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14 Oct 2019 at 01:32
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Bibliography on: Publications by FHCRC Researchers


Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 14 Oct 2019 at 01:32 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: 2019-10-12

Georges GE, Bar M, Onstad L, et al (2019)

Survivorship after Autologous Hematopoietic Cell Transplantation for Lymphoma and Multiple Myeloma: Late Effects and Quality of Life.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30653-6 [Epub ahead of print].

Although autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with lymphoma and multiple myeloma (MM), few studies have addressed late effects and quality of life (QOL) for long-term survivors after AHCT. Using long-term follow-up (LTFU) annual questionnaires with self-reported outcomes, we surveyed 665 patients who were ≥5 years after AHCT for the diagnosis of lymphoma or MM. Three-hundred and eighty-nine patients completed the questionnaire (58% response rate) a median of 11 (range 5-30) years after AHCT. The median age (years, range) among 268 lymphoma patients was 63 (22-88), and for 121 multiple myeloma patients was 69 (34-84). The most commonly reported medical conditions (>10% incidence) included: sexual dysfunction, history of shingles, cataracts, osteoporosis or osteopenia, joint replacement, and skin cancer. Current medication use was more frequent in MM patients for: infection prevention/treatment (19% multiple myeloma vs 5% lymphoma, p<.001), hypertension (41% vs. 26%, p=.004), osteoporosis (23% vs. 10%, p=<0.001), and pain (33% vs. 11%, p<.001). Treated hypothyroidism was more common in lymphoma patients. In multivariate analysis combining lymphoma and MM, worse physical functioning was associated with older age, shorter time since AHCT, comorbidities, relapse and treatment for depression and/or pain. Worse mental functioning was associated with younger age and treatment for anxiety, depression or pain. In conclusion, AHCT survivors report generally good QOL but many late effects and symptoms that are potentially amenable to intervention.

RevDate: 2019-10-12

Ruark J, Mullane E, Cleary N, et al (2019)

Patient-Reported Neuropsychiatric Outcomes of Long-Term Survivors after Chimeric Antigen Receptor-T Cell Therapy.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30657-3 [Epub ahead of print].

CD19-targeted chimeric antigen receptor modified T-cell immunotherapy (CAR-T cell therapy) is a novel treatment with promising results in patients with relapsed/refractory lymphoid malignancies. CAR-T cell therapy has known early toxicities of cytokine release syndrome (CRS) and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have utilized patient-reported outcomes (PROs), including PROMIS® measures, to assess neuropsychiatric and other patient-reported outcomes of 40 patients with relapse/refractory chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia (ALL), one to five years after treatment with CD19-targeted CAR-T cells. Mean T scores of PROMIS domains of Global Mental health, Global Physical Health, Social Function, anxiety, depression, fatigue, pain and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 patients (47.5%) reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety, and 7 patients (17.5%) scored ≤ 40 in Global Mental Health, indicating at least one standard deviation worse than the general population mean. Younger age was associated with worse long-term Global Mental Health (p=0.02), anxiety (p=0.001) and depression (p=0.01). Anxiety prior to CAR-T cell therapy was associated with increased likelihood of anxiety after CAR-T cell therapy (p=0.001). 15 patients (37.5%) reported cognitive difficulties post CAR-T cell therapy. Depression prior to CAR-T cell therapy was statistically significantly associated with higher likelihood of self-reported post CAR-T cognitive difficulties (p=0.02) and there was a trend for association between acute neurotoxicity and self-reported post-CAR-T cognitive difficulties (p=0.08). Having more post-CAR-T cognitive difficulties was associated with worse Global Mental Health and Global Physical Health. Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR-T cell therapy. However, nearly 50% of patients in the cohort reported at least one clinically meaningful negative neuropsychiatric outcome (anxiety, depression or cognitive difficulty), indicating that there is a significant number of patients who would likely benefit from mental health services following CAR-T cell therapy. Younger age, pre-CAR-T anxiety or depression, and acute neurotoxicity may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings.

RevDate: 2019-10-12

Wenger DS, Triplette M, Crothers K, et al (2019)

Incidence, Risk Factors and Outcomes of Idiopathic Pneumonia Syndrome after Allogeneic Hematopoietic Cell Transplantation.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30654-8 [Epub ahead of print].

RevDate: 2019-10-12

Verdial FC, Berfield K, Wood DE, et al (2019)

Safety and Costs of Endobronchial Ultrasound-Guided Nodal Aspiration and Mediastinoscopy.

Chest pii:S0012-3692(19)34002-4 [Epub ahead of print].

BACKGROUND: There remains debate over the best invasive diagnostic modality for mediastinal nodal evaluation. Prior studies have limited generalizability and insufficient power to detect differences in rare adverse events. We compared the risks and costs of endobronchial ultrasound-guided nodal aspiration (EBUS) and mediastinoscopy performed for any indication in a large national cohort.

METHODS: We conducted a retrospective study (2007-2015) using MarketScan-a claims database of individuals with employer-provided insurance in the United States. Patients who underwent multi-modality mediastinal evaluation (n=1,396) or same-day pulmonary resection (n=2,130) were excluded. Regression models were used to evaluate associations between diagnostic modalities and risks and costs while adjusting for patient characteristics, year, concomitant bronchoscopic procedures, and lung cancer diagnosis.

RESULTS: Among 30,570 patients, 49% underwent EBUS. Severe adverse events-pneumothorax, hemothorax, airway/vascular injuries, or death-were rare and invariant between EBUS and mediastinoscopy (0.3% versus 0.4%, p=0.189). The rate of vocal cord paralysis was lower for EBUS (1.4% versus 2.2%, p<0.001). EBUS was associated with a lower adjusted risk of severe adverse events (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.32-0.55) and vocal cord paralysis (OR 0.57, 95% CI 0.54-0.60). The mean cost of EBUS was $2,211 less than mediastinoscopy ($6,816 versus $9,023, p<0.001). After adjustment this difference decreased to $1,650 (95% CI $1,525-$1,776).

CONCLUSIONS: When performed as isolated procedures, EBUS is associated with lower risks and costs compared to mediastinoscopy. Future studies comparing the effectiveness of EBUS versus mediastinoscopy in the community-at-large will help determine which procedure is superior or if trade-offs exist.

RevDate: 2019-10-12

Kapoor PM, Lindström S, Behrens S, et al (2019)

Assessment of interactions between 205 breast cancer susceptibility loci and 13 established risk factors in relation to breast cancer risk, in the Breast Cancer Association Consortium.

International journal of epidemiology pii:5586556 [Epub ahead of print].

BACKGROUND: Previous gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions.

METHODS: Analyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions.

RESULTS: Noteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10-4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10-5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth.

CONCLUSIONS: Overall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors.

RevDate: 2019-10-11

Boonyaratanakornkit J, JJ Taylor (2019)

Immunoglobulin M, more than just an early responder to malaria.

Immunology and cell biology, 97(9):771-773.

RevDate: 2019-10-11

Piepkorn MW, Longton GM, Reisch LM, et al (2019)

Assessment of Second-Opinion Strategies for Diagnoses of Cutaneous Melanocytic Lesions.

JAMA network open, 2(10):e1912597 pii:2752813.

Importance: Histopathologic criteria have limited diagnostic reliability for a range of cutaneous melanocytic lesions.

Objective: To evaluate the association of second-opinion strategies by general pathologists and dermatopathologists with the overall reliability of diagnosis of difficult melanocytic lesions.

This diagnostic study used samples from the Melanoma Pathology Study, which comprises 240 melanocytic lesion samples selected from a dermatopathology laboratory in Bellevue, Washington, and represents the full spectrum of lesions from common nevi to invasive melanoma. Five sets of 48 samples were evaluated independently by 187 US pathologists from July 15, 2013, through May 23, 2016. Data analysis was performed from April 2016 through November 2017.

Main Outcomes and Measures: Accuracy of diagnosis, defined as concordance with an expert consensus diagnosis of 3 experienced pathologists, was assessed after applying 10 different second-opinion strategies.

Results: Among the 187 US pathologists examining the 24 lesion samples, 113 were general pathologists (65 men [57.5%]; mean age at survey, 53.7 years [range, 33.0-79.0 years]) and 74 were dermatopathologists (49 men [66.2%]; mean age at survey, 46.4 years [range, 33.0-77.0 years]). Among the 8976 initial case interpretations, physicians desired second opinions for 3899 (43.4%), most often for interpretation of severely dysplastic nevi. The overall misclassification rate was highest when interpretations did not include second opinions and initial reviewers were all general pathologists lacking subspecialty training (52.8%; 95% CI, 51.3%-54.3%). When considering different second opinion strategies, the misclassification of melanocytic lesions was lowest when the first, second, and third consulting reviewers were subspecialty-trained dermatopathologists and when all lesions were subject to second opinions (36.7%; 95% CI, 33.1%-40.7%). When the second opinion strategies were compared with single interpretations without second opinions, the reductions in misclassification rates for some of the strategies were statistically significant, but none of the strategies eliminated diagnostic misclassification. Melanocytic lesions in the middle of the diagnostic spectrum had the highest misclassification rates (eg, moderately or severely dysplastic nevus, Spitz nevus, melanoma in situ, and pathologic stage [p]T1a invasive melanoma). Variability of in situ and thin invasive melanoma was relatively intractable to all examined strategies.

Conclusions and Relevance: The results of this study suggest that second opinions rendered by dermatopathologists improve reliability of melanocytic lesion diagnosis. However, discordance among pathologists remained high.

RevDate: 2019-10-11

Kuppers DA, Arora S, Lim Y, et al (2019)

N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis.

Nature communications, 10(1):4596 pii:10.1038/s41467-019-12518-6.

Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

RevDate: 2019-10-11

Pantaleo G, Janes H, Karuna S, et al (2019)

Safety and immunogenicity of a multivalent HIV vaccine comprising envelope protein with either DNA or NYVAC vectors (HVTN 096): a phase 1b, double-blind, placebo-controlled trial.

The lancet. HIV pii:S2352-3018(19)30262-0 [Epub ahead of print].

BACKGROUND: Up to now, immunisation regimens that have been assessed for development of HIV vaccines have included purified envelope (Env) protein among the boosting components of the regimen. We postulated that co-administration of Env protein with either a DNA or NYVAC vector during priming would result in early generation of antibody responses to the Env V1/V2 region, which are important markers for effective protection against infection. We aimed to assess the safety and immunogenicity of a multivalent HIV vaccine including either DNA or NYVAC vectors alone or in combination with Env glycoprotein (gp120) followed by a co-delivered NYVAC and Env protein boost.

METHODS: We did a single-centre, double-blind, placebo-controlled phase 1b trial at the Centre Hospitalier Universitaire Vaudois (Lausanne, Switzerland). We included healthy volunteers aged 18-50 years who were at low risk of HIV infection. We randomly allocated participants using computer-generated random numbers to one of four vaccination schedules or placebo (4:1), and within these schedules participants were allocated either active treatment (T1, T2, T3, and T4) or placebo (C1, C2, C3, and C4). T1 consisted of two doses of NYVAC vector followed by two doses of NYVAC vector and gp120 Env protein; T2 comprised four doses of NYVAC vector and gp120 Env protein; T3 was two doses of DNA vector followed by two doses of NYVAC vector and gp120 Env protein; and T4 was two doses of DNA vector and gp120 Env protein followed by two doses of NYVAC vector and gp120 Env protein. Placebo injections were matched to the corresponding active treatment group. Doses were administered by injection at months 0, 1, 3, and 6. Primary outcomes were safety and immunogenicity of the vaccine schedules. Immune response measures included cross-clade and epitope-specific binding antibodies, neutralising antibodies, and antibody-dependent cell-mediated cytotoxicity measured 2 weeks after the month 1, 3, and 6 vaccinations. This trial is registered with ClinicalTrials.gov, NCT01799954.

FINDINGS: Between Aug 23, 2012, and April 18, 2013, 148 healthy adult volunteers were screened for the trial, of whom 96 participants were enrolled. 20 individuals were allocated to each active treatment group (groups T1-4; n=80) and four were assigned to each placebo group (groups C1-4; n=16). Vaccines containing the NYVAC vector (groups T1 and T2) were associated with more frequent severe reactogenicity and more adverse events than were vaccines containing the DNA vector (groups T3 and T4). The most frequent adverse events judged related to study product were lymphadenopathy (n=9) and hypoaesthesia (n=2). Two participants, one in the placebo group and one in the DNA-primed T3 group, had serious adverse events that were judged unrelated to study product. One participant in the T3 group died from cranial trauma after a motor vehicle accident. Across the active treatment groups, IgG responses 2 weeks after the 6-month dose of vaccine were 74-95%. Early administration of gp120 Env protein (groups T2 and T4) was associated with a substantially earlier and higher area under the curve for gp120 Env binding, production of anti-V1/V2 and neutralising antibodies, and better antibody-response coverage over a period of 18 months, compared with vaccination regimens that delayed administration of gp120 Env protein until the 3-month vaccination (groups T1 and T3).

INTERPRETATION: Co-administration of gp120 Env protein components with DNA or NYVAC vectors during priming led to early and potent induction of Env V1/V2 IgG binding antibody responses. This immunisation approach should be considered for induction of preventive antibodies in future HIV vaccine efficacy trials.

FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases, and the Bill & Melinda Gates Foundation.

RevDate: 2019-10-10

Skelding D, Hart SFM, Vidyasagar T, et al (2018)

Developing a low-cost milliliter-scale chemostat array for precise control of cellular growth.

Quantitative biology (Beijing, China), 6(2):129-141.

Background: Multiplexed milliliter-scale chemostats are useful for measuring cell physiology under various degrees of nutrient limitation and for carrying out evolution experiments. In each chemostat, fresh medium containing a growth rate-limiting metabolite is pumped into the culturing chamber at a constant rate, while culture effluent exits at an equal rate. Although such devices have been developed by various labs, key parameters - the accuracy, precision, and operational range of flow rate - are not explicitly characterized.

Methods: Here we re-purpose a published multiplexed culturing device to develop a multiplexed milliliter-scale chemostat. Flow rates for eight chambers can be independently controlled to a wide range, corresponding to population doubling times of 3~13 h, without the use of expensive feedback systems.

Results: Flow rates are precise, with the maximal coefficient of variation among eight chambers being less than 3%. Flow rates are accurate, with average flow rates being only slightly below targets, i.e., 3%-6% for 13-h and 0.6%-1.0% for 3-h doubling times. This deficit is largely due to evaporation and should be correctable. We experimentally demonstrate that our device allows accurate and precise quantification of population phenotypes.

Conclusions: We achieve precise control of cellular growth in a low-cost milliliter-scale chemostat array, and show that the achieved precision reduces the error when measuring biological processes.

RevDate: 2019-10-10

Palumbo PJ, Zhang Y, Fogel JM, et al (2019)

HIV drug resistance in persons who inject drugs enrolled in an HIV prevention trial in Indonesia, Ukraine, and Vietnam: HPTN 074.

PloS one, 14(10):e0223829 pii:PONE-D-19-07824.

BACKGROUND: Persons who inject drugs (PWID) have high HIV incidence and prevalence, and may have limited access to antiretroviral therapy (ART) in some settings. We evaluated HIV drug resistance in PWID in a randomized clinical trial (HPTN 074). The study intervention included ART at any CD4 cell count with enhanced support for ART and substance use treatment.

METHODS: HPTN 074 enrolled HIV-infected PWID (index participants) with viral loads ≥1,000 copies/mL and their HIV-uninfected injection-network partners in Indonesia, Ukraine, and Vietnam; the study limited enrollment of people who reported being on ART. HIV drug resistance testing and antiretroviral (ARV) drug testing were performed using samples collected from index participants at study enrollment.

RESULTS: Fifty-four (12.0%) of 449 participants had HIV drug resistance; 29 (53.7%) of the 54 participants had multi-class resistance. Prevalence of resistance varied by study site and was associated with self-report of prior or current ART, detection of ARV drugs, and a history of incarceration. Resistance was detected in 10 (5.6%) of 177 newly diagnosed participants. Participants with resistance at enrollment were less likely to be virally suppressed after 52 weeks of follow-up, independent of study arm.

CONCLUSIONS: In HPTN 074, many of the enrolled index participants had HIV drug resistance and more than half of those had multi-class resistance. Some newly-diagnosed participants had resistance, suggesting that they may have been infected with drug-resistant HIV strains. Behavioral and geographic factors were associated with baseline resistance. Baseline resistance was associated with reduced viral suppression during study follow-up. These findings indicate the need for enhanced HIV care in this high-risk population to achieve sustained viral suppression on ART.

RevDate: 2019-10-10

Spencer JC, Rotter JS, Eberth JM, et al (2019)

Employment changes following breast cancer diagnosis: the effects of race and place.

Journal of the National Cancer Institute pii:5585013 [Epub ahead of print].

The financial implications of breast cancer diagnosis may be greater among rural and Black women. Women with incident breast cancer were recruited as part of the Carolina Breast Cancer Study. We compared unadjusted and adjusted prevalence of cancer-related job or income loss, and a composite measure of either outcome, by rural residence and stratified by race. 2,435 women were included, 11.7% were rural, 48.5% were Black, and 38.0% reported employment changes after diagnosis. Rural women more often reported employment effects, including reduced household income (43.6% vs. 35.4%, two-sided chi-square test p = 0.04). Rural White, rural Black, and urban Black women each more often reported income reduction (statistically significant vs. urban White women), although these groups did not meaningfully differ from each other. In multivariable regression, rural differences were mediated by socioeconomic factors but racial differences remained. Programs and policies to reduce financial toxicity in vulnerable patients should address indirect costs of cancer, including lost wages and employment.

RevDate: 2019-10-10

Shi Z, Rundle A, Genkinger JM, et al (2019)

Distinct trajectories of fruits and vegetables, dietary fat, and alcohol intake following a breast cancer diagnosis: the Pathways Study.

Breast cancer research and treatment pii:10.1007/s10549-019-05457-9 [Epub ahead of print].

PURPOSE: To identify distinct diet trajectories after breast cancer (BC) diagnosis, and to examine the characteristics associated with diet trajectories.

METHODS: We analyzed 2865 Pathways Study participants who completed ≥ 2 food frequency questionnaires at the time of BC diagnosis (baseline), and at 6 and 24 months after baseline. Trajectory groups of fruit and vegetable (F/V) intake, % calories from dietary fat, and alcohol intake over 24 months were identified using group-based trajectory modeling. Associations between diet trajectories and sociodemographic, psychosocial, and clinical factors were analyzed using multinomial logistic regression.

RESULTS: Analyses identified 3 F/V trajectory groups, 4 dietary fat groups, and 3 alcohol groups. All 3 F/V trajectory groups reported slightly increased F/V intake post-diagnosis (mean increase = 0.2-0.5 serving/day), while 2 groups (48% of participants) persistently consumed < 4 servings/day of F/V. Dietary fat intake did not change post-diagnosis, with 45% of survivors maintaining a high-fat diet (> 40% of calories from fat). While most survivors consumed < 1 drink/day of alcohol at all times, 21% of survivors had 1.4-3.0 drinks/day at baseline and temporarily decreased to 0.1-0.5 drinks/day at 6 months. In multivariable analysis, diet trajectory groups were significantly associated with education (ORs: 1.93-2.49), income (ORs: 1.32-2.57), optimism (ORs: 1.93-2.49), social support (OR = 1.82), and changes in physical well-being (ORs: 0.58-0.61) and neuropathy symptoms after diagnosis (ORs: 1.29-1.66).

CONCLUSIONS: Pathways Study participants reported slightly increasing F/V and decreasing alcohol intake after BC diagnosis. Nearly half of survivors consumed insufficient F/V and excessive dietary fat. It is important to prioritize nutrition counseling and education in BC survivors.

RevDate: 2019-10-10

Zhao YQ, ML LeBlanc (2019)

Designing precision medicine trials to yield greater population impact.

Biometrics [Epub ahead of print].

Traditionally, a clinical trial is conducted comparing treatment to standard care for all patients. However, it could be inefficient given patients' heterogeneous responses to treatments, and rapid advances in the molecular understanding of diseases have made biomarker-based clinical trials increasingly popular. We propose a new targeted clinical trial design, termed as Max-Impact design, which selects the appropriate subpopulation for a clinical trial and aims to optimize population impact once the trial is completed. The proposed design not only gains insights on the patients who would be included in the trial, but also considers the benefit to the excluded patients. We develop novel algorithms to construct enrollment rules for optimizing population impact, which are fairly general and can be applied to various types of outcomes. Simulation studies and a data example from the SWOG Cancer Research Network demonstrate the competitive performance of our proposed method compared to traditional untargeted and targeted designs. This article is protected by copyright. All rights reserved.

RevDate: 2019-10-10

Hart SFM, Skelding D, Waite AJ, et al (2019)

High-throughput quantification of microbial birth and death dynamics using fluorescence microscopy.

Quantitative biology (Beijing, China), 7(1):69-81.

Background: Microbes live in dynamic environments where nutrient concentrations fluctuate. Quantifying fitness in terms of birth rate and death rate in a wide range of environments is critical for understanding microbial evolution and ecology.

Methods: Here, using high-throughput time-lapse microscopy, we have quantified how Saccharomyces cerevisiae mutants incapable of synthesizing an essential metabolite (auxotrophs) grow or die in various concentrations of the required metabolite. We establish that cells normally expressing fluorescent proteins lose fluorescence upon death and that the total fluorescence in an imaging frame is proportional to the number of live cells even when cells form multiple layers. We validate our microscopy approach of measuring birth and death rates using flow cytometry, cell counting, and chemostat culturing.

Results: For lysine-requiring cells, very low concentrations of lysine are not detectably consumed and do not support cell birth, but delay the onset of death phase and reduce the death rate compared to no lysine. In contrast, in low hypoxanthine, hypoxanthine-requiring cells can produce new cells, yet also die faster than in the absence of hypoxanthine. For both strains, birth rates under various metabolite concentrations are better described by the sigmoidal-shaped Moser model than the well-known Monod model, while death rates can vary with metabolite concentration and time.

Conclusions: Our work reveals how time-lapse microscopy can be used to discover non-intuitive microbial birth and death dynamics and to quantify growth rates in many environments.

RevDate: 2019-10-10

Inoue D, Chew GL, Liu B, et al (2019)

Spliceosomal disruption of the non-canonical BAF complex in cancer.

Nature pii:10.1038/s41586-019-1646-9 [Epub ahead of print].

SF3B1 is the most commonly mutated RNA splicing factor in cancer1-4, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L5-7. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.

RevDate: 2019-10-10

Peddu V, Dubuc I, Gravel A, et al (2019)

Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expression in vivo that correlates with increased antibody immune response.

Journal of virology pii:JVI.01418-19 [Epub ahead of print].

Human herpesvirus-6A and 6B (HHV-6A, HHV-6B) are human viruses capable of chromosomal integration. Approximately 1% of the human population carry one copy of HHV-6A/B integrated into every cell in their body, referred to as inherited chromosomally integrated human herpesvirus 6A/B (iciHHV-6A/B). Whether iciHHV-6A/B is transcriptionally active in vivo and how it shapes the immunological response is still unclear. Here, we screened DNA-Seq and RNA-Seq data for 650 individuals available through the Genotype-Tissue Expression (GTEx) project and identified 2 iciHHV-6A and 4 iciHHV-6B positive candidates. When corresponding tissue-specific gene expression signatures were analyzed, low levels HHV-6A/B gene expression was found across multiple tissues, with the highest levels of gene expression in the brain (specifically for HHV-6A), testis, esophagus, and adrenal gland. U90 and U100 were the most highly expressed HHV-6 genes in both iciHHV-6A and iciHHV-6B individuals. To assess whether tissue-specific gene expression from iciHHV-6A/B influences the immune response, a cohort of 15,498 subjects was screened and 85 iciHHV-6A/B+ subjects were identified. Plasma samples from iciHHV-6A/B+ and age and sex matched controls were analyzed for antibodies to control antigens (CMV, EBV, FLU) or HHV-6A/B antigens. Our results indicate that iciHHV-6A/B+ subjects have significantly more antibodies against the U90 gene product (IE1) relative to non-iciHHV-6 individuals. Antibody responses against EBV and FLU antigens or HHV-6A/B gene products either not expressed or expressed at low levels, such as U47, U57 or U72, were identical between controls and iciHHV-6A/B+ subjects. CMV seropositive individuals with iciHHV-6A/B+ have more antibodies against CMV pp150, relative to CMV seropositive controls. These results argue that spontaneous gene expression from integrated HHV-6A/B leads to an increase in antigenic burden that translates into a more robust HHV-6A/B specific antibody response.IMPORTANCE HHV-6A/B are human herpesviruses that have the unique property of being able to integrate into the telomeric regions of human chromosomes. Approximately 1% of the world's population carries integrated HHV-6A/B genome in every cell of their body. Whether viral genes are transcriptionally active in these individuals is unclear. By taking advantage of a unique tissue-specific gene expression dataset, we show the majority of tissues from iciHHV-6 individuals do not show HHV-6 gene expression. Brain and testes showed the highest tissue-specific expression of HHV-6 genes in two separate datasets. Two HHV-6 genes, U90 (immediate early 1 protein) and U100 (glycoproteins Q1 and Q2), were found to be selectively and consistently expressed across several human tissues. Expression of U90 translates into an increase in antigen-specific antibody response in iciHHV-6A/B+ subjects relative to controls. Future studies will be needed to determine the mechanism of gene expression, the effects of these genes on human gene transcription networks and the pathophysiological impact of having increased viral protein expression in tissue in conjunction with increased antigen-specific antibody production.

RevDate: 2019-10-09

Suzuki H, Kumar SA, Shuai S, et al (2019)

Recurrent non-coding U1-snRNA mutations drive cryptic splicing in Shh medulloblastoma.

Nature pii:10.1038/s41586-019-1650-0 [Epub ahead of print].

Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein-coding genes, and are rare in most paediatric cancers1-3. Here we report highly recurrent hotspot mutations of U1 spliceosomal small nuclear RNAs (snRNAs) in ~50% of Sonic hedgehog medulloblastomas (Shh-MB), which were not present across other medulloblastoma subgroups. This U1-snRNA hotspot mutation (r.3a>g), was identified in <0.1% of 2,442 cancers across 36 other tumour types. Largely absent from infant Shh-MB, the mutation occurs in 97% of adults (Shhδ), and 25% of adolescents (Shhα). The U1-snRNA mutation occurs in the 5' splice site binding region, and snRNA mutant tumours have significantly disrupted RNA splicing with an excess of 5' cryptic splicing events. Mutant U1-snRNA-mediated alternative splicing inactivates tumour suppressor genes (PTCH1), and activates oncogenes (GLI2, CCND2), represents a novel target for therapy, and constitutes a highly recurrent and tissue-specific mutation of a non-protein coding gene in cancer.

RevDate: 2019-10-09

Grivas P, DerSarkissian M, Shenolikar R, et al (2019)

Healthcare resource utilization and costs of adverse events among patients with metastatic urothelial cancer in USA.

Future oncology (London, England) [Epub ahead of print].

Aim: To estimate incremental costs and healthcare resource utilization (HRU) associated with select severe adverse events (AEs) and AEs of any severity in patients with metastatic urothelial carcinoma receiving first-line (1L) therapy. Materials & methods: Adults treated with 1L systemic therapy between January 2012 and September 2017 with ≥1 urothelial cancer diagnosis were identified using claims data. Per-patient-per-month cost differences and HRU rate ratios comparing patients with and without select AEs were estimated. Results: Patients with any severe select AEs had higher costs than those without (cost difference = $6130 per-patient-per-month; p < 0.001). Healthcare costs and HRU for patients with select AEs were significantly higher versus those without. Conclusion: Select AEs during 1L therapy for metastatic urothelial carcinoma can result in significant burden to patients and healthcare systems.

RevDate: 2019-10-08

Hagiwara K, Ding L, Edmonson MN, et al (2019)

RNAIndel: discovering somatic coding indels from tumor RNA-Seq data.

Bioinformatics (Oxford, England) pii:5583731 [Epub ahead of print].

MOTIVATION: Reliable identification of expressed somatic insertion/deletion (indels) is an unmet need due to artifacts generated in PCR-based RNA-Seq library preparation and the lack of normal RNA-Seq data, presenting analytical challenges for discovery of somatic indels in tumor trasncriptome.

RESULTS: We present RNAIndel, a tool for predicting somatic, germline and artifact indels from tumor RNA-Seq data. RNAIndel leverages features derived from indel sequence context and biological effect in a machine-learning framework. Except for tumor samples with microsatellite instability, RNAIndel robustly predicts 88‒100% of somatic indels in five diverse test data sets of pediatric and adult cancers, even recovering subclonal (VAF range 0.01-0.15) driver indels missed by targeted deep-sequencing, outperforming the current best-practice for RNA-Seq variant calling which had 57% sensitivity but with 14 times more false positives.

AVAILABILITY: RNAIndel is freely available at https://github.com/stjude/RNAIndel.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RevDate: 2019-10-08

Płachetka M, Żyła-Uklejewicz D, Weigel C, et al (2019)

Streptomycete origin of chromosomal replication with two putative unwinding elements.

Microbiology (Reading, England) [Epub ahead of print].

DNA replication is controlled mostly at the initiation step. In bacteria, replication of the chromosome starts at a single origin of replication called oriC. The initiator protein, DnaA, binds to specific sequences (DnaA boxes) within oriC and assembles into a filament that promotes DNA double helix opening within the DNA unwinding element (DUE). This process has been thoroughly examined in model bacteria, including Escherichia coli and Bacillus subtilis, but we have a relatively limited understanding of chromosomal replication initiation in other species. Here, we reveal new details of DNA replication initiation in Streptomyces, a group of Gram-positive soil bacteria that possesses a long linear (8-10 Mbps) and GC-rich chromosome with a centrally positioned oriC. We used comprehensive in silico, in vitro and in vivo analyses to better characterize the structure of Streptomyces oriC. We identified 14 DnaA-binding motifs and determined the consensus sequence of the DnaA box. Unexpectedly, our in silico analysis using the WebSIDD algorithm revealed the presence of two putative Streptomyces DUEs (DUE1 and DUE2) located very near one another toward the 5' end of the oriC region. In vitro P1 nuclease assay revealed that DNA unwinding occurs at both of the proposed sites, but using an in vivo replication initiation point mapping, we were able to confirm only one of them (DUE2). The previously observed transcriptional activity of the Streptomyces oriC region may help explain the current results. We speculate that transcription itself could modulate oriC activity in Streptomyces by determining whether DNA unwinding occurs at DUE1 or DUE2.

RevDate: 2019-10-08

Bai T, Li J, Sinclair A, et al (2019)

Expansion of primitive human hematopoietic stem cells by culture in a zwitterionic hydrogel.

Nature medicine pii:10.1038/s41591-019-0601-5 [Epub ahead of print].

The ability to expand hematopoietic stem and progenitor cells (HSPCs) ex vivo is critical to fully realize the potential of HSPC-based therapies. In particular, the application of clinically effective therapies, such as cord blood transplantation, has been impeded because of limited HSPC availability. Here, using 3D culture of human HSPCs in a degradable zwitterionic hydrogel, we achieved substantial expansion of phenotypically primitive CD34+ cord blood and bone-marrow-derived HSPCs. This culture system led to a 73-fold increase in long-term hematopoietic stem cell (LT-HSC) frequency, as demonstrated by limiting dilution assays, and the expanded HSPCs were capable of hematopoietic reconstitution for at least 24 weeks in immunocompromised mice. Both the zwitterionic characteristics of the hydrogel and the 3D format were important for HSPC self-renewal. Mechanistically, the impact of 3D zwitterionic hydrogel culture on mitigating HSPC differentiation and promoting self-renewal might result from an inhibition of excessive reactive oxygen species (ROS) production via suppression of O2-related metabolism. HSPC expansion using zwitterionic hydrogels has the potential to facilitate the clinical application of hematopoietic-stem-cell therapies.

RevDate: 2019-10-08

Yagishita Y, Fahey JW, Dinkova-Kostova AT, et al (2019)

Broccoli or Sulforaphane: Is It the Source or Dose That Matters?.

Molecules (Basel, Switzerland), 24(19): pii:molecules24193593.

There is robust epidemiological evidence for the beneficial effects of broccoli consumption on health, many of them clearly mediated by the isothiocyanate sulforaphane. Present in the plant as its precursor, glucoraphanin, sulforaphane is formed through the actions of myrosinase, a β-thioglucosidase present in either the plant tissue or the mammalian microbiome. Since first isolated from broccoli and demonstrated to have cancer chemoprotective properties in rats in the early 1990s, over 3000 publications have described its efficacy in rodent disease models, underlying mechanisms of action or, to date, over 50 clinical trials examining pharmacokinetics, pharmacodynamics and disease mitigation. This review evaluates the current state of knowledge regarding the relationships between formulation (e.g., plants, sprouts, beverages, supplements), bioavailability and efficacy, and the doses of glucoraphanin and/or sulforaphane that have been used in pre-clinical and clinical studies. We pay special attention to the challenges for better integration of animal model and clinical studies, particularly with regard to selection of dose and route of administration. More effort is required to elucidate underlying mechanisms of action and to develop and validate biomarkers of pharmacodynamic action in humans. A sobering lesson is that changes in approach will be required to implement a public health paradigm for dispensing benefit across all spectrums of the global population.

RevDate: 2019-10-07

Thompson IM, Tangen CM, B Kramer (2019)

5α-Reductase Inhibitor Use in Patients With Prostate Cancer.

JAMA internal medicine, 179(10):1440.

RevDate: 2019-10-07

Krakow EF (2019)

Current state of nonengrafting donor leukocyte infusion (focus on microtransplantation for acute myeloid leukemia).

Current opinion in hematology, 26(6):373-378.

PURPOSE OF REVIEW: Microtransplantation (or micro-stem cell transplantation, MST) is one permutation of alloreactive immunotherapy increasingly studied in clinical trials. It is most commonly applied to patients with myeloid malignancies who are not suitable candidates for allogeneic hematopoietic cell transplantation. This review highlights the past 2 years of work on stem/progenitor cell products in the field of nonengrafting donor leukocyte infusion (NE-DLI), with a focus on applications of MST in acute myeloid leukemia (AML).

RECENT FINDINGS: Assessing the utility of MST is hampered by lack of randomized controlled trials and by variability in donor selection algorithms, treatment timing, and unknown factors. The inherent complexity of the bidirectional alloreactive reactions, implicating many cell types, makes it challenging to move beyond correlative, population-level biology toward mechanistic explanations for MST's actions in any given patient-donor pair. Yet there are indicators that by stimulating a recipient-vs.-tumor effect, MST might substantially improve complete remission rates in AML and that it might find a role in postremission therapy.

SUMMARY: The mechanistic underpinnings of MST are gradually being disentangled and its clinical development remains in early stages.

RevDate: 2019-10-07

Neidich SD, Fong Y, Li SS, et al (2019)

Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk.

The Journal of clinical investigation pii:126391 [Epub ahead of print].

HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ad5-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fcγ receptors (FcγRs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to FcγRIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific FcγRIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-FcγRIIa, and IgG3 binding were high. Additionally, FcγRIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention.

RevDate: 2019-10-07

Xu J, Bricker J, Fu X, et al (2019)

Design and Development of Smoking Cessation Apps Based on Smokers' and Providers' Perspectives in China: Survey Study.

JMIR mHealth and uHealth, 7(10):e12200 pii:v7i10e12200.

BACKGROUND: Although there are more than 60 smartphone apps for smoking cessation in China, many of them do not include the content and features that health care professionals and smokers prefer-which may make them impractical, unengaging, and ineffective. Therefore, we investigated both health care providers' and smokers' preferences for features of future smoking cessation apps.

OBJECTIVE: This study aimed to investigate Chinese health care providers' and smokers' desired features of a smoking cessation app, with the goal of providing design recommendations for app designers and researchers.

METHODS: Both Chinese smokers who own smartphones (n=357) and Chinese health care providers (n=224) responded to a survey collecting data on their sociodemographic characteristics and opinions on the importance of 20 smoking cessation app design features studied in previous US research.

RESULTS: Chinese health care providers expressed strong support of smoking cessation apps on a number of attitude indicators (range 153/224, 68.3% to 204/224, 91.1%). They rated nearly all (18/20) features as very or extremely important (range 52.2%-83.4%) and rated nearly all features (17/20) as more important than the smokers did. More than 60% of smokers rated the following 4 features as very or extremely important: allow sharing the process of smoking cessation with family members and friends (216/319, 67.7%), helping smokers track their progress (such as the amount of smoking per day; 213/319, 66.8%), helping with the side effects of medications and nicotine withdrawal symptoms (201/319, 63.0%), and adapting to ongoing needs and interests of smokers (194/319, 60.8%). Contrary to a similar study of US smokers and health care providers, Chinese smokers and providers rated reputation and ability to communicate with family members and friends as important features, whereas Chinese smokers rated privacy and security as less important.

CONCLUSIONS: The design of future smoking cessation and health behavior change apps should consider perspectives of both providers and smokers as well as the role of culture.

RevDate: 2019-10-07

Lam TBL, MacLennan S, Willemse PM, et al (2019)

EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guideline Panel Consensus Statements for Deferred Treatment with Curative Intent for Localised Prostate Cancer from an International Collaborative Study (DETECTIVE Study).

European urology pii:S0302-2838(19)30740-7 [Epub ahead of print].

BACKGROUND: There is uncertainty in deferred active treatment (DAT) programmes, regarding patient selection, follow-up and monitoring, reclassification, and which outcome measures should be prioritised.

OBJECTIVE: To develop consensus statements for all domains of DAT.

A protocol-driven, three phase study was undertaken by the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Association of Urology Section of Urological Research (ESUR)-International Society of Geriatric Oncology (SIOG) Prostate Cancer Guideline Panel in conjunction with partner organisations, including the following: (1) a systematic review to describe heterogeneity across all domains; (2) a two-round Delphi survey involving a large, international panel of stakeholders, including healthcare practitioners (HCPs) and patients; and (3) a consensus group meeting attended by stakeholder group representatives. Robust methods regarding what constituted the consensus were strictly followed.

RESULTS AND LIMITATIONS: A total of 109 HCPs and 16 patients completed both survey rounds. Of 129 statements in the survey, consensus was achieved in 66 (51%); the rest of the statements were discussed and voted on in the consensus meeting by 32 HCPs and three patients, where consensus was achieved in additional 27 statements (43%). Overall, 93 statements (72%) achieved consensus in the project. Some uncertainties remained regarding clinically important thresholds for disease extent on biopsy in low-risk disease, and the role of multiparametric magnetic resonance imaging in determining disease stage and aggressiveness as a criterion for inclusion and exclusion.

CONCLUSIONS: Consensus statements and the findings are expected to guide and inform routine clinical practice and research, until higher levels of evidence emerge through prospective comparative studies and clinical trials.

PATIENT SUMMARY: We undertook a project aimed at standardising the elements of practice in active surveillance programmes for early localised prostate cancer because currently there is great variation and uncertainty regarding how best to conduct them. The project involved large numbers of healthcare practitioners and patients using a survey and face-to-face meeting, in order to achieve agreement (ie, consensus) regarding best practice, which will provide guidance to clinicians and researchers.

RevDate: 2019-10-07

Burr RL, Gu H, Cain K, et al (2019)

Tryptophan Metabolites in Irritable Bowel Syndrome: An Overnight Time-course Study.

Journal of neurogastroenterology and motility, 25(4):551-562.

Background/Aims: Patients with irritable bowel syndrome (IBS) often report poor sleep quality. Whether poor sleep is associated with tryptophan (Trp) metabolites is unknown. We compared serum Trp metabolites in women with IBS and healthy controls (HCs) using targeted liquid chromatography mass spectrometry (LC-MS)-based profiling. In IBS only, we explored whether Trp metabolites are associated with IBS symptoms and subjective and objective sleep indices, serum cortisol, plasma adrenocorticotropic hormone (ACTH), and cortisol/ACTH levels.

Methods: Blood samples were obtained every 80 minutes in 21 HCs and 38 IBS subjects following an anticipation-of-public-speaking stressor during a sleep laboratory protocol. Subjects completed symptom diaries for 28 days. Adjacent values of metabolites were averaged to represent 4 time-periods: awake, early sleep, mid-sleep, and mid-to-late sleep. Thirteen of 20 targeted Trp metabolites were identified.

Results: Ten of 13 Trp metabolites decreased across the night, while nicotinamide increased in both groups. A MANOVA omnibus test performed after principal component analysis showed a significant difference in these 13 principal component (P = 0.014) between groups. Compared to HCs, nicotinamide levels were higher and indole-3-lactic acid levels lower in the IBS group. Melatonin and indole-3-acetic acid levels were associated with several subjective/objective sleep measures; decreased stool consistency/frequency and abdominal pain were positively associated with melatonin and serotonin in the IBS group. The kynurenine and kynurenic acid were associated with ACTH (positively) and cortisol/ACTH (negatively).

Conclusion: Nighttime Trp metabolites may provide clues to poor sleep and stress with IBS. Further study of the mechanism of metabolite action is warranted.

RevDate: 2019-10-06

Chang CP, Chang SC, Chuang SC, et al (2019)

Age at start of using tobacco on the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium (INHANCE).

Cancer epidemiology, 63:101615 pii:S1877-7821(19)30126-2 [Epub ahead of print].

BACKGROUND: Tobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk.

METHODS: We analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects logistic regression models.

RESULTS: Without adjusting for tobacco packyears, we observed that younger age at starting tobacco use was associated with an increased HNC risk for ever smokers (OR<10 years vs. ≥30 years: 1.64, 95% CI: 1.35, 1.97). However, the observed association between age at starting tobacco use and HNC risk became null after adjusting for tobacco packyears (OR<10 years vs. ≥30 years: 0.97, 95% CI: 0.80, 1.19). In the stratified analyses on HNC subsites by tobacco packyears or years since quitting, no difference in the association between age at start and HNC risk was observed.

CONCLUSIONS: Results from this pooled analysis suggest that increased HNC risks observed with earlier age at starting tobacco smoking are largely due to longer duration and higher cumulative tobacco exposures.

RevDate: 2019-10-05

Halpern AB, Howard NP, Othus M, et al (2019)

Early hospital discharge after intensive induction chemotherapy for adults with acute myeloid leukemia or other high-grade myeloid neoplasm.

RevDate: 2019-10-05

Golob JL, DeMeules MM, Loeffelholz T, et al (2019)

Butyrogenic bacteria after acute graft-versus-host disease (GVHD) are associated with the development of steroid-refractory GVHD.

Blood advances, 3(19):2866-2869.

RevDate: 2019-10-05

Gartlan KH, Koyama M, Lineburg KE, et al (2019)

Donor T-cell-derived GM-CSF drives alloantigen presentation by dendritic cells in the gastrointestinal tract.

Blood advances, 3(19):2859-2865.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has recently emerged as an important pathogenic cytokine in acute graft-versus-host disease (GVHD), but the nature of the T-cell lineages secreting the cytokine and the mechanisms of action are less clear. Here we used interleukin 17A-fate reporter systems with transcriptional analysis and assays of alloantigen presentation to interrogate the origins of GM-CSF-secreting T cells and the effects of the cytokine on antigen-presenting cell (APC) function after experimental allogeneic stem cell transplantation (SCT). We demonstrated that although GM-CSF-secreting Th17 and non-Th17 cells expanded in the colon over time after SCT, the Th17 lineage expanded to represent 10% to 20% of the GM-CSF secreting T cells at this site by 4 weeks. Donor T-cell-derived GM-CSF expanded alloantigen-presenting donor dendritic cells (DCs) in the colon and lymph nodes. In the mesenteric lymph nodes, GM-CSF-dependent DCs primed donor T cells and amplified acute GVHD in the colon. We thus describe a feed-forward cascade whereby GM-CSF-secreting donor T cells accumulate and drive alloantigen presentation in the colon to amplify GVHD severity. GM-CSF inhibition may be a tractable clinical intervention to limit donor alloantigen presentation and GVHD in the lower gastrointestinal tract.

RevDate: 2019-10-04

Kim A, Stevenson P, Cassaday RD, et al (2019)

Impact of double/triple hit pathology on rates and durability of RT response among patients with relapsed/refractory large B-cell lymphoma.

Practical radiation oncology pii:S1879-8500(19)30277-2 [Epub ahead of print].

PURPOSE: Double/triple-hit lymphomas (DHL/THL), also known as high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, are associated with chemoresistance and inferior survival. However, whether RT efficacy is altered in DHL/THL is less well characterized. Among patients with relapsed/refractory (R/R) large B-cell lymphoma (LCBL), we compared rates and durability of response between patients with and without DHL/THL.

METHODS AND MATERIALS: We retrospectively reviewed consecutive R/R LBCL patients that were irradiated at a single institution from 1/2008-6/2017. Patients in whom c-MYC rearranged status was known were evaluated for response to RT, in-field control, progression-free (PFS) and overall survival (OS).

RESULTS: Among 245 irradiated patients with LBCL, 41 patients with confirmed c-MYC status were treated for R/R disease (14 DHL/THL, 27 non-DHL/THL) and formed our cohort. Compared to non-DHL/THL, more DHL/THL patients had progressive disease at RT (71% vs 48%), had larger gross tumor volumes (GTV; median 696 mL vs 117 mL), and were treated with palliative intent (71% vs 41%). Despite similar RT doses (median 35 Gy), radiographic complete response rate was lower among DHL/THL patients: 14.3% vs 64.7% (p=0.01). With a median 2 years of follow-up, one in-field failure was observed in each group. DHL/THL patients had inferior PFS (7% vs 46%; p=0.02) and OS (14% vs 68%; p=0.03) at 6 months.

CONCLUSIONS: R/R LBCL is responsive to RT, although RR are lower among DHL/THL patients. Given poor survival after RT, in-field control was hard to evaluate in this cohort. Larger cohorts are required to better elucidate whether differences in response rates are driven by larger disease burden at RT versus tumor biology. These findings are of increasing pertinence in light of use of RT as bridging therapy to cellular immunotherapies.

RevDate: 2019-10-04

Miller MP, Evans RK, Zelter A, et al (2019)

Kinetochore-associated Stu2 promotes chromosome biorientation in vivo.

PLoS genetics, 15(10):e1008423 pii:PGENETICS-D-19-01481 [Epub ahead of print].

Accurate segregation of chromosomes to daughter cells is a critical aspect of cell division. It requires the kinetochores on duplicated chromosomes to biorient, attaching to microtubules from opposite poles of the cell. Bioriented attachments come under tension, while incorrect attachments lack tension and must be released to allow proper attachments to form. A well-studied error correction pathway is mediated by the Aurora B kinase, which destabilizes low tension-bearing attachments. We recently discovered that in vitro, kinetochores display an additional intrinsic tension-sensing pathway that utilizes Stu2. The contribution of kinetochore-associated Stu2 to error correction in cells, however, was unknown. Here, we identify a Stu2 mutant that abolishes its kinetochore function and show that it causes biorientation defects in vivo. We also show that this Stu2-mediated pathway functions together with the Aurora B-mediated pathway. Altogether, our work indicates that cells employ multiple pathways to ensure biorientation and the accuracy of chromosome segregation.

RevDate: 2019-10-04

Stikbakke E, Richardsen E, Knutsen T, et al (2019)

Inflammatory serum markers and risk and severity of prostate cancer. The PROCA-life Study.

International journal of cancer [Epub ahead of print].

Whether chronic inflammation mirrored by high levels of systemic inflammatory markers such as high sensitive-CRP (hs-CRP) and white blood cell count (WBC) are associated with prostate cancer development remains unclear. In the Prostate Cancer Study throughout Life (PROCA-life), a prospective population-based cohort study, 7,356 men were included. Pre-diagnostic WBC and hs-CRP were assessed from blood collected at study entry; 2,210 participants also had a second CRP measure during follow-up. During a mean 11.8 years follow-up, 509 men developed prostate cancer (mean age at diagnosis 71.7 years). Multivariable Cox proportional hazard regression models were used to study whether individual biomarkers (WBC, hs-CRP), a combined score based on analyte tertiles (score range 2-6), or change in CRP were associated with risk and severity of prostate cancer. We observed a positive dose-response relationship between hs-CRP and prostate cancer risk with a Hazard Ratio (HR) per mg/L of 1.3, 95% CI 1.00-1.07. Men with an increase in hs-CRP between two measurements (Δhs-CRP) of ≥1.00 mg/l had a 36% increased risk of prostate cancer (HR 1.36, 95% CI 1.02-1.82), compared to men with no change or decrease in hs-CRP. Men with a systemic inflammatory score of 5 or 6 had a 68% higher risk of being diagnosed with metastatic disease (HR 1.68, 95% CI, 1.04-2.73) compared to men with lower scores. Our study supports that hs-CRP including repeated measurements alone or in combination with WBC may be a useful inflammation-related biomarker for prostate cancer risk and prognosis. This article is protected by copyright. All rights reserved.

RevDate: 2019-10-04

Vo P, Gooley TA, Rajendran JG, et al (2019)

Yttrium-90-labeled anti-CD45 antibody followed by a reduced-intensity hematopoietic cell transplantation for patients with relapsed/refractory leukemia or myelodysplasia.

Haematologica pii:haematol.2019.229492 [Epub ahead of print].

Outcomes of patients with persistent high-risk leukemia or myelodysplasia prior to allogeneic hematopoietic cell transplantation are dismal. We therefore conducted a phase I trial evaluating the use of CD45-targeted radiotherapy preceding hematopoietic cell transplantation with the goal to improve outcomes for this high-risk scenario. Fifteen patients, median age of 62 (range 37-76) years, were treated (10 with advanced acute myeloid leukemia, 5 with high-risk myelodysplastic syndrome). All patients had evidence of disease prior to treatment including nine with marrow blast counts ranging from 7-84% and 6 with minimal residual disease. Patients received escalating doses of yttrium-90-labeled anti-CD45 antibody followed by fludarabine and 2 Gy total body irradiation prior to human leukocyte antigen-matched, related or unrelated hematopoietic cell transplantation. Although a maximum dose of 30 Gy was delivered to the liver, no dose-limiting toxicity was observed. Therefore, the maximum-tolerated dose could not be estimated. Treatment led to complete remission in 13 patients (87%). All patients engrafted by day 28. Six patients relapsed, median of 59 (range 6-351) days, after transplantation. The 1-year estimate of relapse was 41%. Eight patients (53%) are surviving with median follow-up of 1.8 (range 0.9-5.9) years. Estimated overall survival at 1 and 2 years was 66% and 46%, respectively, with progression-free survival estimated to be 46% at each time point. In conclusion, the combination of 90Y-DOTA-BC8 with an allogeneic hematopoietic cell transplantation regimen was feasible and tolerable. This approach appears promising in this high-risk leukemia/myelodysplasia patient population with active disease. Clinicaltrials.gov identifier: NCT01300572.

RevDate: 2019-10-04

Bhatia S, Longino NV, Miller NJ, et al (2019)

Intratumoral delivery of plasmid interleukin-12 via electroporation leads to regression of injected and non-injected tumors in Merkel cell carcinoma.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-0972 [Epub ahead of print].

PURPOSE: Interleukin-12 (IL-12) promotes adaptive type-1 immunity and has demonstrated anti-tumor efficacy, but systemic administration leads to severe adverse events (AEs), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL-12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer.

EXPERIMENTAL DESIGN: Fifteen MCC patients with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (Cohort A, N=3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (Cohort B, N=12) received up to 4 cycles total, administered at least six weeks apart. Serial tumor and blood samples were collected.

RESULTS: All patients successfully completed at least one cycle with transient, mild (Grade 1, 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL-12 protein was observed along with local inflammation and increased tumor-specific CD8+ T cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in Cohort B, with two patients experiencing durable clinical benefit (16 and 55+ months respectively). Two Cohort A patients (one with pathologic complete remission) were recurrence-free at 44+ and 75+ months.

CONCLUSIONS: I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL-12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.

RevDate: 2019-10-04

Barrington WE, SAA Beresford (2019)

Eating Occasions, Obesity and Related Behaviors in Working Adults: Does it Matter When You Snack?.

Nutrients, 11(10): pii:nu11102320.

Reported relationships between frequency, type, and timing of eating occasions and obesity-risk among adults are mixed while associations with obesogenic eating behaviors remain unexplored. The Physical Activity and Changes in Eating (PACE) study was a group-randomized controlled trial to prevent weight gain among 34 small worksites in Seattle from 2005-2009. Baseline surveys assessed body mass index (BMI), obesogenic eating behaviors (e.g., fast food and distracted-eating), and eating occasions (i.e., snacks and meals) among 2265 employees. BMI and waist circumference were measured on a subset (n = 567). Time-periods for analyses included: morning (12:00 a.m. to 10:59 a.m.), mid-day (11:00 a.m. to 4:29 p.m.), and evening (4:30 p.m. to 11:59 p.m.). Multilevel linear models estimated associations between snack timing, obesity, and related behaviors while adjusting for meal timing, gender, and worksite random effects. Greater morning snacking was associated with increased fruit and vegetable consumption, while greater evening snacking was associated with higher BMI, higher obesogenic dietary index (intake of fast food, French fries, and soft drinks), and higher percent time eating while distracted. Associations with mid-day snacking were mixed. Patterns of association were consistent across repeated and objective measures. Findings suggest that evening snacking is more detrimental to healthy weight compared to snacking at other times of day. Reducing evening snacks may be an important and simple message for population-level obesity prevention efforts.

RevDate: 2019-10-03

Hall ET, KG Paulson (2019)

Reducing Head and Neck UV Exposure in Younger Persons-Millennials, Wear a Hat (or Grow Your Hair Longer).

JAMA otolaryngology-- head & neck surgery pii:2751951 [Epub ahead of print].

RevDate: 2019-10-03

Morrow M, ML Disis (2019)

Crafting a JAMA Oncology Clinical Challenge.

JAMA oncology pii:2752370 [Epub ahead of print].

RevDate: 2019-10-03

Yoshimi A, Lin KT, Wiseman DH, et al (2019)

Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis.

Nature pii:10.1038/s41586-019-1618-0 [Epub ahead of print].

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.

RevDate: 2019-10-03

Saha A, Taylor PA, Lees CJ, et al (2019)

Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality.

JCI insight, 4(19): pii:127716.

B7-H4 is a negative regulatory B7 family member. We investigated the role of host and donor B7-H4 in regulating acute graft-versus-host disease (GVHD). Allogeneic donor T cells infused into B7-H4-/- versus WT recipients markedly accelerated GVHD-induced lethality. Chimera studies pointed toward B7-H4 expression on host hematopoietic cells as more critical than parenchymal cells in controlling GVHD. Rapid mortality in B7-H4-/- recipients was associated with increased donor T cell expansion, gut T cell homing and loss of intestinal epithelial integrity, increased T effector function (proliferation, proinflammatory cytokines, cytolytic molecules), and reduced apoptosis. Higher metabolic demands of rapidly proliferating donor T cells in B7-H4-/- versus WT recipients required multiple metabolic pathways, increased extracellular acidification rates (ECARs) and oxygen consumption rates (OCRs), and increased expression of fuel substrate transporters. During GVHD, B7-H4 expression was upregulated on allogeneic WT donor T cells. B7-H4-/- donor T cells given to WT recipients increased GVHD mortality and had function and biological properties similar to WT T cells from allogeneic B7-H4-/- recipients. Graft-versus-leukemia responses were intact regardless as to whether B7-H4-/- mice were used as hosts or donors. Taken together, these data provide new insights into the negative regulatory processes that control GVHD and provide support for developing therapeutic strategies directed toward the B7-H4 pathway.

RevDate: 2019-10-03

Wilkinson AN, Chang K, Kuns RD, et al (2019)

IL-6 dysregulation originates in dendritic cells and initiates graft-versus-host disease via classical signaling.

Blood pii:blood.2019000396 [Epub ahead of print].

Graft-versus-host-disease (GVHD) after allogeneic stem cell transplantation (alloSCT) is characterized by interleukin 6 (IL-6) dysregulation. IL-6 can mediate effects via various pathways, including classical, trans and cluster signaling. Given the recent availability of agents that differentially inhibit these discrete signaling cascades, understanding the source, signaling and cellular targets of this cytokine is paramount to inform the design of clinical studies. Here we demonstrate that IL-6 secretion from recipient dendritic cells (DC) initiates the systemic dysregulation of this cytokine. Inhibition of DC-driven classical signaling following targeted IL-6 receptor (IL-6R) deletion in T-cells eliminated pathogenic donor Th17/Th22 cell differentiation and resulted in long-term survival. Following engraftment, donor DC assume the same role, maintaining classical IL-6 signaling-dependent GVHD responses. Surprisingly, cluster-signaling was not active after transplant, while inhibition of trans-signaling with sgp130Fc promoted severe, chronic cutaneous GVHD. The latter was a result of exaggerated polyfunctional Th22 cell expansion that was reversed by IL-22 deletion or IL-6R inhibition. Importantly, inhibition of IL-6 classical-signaling did not impair the graft-versus-leukemia effect. Together, these data highlight IL-6 classical-signaling and downstream Th17/Th22 differentiation as key therapeutic targets after alloSCT.

RevDate: 2019-10-03

Nyquist MD, Corella A, Mohamad O, et al (2019)

Molecular determinants of response to high-dose androgen therapy in prostate cancer.

JCI insight, 4(19): pii:129715.

Clinical trials of high-dose androgen (HDA) therapy for prostate cancer (PC) have shown promising efficacy but are limited by lack of criteria to identify likely responders. To elucidate factors that govern the growth-repressive effects of HDAs, we applied an unbiased integrative approach using genetic screens and transcriptional profiling of PC cells with or without demonstrated phenotypic sensitivity to androgen-mediated growth repression. Through this comprehensive analysis, we identified genetic events and related signaling networks that determine the response to both HDA and androgen withdrawal. We applied these findings to develop a gene signature that may serve as an early indicator of treatment response and identify men with tumors that are amenable to HDA therapy.

RevDate: 2019-10-02

Dai J, Huang M, Amos CI, et al (2019)

Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk.

International journal of cancer [Epub ahead of print].

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, P = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, P = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, P = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, P = 7.64 × 10-8). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis. This article is protected by copyright. All rights reserved.

RevDate: 2019-10-02

Lind A, Akel O, Wallenius M, et al (2019)

HLA high-resolution typing by next-generation sequencing in Pandemrix-induced narcolepsy.

PloS one, 14(10):e0222882 pii:PONE-D-19-08679.

The incidence of narcolepsy type 1 (NT1) increased in Sweden following the 2009-2010 mass-vaccination with the influenza Pandemrix-vaccine. NT1 has been associated with Human leukocyte antigen (HLA) DQB1*06:02 but full high-resolution HLA-typing of all loci in vaccine-induced NT1 remains to be done. Therefore, here we performed HLA typing by sequencing HLA-DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 in 31 vaccine-associated NT1 patients and 66 of their first-degree relatives (FDR), and compared these data to 636 Swedish general population controls (GP). Previously reported disease-related alleles in the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 extended haplotype were increased in NT1 patients (34/62 haplotypes, 54.8%) compared to GP (194/1272 haplotypes, 15.3%, p = 6.17E-16). Indeed, this extended haplotype was found in 30/31 patients (96.8%) and 178/636 GP (28.0%). In total, 15 alleles, four extended haplotypes, and six genotypes were found to be increased or decreased in frequency among NT1 patients compared to GP. Among subjects with the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02-DQB1*06:02 haplotype, a second DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype (p = 2.02E-2), but not homozygosity for DRB1*15:01:01-DQB1*06:02:01 (p = 7.49E-1) conferred association to NT1. Alleles with increased frequency in DQA1*01:02:01 (p = 1.07E-2) and DQA1*03:02//*03:03:01 (p = 3.26E-2), as well as with decreased frequency in DRB3*01:01:02 (p = 8.09E-3), DRB1*03:01:01 (p = 1.40E-2), and DQB1*02:01:01 (p = 1.40E-2) were found among patients compared to their FDR. High-resolution HLA sequencing in Pandemrix-associated NT1 confirmed the strong association with the DQB1*06:02:01-containing haplotype but also revealed an increased association to the not previously reported extended HLA-DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype. High-resolution HLA typing should prove useful in dissecting the immunological mechanisms of vaccination-associated NT1.

RevDate: 2019-10-02

Kon E, Calvo-Jimenez E, Cossard A, et al (2019)

N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration.

eLife, 8: pii:47673 [Epub ahead of print].

The functions of FGF receptors (FGFRs) in early development of the cerebral cortex are well established. Their functions in the migration of neocortical projection neurons, however, are unclear. We have found that FGFRs regulate multipolar neuron orientation and the morphological change into bipolar cells necessary to enter the cortical plate. Mechanistically, our results suggest that FGFRs are activated by N-Cadherin. N-Cadherin cell-autonomously binds FGFRs and inhibits FGFR K27- and K29-linked polyubiquitination and lysosomal degradation. Accordingly, FGFRs accumulate and stimulate prolonged Erk1/2 phosphorylation. Neurons inhibited for Erk1/2 are stalled in the multipolar zone. We found that Reelin, prevents FGFR degradation in an N-Cadherin-dependent manner and stimulates prolonged, FGFR-dependent, Erk1/2 phosphorylation. These findings reveal novel functions for FGFRs in cortical projection neuron migration, suggest a physiological role for FGFR and N-Cadherin interaction in vivo and identify Reelin as an extracellular upstream regulator and Erk1/2 as downstream effectors of FGFRs during neuron migration.

RevDate: 2019-10-02

Gauthier J, Wu QV, TA Gooley (2019)

Cubic splines to model relationships between continuous variables and outcomes: a guide for clinicians.

SERIES EDITORS' NOTE: We are pleased to add this typescript to the Bone Marrow Transplantation Statistics Series. We realize the term cubic splines may be a bit off-putting to some readers, but stay with us and don't get lost in polynomial equations. What the authors describe is important conceptually and in practice. Have you ever tried to buy a new pair of hiking boots? Getting the correct fit is critical; shoes that are too small or too large will get you in big trouble! Now imagine if hiking shoes came in only 2 sizes, small and large, and your foot size was somewhere in between. You are in trouble. Sailing perhaps?Transplant physicians are often interested in the association between two variables, say pre-transplant measurable residual disease (MRD) test state and an outcome, say cumulative incidence of relapse (CIR). We typically reduce the results of an MRD test to a binary, negative or positive, often defined by an arbitrary cut-point. However, MRD state is a continuous biological variable, and reducing it to a binary discards what may be important, useful data when we try to correlate it with CIR. Put otherwise, we may miss the trees from the forest.Another way to look at splines is a technique to make smooth curves out of irregular data points. Consider, for example, trying to describe the surface of an egg. You could do it with a series of straight lines connecting points on the egg surface but a much better representation would be combining groups of points into curves and then combining the curves. To prove this try drawing an egg using the draw feature in Microsoft Powerpoint; you are making splines.Gauthier and co-workers show us how to use cubic splines to get the maximum information from data points, which may, unkindly, not lend themselves to dichotomization or a best fit line. Please read on. We hope readers will find their typescript interesting and exciting, and that it will give them a new way to think about how to analyse data. And no, a spline is not a bunch of cactus spines. Robert Peter Gale, Imperial College London, and Mei-Jie Zhang, Medical College of Wisconsin and CIBMTR.

RevDate: 2019-10-02

Sarthy JF, S Henikoff (2019)

Bringing Oncohistones into the Fold.

Cancer discovery, 9(10):1346-1348.

Identification of cancer-associated mutations in core histone genes has proved challenging due to these genes' highly conserved nature and presence in large arrays. Recent analyses of cancer genomes, including one in this issue of Cancer Discovery, show that mutations in the histone fold can affect nucleosome stability, providing a novel mechanism by which oncohistones contribute to tumorigenesis.See related article by Bennett et al., p. 1438.

RevDate: 2019-10-01

Redwood AJ, Rwandamuriye F, Chopra A, et al (2019)

Single cell transcriptomics reveal polyclonal memory T cell responses in abacavir patch test positive skin.

The Journal of allergy and clinical immunology pii:S0091-6749(19)31249-7 [Epub ahead of print].

CAPSULE SUMMARY: Single-cell responses in HLA-B*57:01 abacavir patch test positive skin remote to the acute hypersensitivity reaction demonstrate polyclonal T-cell activation and proliferation characterized by a transcriptional and cellular response consistent with memory responses to altered peptides.

RevDate: 2019-10-01

Colón-Thillet R, Hsieh E, Graf L, et al (2019)

Combinatorial mutagenesis of rapidly evolving residues yields super-restrictor antiviral proteins.

PLoS biology, 17(10):e3000181 pii:PBIOLOGY-D-19-00458.

Antagonistic interactions drive host-virus evolutionary arms races, which often manifest as recurrent amino acid changes (i.e., positive selection) at their protein-protein interaction interfaces. Here, we investigated whether combinatorial mutagenesis of positions under positive selection in a host antiviral protein could enhance its restrictive properties. We tested approximately 700 variants of human MxA, generated by combinatorial mutagenesis, for their ability to restrict Thogotovirus (THOV). We identified MxA super-restrictors with increased binding to the THOV nucleoprotein (NP) target protein and 10-fold higher anti-THOV restriction relative to wild-type human MxA, the most potent naturally occurring anti-THOV restrictor identified. Our findings reveal a means to elicit super-restrictor antiviral proteins by leveraging signatures of positive selection. Although some MxA super-restrictors of THOV were impaired in their restriction of H5N1 influenza A virus (IAV), other super-restrictor variants increased THOV restriction without impairment of IAV restriction. Thus, broadly acting antiviral proteins such as MxA mitigate breadth-versus-specificity trade-offs that could otherwise constrain their adaptive landscape.

RevDate: 2019-10-01

Jones SMW, Parchman M, McDonald S, et al (2019)

Measuring attributes of team functioning in primary care settings: development of the TEAMS tool.

Journal of interprofessional care [Epub ahead of print].

This study examines attributes of a high-functioning primary care team by creating a survey measuring staff perceptions of team culture in primary care practices with innovative team-based workforce models. Survey data from a national study of 30 exemplar primary care practices with innovative team-based workforce models was used. Staff and clinicians (n = 943) at the 30 primary care sites completed a 31-item survey online. Survey items came from previous surveys of adaptive reserve and team culture. Factor analysis, reliability and validity were examined for the survey. Case summaries from site visits and survey comments were compared for high and low scoring sites to establish validity. Three core attributes of a high-functioning team were identified: joy in practice (4 items), personal growth (3 items), and leadership and learning (20 items). Four items did not measure any attribute. Using item correlations, the 20 items for leadership and learning were reduced to 7 items. All three attribute subscales had good reliability and validity. The final 14-item survey measuring joy in practice, personal growth and leadership and learning may be useful in clinical practice as a practical tool to gauge progress in developing a high-functioning team. Further research is needed to determine the sensitivity of this instrument to change over time with interventions designed to improve team functioning in primary care.

RevDate: 2019-10-01

Kessler RC, Bossarte RM, Luedtke A, et al (2019)

Suicide prediction models: a critical review of recent research with recommendations for the way forward.

Molecular psychiatry pii:10.1038/s41380-019-0531-0 [Epub ahead of print].

Suicide is a leading cause of death. A substantial proportion of the people who die by suicide come into contact with the health care system in the year before their death. This observation has resulted in the development of numerous suicide prediction tools to help target patients for preventive interventions. However, low sensitivity and low positive predictive value have led critics to argue that these tools have no clinical value. We review these tools and critiques here. We conclude that existing tools are suboptimal and that improvements, if they can be made, will require developers to work with more comprehensive predictor sets, staged screening designs, and advanced statistical analysis methods. We also conclude that although existing suicide prediction tools currently have little clinical value, and in some cases might do more harm than good, an even-handed assessment of the potential value of refined tools of this sort cannot currently be made because such an assessment would depend on evidence that currently does not exist about the effectiveness of preventive interventions. We argue that the only way to resolve this uncertainty is to link future efforts to develop or evaluate suicide prediction tools with concrete questions about specific clinical decisions aimed at reducing suicides and to evaluate the clinical value of these tools in terms of net benefit rather than sensitivity or positive predictive value. We also argue for a focus on the development of individualized treatment rules to help select the right suicide-focused treatments for the right patients at the right times. Challenges will exist in doing this because of the rarity of suicide even among patients considered high-risk, but we offer practical suggestions for how these challenges can be addressed.

RevDate: 2019-10-01

Coffey DG, Wu QV, Towlerton AMH, et al (2019)

Ultradeep, targeted sequencing reveals distinct mutations in blood compared to matched bone marrow among patients with multiple myeloma.

Blood cancer journal, 9(10):77 pii:10.1038/s41408-019-0238-0.

RevDate: 2019-10-01

Murray SM, ML Linial (2019)

Simian Foamy Virus Co-Infections.

Viruses, 11(10): pii:v11100902.

Foamy viruses (FVs), also known as spumaretroviruses, are complex retroviruses that are seemingly nonpathogenic in natural hosts. In natural hosts, which include felines, bovines, and nonhuman primates (NHPs), a large percentage of adults are infected with FVs. For this reason, the effect of FVs on infections with other viruses (co-infections) cannot be easily studied in natural populations. Most of what is known about interactions between FVs and other viruses is based on studies of NHPs in artificial settings such as research facilities. In these settings, there is some indication that FVs can exacerbate infections with lentiviruses such as simian immunodeficiency virus (SIV). Nonhuman primate (NHP) simian FVs (SFVs) have been shown to infect people without any apparent pathogenicity. Humans zoonotically infected with simian foamy virus (SFV) are often co-infected with other viruses. Thus, it is important to know whether SFV co-infections affect human disease.

RevDate: 2019-09-19

Koehn BH, Saha A, McDonald-Hyman C, et al (2019)

Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GvHD.

Blood pii:blood.2019001950 [Epub ahead of print].

Myeloid-derived suppressor cells (MDSC) can subdue inflammation. Donor MDSC infusion enhances survival in acute graft-versus-host disease (GvHD) mice that is only partial and transient due to MDSC inflammasome activation early post-transfer resulting in differentiation and loss of suppressor function. Here we demonstrate that conditioning regimen-induced ATP release is a primary driver of MDSC dysfunction through ATP receptor (P2x7R) engagement and NLRP3 inflammasome activation. P2x7R or NLRP3 knockout (KO) donor MDSC provided significantly higher survival than wild-type MDSC. Although in vivo pharmacologic targeting of NLRP3 or P2x7R promoted recipient survival, indicating in vivo biological effects, no synergistic survival advantage was seen when combined with MDSC. Since activated inflammasomes release mature IL-1ß, we expected that IL-1ß KO donor MDSC would be superior in subverting GvHD but such MDSC proved inferior relative to wild-type. IL-1ß release and IL-1R expression was required for optimal MDSC function and exogenous IL-1ß added to suppression assays that included MDSC increased suppressor potency. These data indicate that prolonged systemic NLRP3 inflammasome inhibition and decreased IL-1ß could diminish survival in GvHD. However, loss of inflammasome activation and IL-1ß release restricted to MDSC rather than systemic inhibition allows non-MDSC IL-1ß signaling, improving survival. Extracellular ATP catalysis with peri-transplant apyrase given into the peritoneum, the ATP-release site, synergized with wild-type MDSC as did regulatory T cell infusion which we showed reduced but did not eliminate MDSC inflammasome activation assessed with a novel inflammasome reporter strain. These findings inform future clinical trials that would use MDSC to decrease alloresponses in inflammatory environments.

RevDate: 2019-09-30

Halasz LM, Patel SA, McDougall JA, et al (2019)

Intensity modulated radiation therapy following lumpectomy in early-stage breast cancer: Patterns of use and cost consequences among Medicare beneficiaries.

PloS one, 14(9):e0222904 pii:PONE-D-19-20654.

PURPOSE: In 2013, the American Society for Radiation Oncology (ASTRO) issued a Choosing Wisely recommendation against the routine use of intensity modulated radiotherapy (IMRT) for whole breast irradiation. We evaluated IMRT use and subsequent impact on Medicare expenditure in the period immediately preceding this recommendation to provide a baseline measure of IMRT use and associated cost consequences.

METHODS AND MATERIALS: SEER records for women ≥66 years with first primary diagnosis of Stage I/II breast cancer (2008-2011) were linked with Medicare claims (2007-2012). Eligibility criteria included lumpectomy within 6 months of diagnosis and radiotherapy within 6 months of lumpectomy. We evaluated IMRT versus conventional radiotherapy (cRT) use overall and by SEER registry (12 sites). We used generalized estimating equations logit models to explore adjusted odds ratios (OR) for associations between clinical, sociodemographic, and health services characteristics and IMRT use. Mean costs were calculated from Medicare allowable costs in the year after diagnosis.

RESULTS: Among 13,037 women, mean age was 74.4, 50.5% had left-sided breast cancer, and 19.8% received IMRT. IMRT use varied from 0% to 52% across SEER registries. In multivariable analysis, left-sided breast cancer (OR 1.75), living in a big metropolitan area (OR 2.39), living in a census tract with ≤$90,000 median income (OR 1.75), neutral or favorable local coverage determination (OR 3.86, 1.72, respectively), and free-standing treatment facility (OR 3.49) were associated with receipt of IMRT (p<0.001). Mean expenditure in the year after diagnosis was $8,499 greater (p<0.001) among women receiving IMRT versus cRT.

CONCLUSION: We found highly variable use of IMRT and higher expenditure in the year after diagnosis among women treated with IMRT (vs. cRT) with early-stage breast cancer and Medicare insurance. Our findings suggest a considerable opportunity to reduce treatment variation and cost of care while improving alignment between practice and clinical guidelines.

RevDate: 2019-09-30

Onyango-Makumbi C, Owora AH, Mwiru RS, et al (2019)


Journal of acquired immune deficiency syndromes (1999) [Epub ahead of print].

BACKGROUND: Effects of prolonged nevirapine prophylaxis exposure on growth among HIV-exposed uninfected (HEU) infants are unknown. This study examines the impact of extended nevirapine prophylaxis from 6 weeks to 6 months on the growth of HEU infants followed for 18 months and also identifies correlates of incident wasting, stunting, underweight, and low head circumference in the HPTN 046 trial.

METHODS: Intention-to-treat analysis examined the effect of extended nevirapine exposure on: weight-for-age Z-score (WAZ), length-for-age Z-score (LAZ), weight-for-length Z-score (WLZ) and head circumference-for-age (HCZ). Multivariable linear mixed-effects and Cox proportional hazard models were used to compare growth outcomes between the study arms and identify correlates of incident adverse growth outcomes, respectively.

RESULTS: Compared to placebo, extended prophylactic nevirapine given daily from 6 weeks to 6 months did not affect growth in HEU breastfeeding (BF) infants over time (treatment x time: p>.05). However, overall growth declined over time (time effect: p<.01) when compared to WHO general population norms. Male sex was associated with higher risk of all adverse growth outcomes (p<.05), while short BF duration was associated with wasting (p=.03). Maternal ART exposure was protective against underweight (p=.02). Zimbabwe tended to have worse growth outcomes especially stunting, compared to South Africa, Uganda and Tanzania (p<.05).

CONCLUSION: It is reassuring that prolonged exposure to nevirapine for prevention-of- maternal-to-child HIV transmission does not restrict growth. However, targeted interventions are needed to improve growth outcomes among at-risk HEU infants (i.e. male sex, short BF duration, lack of maternal ART exposure, and resident in Zimbabwe).

RevDate: 2019-09-30

Greenlee H, Santiago-Torres M, McMillen KK, et al (2019)

Helping Patients Eat Better During and Beyond Cancer Treatment: Continued Nutrition Management Throughout Care to Address Diet, Malnutrition, and Obesity in Cancer.

Cancer journal (Sudbury, Mass.), 25(5):320-328.

Cancer patients and survivors are at risk of poor clinical outcomes due to poor nutritional intake following cancer diagnosis. During cancer treatment, treatment toxicities can affect eating patterns and can lead to malnutrition resulting in loss of lean body mass and excessive weight loss. Following treatment and throughout survivorship, patients are at risk of not meeting national nutrition guidelines for cancer survivors, which can affect recurrence and survival. Obesity, which is highly prevalent in cancer patients and survivors, can affect clinical outcomes during treatment by masking malnutrition and is also a risk factor for cancer recurrence and poorer survival in some cancers. Appropriate and effective nutritional education and guidance by trained clinicians are needed throughout the cancer continuum. This article presents an overview of recommendations and guidelines for nutrition and weight management and provides recent examples of behavioral theory-based targeted lifestyle interventions designed to increase adherence to recommendation by cancer patients and survivors.

RevDate: 2019-09-30

Hill JA (2019)

Human herpesvirus 6 in transplant recipients: an update on diagnostic and treatment strategies.

Current opinion in infectious diseases [Epub ahead of print].

PURPOSE OF REVIEW: The current review article focuses on recent advances in the approach to the diagnosis and treatment of human herpesvirus 6B (HHV-6B) in hematopoietic cell and solid organ transplant recipients.

RECENT FINDINGS: Over the past few years, key studies have broadened our understanding of best practices for the prevention and treatment of HHV-6B encephalitis after transplantation. Moreover, important data have been reported that support a potential role of HHV-6B reactivation in the development of acute graft-versus-host disease and lower respiratory tract disease in transplant recipients. Finally, increasing recognition of inherited chromosomally integrated HHV-6 (iciHHV-6) and an expanding array of diagnostic tools have increased our understanding of the potential for complications related to viral reactivation originating from iciHHV-6 in donors or recipients.

SUMMARY: Recent advances in diagnostic tools, disease associations, and potential treatments for HHV-6B present abundant opportunities for improving our understanding and management of this complex virus in transplant recipients.

RevDate: 2019-09-30

Rouphael NG, Morgan C, Li SS, et al (2019)

DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial.

The Journal of clinical investigation pii:128699 [Epub ahead of print].

BACKGROUNDRV144 is the only preventive HIV vaccine regimen demonstrating efficacy in humans. Attempting to build upon RV144 immune responses, we conducted a phase 1, multicenter, randomized, double-blind trial to assess the safety and immunogenicity of regimens substituting the DNA-HIV-PT123 (DNA) vaccine for ALVAC-HIV in different sequences or combinations with AIDSVAX B/E (protein).METHODSOne hundred and four HIV-uninfected participants were randomized to 4 treatment groups (T1, T2, T3, and T4) and received intramuscular injections at 0, 1, 3, and 6 months (M): T1 received protein at M0 and M1 and DNA at M3 and M6; T2 received DNA at M0 and M1 and protein at M3 and M6; T3 received DNA at M0, M1, M3, and M6 with protein coadministered at M3 and M6; and T4 received protein and DNA coadministered at each vaccination visit.RESULTSAll regimens were well tolerated. Antibodies binding to gp120 and V1V2 scaffold were observed in 95%-100% of participants in T3 and T4, two weeks after final vaccination at high magnitude. While IgG3 responses were highest in T3, a lower IgA/IgG ratio was observed in T4. Binding antibodies persisted at 12 months in 35%-100% of participants. Antibody-dependent cell-mediated cytotoxicity and tier 1 neutralizing-antibody responses had higher response rates for T3 and T4, respectively. CD4+ T cell responses were detectable in all treatment groups (32%-64%) without appreciable CD8+ T cell responses.CONCLUSIONThe DNA/protein combination regimens induced high-magnitude and long-lasting HIV V1V2-binding antibody responses, and early coadministration of the 2 vaccines led to a more rapid induction of these potentially protective responses.TRIAL REGISTRATIONClinicalTrials.gov NCT02207920.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID) grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069511, UM1 AI069470, UM1 AI069534, P30 AI450008, UM1 AI069439, UM1 AI069481, and UM1 AI069496; the National Center for Advancing Translational Sciences, NIH (grant UL1TR001873); and the Bill & Melinda Gates Foundation (grant OPP52845).

RevDate: 2019-09-30

Lees W, Busse CE, Corcoran M, et al (2019)

OGRDB: a reference database of inferred immune receptor genes.

Nucleic acids research pii:5576123 [Epub ahead of print].

High-throughput sequencing of the adaptive immune receptor repertoire (AIRR-seq) is providing unprecedented insights into the immune response to disease and into the development of immune disorders. The accurate interpretation of AIRR-seq data depends on the existence of comprehensive germline gene reference sets. Current sets are known to be incomplete and unrepresentative of the degree of polymorphism and diversity in human and animal populations. A key issue is the complexity of the genomic regions in which they lie, which, because of the presence of multiple repeats, insertions and deletions, have not proved tractable with short-read whole genome sequencing. Recently, tools and methods for inferring such gene sequences from AIRR-seq datasets have become available, and a community approach has been developed for the expert review and publication of such inferences. Here, we present OGRDB, the Open Germline Receptor Database (https://ogrdb.airr-community.org), a public resource for the submission, review and publication of previously unknown receptor germline sequences together with supporting evidence.

RevDate: 2019-09-30

Sarnowski C, Leong A, Raffield LM, et al (2019)

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

American journal of human genetics pii:S0002-9297(19)30314-3 [Epub ahead of print].

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

RevDate: 2019-09-28

Nicholas TP, Haick AK, Bammler TK, et al (2019)

The Effects of Genotype × Phenotype Interactions on Transcriptional Response to Silver Nanoparticle Toxicity in Organotypic Cultures of Murine Tracheal Epithelial Cells.

Toxicological sciences : an official journal of the Society of Toxicology pii:5575766 [Epub ahead of print].

The airway epithelium is critical for maintaining innate and adaptive immune responses, and occupational exposures that disrupt its immune homeostasis may initiate and amplify airway inflammation. In our previous study, we demonstrated that silver nanoparticles (AgNP), which are engineered nanomaterials used in multiple applications but primarily in the manufacturing of many antimicrobial products, induce toxicity in organotypic cultures derived from murine tracheal epithelial cells (MTEC), and those differentiated toward a "Type 2 [T2]-Skewed" phenotype experienced an increased sensitivity to AgNP toxicity, suggesting that asthmatics could be a sensitive population to AgNP exposures in occupational settings. However, the mechanistic basis for this genotype × phenotype interaction (G×P) has yet to be defined. In the present study, we conducted transcriptional profiling using RNA-sequencing (RNA-seq) to predict the enrichment of specific canonical pathways and upstream transcriptional regulators to assist in defining a mechanistic basis for G×P effects on AgNP toxicity. Organotypic cultures were derived from MTEC across two genetically inbred mouse strains (A/J and C57BL/6J mice), two phenotypes ("Normal" and "T2-Skewed"), and one AgNP exposure (an acute 24 h exposure) to characterize G×P effects on transcriptional response to AgNP toxicity. The "T2-Skewed" phenotype was marked by increased pro-inflammatory T17 responses to AgNP toxicity, which are significant predictors of neutrophilic/difficult-to-control asthma and suggests that asthmatics could be a sensitive population to AgNP exposures in occupational settings. This study highlights the importance of considering G×P effects when identifying these sensitive populations, whose underlying genetics or diseases could directly modify their response to AgNP exposures.

RevDate: 2019-09-27

Watt GP, Reiner AS, Smith SA, et al (2019)

Association of a Pathway-Specific Genetic Risk Score With Risk of Radiation-Associated Contralateral Breast Cancer.

JAMA network open, 2(9):e1912259 pii:2752103.

Importance: Radiation therapy for breast cancer is associated with increased risk of a second primary contralateral breast cancer, but the genetic factors modifying this association are not well understood.

Objective: To determine whether a genetic risk score comprising single nucleotide polymorphisms in the nonhomologous end-joining DNA repair pathway is associated with radiation-associated contralateral breast cancer.

This case-control study included a case group of women with contralateral breast cancer that was diagnosed at least 1 year after a first primary breast cancer who were individually matched to a control group of women with unilateral breast cancer. Inclusion criteria were receiving a first invasive breast cancer diagnosis prior to age 55 years between 1985 and 2008. Women were recruited through 8 population-based cancer registries in the United States, Canada, and Denmark as part of the Women's Environment, Cancer, and Radiation Epidemiology Studies I (November 2000 to August 2004) and II (March 2010 to December 2012). Data analysis was conducted from July 2017 to August 2019.

Exposures: Stray radiation dose to the contralateral breast during radiation therapy for the first breast cancer. A novel genetic risk score comprised of genetic variants in the nonhomologous end-joining DNA repair pathway was considered the potential effect modifier, dichotomized as high risk if the score was above the median of 74 and low risk if the score was at or below the median.

Main Outcomes and Measures: The main outcome was risk of contralateral breast cancer associated with stray radiation dose stratified by genetic risk score, age, and latency.

Results: A total of 5953 women were approached for study participation, and 3732 women (62.7%) agreed to participate. The median (range) age at first diagnosis was 46 (23-54) years. After 5 years of latency or more, among women who received the first diagnosis when they were younger than 40 years, exposure to 1.0 Gy (to convert to rad, multiply by 100) or more of stray radiation was associated with a 2-fold increased risk of contralateral breast cancer compared with women who were not exposed (rate ratio, 2.0 [95% CI, 1.1-3.6]). The risk was higher among women with a genetic risk score above the median (rate ratio, 3.0 [95% CI, 1.1-8.1]), and there was no association among women with a genetic risk score below the median (rate ratio, 1.3 [95% CI, 0.5-3.7]). Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%.

Conclusions and Relevance: This study found an increased risk of contralateral breast cancer that was attributable to stray radiation exposure among women with a high genetic risk score and who received a first breast cancer diagnosis when they were younger than 40 years after 5 years or more of latency. This genetic risk score may help guide treatment and surveillance for women with breast cancer.

RevDate: 2019-09-27

Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Abate D, et al (2019)

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study.

JAMA oncology pii:2752381 [Epub ahead of print].

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data.

Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning.

Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence.

Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs).

Conclusions and Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.

RevDate: 2019-09-27

Luft T, Benner A, Terzer T, et al (2019)

EASIX and mortality after allogeneic stem cell transplantation.

Bone marrow transplantation pii:10.1038/s41409-019-0703-1 [Epub ahead of print].

Allogeneic stem cell transplantation (alloSCT) is an effective immunotherapy in patients with hematological malignancies. Endothelial dysfunction was linked to major complications after alloSCT. We asked the question if the "Endothelial Activation and Stress Index" (EASIX; [(creatinine × LDH) ÷ thrombocytes]) can predict mortality after alloSCT. We performed a retrospective cohort analysis in five alloSCT centers in the USA and Germany. EASIX was assessed prior to conditioning (EASIX-pre) and correlated with mortality in 755 patients of a training cohort in multivariable models. The predictive model established in the training cohort was validated in 1267 adult allo-recipients. Increasing EASIX-pre predicted lower overall survival (OS) after alloSCT, and successful model validation was achieved for the validation cohort. We found that EASIX-pre predicts OS irrespective of established scores. Moreover, EASIX-pre was also a significant prognostic factor for transplant-associated microangiopathy. Finally, EASIX-pre correlated with biomarkers of endothelial homeostasis such as CXCL8, interleukin-18, and insulin-like-growth-factor-1 serum levels. This study establishes EASIX-pre based on a standard laboratory biomarker panel as a predictor of individual risk of mortality after alloSCT independently from established clinical criteria.

RevDate: 2019-09-27

Wang M, Rule S, Zinzani PL, et al (2019)

Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma.

RevDate: 2019-09-27

Lazaryan A, Dolan M, Zhang MJ, et al (2019)

Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research.

Haematologica pii:haematol.2019.220756 [Epub ahead of print].

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia. To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative acute lymphoblastic leukemia in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. Patients with abnormal cytogenetics had 40% leukemia-free survival and 42% overall survival at 5-years post-transplant, which was similar to those with normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (p=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse (hazard ratio=2.11; 95% confidence interval, 1.04-4.27) and treatment failure (hazard ratio=1.97; 1.20-3.24). Complex karyotype was prognostic for relapse (hazard ratio=1.69; 1.06-2.69), whereas t(8;14) predicted treatment failure (hazard ratio=2.85; 1.35-6.02) and overall mortality (hazard ratio=3.03; 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse (monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy), intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (p=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities of acute lymphoblastic leukemia can be overcome by transplant, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.

RevDate: 2019-09-27

Drinnenberg IA, Berger F, Elsässer SJ, et al (2019)

EvoChromo: towards a synthesis of chromatin biology and evolution.

Development (Cambridge, England), 146(19): pii:146/19/dev178962.

Over the past few years, interest in chromatin and its evolution has grown. To further advance these interests, we organized a workshop with the support of The Company of Biologists to debate the current state of knowledge regarding the origin and evolution of chromatin. This workshop led to prospective views on the development of a new field of research that we term 'EvoChromo'. In this short Spotlight article, we define the breadth and expected impact of this new area of scientific inquiry on our understanding of both chromatin and evolution.

RevDate: 2019-09-27

Pont MJ, Hill T, Cole GO, et al (2019)

γ-secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma.

Blood pii:blood.2019000050 [Epub ahead of print].

B cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase complex, which reduces ligand density on tumor cells for CAR-T cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR-T cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR-T cell recognition of tumor cells, and potentially limit efficacy of BCMA directed adoptive T cell therapy. We investigated whether blocking BCMA cleavage by small molecule γ-secretase inhibitors (GSIs) could augment BCMA-targeted CAR-T cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR-T cells in vitro GSI treatment of MM tumor bearing NOD/SCID/γc-/- mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR-T cell therapy. Importantly, short term GSI administration to MM patients markedly increases the percentage of BCMA+tumor cells, and the levels of BCMA surface expression in vivo Based on these data, an FDA-approved clinical trial (NCT03502577) has been initiated, combining GSI with concurrent BCMA CAR-T cell therapy.

RevDate: 2019-09-27

Newman LP, Pagkas-Bather J, Njoroge A, et al (2019)

Virological failure in children living with HIV on antiretroviral therapy: correlates and predictive value of clinical measurements and CD4 cell count.

International journal of STD & AIDS [Epub ahead of print].

RevDate: 2019-09-26

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: 2019-09-26

Pidala J, Martens M, Anasetti C, et al (2019)

Factors Associated With Successful Discontinuation of Immune Suppression After Allogeneic Hematopoietic Cell Transplantation.

JAMA oncology pii:2751877 [Epub ahead of print].

Importance: Immune suppression discontinuation is routinely attempted after allogeneic hematopoietic cell transplantation (HCT) and under current practices may lead to graft-vs-host disease (GVHD)-associated morbidity and death. However, the likelihood and predictive factors associated with successful immune suppression discontinuation after HCT are poorly understood.

Objectives: To examine factors associated with successful immune suppression discontinuation and risk for immune suppression discontinuation failure under conventional HCT approaches and develop a practical tool to estimate successful immune suppression discontinuation likelihood at the clinical point of care.

Using long-term follow-up data from 2 national Blood and Marrow Transplant Clinical Trial Network studies (N = 827), a multistate model was developed to investigate the probability and variables associated with immune suppression discontinuation success. The study began in July 2015, and analyses were completed in August 2019.

Main Outcomes and Measures: Immune suppression discontinuation and immune suppression discontinuation failure.

Results: Of the 827 patients included in the analysis, 456 were men (55.1%). Median age at transplant was 44 (range, <1-67) years. With median follow-up of 72 (range, 11-124) months, 20.0% of the patients were alive and not receiving immune suppression at 5 years. Older recipient age (adjusted odds ratio [aOR] of >50 vs <30 years, 0.27, 99% CI, 0.14-0.50; P < .001), mismatched unrelated donor (aOR, mismatched unrelated vs matched related, 0.37; 99% CI, 0.14-0.97; P = .008), peripheral blood graft (aOR of peripheral blood graft vs bone marrow, 0.46; 99% CI, 0.26-0.82; P < .001), and advanced stage disease (aOR of advanced vs early disease, 0.45; 99% CI, 0.23-0.86, P = 0.002), were significantly associated with decreased odds of immune suppression discontinuation. Failed attempts at immune suppression discontinuation (127 patients [37.1% of total immune suppression discontinuation events]) resulting in GVHD were significantly associated with use of peripheral blood stem cells (HR, 2.62; 99% CI, 1.30-5.29; P < .001), prior GVHD, and earlier immune suppression discontinuation attempts. Earlier immune suppression discontinuation was not associated with protection from cancer relapse after HCT (adjusted hazard ratio for discontinuation vs not, 1.95; 99% CI, 0.88-4.31; P = .03).Dynamic prediction models were developed to provide future immune suppression discontinuation probability according to individual patient characteristics.

Conclusions and Relevance: Successful immune suppression discontinuation is uncommon in the setting of peripheral blood stem cell grafts. The data suggest earlier attempts at ISD conferred no long-term benefit, given frequent ISD failure, limited subsequent success after initial failed ISD attempt, and no evidence of relapse reduction. Using a risk model-based clinical application, physicians may be able to identify individual patients' probability of successful immune suppression discontinuation.

RevDate: 2019-09-26

Schwartz NRM, Flanagan MR, Babigumira JB, et al (2019)

Cost-Effectiveness Analysis of Adjuvant Neratinib Following Trastuzumab in Early-Stage HER2-Positive Breast Cancer.

Journal of managed care & specialty pharmacy, 25(10):1133-1139.

BACKGROUND: Disease-free survival (DFS) in early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer is significantly greater with the addition of neratinib after adjuvant trastuzumab versus no additional therapy. However, it remains uncertain whether these survival gains represent good value for the money, given the substantial cost of neratinib.

OBJECTIVE: To evaluate clinical and economic implications of adding neratinib after adjuvant trastuzumab based on results from the phase III ExteNET trial.

METHODS: A 3-state Markov model was developed to estimate the cost-effectiveness of neratinib for women with early-stage (I-III) HER2-positive breast cancer. Five-year recurrence rates were derived from the ExteNET trial. Mortality and recurrence rates after 5 years were derived from the HERceptin Adjuvant (HERA) trial. Outcomes included life-years, quality-adjusted life-years (QALYs), and direct medical expenditures. The analysis was performed from a payer perspective over a lifetime horizon. One-way sensitivity and probabilistic analyses were conducted to evaluate uncertainty.

RESULTS: Total cost of neratinib following adjuvant trastuzumab was $317,619 versus $152,812 for adjuvant trastuzumab alone. A gain of 0.4 QALYs (15.7 vs. 15.3) and 0.1 years of projected life expectancy (18.3 vs. 18.2) favored neratinib after trastuzumab versus trastuzumab alone. The neratinib cost per QALY gained was $416,106. At standard willingness-to-pay thresholds of $50,000, $100,000, and $200,000 per QALY gained, neratinib has a probability of 2.8%, 16.7%, and 33.9% of cost-effectiveness, respectively. The cost per QALY gained in a scenario analysis only including patients with hormone-receptor positive disease was $275,311.

CONCLUSIONS: Based on 5-year data from ExteNET, neratinib following adjuvant trastuzumab is not projected to be cost-effective, even among those patients shown to derive the greatest clinical benefit. Future analyses should reassess the cost-effectiveness associated with neratinib treatment as trial data mature.

DISCLOSURES: No outside funding supported this study. Roth reports consulting fees from Genentech. Steuten reports grants from AstraZeneca, EMD Serono, and Genomic Health, along with personal fees from Agendia, unrelated to this study. The other authors have no conflicts of interest in connection with this study.

RevDate: 2019-09-26

Puronen CE, Ford ES, TS Uldrick (2019)

Immunotherapy in People With HIV and Cancer.

Frontiers in immunology, 10:2060.

HIV infection alters the natural history of several cancers, in large part due to its effect on the immune system. Immune function in people living with HIV may vary from normal to highly dysfunctional and is largely dependent on the timing of initiation (and continuation) of effective antiretroviral therapy (ART). An individual's level of immune function in turn affects their cancer risk, management, and outcomes. HIV-associated lymphocytopenia and immune dysregulation permit immune evasion of oncogenic viruses and premalignant lesions and are associated with inferior outcomes in people with established cancers. Various types of immunotherapy, including monoclonal antibodies, interferon, cytokines, immunomodulatory drugs, allogeneic hematopoietic stem cell transplant, and most importantly ART have shown efficacy in HIV-related cancer. Emerging data suggest that checkpoint inhibitors targeting the PD-1/PD-L1 pathway can be safe and effective in people with HIV and cancer. Furthermore, some cancer immunotherapies may also affect HIV persistence by influencing HIV latency and HIV-specific immunity. Studying immunotherapy in people with HIV and cancer will advance clinical care of all people living with HIV and presents a unique opportunity to gain insight into mechanisms for HIV eradication.

RevDate: 2019-09-25

Faltermeier C, Chai T, Syed S, et al (2019)

Survival of infants ≤24 months of age with brain tumors: A population-based study using the SEER database.

PloS one, 14(9):e0223051 pii:PONE-D-19-21460.

INTRODUCTION: Brain tumors are the most common solid malignancy and leading cause of cancer-related deaths in infants. Current epidemiological data is limited by low numbers of reported cases. This study used a population-based approach with analysis of contemporary and historical survival curves to provide up-to-date prognostication.

METHODS: Observational cohort analysis was performed using the Surveillance, Epidemiology and End Results (SEER) database. Infants with brain tumors diagnosed from 1973 to 2013 were categorized by the most common tumor types (diffuse astrocytic and oligodendroglioma, choroid plexus, embryonal, ependymal, medulloblastoma and pilocytic astrocytoma). The 1, 5 and 10 year survival was stratified by decade, with trends in management and outcomes analyzed.

RESULTS: We identified 2996 affected infants satisfying inclusion criteria. All tumor types, except embryonal and choroid plexus, demonstrated improving survival with time. Infants with embryonal tumors showed a decline in survival from the 1970s to 1990s (p = 0.009), whereas infants with choroid plexus tumors had no change in survival. Infants with ependymal tumors experienced the greatest improvement in survival from 1980s to 1990s and 1990s to 2000s (p = 0.0001, p = 0.01), with 5-year survival probability improving from 28% (95% CI 15-42%) in the 1980s to 77% (95% CI 69-83%) the 2000s. The use of radiation declined from 1970 to 2000 for all tumors; however, radiation treatment for embryonal and ependymal subtypes increased after 2000.

CONCLUSIONS: While overall survival for infants with brain tumors has improved from the 1970s onwards, not every tumor type has seen a statistically significant change. Given changes in management and survival, prognostication of infants with brain tumor should be updated.

RevDate: 2019-09-25

Dashti SG, Li WY, Buchanan DD, et al (2019)

Type 2 diabetes mellitus, blood cholesterol, triglyceride and colorectal cancer risk in Lynch syndrome.

British journal of cancer pii:10.1038/s41416-019-0580-9 [Epub ahead of print].

BACKGROUND: Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer.

METHODS: This study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk.

RESULTS: Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03-3.58) and high cholesterol (HR 1.76; CI 1.23-2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk.

CONCLUSION: For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.

RevDate: 2019-09-25

Greninger AL, Naccache SN, Pannaraj P, et al (2019)

Closing the Brief Case: Inherited Chromosomally Integrated Human Herpesvirus 6 (HHV-6) in the Age of Multiplex HHV-6 Testing.

Journal of clinical microbiology, 57(10): pii:57/10/e02018-18.

RevDate: 2019-09-25

Greninger AL, Naccache SN, Pannaraj P, et al (2019)

The Brief Case: Inherited Chromosomally Integrated Human Herpesvirus 6 (HHV-6) in the Age of Multiplex HHV-6 Testing.

Journal of clinical microbiology, 57(10): pii:57/10/e02016-18.

RevDate: 2019-09-25

Inamoto Y, White J, Ito R, et al (2019)

Comparison of characteristics and outcomes of late acute and NIH chronic GVHD between Japanese and white patients.

Blood advances, 3(18):2764-2777.

Although differences in the incidence of chronic graft-versus-host disease (GVHD) across the races have been suggested, these have not been systematically investigated. This study compared the incidence, sites, severity, and outcomes of late acute GVHD and chronic GVHD according to National Institutes of Health (NIH) consensus criteria between Japanese (n = 413) and white (n = 708) patients after first allogeneic hematopoietic cell transplantation. Analysis was stratified according to bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). Japanese patients, compared with white patients, had a similar incidence of late acute GVHD (BMT, 19% vs 16%; PBSCT, 19% vs 16%) but experienced more frequent liver late acute GVHD as defined by transaminase elevation (BMT, 79% vs 8%; PBSCT, 92% vs 33%) and less frequent gastrointestinal late acute GVHD (BMT, 11% vs 58%; PBSCT, 20% vs 68%). Japanese patients were more likely to discontinue systemic immunosuppression after late acute GVHD than white patients (hazard ratio, 3.68; 95% confidence interval, 1.96-6.94; P < .001). Japanese patients, compared with white patients, had a lower incidence of chronic GVHD (BMT, 15% vs 30% [P = .002]; PBSCT, 37% vs 45% [P < .001]) and experienced more frequent chronic GVHD of the mouth, eyes, and liver and less frequent gastrointestinal chronic GVHD. The duration of immunosuppressive treatment of NIH chronic GVHD was similar between the races. These differences could not be entirely attributed to practice variation between the centers. This study shows that the incidence, affected sites, severity, and clinical outcomes of late acute GVHD and NIH chronic GVHD differ between Japanese and white patients.

RevDate: 2019-09-24

Munch MM, Chambers LC, Manhart LE, et al (2019)

Optimizing bacterial DNA extraction in urine.

PloS one, 14(9):e0222962 pii:PONE-D-19-13657.

Urine is an acceptable, non-invasive sample for investigating the human urogenital microbiota and for the diagnosis of sexually transmitted infections. However, low quantities of bacterial DNA and PCR inhibitors in urine may prevent efficient PCR amplification for molecular detection of bacteria. Furthermore, cold temperatures used to preserve DNA and bacteria in urine can promote precipitation of crystals that interfere with DNA extraction. Saline, Dulbecco's Phosphate Buffered Saline, or Tris-EDTA buffer were added to urine from adult men to determine if crystal precipitation could be reversed without heating samples beyond ambient temperature. Total bacterial DNA concentrations and PCR inhibition were measured using quantitative PCR assays to compare DNA yields with and without buffer addition. Dissolution of crystals with Tris-EDTA prior to urine centrifugation was most effective in increasing bacterial DNA recovery and reducing PCR inhibition. DNA recovery using Tris-EDTA was further tested by spiking urine with DNA from bacterial isolates and median concentrations of Lactobacillus jensenii and Escherichia coli 16S rRNA gene copies were found to be higher in urine processed with Tris-EDTA. Maximizing bacterial DNA yield from urine may facilitate more accurate assessment of bacterial populations and increase detection of specific bacteria in the genital tract.

RevDate: 2019-09-24

Jiang X, Finucane HK, Schumacher FR, et al (2019)

Publisher Correction: Shared heritability and functional enrichment across six solid cancers.

Nature communications, 10(1):4386 pii:10.1038/s41467-019-12095-8.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RevDate: 2019-09-24

Balakrishnan A, Rajan A, Salter AI, et al (2019)

Multispecific targeting with synthetic ankyrin repeat motif chimeric antigen receptors.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-1479 [Epub ahead of print].

PURPOSE: The outgrowth of antigen negative variants is a significant challenge for adoptive therapy with T cells that target a single specificity. Chimeric antigen receptors (CARs) are typically designed with one or two scFvs that impart antigen specificity fused to activation and costimulation domains of T cell signaling molecules. We designed and evaluated the function of CARs with up to three specificities for overcoming tumor escape using Designed Ankyrin Repeat Proteins (DARPins) rather than scFvs for tumor recognition.

EXPERIMENTAL DESIGN: A monospecific CAR was designed with a DARPin binder (E01) specific for EGFR and compared to a CAR designed using an anti-EGFR scFv. CAR constructs in which DARPins specific for EGFR, EpCAM and HER2 were linked together in a single CAR were then designed and optimized to achieve multispecific tumor recognition. The efficacy of CAR-T cells bearing a multispecific DARPin CAR for treating tumors with heterogeneous antigen expression was evaluated in vivo.

RESULTS: The monospecific anti-EGFR E01 DARPin conferred potent tumor regression against EGFR+ targets that was comparable to an anti-EGFR scFv CAR. Linking three separate DARPins in tandem was feasible and in an optimized format generated a single tumor recognition domain that targeted a mixture of heterogeneous tumor cells, each expressing a single antigen, and displayed synergistic activity when tumor cells expressed more than one target antigen.

CONCLUSIONS: DARPins can serve as high-affinity recognition motifs for CAR design, and their robust architecture enable linking of multiple binders against different antigens to achieve functional synergy and reduce antigen escape.

RevDate: 2019-09-23

Scott J, Thakar S, Mao Y, et al (2019)

Apical-Basal Polarity Signaling Components, Lgl1 and aPKCs, Control Glutamatergic Synapse Number and Function.

iScience, 20:25-41 pii:S2589-0042(19)30342-6 [Epub ahead of print].

Normal synapse formation is fundamental to brain function. We show here that an apical-basal polarity (A-BP) protein, Lgl1, is present in the postsynaptic density and negatively regulates glutamatergic synapse numbers by antagonizing the atypical protein kinase Cs (aPKCs). A planar cell polarity protein, Vangl2, which inhibits synapse formation, was decreased in synaptosome fractions of cultured cortical neurons from Lgl1 knockout embryos. Conditional knockout of Lgl1 in pyramidal neurons led to reduction of AMPA/NMDA ratio and impaired plasticity. Lgl1 is frequently deleted in Smith-Magenis syndrome (SMS). Lgl1 conditional knockout led to increased locomotion, impaired novel object recognition and social interaction. Lgl1+/- animals also showed increased synapse numbers, defects in open field and social interaction, as well as stereotyped repetitive behavior. Social interaction in Lgl1+/- could be rescued by NMDA antagonists. Our findings reveal a role of apical-basal polarity proteins in glutamatergic synapse development and function and also suggest a potential treatment for SMS patients with Lgl1 deletion.

RevDate: 2019-09-23

Lamar M, Durazo-Arvizu RA, Rodriguez CJ, et al (2019)

Associations of Lipid Levels and Cognition: Findings from the Hispanic Community Health Study/Study of Latinos.

Journal of the International Neuropsychological Society : JINS pii:S1355617719001000 [Epub ahead of print].

OBJECTIVE: Hispanics/Latinos in the United States are less aware of their cholesterol levels and have a higher burden of associated adverse cardiovascular and cerebrovascular outcomes than non-Latino whites. Investigations of the associations between cholesterol levels and cognition in this population have often occurred within the context of metabolic syndrome and are limited to select lipids despite the fact that triglycerides (TGs) may be more relevant to the health of Hispanics/Latinos.

METHODS: Baseline data from the Hispanic Community Health Study/Study of Latinos, collected from 2008 to 2011, was used to investigate the associations of lipid levels (i.e., TG, total cholesterol, TC; low-density and high-density lipoprotein cholesterol, LDL-C and HDL-C) with cognition (i.e., learning, memory, verbal fluency, and digit symbol substitution, DSS), adjusting for relevant confounders.

RESULTS: In 7413 participants ages 45 to 74 years from Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American backgrounds, separate, fully adjusted linear regression models revealed that TG levels were inversely associated with DSS performance; however, this relationship was no longer significant once additional cardiovascular disease risk factors were added to the model (p = .06). TC and LDL-C levels (separately) were positively associated with learning and verbal fluency regardless of adjustments (p-values < .05). Separate analyses investigating the effect modification by background and sex revealed a particularly robust association between TC levels and DSS performance for Puerto Ricans and Central Americans (albeit in opposite directions) and an inverse relationship between TG levels and DSS performance for women (p-values < .02).

CONCLUSIONS: It is important to consider individual lipid levels and demographic characteristics when investigating associations between cholesterol levels and cognition in Hispanics/Latinos.

RevDate: 2019-09-22

Trabert B, Coburn SB, Falk RT, et al (2019)

Circulating estrogens and postmenopausal ovarian and endometrial cancer risk among current hormone users in the Women's Health Initiative Observational Study.

Cancer causes & control : CCC pii:10.1007/s10552-019-01233-8 [Epub ahead of print].

PURPOSE: Menopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users.

METHODS: We conducted a nested case-control study among postmenopausal women using MHT at baseline in the Women's Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype.

RESULTS: Estrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17-7.73); p-trend = 0.03; p-het < 0.01]. Endometrial cancer risk was unrelated to estrogen/estrogen metabolite levels among women who took combined estrogen/progestin therapy (EPT).

CONCLUSIONS: These findings provide novel evidence that may support a heterogeneous hormonal etiology across ovarian cancer subtypes. Circulating estrogens did not influence endometrial cancer risk among women with EPT-induced high-estrogen levels. Larger studies are needed to delineate the relationship between ovarian/endometrial cancer subtypes and estrogen levels in the context of MHT use.

RevDate: 2019-09-22

Koyama M, Mukhopadhyay P, Schuster IS, et al (2019)

MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota.

Immunity pii:S1074-7613(19)30362-0 [Epub ahead of print].

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.

RevDate: 2019-09-22

Oster NV, Williams EC, Unger JM, et al (2019)

Hepatitis B Birth Dose: First Shot at Timely Early Childhood Vaccination.

American journal of preventive medicine, 57(4):e117-e124.

INTRODUCTION: Current U.S. recommendations state that newborns weighing ≥2,000 grams should receive a birth dose of hepatitis B vaccine, yet approximately one quarter do not receive this first dose as scheduled. The relationship between timely receipt of the first hepatitis B vaccine and other early childhood vaccines remains unclear.

METHODS: Washington State newborns (birth weight ≥2,000 grams) who received birth hospitalization care at an urban academic medical center between 2008 and 2013 were included. Multivariable logistic regression was used to assess whether hepatitis B vaccine receipt during the birth hospitalization was associated with completing the seven-vaccine series by 19 months, adjusting for select sociodemographic, clinical, and birth hospitalization characteristics. Analyses were conducted in 2017-2018.

RESULTS: Of the 9,080 study participants, 75.5% received hepatitis B vaccine during the birth hospitalization, and 53.6% completed the seven-vaccine series by 19 months. Overall, 60.0% of infants vaccinated against hepatitis B during the birth hospitalization completed the seven-vaccine series by 19 months compared with 33.8% of those who were unvaccinated at discharge (p<0.001). The odds of series completion were nearly 3 times higher among infants who received versus did not receive hepatitis B vaccine during the birth hospitalization (AOR=2.92, 95% CI=2.61, 3.26).

CONCLUSIONS: Infants who received hepatitis B vaccine during their birth hospitalization had higher odds of receiving all recommended vaccines by 19 months independent of other factors associated with vaccine receipt. Understanding the factors that influence this first parental vaccine decision and how hepatitis B vaccine delay or declination may affect subsequent vaccination requires further research.

RevDate: 2019-09-21

Boonyaratanakornkit J, Vivek M, Xie H, et al (2019)

Predictive Value of Respiratory Viral Detection in the Upper Respiratory Tract for Infection of the Lower Respiratory Tract with Hematopoietic Stem Cell Transplantation.

The Journal of infectious diseases pii:5572451 [Epub ahead of print].

BACKGROUND: Hematopoietic cell transplant (HCT) recipients are frequently infected with respiratory viruses (RVs) in the upper respiratory tract (URT) but the concordance between URT and lower respiratory tract (LRT) RV detection is not well characterized.

METHODS: HCT candidates and recipients with respiratory symptoms and LRT and URT RV testing via multiplex PCR from 2009 to 2016 were included. Logistic regression models were used to analyze risk factors for LRT RV detection.

RESULTS: 235 HCT candidates or recipients had URT and LRT RV testing within 3 days. Among 115 subjects (49%) positive for a RV, 37%(42/115) had discordant sample pairs. 40%(17/42) of discordant pairs were positive in the LRT but negative in the URT. Discordance was common for adenovirus (100%), metapneumovirus (44%), rhinovirus (34%), and parainfluenza virus type 3 (28%); respiratory syncytial virus was highly concordant (92%). Likelihood of LRT detection was increased with URT detection (OR 73.7; 95%CI 26.7-204) and in CMV+ recipients (OR 3.70, 95%CI 1.30-10.0).

CONCLUSIONS: High rates of discordance were observed for certain RVs. BAL sampling may provide useful diagnostic information to guide management in symptomatic HCT candidates and recipients.

RevDate: 2019-09-21

Mikheeva SA, Camp ND, Huang L, et al (2019)

TWIST1 Heterodimerization with E12 Requires Coordinated Protein Phosphorylation to Regulate Periostin Expression.

Cancers, 11(9): pii:cancers11091392.

Diffuse invasion into adjacent brain matter by glioblastoma (GBM) is largely responsible for their dismal prognosis. Previously, we showed that the TWIST1 (TW) bHLH transcription factor and its regulated gene periostin (POSTN) promote invasive phenotypes of GBM cells. Since TW functional effects are regulated by phosphorylation and dimerization, we investigated how phosphorylation of serine 68 in TW regulates TW dimerization, POSTN expression, and invasion in glioma cells. Compared with wild-type TW, the hypophosphorylation mutant, TW(S68A), impaired TW heterodimerization with the E12 bHLH transcription factor and cell invasion in vitro but had no effect on TW homodimerization. Overexpression of TW:E12 forced dimerization constructs (FDCs) increased glioma cell invasion and upregulated pro-invasive proteins, including POSTN, in concert with cytoskeletal reorganization. By contrast, TW:TW homodimer FDCs inhibited POSTN expression and cell invasion in vitro. Further, phosphorylation of analogous PXSP phosphorylation sites in TW:E12 FDCs (TW S68 and E12 S139) coordinately regulated POSTN and PDGFRa mRNA expression. These results suggested that TW regulates pro-invasive phenotypes in part through coordinated phosphorylation events in TW and E12 that promote heterodimer formation and regulate downstream targets. This new mechanistic understanding provides potential therapeutic strategies to inhibit TW-POSTN signaling in GBM and other cancers.

RevDate: 2019-09-21

Paulson VA, Rudzinski ER, DS Hawkins (2019)

Thyroid Cancer in the Pediatric Population.

Genes, 10(9): pii:genes10090723.

Thyroid cancer is rare in the pediatric population, but thyroid carcinomas occurring in children carry a unique set of clinical, pathologic, and molecular characteristics. In comparison to adults, children more often present with aggressive, advanced stage disease. This is at least in part due to the underlying biologic and molecular differences between pediatric and adult thyroid cancer. Specifically, papillary thyroid carcinoma (which accounts for approximately 90% of pediatric thyroid cancer) has a high rate of gene fusions which influence the histologic subtypes encountered in pediatric thyroid tumors, are associated with more extensive extrathyroidal disease, and offer unique options for targeted medical therapies. Differences are also seen in pediatric follicular thyroid cancer, although there are few studies of non-papillary pediatric thyroid tumors published in the literature due to their rarity, and in medullary carcinoma, which is most frequently diagnosed in the pediatric population in the setting of prophylactic thyroidectomies for known multiple endocrine neoplasia syndromes. The overall shift in the spectrum of histotypes and underlying molecular alterations common in pediatric thyroid cancer is important to recognize as it may directly influence diagnostic test selection and therapeutic recommendations.

RevDate: 2019-09-19

Bloomhardt HM, Sint K, Ross WL, et al (2019)

Severity of reduced bone mineral density and risk of fractures in long-term survivors of childhood leukemia and lymphoma undergoing guideline-recommended surveillance for bone health.

Cancer [Epub ahead of print].

BACKGROUND: Survivors of childhood leukemia/lymphoma are at increased risk for reduced bone mineral density (BMD). The authors sought to determine the frequency of reduced BMD detected by off-therapy surveillance, factors associated with reduced BMD, and the association of reduced BMD with fractures.

METHODS: This cross-sectional study included childhood leukemia/lymphoma survivors attending 2 survivorship clinics who received guideline-recommended BMD surveillance ≥2 years post-therapy with dual-energy x-ray absorptiometry (from January 1, 2004 to August 31, 2016). Lumbar spine BMD z-scores were height-for-age-adjusted. Low and very low BMD were >1 SD and >2 SDs below norms, respectively. Treatment, chronic conditions, and fractures were abstracted from medical records. Logistic regression was used to examine the association of low BMD with patient/treatment factors and fractures.

RESULTS: In total, 542 patients (51.5% female) with a mean age of 15.5 years (range, 4.4-52.2 years) who were 6 years post-therapy (range, 2.0-35.1 years) were evaluated, including 116 who reported post-therapy fractures. Lumbar spine low BMD was identified in 17.2% of survivors, and very low BMD was identified in 3.5% of survivors, but frequencies varied considerably between subgroups; 10.8% of survivors aged 15 to 19 years at diagnosis had very low BMD. In multivariable analyses, older age at diagnosis, white race, and being underweight were significantly associated with low BMD. Survivors with low BMD had greater odds of nondigit fractures (odds ratio, 2.2; 95% CI, 1.3-3.7) and specifically long-bone fractures (odds ratio, 2.7; 95% CI, 1.5-4.7).

CONCLUSIONS: In this study of childhood leukemia/lymphoma survivors undergoing guideline-recommended dual-energy x-ray absorptiometry surveillance, patients who were older at diagnosis, white, and underweight were at the highest risk for lumbar spine low BMD. Low BMD was associated with a greater risk of fractures, emphasizing the clinical importance of surveillance.

RevDate: 2019-09-19

Janes H, Brown MD, Glidden DV, et al (2019)

Evaluating the impact of policies recommending PrEP to subpopulations of men and transgender women who have sex with men based on demographic and behavioral risk factors.

PloS one, 14(9):e0222183 pii:PONE-D-18-36159.

INTRODUCTION: Developing guidelines to inform the use of antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention in resource-limited settings must necessarily be informed by considering the resources and infrastructure needed for PrEP delivery. We describe an approach that identifies subpopulations of cisgender men who have sex with men (MSM) and transgender women (TGW) to prioritize for the rollout of PrEP in resource-limited settings.

METHODS: We use data from the iPrEx study, a multi-national phase III study of PrEP for HIV prevention in MSM/TGW, to build statistical models that identify subpopulations at high risk of HIV acquisition without PrEP, and with high expected PrEP benefit. We then evaluate empirically the population impact of policies recommending PrEP to these subpopulations, and contrast these with existing policies.

RESULTS: A policy recommending PrEP to a high risk subpopulation of MSM/TGW reporting condomless receptive anal intercourse over the last 3 months (estimated 3.3% 1-year HIV incidence) yields an estimated 1.95% absolute reduction in 1-year HIV incidence at the population level, and 3.83% reduction over 2 years. Importantly, such a policy requires rolling PrEP out to just 59.7% of MSM/TGW in the iPrEx population. We find that this policy is identical to that which prioritizes MSM/TGW with high expected PrEP benefit. It is estimated to achieve nearly the same reduction in HIV incidence as the PrEP guideline put forth by the US Centers for Disease Control, which relies on the measurement of more behavioral risk factors and which would recommend PrEP to a larger subset of the MSM/TGW population (86% vs. 60%).

CONCLUSIONS: These findings may be used to focus future mathematical modelling studies of PrEP in resource-limited settings on prioritizing PrEP for high-risk subpopulations of MSM/TGW. The statistical approach we took could be employed to develop PrEP policies for other at-risk populations and resource-limited settings.

RevDate: 2019-09-19

Gray GE, Huang Y, Grunenberg N, et al (2019)

Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa.

Science translational medicine, 11(510):.

One of the most successful HIV vaccines to date, the RV144 vaccine tested in Thailand, demonstrated correlates of protection including cross-clade V1V2 immunoglobulin G (IgG) breadth, Env-specific CD4+ T cell polyfunctionality, and antibody-dependent cellular cytotoxicity (ADCC) in vaccinees with low IgA binding. The HIV Vaccine Trials Network (HVTN) 097 trial evaluated this vaccine regimen in South Africa, where clade C HIV-1 predominates. We compared cellular and humoral responses at peak and durability immunogenicity time points in HVTN 097 and RV144 vaccinee samples, and evaluated vaccine-matched and cross-clade immune responses. At peak immunogenicity, HVTN 097 vaccinees exhibited significantly higher cellular and humoral immune responses than RV144 vaccinees. CD4+ T cell responses were more frequent in HVTN 097 irrespective of age and sex, and CD4+ T cell Env-specific functionality scores were higher in HVTN 097. Env-specific CD40L+ CD4+ T cells were more common in HVTN 097, with individuals having this pattern of expression demonstrating higher median antibody responses to HIV-1 Env. IgG and IgG3 binding antibody rates and response magnitude to gp120 vaccine- and V1V2 vaccine-matched antigens were higher or comparable in HVTN 097 than in RV144 ADCC, and ADCP functional antibody responses were elicited in HVTN 097. Env-specific IgG and CD4+ Env responses declined significantly over time in both trials. Overall, cross-clade immune responses associated with protection were better than expected in South Africa, suggesting wider applicability of this regimen.

RevDate: 2019-09-19

Radich J, Yeung C, D Wu (2019)

New approaches of molecular monitoring in CML (and other diseases).

Blood pii:blood.2019000838 [Epub ahead of print].

In chronic myeloid leukemia (CML), the BCR-ABL1 fusion gene is both the therapeutic target of tyrosine kinase inhibitors, and the indisputable direct marker of disease burden. Sensitive assays for BCR-ABL1drive therapeutic options and are good surrogates for short and long-term outcomes. Because CML is such an ideal model, new methods are arising that should make testing in CML faster, more reliable, and reach a greater sensitivity. New ultra-sensitive sequencing approaches, coupled with single cell genomic approaches, further the study of measurable residual disease, clonal heterogeneity, and promise to make clinical trials more innovative and informative. These methods should be able to be transferred to other hematological and solid malignancies.

RevDate: 2019-09-18

Park H, AR Subramaniam (2019)

Inverted translational control of eukaryotic gene expression by ribosome collisions.

PLoS biology, 17(9):e3000396 pii:PBIOLOGY-D-19-00553.

The canonical model of eukaryotic translation posits that efficient translation initiation increases protein expression and mRNA stability. Contrary to this model, we find that increasing initiation rate can decrease both protein expression and stability of certain mRNAs in the budding yeast Saccharomyces cerevisiae. These mRNAs encode a stretch of polybasic residues that cause ribosome stalling. Our computational modeling predicts that the observed decrease in gene expression at high initiation rates occurs when ribosome collisions at stalls stimulate abortive termination of the leading ribosome or cause endonucleolytic mRNA cleavage. Consistent with this prediction, the collision-associated quality-control factors Asc1 and Hel2 (orthologs of human RACK1 and ZNF598, respectively) decrease gene expression from stall-containing mRNAs only at high initiation rates. Remarkably, hundreds of S. cerevisiae mRNAs that contain ribosome stall sequences also exhibit lower translation efficiency. We propose that inefficient translation initiation allows these stall-containing endogenous mRNAs to escape collision-stimulated reduction in gene expression.

RevDate: 2019-09-18

Shapiro CL, Van Poznak C, Lacchetti C, et al (2019)

Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline.

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

PURPOSE: The aim of this work is to provide evidence-based guidance on the management of osteoporosis in survivors of adult cancer.

METHODS: ASCO convened a multidisciplinary Expert Panel to develop guideline recommendations based on a systematic review of the literature.

RESULTS: The literature search of the 2018 systematic review by the US Preventive Services Task Force in the noncancer population was used as the evidentiary base upon which the Expert Panel based many of its recommendations. A total of 61 additional studies on topics and populations not covered in the US Preventive Services Task Force review were also included. Patients with cancer with metastatic disease and cancer survival outcomes related to bone-modifying agents are not included in this guideline.

RECOMMENDATIONS: Patients with nonmetastatic cancer may be at risk for osteoporotic fractures due to baseline risks or due to the added risks that are associated with their cancer therapy. Clinicians are advised to assess fracture risk using established tools. For those patients with substantial risk of osteoporotic fracture, the clinician should obtain a bone mineral density test. The bone health of all patients may benefit from optimizing nutrition, exercise, and lifestyle. When a pharmacologic agent is indicated, bisphosphonates or denosumab at osteoporosis-indicated dosages are the preferred interventions.

RevDate: 2019-09-18

Khodadoust MS, Rook AH, Porcu P, et al (2019)

Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study.

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

PURPOSE: To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS).

PATIENTS AND METHODS: CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria.

RESULTS: Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature.

CONCLUSION: Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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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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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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