iPSCs and facilitate their rapid and coordinated upregulation during neural induction. These effects are both achieved by destabilization of the targeted transcripts.

RevDate: 2020-03-14

Matesan MC, Fisher DR, Wong R, et al (2020)

Biokinetics of Radiolabeled Monoclonal Antibody BC8: Differences in Biodistribution and Dosimetry among Hematologic Malignancies.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine pii:jnumed.119.234443 [Epub ahead of print].

We reviewed 111In-DOTA-anti-CD45 antibody (BC8) imaging and bone marrow biopsy measurements to ascertain biodistribution and biokinetics of the radiolabeled antibody and to investigate differences based on type of hematologic malignancy. Methods: Serial whole-body scintigraphic images (4 time-points) were obtained after infusion of the 111In-DOTA-BC8 (176-406 MBq) in 52 adult patients with hematologic malignancies (lymphoma, multiple myeloma, acute myeloid leukemia and myelodysplastic syndrome). Counts were obtained for the regions of interest for spleen, liver, kidneys, testicles (in males), and two marrow sites (acetabulum and sacrum) and correction for attenuation and background was made. Bone marrow biopsies were obtained 14-24 hours post-infusion and percent of administered activity was determined. Radiation absorbed doses were calculated. Results: Initial uptake in liver averaged 32% ± 8.4% (S.D.) of administered activity (52 patients), which cleared monoexponentially with biological half-time of 293 ± 157 hours (33 patients) or did not clear (19 patients). Initial uptake in spleen averaged 22% ± 12% and cleared with a biological half-time 271 ± 185 hours (36 patients) or longer (6 patients). Initial uptake in kidney averaged 2.4% ± 2.0% and cleared with a biological half-time of 243 ± 144 hours (27 patients) or longer (9 patients). Initial uptake in red marrow averaged 23% ± 11% and cleared with half-times of 215 ± 107 hours (43 patients) or longer (5 patients). Whole-body retention half-times averaged 198 ± 75 hours. Splenic uptake was higher in the AML/MDS group when compared to the lymphoma group (p ≤ 0.05) and to the multiple myeloma group (p ≤ 0.10). Liver represented the dose-limiting organ. For liver uptake, no significant differences were observed between the three malignancy groups. Average calculated radiation absorbed doses per unit administered activity for a therapy infusions of 90Y-DOTA-BC8 were for red marrow: 470 ± 260 cGy/MBq, liver 1100 ± 330 cGy/MBq, spleen 4120 ± 1950 cGy/MBq, total body 7520 ± 20 cGy/MBq, osteogenic cells 290 ± 200 cGy/MBq, and kidneys 240 ± 200 cGy/MBqR. Conclusion:111In-DOTA-BC8 had long retention time in liver, spleen, kidneys, and red marrow, and the highest absorbed doses were calculated for spleen and liver. Few differences were observed by malignancy type. The exception was greater splenic uptake among leukemia/MDS group when compared to lymphoma and multiple myeloma groups.

RevDate: 2020-03-16

Lee CJ, Kim S, Tecca HR, et al (2020)

Late effects after ablative allogeneic stem cell transplantation for adolescent and young adult acute myeloid leukemia.

Blood advances, 4(6):983-992.

There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.

RevDate: 2020-03-13

Schwartz NRM, Crane DA, Doody DR, et al (2020)

Assessment of the Accuracy of Identification of Selected Disabilities and Conditions in Hospital Discharge Data for Pregnant Women.

Epidemiology (Cambridge, Mass.) [Epub ahead of print].

BACKGROUND: Linked birth certificate-hospital discharge records are a valuable resource for examining pregnancy outcomes among women with disability conditions. Few studies relying on these data have been able to assess the accuracy of identification of pre-existing disability conditions. We assessed the accuracy of International Classification of Diseases version 9 (ICD9) codes for identifying selected physical, sensory, and intellectual conditions that may result in disability. As ICD9 codes were utilized until recently in most states, this information is useful to inform analyses with these records.

METHODS: We reviewed 280 of 311 (90%) medical records of pregnant women with disabilities based on ICD9 codes and 390 of 8,337 (5%) records of pregnant women without disabilities who had deliveries at a large university medical center. We estimated sensitivity, specificity, and positive predictive values (PPV) using the medical record as gold standard. We adjusted for verification bias using inverse probability weighting and imputation.

RESULTS: The estimated sensitivity of ICD9 codes to identify women with disabilities with deliveries 2009-2012 was 44%; PPV was 98%, improving over time. Although sensitivity was <50% for some conditions, PPVs were 87%-100% for all conditions except intellectual disability (67%). Many physical conditions had complete verification and no underreporting.

CONCLUSIONS: These results are helpful for new studies using historical data comparing outcomes among women with and without these conditions, and to inform interpretation of results from earlier studies. Assessment of the accuracy of disabilities as identified by ICD version 10 codes is warranted.

RevDate: 2020-03-13

Han CJ, Gigic B, Schneider M, et al (2020)

Risk factors for cancer-related distress in colorectal cancer survivors: one year post surgery.

Journal of cancer survivorship : research and practice pii:10.1007/s11764-019-00845-y [Epub ahead of print].

PURPOSES: Cancer-related distress is known to persist long after completion of treatment. Factors related to distress are largely unexplored in colorectal cancer (CRC) survivors. We examined changes over time and risk factors for distress in CRC patients over the first year after surgery.

METHODS: We included 212 CRC patients with data at 6 and 12 months post-surgery from the ColoCare Study in Heidelberg, Germany. Sociodemographic and lifestyle factors, social support, and health-related quality of life (HrQOL) prior to surgery were evaluated as predictors of cancer-related distress. Distress was measured with the Cancer and Treatment Distress instrument (CTXD). Linear regression analyses examined associations between risk factors and distress.

RESULTS: Distress subscale scores varied significantly over time: health burden subscale score increased (P < .001), while finances (P = .004), medical demands (P < .001), and identity (P < .001) subscale scores decreased over time. Uncertainty and family strain subscale scores did not change. Younger age, lower income, advanced tumor stage, poorer social support, and poorer baseline HrQOL predicted higher level distress at 6 and 12 months.

CONCLUSION: Cancer-related distress continues unresolved after surgery. Although some risk factors are difficult to alter, those at highest risk can be identified earlier for possible preventive strategies.

Screening for risk factors pre-surgery would allow for targeted interventions including strategies to improve resources for those with low support, thereby reducing long-term distress in CRC survivors.

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ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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

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Papers in Classical Genetics

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

Digital Books

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

Timelines

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

Biographies

Biographical information about many key scientists.

Selected Bibliographies

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

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