The JAK1/2 inhibitor ruxolitinib downregulates the immune checkpoint protein B7H3 in multiple myeloma.

We hypothesized that ruxolitinib may inhibit the immune checkpoint protein, B7H3; and, thus, investigated its effects on this immune inhibitor using multiple myeloma (MM) cell lines, bone marrow (BM) mononuclear cells from MM patients and human MM LAGλ -1A xenografts. Ruxolitinib reduced B7H3 gene and protein expression and increased IL-2 and CD8 gene expression. These results suggest that ruxolitinib inhibition of B7H3 may restore exhausted T-cell activity in the MM BM tumor microenvironment.

Penetrance of male breast cancer susceptibility genes: a systematic review.

PURPOSE: Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e., penetrance) remains unclear. We conducted a systematic review of studies reporting the penetrance of MBC susceptibility genes to better summarize current estimates of penetrance. METHODS: A search query was developed to identify MBC-related papers indexed in PubMed/MEDLINE. A validated natural language processing method was applied to identify papers reporting penetrance estimates. These penetrance studies' bibliographies were reviewed to ensure comprehensiveness. We accessed the potential ascertainment bias for each enrolled study. RESULTS: Fifteen penetrance studies were identified from 12,182 abstracts, covering five purported MBC susceptibility genes: ATM, BRCA1, BRCA2, CHEK2, and PALB2. Cohort (n = 6, 40%) and case-control (n = 5, 33%) studies were the two most common study designs, followed by family-based (n = 3, 20%), and a kin-cohort study (n = 1, 7%). Seven of the 15 studies (47%) adjusted for ascertainment adequately and therefore the MBC risks reported by these seven studies can be considered applicable to the general population. Based on these seven studies, we found pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 show an increased risk for MBC. The association between BRCA1 and MBC was not statistically significant. CONCLUSION: This work supports the conclusion that pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 increase the risk of MBC, whereas pathogenic variants in BRCA1 may not be associated with increased MBC risk.

Testing psychosocial mediators of a mind-body resiliency intervention for cancer survivors.

PURPOSE: Group-based mind-body interventions such as the Stress Management and Resiliency Training-Relaxation Response Resiliency Program (SMART-3RP) hold promise for enhancing resiliency among cancer survivors. Mechanisms underlying improvements in psychological outcomes are theoretically established but remain unexamined empirically. METHODS: Adult cancer survivors (n = 105) participating in the SMART-3RP completed surveys of resiliency and five hypothesized mediators: coping (ability to relax physical tension and assertive social support-seeking), mindfulness, positive affect, and worry. Pre-post intervention changes were assessed using repeated-measures t-tests. Bivariate correlations between change scores and a more conservative within-person parallel mediation model tested covariance between resiliency and mediators. RESULTS: Participants experienced moderate to large improvements in all patient-reported outcomes (ds = 1.01-0.46). Increased resiliency was significantly associated with increases in mindfulness, positive affect, and assertive social support-seeking (rs = 0.36-0.50); smaller associations with increased relaxation and decreased worry were not significant. Mindfulness and positive affect explained the largest proportion of variance in resiliency increase in the full multivariate model. CONCLUSIONS: Cancer survivors completing the SMART-3RP had increased resiliency, which was associated with improvements in mindfulness, positive affect, and the ability to assertively seek social support. Enhancing mindfulness and positive affect were critical components for enhancing resiliency. Implications for resiliency interventions with cancer survivors are discussed.

Estimating a normal reference range for serum B-cell maturation antigen levels for multiple myeloma patients.

The serum B-cell maturation antigen (sBCMA) has been identified as a novel serum biomarker for patients with multiple myeloma. However, no study has yet established a reference range for sBCMA levels. Its levels were determined in 196 healthy subjects and showed a right-tailed distribution with a median value of 37·51 ng/ml with a standard deviation of 22·54 ng/ml (range 18·78-180·39 ng/ml). Partitioning of subgroup reference ranges was considered but determined to be irrelevant. A non-parametric method using the median ± 2 standard deviations suggests using a universal reference interval of <82·59 ng/ml.

Normalization of serum B-cell maturation antigen levels predicts overall survival among multiple myeloma patients starting treatment.

Serum B-cell maturation antigen (sBCMA) is a novel biomarker for B-cell malignancies. A normal reference range (<82·59 ng/ml) has been recently established but the impact of achieving normal levels to outcomes for patients receiving treatment for B-cell malignancies has not been studied. We first found that among multiple myeloma (MM) patients starting a new treatment, those who begin treatment within normal sBCMA limits (<82·59 ng/ml) have improved progression-free survival (PFS; P = 0·0398) and overall survival (OS; P = 0·0217) than those who do not. Furthermore, among patients who begin treatment with elevated (≥82·59 ng/ml) sBCMA levels, we assessed the relationship of a decrease in sBCMA to the normal range to OS and found that those who normalize sBCMA demonstrated improved OS (P = 0·0078). Normalizing patients also experienced a markedly improved overall response rate (P < 0·0001). Moreover, all patients who achieved complete remission (CR) showed normalization of sBCMA, and time to normalization (median 0·9 months) was faster than time to CR (5·0 months; P = 0·0036) for these patients. These results suggest that normalization of sBCMA may be an accurate predictor of OS for MM patients during treatment and predict for a higher likelihood of response.

Ruxolitinib reverses checkpoint inhibition by reducing programmed cell death ligand-1 (PD-L1) expression and increases anti-tumour effects of T cells in multiple myeloma.

Multiple myeloma (MM) tumour cells evade host immunity through a variety of mechanisms, which may potentially include the programmed cell death ligand-1 (PD-L1):programmed cell death protein-1 (PD-1) axis. This interaction contributes to the immunosuppressive bone marrow (BM) microenvironment, ultimately leading to reduced effector cell function. PD-L1 is overexpressed in MMBM and is associated with the resistance to immune-based approaches for treating MM. Ruxolitinib (RUX), an inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases, is approved for myeloproliferative diseases. We investigated the effects of RUX alone or in combination with anti-MM agents on the expression of PD-L1 and T-cell cytotoxicity in MM. We showed that the expression of the PD-L1 gene was markedly increased in BM mononuclear cells from patients with MM with progressive disease versus those in complete remission. Furthermore, RUX treatment resulted in a concentration-dependent reduction of PD-L1 gene expression in the MM tumour cells cultured alone or co-cultured with stromal cells compared with untreated cells. The results also demonstrated that RUX increased MM cell apoptosis in the presence of interleukin-2-stimulated T cells to a similar degree as the treatment with anti-PD-1 or anti-PD-L1 antibodies. In summary, these results indicate that RUX can block PD-L1 expression resulting in augmentation of anti-MM effects of T cells.

Baseline serum B-cell maturation antigen levels predict time to disease progression for patients with smoldering multiple myeloma.

Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M-protein, serum-free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B-cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. A receiver operating characteristic curve was used to establish a definition for high-risk baseline sBCMA. Mantel Byar analysis was used to examine whether high-risk sBCMA was correlated with shorter time to transformation, and a time-dependent cox proportional hazard was used to determine whether it is independent of other risk factors. A z test for proportions was used to compare the percentage of patients that progressed among high-risk versus low-risk sBCMA patients. A baseline sBCMA level ≥137.5 mg/ml was found to be the optimal cutoff between high- and low-risk SMM patients. Patients with high-risk sBCMA levels had a shorter time to transformation (P = .000332). sBCMA was also higher at the time of transformation than baseline levels (P = .0116). sBCMA was the only variable found to be significantly predictive of time to transformation and additionally was found to be independent of other risk factors. In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression.

Establishing and Evaluating an ASCO Learning Cohort: a Longitudinal Project Assessing the Learning Needs and Behaviors of Oncology Professionals.

BACKGROUND: In 2013, the American Society of Clinical Oncology (ASCO)'s Continuing Education Committee recommended establishing an interprofessional, longitudinal cohort pilot project. The main goals of the cohort were to gain feedback from oncology providers on how they use resources to address their learning needs and gain insights into the utility of different ASCO educational activities. METHODS: The ASCO Learning Cohort Pilot Project included 49 ASCO members that were representative of the overall Society membership demographics and ran from November 2015 through August 2016. Participants documented monthly learning needs and completed monthly feedback activities focused on specific ASCO educational resources. RESULTS: The Learning Cohort Pilot Project proved a viable and innovative cohort model for analyzing the learning process for oncology healthcare professionals. The development, operations, and compliance required unique infrastructure to accomplish this project. Relationships between participant demographic variables and learning preferences are reported elsewhere. CONCLUSION: The ASCO Learning Cohort Project is a unique educational project that demonstrated feasibility and has met its goals. This paper outlines the processes of establishing a learning cohort, including participant selection, project design, and participant feedback. We evaluate the project model as a means to better understand the learning needs and behaviors of oncology healthcare professionals.

Quantitative Assessment of Learning Behaviors for Oncology Providers.

How health care providers select topics and activities for learning is key to meeting their needs. The goal of this study was to investigate how oncology providers identify knowledge gaps and choose learning activities. An online focus group within a larger longitudinal study was conducted between November 2015 and August 2016. Participants were chosen by convenience and stratified random sampling of diverse types of oncology providers. Providers were asked monthly to identify learning needs, explain how they identified those needs, and describe the learning activity they chose to meet those needs. Thirty-two oncology providers recorded 201 learning needs via online journal entries (mean 6 entries per person). Needs were associated with practice setting and professional role (p < .05). Colleague recommendation predicted learning needs for advanced practice providers (APPs) (p = .003). Patient cases drove > 50% of identified learning needs across groups. Learning activity preferences were associated with practice setting (p < .05). Choice of learning activity was associated with practice setting, professional role, and geographic location. Colleague recommendation was important for APPs (p = .025). Over 75% of learner responses identify convenience and content quality as important factors in choosing an activity. This study represents a quantitative assessment of learning behaviors for oncology providers and shows that identification of learning needs and activity selection differ by provider demographics. Limitations include small size and underrepresentation of some groups. Our findings should be confirmed with larger samples. Future research should focus on assessment of cohort versus individual needs and learning priorities.

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression.

Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.

A flexible nonlinear mixed effects model for HIV viral load rebound after treatment interruption.

Characterization of HIV viral rebound after the discontinuation of antiretroviral therapy is central to HIV cure research. We propose a parametric nonlinear mixed effects model for the viral rebound trajectory, which often has a rapid rise to a peak value followed by a decrease to a viral load set point. We choose a flexible functional form that captures the shapes of viral rebound trajectories and can also provide biological insights regarding the rebound process. Each parameter can incorporate a random effect to allow for variation in parameters across individuals. Key features of viral rebound trajectories such as viral set points are represented by the parameters in the model, which facilitates assessment of intervention effects and identification of important pretreatment interruption predictors for these features. We employ a stochastic expectation-maximization (StEM) algorithm to incorporate HIV-1 RNA values that are below the lower limit of assay quantification. We evaluate the performance of our model in simulation studies and apply the proposed model to longitudinal HIV-1 viral load data from five AIDS Clinical Trials Group treatment interruption studies.

The anti-myeloma effects of the selective JAK1 inhibitor (INCB052793) alone and in combination in vitro and in vivo.

The Janus kinase (JAK) pathway has been shown to play key roles in the growth and resistance to drugs that develop in multiple myeloma (MM) patients. The anti-MM effects of the selective JAK1 inhibitor INCB052793 (INCB) alone and in combination with anti-MM agents were evaluated in vitro and in vivo. Significant inhibition of cell viability of primary MM cells obtained fresh from MM patients, and the MM cell lines RPMI8226 and U266, was observed with single agent INCB and was enhanced in combination with other anti-MM agents including proteasome inhibitors and glucocorticosteroids. Single-agent INCB resulted in decrease in tumor growth of the MM xenograft LAGκ-1A growing in severe combined immunodeficient mice. Mice dosed with INCB (30 mg/kg) showed significant reductions in tumor volume on days 28, 35, 42, 49, 56, and 63. Similarly, INCB at 10 mg/kg showed anti-tumor effects on days 56 and 63. Tumor-bearing mice receiving combinations of INCB with carfilzomib, bortezomib, dexamethasone, or lenalidomide showed significantly smaller tumors when compared to vehicle control and mice treated with single agents. These results provide further support for the clinical evaluation of INCB052793 alone and in combination treatment for MM patients.

The clinical applications of genome editing in HIV.

HIV/AIDS has long been at the forefront of the development of gene- and cell-based therapies. Although conventional gene therapy approaches typically involve the addition of anti-HIV genes to cells using semirandomly integrating viral vectors, newer genome editing technologies based on engineered nucleases are now allowing more precise genetic manipulations. The possible outcomes of genome editing include gene disruption, which has been most notably applied to the CCR5 coreceptor gene, or the introduction of small mutations or larger whole gene cassette insertions at a targeted locus. Disruption of CCR5 using zinc finger nucleases was the first-in-human application of genome editing and remains the most clinically advanced platform, with 7 completed or ongoing clinical trials in T cells and hematopoietic stem/progenitor cells (HSPCs). Here we review the laboratory and clinical findings of CCR5 editing in T cells and HSPCs for HIV therapy and summarize other promising genome editing approaches for future clinical development. In particular, recent advances in the delivery of genome editing reagents and the demonstration of highly efficient homology-directed editing in both T cells and HSPCs are expected to spur the development of even more sophisticated applications of this technology for HIV therapy.

Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients.

B-cell maturation antigen is expressed on plasma cells. In this study, we have identified serum B-cell maturation antigen as a novel biomarker that can monitor and predict outcomes for multiple myeloma patients. Compared to healthy donors, patients with multiple myeloma showed elevated serum B-cell maturation antigen levels (P<0.0001). Serum B-cell maturation antigen levels correlated with the proportion of plasma cells in bone marrow biopsies (Spearman's rho = 0.710; P<0.001), clinical status (complete response vs partial response, P=0.0374; complete response vs progressive disease, P<0.0001), and tracked with changes in M-protein levels. Among patients with non-secretory disease, serum B-cell maturation antigen levels correlated with bone marrow plasma cell levels and findings from positron emission tomography scans. Kaplan-Meier analysis demonstrated that serum B-cell maturation antigen levels above the median levels were predictive of a shorter progression-free survival (P=0.0006) and overall survival (P=0.0108) among multiple myeloma patients (n=243). Specifically, patients with serum B-cell maturation antigen levels above the median level at the time of starting front-line (P=0.0043) or a new salvage therapy (P=0.0044) were found to have shorter progression-free survival. Importantly, serum B-cell maturation antigen levels did not show any dependence on renal function and maintained independent significance when tested against other known prognostic markers for multiple myeloma such as age, serum ß2 microglobulin, hemoglobin, and bone disease. These data identify serum B-cell maturation antigen as a new biomarker to manage multiple myeloma patients.

Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells.

Transplantation of genetically modified hematopoietic stem cells (HSCs) is a promising therapeutic strategy for genetic diseases, HIV, and cancer. However, a barrier for clinical HSC gene therapy is the limited efficiency of gene delivery via lentiviral vectors (LVs) into HSCs. We show here that rapamycin, an allosteric inhibitor of the mammalian target of rapamycin complexes, facilitates highly efficient lentiviral transduction of mouse and human HSCs and dramatically enhances marking frequency in long-term engrafting cells in mice. Mechanistically, rapamycin enhanced postbinding endocytic events, leading to increased levels of LV cytoplasmic entry, reverse transcription, and genomic integration. Despite increasing LV copy number, rapamycin did not significantly alter LV integration site profile or chromosomal distribution in mouse HSCs. Rapamycin also enhanced in situ transduction of mouse HSCs via direct intraosseous infusion. Collectively, rapamycin strongly augments LV transduction of HSCs in vitro and in vivo and may prove useful for therapeutic gene delivery.

The effect of melatonin on sleep and quality of life in patients with advanced breast cancer.

BACKGROUND: Fatigue and sleep problems are prevalent in cancer patients and can be associated with disruption of circadian rhythmicity. In this prospective phase II trial, we sought to assess the effect of melatonin on circadian biomarkers, sleep, and quality of life in breast cancer patients. METHODS: Thirty-two patients with metastatic breast cancer, receiving hormonal or trastuzumab therapy, took 5 mg of melatonin at bedtime for 2 months. Before starting and after 2 months on melatonin therapy, sleep and circadian rhythmicity were assessed by actigraphy, diurnal patterns of serum cortisol, and the expression of the core clock genes PER2 and BMAL1 in peripheral blood mononuclear cells. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire was completed for subjective parameters. RESULTS: Bedtime melatonin was associated with a significant improvement in a marker of objective sleep quality, sleep fragmentation and quantity, subjective sleep, fatigue severity, global quality of life, and social and cognitive functioning scales. Morning clock gene expression was increased following bedtime melatonin intake. Melatonin did not affect actigraphy measure of circadian rhythmicity, or the diurnal cortisol pattern. CONCLUSION: These results invite further investigation of melatonin as a potentially useful therapeutic agent for improving sleep and quality of life in cancer patients.

Role of the mammalian target of rapamycin pathway in lentiviral vector transduction of hematopoietic stem cells.

PURPOSE OF REVIEW: A major goal in repopulating hematopoietic stem cell (HSC) gene therapies is achieving high-efficacy gene transfer, while maintaining robust HSC engraftment and differentiation in vivo. Recent studies have documented that rapamycin treatment of HSC during lentiviral vector transduction enhances gene transfer to human and mouse HSCs and maintains engraftment capacity. In this review, we place into context the role of mammalian target of rapamycin (mTOR) pathways in HSC quiescence and function, endocytic regulation, and lentiviral gene delivery. RECENT FINDINGS: Lentiviral vector transduction of human and mouse HSCs is considerably enhanced by rapamycin treatment. Furthermore, rapamycin preserves long-term engraftment of human and mouse HSCs. Investigations of cellular mechanisms that contribute to increased transduction in HSCs uncover a role for mTOR inhibition-dependent activation of endocytosis. SUMMARY: Rapamycin enhances lentiviral vector transduction of HSCs through regulation of endocytic activity via mTOR inhibition. An important attribute of rapamycin treatment during transduction is the preservation of HSC function, allowing reconstitution of long-term hematopoiesis in vivo in murine models.

The Alzheimer's Disease Neuroimaging Initiative phase 2: Increasing the length, breadth, and depth of our understanding.

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multisite study designed to characterize the trajectories of biomarkers across the aging process. We present ADNI Biostatistics Core analyses that integrate data over the length, breadth, and depth of ADNI. METHODS: Relative progression of key imaging, fluid, and clinical measures was assessed. Individuals with subjective memory complaints (SMC) and early mild cognitive impairment (eMCI) were compared with normal controls (NC), MCI, and individuals with Alzheimer's disease. Amyloid imaging and magnetic resonance imaging (MRI) summaries were assessed as predictors of disease progression. RESULTS: Relative progression of markers supports parts of the amyloid cascade hypothesis, although evidence of earlier occurrence of cognitive change exists. SMC are similar to NC, whereas eMCI fall between the cognitively normal and MCI groups. Amyloid leads to faster conversion and increased cognitive impairment. DISCUSSION: Analyses support features of the amyloid hypothesis, but also illustrate the considerable heterogeneity in the aging process.

Assessment of urine colour using a wallet card: a randomised study of a novel patient self-care tool during chemoradiation for oesophageal cancer.

BACKGROUND: Patients undergoing neoadjuvant chemoradiation for oesophageal cancer often experience dehydration from decreased fluid intake and increased losses. Despite frequent clinical visits during treatment, patients can still present with dehydration, suggesting the need for increased patient awareness and engagement around adverse event management at home. Evidence for benefits of self-monitoring may help motivate patients to engage proactively in their own care to improve their treatment experience. METHODS: We performed a randomised single-centre study of a urine colour self-monitoring card (UCC) during chemoradiation therapy for oesophageal cancer, compared with standard dietitian counselling. Primary outcome was self-efficacy as determined by the Self-Management Resource Centre Self-Efficacy for Managing Chronic Disease Scale (SMCD). Secondary outcomes included Burge thirst scores, Edmonton Symptom Assessment System scores (ESAS), patient-initiated hydrations, creatinine rise and satisfaction with the UCC. RESULTS: Thirty-five patients were randomised. UCC use was not associated with improved SMCD or ESAS scores compared with standard counselling. The card was highly rated by patients as a welcome tool for self-monitoring. CONCLUSIONS: No beneficial effect on self-efficacy or dehydration markers with UCC use was demonstrated. The study nonetheless drew attention to several factors potentially hindering its use for effective self-care: the unexpected severity of other symptoms consuming patients' attention, reduced sensitivity of urine colour due to chemotherapy, absence of active inquiry by the healthcare team and the inconvenient location of the UCC in wallet/purse. Urine colour monitoring in patients with oesophageal cancer to improve the patient experience during treatment warrants further study but supported by active healthcare provider inquiry, more accessible format of the card, and possibly home vital checks to increase its sensitivity in the clinical context.

Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival.

Although TNFRSF17 (also designated as B-cell maturation antigen (BCMA)) is expressed on tumour cells in B-cell malignancies, it has not been found in serum. The present study found that BCMA concentrations were higher in the supernatants of cultured bone marrow mononuclear cells from multiple myeloma (MM) patients than in healthy subjects. Serum BCMA levels were measured in samples from MM patients (n = 209), monoclonal gammopathy of undetermined significance (MGUS) individuals (n = 23) and age-matched controls (n = 40). BCMA was detected in the serum of untreated MM patients (n = 50) and levels were higher than in MGUS patients (P = 0·0157) and healthy subjects (P < 0·0001). Serum BCMA levels were higher among patients with progressive disease (n = 80) compared to those with responsive disease (n = 79; P = 0·0038). Among all MM patients, overall survival was shorter among patients whose serum BCMA levels were above the median (P = 0·001). We also demonstrated that sera from mice with human MM xenografts contained human BCMA, and levels correlated with the change in tumour volume in response to melphalan or cyclophosphamide with bortezomib. These results suggest that serum BCMA levels may be a new biomarker for monitoring disease status and overall survival of MM patients.