Comparable efficacy of oral bendamustine versus intravenous administration in treating hematologic malignancies.

PURPOSE: The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine and a novel orally administered (PO) bendamustine agent that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles. METHODS: Pharmacokinetics of IV versus PO bendamustine were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO bendamustine. Plasma samples were analyzed using liquid chromatography-mass spectrometry following a liquid-liquid extraction to determine peak bendamustine concentration, area under the concentration-time curve, and the half-life in-vivo. In-vitro cytotoxicity of bendamustine against human non-Hodgkin Burkitt's Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo bendamustine cytotoxicity of IV versus PO bendamustine at two different doses. RESULTS: Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor activity between IV and novel PO bendamustine at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of bendamustine in mice to be 51.4%. CONCLUSIONS: The novel oral bendamustine agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV bendamustine. An oral bendamustine formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

Comparable Efficacy of Oral Bendamustine versus Intravenous Administration in Treating Hematologic Malignancies.

Purpose: The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine (BEN) and a novel orally administered bendamustine agent (PO) that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles. Methods: Pharmacokinetics of IV versus PO BEN were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO BEN. Plasma samples were analyzed using liquid chromatography-mass spectrometry (LC/MS/MS) following a liquid-liquid extraction to determine peak BEN concentration (Cmax), area under the concentration-time curve (AUC) and the half-life (t1/2) in-vivo. in-vitro cytotoxicity of BEN against human non-Hodgkin's Burkitt's Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo BEN cytotoxicity of IV versus PO BEN at two different doses. Results: Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor efficacy between IV and novel PO BEN at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of BEN in mice to be 51.4%. Conclusions: The novel oral BEN agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV BEN. An oral BEN formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

Australian Donation and Transplantation Biobank: A Research Biobank Integrated Within a Deceased Organ and Tissue Donation Program.

We aimed to facilitate the donation of tissue samples for research by establishing a centralized system integrated in the organ donation program for collection, storage, and distribution of samples (the Australian Donation and Transplantation Biobank [ADTB]). Methods: Feasibility of a research biobank integrated within the deceased organ and tissue donation program was assessed. DonateLife Victoria sought consent for ADTB donation after consent was received for organ donation for transplantation from the donor's senior available next of kin. ADTB samples were collected during donation surgery and distributed fresh to researchers or stored for future research. The main outcome measures were ADTB donation rates, ADTB sample collection, ADTB sample use, and to identify ethical considerations. Results: Over 2 y, samples were collected for the ADTB from 69 donors (28% of 249 donors). Samples were obtained from the spleen (n = 59, 86%), colon (n = 57, 83%), ileum (n = 56, 82%), duodenum (n = 55, 80%), blood (n = 55, 80%), bone marrow (n = 55, 80%), skin (n = 54, 78%), mesenteric lymph nodes (n = 56, 81%), liver (n = 21, 30%), lung (n = 29, 42%), and lung-draining lymph node (n = 29, 42%). Heart (n = 20), breast (n = 1), and lower urinary tract (n = 1) samples were obtained in the second year. Five hundred fifty-six samples were used in 19 ethics-approved research projects spanning the fields of immunology, microbiology, oncology, anatomy, physiology, and surgery. Conclusions: The integration of routine deceased donation and transplantation activities with a coordinated system for retrieval and allocation of donor samples for use in a range of research projects is feasible and valuable.

Family-Based Telehealth Initiative to Improve Nutrition and Physical Activity for Children With Obesity and Its Utility During COVID-19: A Mixed Methods Evaluation.

Guidelines recommend primary care providers refer children with obesity to behavioral interventions, but given limited program availability, access, and parental engagement, referrals remain rare. We developed telehealth coaching interventions for families whose children received care at a health system in Pennsylvania, United States in 2019-2020. Intervention referrals were facilitated by the pediatrician and/or project team for 6-12-year-old children with obesity following well-child visits. Participants chose one of three 26-week interventions focused on healthy eating, physical activity, or a hybrid clinical/nutrition intervention. Interventions engaged parents as change agents, enhancing self-efficacy to model and reinforce behavior and providing resources to help create a healthy home environment. We enrolled 77 of 183 eligible parent/child dyads. We used mixed methods to evaluate the interventions. Repeated measures models among participants showed significant reductions in obesogenic nutrition behaviors post-intervention and at 1-year follow-up, including a reduction in sugar-sweetened beverage intake of 2.14 servings/week (95% confidence interval: -3.45, -0.82). There were also improvements in obesoprotective nutrition behaviors (e.g., frequency of family meals, parental self-efficacy related to meal management). One year post-baseline, we observed no significant differences in changes in body mass index (BMI) z-scores comparing child participants with matched controls. Given potential impacts of COVID-19 community restrictions on study outcomes, we conducted qualitative interviews with 13 participants during restrictions, which exemplified how disrupted routines constrained children's healthy behaviors but that intervention participation prepared parents by providing cooking and physical activities at home. Findings support the potential of a telehealth-delivered nutrition intervention to support adoption of healthy weight behaviors.

Clinical Study of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers.

The chemopreventive effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on lung cancer risk is supported by epidemiologic and preclinical studies. Zileuton, a 5-lipoxygenase inhibitor, has additive activity with NSAIDs against tobacco carcinogenesis in preclinical models. We hypothesized that cyclooxygenase plus 5-lipoxygenase inhibition would be more effective than a placebo in modulating the nasal epithelium gene signatures of tobacco exposure and lung cancer. We conducted a randomized, double-blinded study of low-dose aspirin plus zileuton vs. double placebo in current smokers to compare the modulating effects on nasal gene expression and arachidonic acid metabolism. In total, 63 participants took aspirin 81 mg daily plus zileuton (Zyflo CR) 600 mg BID or the placebo for 12 weeks. Nasal brushes from the baseline, end-of-intervention, and one-week post intervention were profiled via microarray. Aspirin plus zilueton had minimal effects on the modulation of the nasal or bronchial gene expression signatures of smoking, lung cancer, and COPD but favorably modulated a bronchial gene expression signature of squamous dysplasia. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents.

Effects of Dietary App-Supported Tele-Counseling on Sodium Intake, Diet Quality, and Blood Pressure in Patients With Diabetes and Kidney Disease.

OBJECTIVES: The aim of this study is to examine the effect of a telehealth intervention that used a dietary app, educational website, and weekly dietitian tele-counseling on sodium intake, diet quality, blood pressure, and albuminuria among individuals with diabetes and early-stage chronic kidney disease. DESIGN AND METHODS: We examined the effects of a dietary app-supported tele-counseling intervention in a single center, single arm study of 44 participants with type 2 diabetes and stage 1-3a chronic kidney disease. Participants recorded and shared dietary data via MyFitnessPal with registered dietitians, who used motivational interviewing to provide telephone counseling weekly for 8 weeks. After the 8-week intensive intervention, participants were followed at 6 and 12 months. Outcomes included 24-hour urine sodium (2 collections per timepoint), Healthy Eating Index 2015 score (three 24-hour dietary recalls per timepoint), 24-hour systolic blood pressure (SBP) and diastolic blood pressure (DBP), and 24-hour urine albumin excretion. RESULTS: Out of 44 consented participants (mean age 60.3 ± 11.9 years, 43% female, 89% white, median estimated glomerular filtration rate was 78.5 mL/min/1.73 m2, median urine albumin excretion 52.9 mg/day, 84% hypertension), 32 (73%) completed 8-week follow-up, 27 (61%) completed 6-month follow-up, and 25 (57%) completed 12-month follow-up. Among participants who completed 12-month follow-up, reported sodium intake decreased by 638 mg/day from baseline of 2,919 mg/day (P < .001). The 24-hour mean urine sodium and albumin excretion did not decline over the study period. Healthy Eating Index 2015 score improved by 7.76 points at 12 months from a mean baseline of 54.6 (P < .001). Both 24-hour SBP and DBP declined at 12 months from baseline (SBP -5.7 mm Hg, 95% confidence interval -10.5 to -1.0, P = .02; DBP -4.1 mm Hg, 95% confidence interval -7.2 to -1.1, P = .01). CONCLUSIONS: Overall, this study demonstrates that a short, intensive, remotely delivered dietary intervention for adults with type 2 diabetes and early chronic kidney disease at high risk for disease progression and cardiovascular complications led to improvement in blood pressure and self-reported sodium intake and diet quality, but no improvement in albuminuria. Future research studies are needed to examine whether remotely delivered dietary interventions can ultimately improve kidney health over time.

Effects of sustained weight loss on outcomes associated with obesity comorbidities and healthcare resource utilization.

OBJECTIVE: Determine the impact of long-term non-surgical weight loss maintenance on clinical relevance for osteoarthritis, cancer, opioid use, and depression/anxiety and healthcare resource utilization. METHODS: A cohort of adults receiving primary care within Geisinger Health System between 2001-2017 was retrospectively studied. Patients with ≥3 weight measurements in the two-year index period and obesity at baseline (BMI ≥30 kg/m2) were categorized: Obesity Maintainers (reference group) maintained weight within +/-3%; Weight Loss Rebounders lost ≥5% body weight in year one, regaining ≥20% of weight loss in year two; Weight Loss Maintainers lost ≥5% body weight in year one, maintaining ≥80% of weight loss. Association with development of osteoarthritis, cancer, opioid use, and depression/anxiety, was assessed; healthcare resource utilization was quantified. Magnitude of weight loss among maintainers was evaluated for impact on health outcomes. RESULTS: In total, 63,567 patients were analyzed including 67% Obesity Maintainers, 19% Weight Loss Rebounders, and 14% Weight Loss Maintainers; median follow-up was 9.7 years. Time until osteoarthritis onset was delayed for Weight Loss Maintainers compared to Obesity Maintainers (Logrank test p <0.0001). Female Weight Loss Maintainers had a 19% and 24% lower risk of developing any cancer (p = 0.0022) or obesity-related cancer (p = 0.0021), respectively. No significant trends were observed for opioid use. Weight loss Rebounders and Maintainers had increased risk (14% and 25%) of future treatment for anxiety/depression (both <0.0001). Weight loss maintenance of >15% weight loss was associated with the greatest decrease in incident osteoarthritis. Healthcare resource utilization was significantly higher for Weight Loss Rebounders and Maintainers compared to Obesity Maintainers. Increased weight loss among Weight Loss Maintainers trended with lower overall healthcare resource utilization, except for hospitalizations. CONCLUSIONS: In people with obesity, sustained weight loss was associated with greater clinical benefits than regained short-term weight loss and obesity maintenance. Higher weight loss magnitudes were associated with delayed onset of osteoarthritis and led to decreased healthcare utilization.

Telehealth versus self-directed lifestyle intervention to promote healthy blood pressure: a protocol for a randomised controlled trial.

INTRODUCTION: Weight loss, consumption of a Dietary Approaches to Stop Hypertension dietary pattern, reduced sodium intake and increased physical activity have been shown to lower blood pressure (BP). Use of web-based tools and telehealth to deliver lifestyle counselling could be potentially scalable solutions to improve BP through behavioural modification though limited data exists to support these approaches in clinical practice. METHODS AND ANALYSIS: This randomised controlled trial will compare the efficacy of a telehealth versus self-directed lifestyle intervention in lowering 24-hour SBP in patients with overweight/obesity (body mass index ≥25 kg/m2) and 24-hour SBP 120-160 mm Hg. All participants receive personalised recommendations to improve dietary quality based on a web-based Food Frequency Questionnaire, access to an online comprehensive weight management programme and a smartphone dietary app. The telehealth arm additionally includes weekly calls with registered dietitian nutritionists who use motivational interviewing. The primary outcome is change from baseline to 12 weeks in 24-hour SBP. Secondary outcomes include changes from baseline in 24-hour diastolic BP, daytime SBP, nighttime SP, daytime diastolic BP, nighttime diastolic BP, total Healthy Eating Index-2015 score, weight, waist circumference and physical activity. Other prespecified outcomes will include change in individual components of the Healthy Eating Index-2015 score, and satisfaction with the Healthy BP research study measured on a 5-point Likert scale. ETHICS AND DISSEMINATION: The study has been approved by the Geisinger Institutional Review Board. Results will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03700710.

Monitoring of tisagenlecleucel transgene DNA using a quantitative polymerase chain reaction assay.

Chimeric antigen receptor (CAR)-T cell therapies reprogram T cells to engage and eliminate cancer cells. Patients' T cells are transduced in vitro using lentiviral or retroviral vectors containing a CAR transgene. Following infusion, CAR-T cells expand in vivo and may persist in the peripheral blood and bone marrow for years. Therefore, monitoring in vivo copies of the CAR transgene requires highly sensitive, validated analytical methods. Herein, we describe the validation of a qPCR assay to detect tisagenlecleucel transgene in patient samples. The limit of detection and lower limit of quantitation were 3.1 and 10 copies/200 ng genomic DNA, respectively, equivalent to ∼50 copies/µg genomic DNA and in alignment with US Food and Drug Administration guidance on bioanalytical method validation. The assay allowed quantitation of the tisagenlecleucel transgene over a wide dynamic range with a high degree of linearity, that is, 101-106 copies/200 ng genomic DNA (R2 ≥ 0.9988). Coefficients of variation of measured transgene copies ranged from 0.2% to 12.8%. A droplet digital PCR assay was performed as a method of validation and showed a strong correlation with the qPCR assay (R2 = 0.9980, p < 0.0001). This qPCR assay is being utilized to monitor tisagenlecleucel expansion and persistence in clinical trials.

Development, Applications, and Refinement of the Family Nutrition and Physical Activity (FNPA) Child Obesity Prevention Screening.

Concerns regarding the continued high prevalence of childhood overweight and obesity have created a need for proactive approaches to behavior change. The Family Nutrition and Physical Activity (FNPA) screening tool was developed for research and clinical use to identify home environments and behaviors that could predispose youth to increased weight. FNPA scores have been shown to correlate with body mass index (BMI) percentiles in first-grade students and to predict unique variance in change in BMI percentiles from first to second grade. The FNPA has been used for family behavior counseling and is now a standard component of well-child visits throughout the Geisinger Health System in Pennsylvania. Parents complete the FNPA prior to annual visits, and providers can discuss areas of concern based on screening results. Children of parents who complete the FNPA have shown smaller increases in BMI z-scores over the following year than children of parents who did not complete the FNPA. The FNPA is also used to inform the arrangement of family-centered obesity treatment for children. Recently, the FNPA has undergone a systematic update to ensure its continued relevance and utility. The updated tool is provided, and current and future users can access more information about the tool at myfnpa.org.

A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer.

PIK3CA mutation frequency varies among breast cancer (BC) subtypes. Recent evidence suggests combination therapy with the PI3K inhibitor (PI3Ki) alpelisib and endocrine therapy (ET) improves response rates and progression-free survival (PFS) in PIK3CA-mutant, hormone receptor positive (HR+) BC versus ET alone; thus, better understanding the clinical and epidemiologic elements of these mutations is warranted. This systematic review characterizes the PIK3CA mutation epidemiology, type of testing approaches (e.g., liquid or tissue tumor biopsy), and stability/concordance (e.g., consistency in results by liquid versus solid tumor sample, by the same method over time) in patients with HR+/HER2- advanced (locally unresectable) or metastatic disease (HR+/HER2- mBC) and explores performance (e.g., pairwise concordance, sensitivity, specificity, or predictive value) of respective mutation findings. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts (i.e., AACR, ASCO, SABCS, ECCO, and ESMO conferences between 2014 and 2017) identified 39 studies of patients with HR+, HER2- mBC. The median prevalence of PIK3CA mutation was 36% (range: 13.3% to 61.5%); identified testing approaches more commonly used tissue over liquid biopsies and primarily utilized next-generation sequencing (NGS), polymerase chain reaction (PCR), or Sanger sequencing. There was concordance and stability between tissues (range: 70.4% to 94%) based on limited data. Given the clinical benefit of the PI3Ki alpelisib in patients with PIK3CA mutant HR+/HER2- mBC, determination of tumor PIK3CA mutation status is of importance in managing patients with HR+/HER2- mBC. Prevalence of this mutation and utility of test methodologies likely warrants PIK3CA mutation testing in all patients with this breast cancer subtype via definitive assessment of PIK3CA mutational status.

A Systematic Literature Review of the Prognostic and Predictive Value of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer.

PIK3CA mutations may have prognostic value for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer, representing an important potential target for systemic therapy. Prognostic and predictive values associated with PIK3CA mutations are not well understood. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and conference abstracts was performed for English-language articles published January 1993 through April 2019. Articles were categorized by treatment arms based on experimental and treatment drug classes. Information on progression-free survival (PFS), hazard ratios, overall survival, response rate, and clinical benefit rate was obtained. A total of 17 studies were included. Among those evaluating non-PI3Ki based therapies, 91% showed numerically shorter median PFS, ranging from 1.5 to 19.2 months and 1.8 to 29.6 months for the mutant versus non-mutant subgroups, respectively. Where reported (n = 13 studies), PFS was shorter between those arms offering endocrine monotherapy (range, 1.6-14.7 months) compared with a corresponding targeted therapy + endocrine monotherapy (range, 3.9-29.6 months). Of 5 PI3Ki-based arms comparing PFS, higher median PFS in PIK3CA mutant versus non-mutant cases was demonstrated. PFS was shorter for patients with PIK3CA mutant (range, 1.6-19.2 months) compared with PIK3CA wild-type (range, 1.8-29.6 months) in 10 (71%) of 14 treatment arms reporting PFS. Studies (n = 4) not reporting PFS reported response rate, but there were no clear directional trends. The presence of PIK3CA mutations may be associated with worse clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Clinical outcomes such as PFS may be improved using a combination of PI3Ki-based therapies and endocrine therapies among this population. However, more research is warranted to fully elucidate this association.

Effect of Intermittent Versus Continuous Low-Dose Aspirin on Nasal Epithelium Gene Expression in Current Smokers: A Randomized, Double-Blinded Trial.

A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, double-blinded study in current heavy smokers to compare modulating effects of intermittent versus continuous low-dose ASA on nasal epithelium gene expression and arachidonic acid (ARA) metabolism. Fifty-four participants were randomized to intermittent (ASA 81 mg daily for one week/placebo for one week) or continuous (ASA 81 mg daily) for 12 weeks. Low-dose ASA suppressed urinary prostaglandin E2 metabolite (PGEM; change of -4.55 ± 11.52 from baseline 15.44 ± 13.79 ng/mg creatinine for arms combined, P = 0.02), a surrogate of COX-mediated ARA metabolism, but had minimal effects on nasal gene expression of nasal or bronchial gene-expression signatures associated with smoking, lung cancer, and chronic obstructive pulmonary disease. Suppression of urinary PGEM correlated with favorable changes in a smoking-associated gene signature (P < 0.01). Gene set enrichment analysis (GSEA) showed that ASA intervention led to 1,079 enriched gene sets from the Canonical Pathways within the Molecular Signatures Database. In conclusion, low-dose ASA had minimal effects on known carcinogenesis gene signatures in nasal epithelium of current smokers but results in wide-ranging genomic changes in the nasal epithelium, demonstrating utility of nasal brushings as a surrogate to measure gene-expression responses to chemoprevention. PGEM may serve as a marker for smoking-associated gene-expression changes and systemic inflammation. Future studies should focus on NSAIDs or agent combinations with broader inhibition of pro-inflammatory ARA metabolism to shift gene signatures in an anti-carcinogenic direction.

PD-1 Inhibition Achieves a Complete Metabolic Response in a Patient with Malignant Peripheral Nerve Sheath Tumor.

High-grade malignant peripheral nerve sheath tumors (MPNST) have a poor prognosis with limited responsiveness to systemic therapy. We document a case of a complete metabolic response to pembrolizumab monotherapy in metastatic disease. Tumor molecular profiling identified programmed-death ligand-1 (PD-L1) positivity. This characteristic provided a rationale for immune-checkpoint therapy. Treatment with pembrolizumab resulted in a complete metabolic response after four cycles of therapy. Patients with PD-L1-positive, metastatic MPNST may be candidates for immune-checkpoint therapy, which may produce a durable complete remission. Future study of anti-PD-1/PD-L1 therapy is warranted.

A Multidisciplinary Evaluation of Barriers to Enrolling Cancer Patients into Early Phase Clinical Trials: Challenges and Patient-centric Recommendations.

Introduction: Early phase clinical trials are the first clinical research step to bringing new cancer therapeutics to patients. At this stage, a new drug's safety, dosing, and scheduling profiles are established as the main endpoints. However, excellent responses due to biomarker-guided and immune checkpoint trials in early phase have resulted in direct approvals of new anti-cancer drugs. Despite doubling of the success rate of new drug approvals, many barriers exist to expeditiously bring active new drugs to the clinic. Areas covered: This review covers roles of members of the early phase program and the challenges they face in enrolling advanced cancer patients to trials. Practical solutions are provided from the perspective of the investigators, regulatory, investigational pharmacy, research nurses, clinical research coordinators, budgets, contracts, and data management. Expert opinion: We are witnessing a burgeoning era in drug development with rapid approval of efficacious drugs. This is achieved by a strong collaboration between investigators, academic institutions, pharmaceutical sponsors, scientists, Food and Drug Administration (FDA), and community practices. Herein, we discuss some of the challenges faced by early phase clinical trials programs and discuss methods of improvement.

Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma.

PURPOSE: Everolimus inhibits the mTOR, activating cytoprotective autophagy. Hydroxychloroquine inhibits autophagy. On the basis of preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and hydroxychloroquine, to determine its safety and activity in patients with clear-cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: Three centers conducted a phase I/II trial of everolimus 10 mg daily and hydroxychloroquine in patients with advanced ccRCC. The objectives were to determine the MTD of hydroxychloroquine with daily everolimus, and to estimate the rate of 6-month progression-free survival (PFS) in patients with ccRCC receiving everolimus/hydroxychloroquine after 1-3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy, and next-generation tumor sequencing. RESULTS: No dose-limiting toxicity was observed in the phase I trial. The recommended phase II dose of hydroxychloroquine 600 mg twice daily with everolimus was identified. Disease control [stable disease + partial response (PR)] occurred in 22 of 33 (67%) evaluable patients. PR was observed in 2 of 33 patients (6%). PFS ≥ 6 months was achieved in 15 of 33 (45%) of patients who achieved disease control. CONCLUSIONS: Combined hydroxychloroquine 600 mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6-month PFS rate was met. Hydroxychloroquine is a tolerable autophagy inhibitor in future RCC or other trials.

The evolution of biomarkers to guide the treatment of metastatic colorectal cancer.

In the United States, colon cancer is one of the leading causes of death and cancer-related death. There is a critical need to improve clinical outcomes in patients with metastatic colorectal cancer (mCRC), as current survival rates are unsatisfactory. There have been significant advances in the treatment of mCRC over the past decade. Molecular characteristics of mCRC and identification of mutations can serve predictive and prognostic indicators of disease response to treatment. These biomarkers can be incorporated into clinical decision making when developing an individualized treatment plan. Targeted therapies have improved the survival of patients with mCRC. As we learn about the various molecular alterations in this disease, additional emerging therapies can be developed to improve clinical outcomes in patients with mCRC.

Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis Is Associated With Changes in Blood Pressure.

PURPOSE: This study reports the effect of disease-modifying therapies for rheumatoid arthritis (RA) on systolic and diastolic blood pressure (SBP, DBP) over 6 months and incident hypertension over 3 years in a large administrative database. METHODS: We used administrative Veterans Affairs databases to define unique dispensing episodes of methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, tumor necrosis factor inhibitors, and prednisone among patients with RA. Changes in SBP and DBP in the 6 months before disease-modifying antirheumatic drug initiation were compared with changes observed in the 6 months after initiation. The risk of incident hypertension within 3 years (new diagnosis code for hypertension and prescription for antihypertensive) was also assessed. Multivariable models and propensity analyses assessed the impact of confounding by indication. RESULTS: A total of 37,900 treatment courses in 21,216 unique patients contributed data. Overall, there were no changes in SBP or DBP in 6 months prior to disease-modifying antirheumatic drug initiation (all P > 0.62). In contrast, there was a decline in SBP (ß = -1.08 [-1.32 to -0.85]; P < 0.0001) and DBP (ß = -0.48 [-0.62 to -0.33]; P < 0.0001) over the 6 months following initiation. The greatest decline was observed among methotrexate and hydroxychloroquine users. Methotrexate users were 9% more likely to have optimal blood pressure (BP) after 6 months of treatment. Patients treated with leflunomide had increases in BP and a greater risk of incident hypertension compared with patients treated with methotrexate (hazard ratio, 1.53 [1.21-1.91]; P < 0.001). CONCLUSIONS: Blood pressure may improve with treatment of RA, particularly with methotrexate or hydroxychloroquine. Leflunomide use, in contrast, is associated with increases in BP and a greater risk of incident hypertension.

Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis.

AIM: To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS: Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs (DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics. RESULTS: Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events (-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events (+5.85 mg/dL, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events (-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (ß = -0.58, P = 0.01) and hydroxychloroquine (ß = -5.78, P = 0.01) use as predictors of lower post-medication-initiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure (ß = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events. CONCLUSION: No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.

Body Mass Index, Weight Loss, and Cause-Specific Mortality in Rheumatoid Arthritis.

OBJECTIVE: To examine associations of body mass index (BMI) and weight loss with cause-specific mortality in rheumatoid arthritis (RA). METHODS: A cohort of US veterans with RA was followed until death or through 2013. BMI was categorized as underweight, normal, overweight, and obese. Weight loss was calculated as the 1) annualized rate of change over the preceding 13 months, and 2) cumulative percent. Vital status and cause of death were obtained from the National Death Index. Multivariable competing-risks regression models were utilized to assess the time-varying associations of BMI and weight loss with cause-specific mortality. RESULTS: Among 1,600 participants and 5,789 patient-years of followup, 303 deaths occurred (95 cardiovascular, 74 cancer, and 46 respiratory). The highest weight-loss rate and weight-loss percent were associated with a higher risk of cardiovascular mortality (rate: subdistribution hazard ratio [sHR] 2.27 [95% confidence interval (95% CI) 1.61-3.19]; percent: sHR 2.31 [95% CI 1.06-5.01]) and cancer mortality (rate: sHR 2.36 [95% CI 1.11-5.01]; percent: sHR 1.90 [95% CI 1.00-3.62]). Overweight BMI was protective of cardiovascular mortality (sHR 0.59 [95% CI 0.38-0.91]), while underweight BMI was associated with a near 3-fold increased risk of respiratory mortality (sHR 2.93 [95% CI 1.28-6.67]). Incorporation of time-varying BMI and weight loss in the same models did not substantially alter individual associations for cardiovascular and cancer mortality, but an association between weight-loss percentage and respiratory mortality was attenuated after BMI adjustment. CONCLUSION: Both BMI and weight loss are predictors of cause-specific mortality in RA. Weight loss is a strong predictor of cardiovascular and cancer mortality, while underweight BMI is a stronger predictor of respiratory mortality.