Circadian Timekeeping in Anticancer Therapeutics: An Emerging Vista of Chronopharmacology Research.

BACKGROUND: Intrinsic rhythms in host and cancer cells play an imperative role in tumorigenesis and anticancer therapy. Circadian medicine in cancer is principally reliant on the control of growth and development of cancer cells or tissues by targeting the molecular clock and implementing time-of-day-based anticancer treatments for therapeutic improvements. In recent years, based on extensive high-throughput studies, we witnessed the arrival of several drugs and drug-like compounds that can modulate circadian timekeeping for therapeutic gain in cancer management. OBJECTIVE: This perspective article intends to illustrate the current trends in circadian medicine in cancer, focusing on clock-modulating pharmacological compounds and circadian regulation of anticancer drug metabolism and efficacy. Scope and Approach: Considering the critical roles of the circadian clock in metabolism, cell signaling, and apoptosis, chronopharmacology research is exceedingly enlightening for understanding cancer biology and improving anticancer therapeutics. In addition to reviewing the relevant literature, we investigated the rhythmic expression of molecular targets for many anticancer drugs frequently used to treat different cancer types. Key Findings and Conclusion: There are adequate empirical pieces of evidence supporting circadian regulation of drug metabolism, transport, and detoxification. Administration of anticancer drugs at specific dosing times can improve their effectiveness and reduce the toxic effects. Moreover, pharmacological modulators of the circadian clock could be used for targeted anticancer therapeutics such as boosting circadian rhythms in the host can markedly reduce the growth and viability of tumors. All in all, precision chronomedicine can offer multiple advantages over conventional anticancer therapy.

Advances in maintenance strategy in newly diagnosed multiple myeloma patients eligible for autologous transplantation.

INTRODUCTION: Multiple myeloma (MM) lacks curative therapy. Therefore, researchers continue to conduct studies in an effort to improve progression-free survival (PFS) and overall survival (OS). Maintenance therapy (MT) after autologous stem cell transplant (ASCT) was extensively studied in the last decade and now considered a standard approach. AREAS COVERED: This review evaluated the evidence and updates on various maintenance agents in newly diagnosed multiple myeloma (NDMM) after ASCT. Articles were searched on PubMed and Embase that were published in last 10 years. Both clinical trials and observational studies were evaluated. EXPERT OPINION: Maintenance strategy after ASCT has consistent PFS benefit but lacks conclusive OS improvement. Lenalidomide is superior to thalidomide given reduced neurotoxicity. OS advantage is controversial for both due to inconsistent evidence. Lenalidomide may confer a PFS advantage even at lower doses due to toxicity with higher doses. Bortezomib-based maintenance has some evidence for OS benefit in high-risk MM (HRMM) and renal dysfunction. Ixazomib has preliminary promising results. Two or three drug combinations for MT are potentially safe and more effective, particularly in HRMM although data on this subject is still evolving. Efficacy of various MT regimens in terms of minimal residual disease status needs to be further investigated.

Ovarian Cancer Maintenance: Practice-Changing Data Calls for Changing Practice.

Staying current on the rapidly evolving therapeutic landscape in oncology is challenging for clinicians. This commentary discusses exciting practice­changing data specific to ovarian cancer.

Maintenance Adalimumab Concentrations Are Associated with Biochemical, Endoscopic, and Histologic Remission in Inflammatory Bowel Disease.

BACKGROUND: A treat-to-target therapeutic approach is emerging as the new standard of care for treating inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC). AIMS: We aimed to investigate the association of serum adalimumab concentrations during maintenance therapy with biochemical, endoscopic, and histologic remission in IBD. METHODS: This retrospective multicenter study included consecutive IBD patients on adalimumab maintenance therapy who had a C-reactive protein (CRP) within 1 week and/or endoscopic evaluation within 12 weeks of therapeutic drug monitoring between July 2013 and December 2016. Biochemical remission was defined as a normal CRP (≤ 5 mg/L). Endoscopic remission was defined as the absence of any ulceration/erosion or a Rutgeerts score of ≤ i1 for patients with an ileocolonic resection for CD and a Mayo endoscopic score of ≤ 1 for UC. Histologic remission was defined as the absence of any sign of active inflammation. Adalimumab concentrations were measured using the homogeneous mobility shift assay. RESULTS: Ninety-one CRP levels and 72 colonoscopies from 98 IBD patients [CD: n = 72 (73%)] were evaluated. Based on receiver operating characteristic analyses, we identified an adalimumab concentration threshold of 11.8, 12, and 12.2 µg/mL in CD and 10.5, 16.2, and 16.2 µg/mL in UC to stratify patients with or without biochemical, endoscopic, or histologic remission, respectively. Adalimumab concentrations ≥ 12 µg/mL (OR 8; 95% CI 2-31.9; p = 0.003) and ≥ 12.2 µg/mL (OR 9.6; 95% CI 1.7-56.1; p = 0.012) were independently associated with endoscopic and histologic remission in CD, respectively. CONCLUSIONS: This study demonstrates that higher maintenance adalimumab concentrations are associated with objective therapeutic outcomes in IBD.

Pharmacological Approaches in the Treatment and Maintenance of Weight Loss.

Obesity is a growing global health concern, associated with a number of important comorbid conditions. It increases the risk of diabetes and contributes to development of cardiovascular disease. While the benefits of weight loss are well established, weight reduction remains a difficult-to-reach goal in overweight and obese individuals due to several metabolic and psychological factors. For many patients, lifestyle intervention is insufficient to achieve long-term weight loss, and additional options, such as pharmacotherapy, need to be considered. Besides the challenging enterprise of weight reduction, weight maintenance remains an even more crucial and outcome-determining aspect of weight management. This article focuses on the potential of currently available pharmacological strategies to support weight loss and maintenance goals in individuals at risk. Two pharmacotherapy types are considered: those developed primarily to induce weight loss and those developed primarily for blood glucose control that have a favorable effect on body weight. Finally, the potential of very low- and low-calorie diets combined with pharmacotherapy and pharmacological combination therapies are discussed, as well as emerging approaches in development.

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma.

BACKGROUND: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. PATIENTS AND METHODS: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. RESULTS: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. CONCLUSIONS: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.

Re-examination of maintenance therapy in non-small cell lung cancer with the advent of new anti-cancer agents.

Metastatic non-small cell lung cancer remains a disease with a high annual incidence and annual mortality worldwide, with limitations in first-line treatment past a fixed amount of platinum doublet chemotherapy for patients that do not harbor a targetable genetic abnormality such as an EGFR mutation or ALK gene rearrangement. Previous attempts to extend first-line treatment past 4-6 cycles of conventional cytotoxic chemotherapy have been disappointing, resulting in diminished quality of life and increased toxicity without improvement of progression-free or overall survival. Several advances in third-generation chemotherapy and targeted agents have generated a renewed interest in maintenance therapy, with several randomized phase III trials reporting a significant improvement in progression-free and overall survival with manageable toxicity profiles. The availability of new chemotherapy agents, tyrosine kinase inhibitors, and immunotherapy agents with a more tolerable or nonoverlapping toxicity profile have resulted in improvements in progression-free survival and median overall survival in maintenance settings with specific agents such as pemetrexed and erlotinib. Patients who are responding to first-line therapy, have not suffered a detrimental decrease in quality of life or performance status, and understand the risks and benefits of further immediate chemotherapy should be considered for maintenance treatment.

Integrating buprenorphine maintenance therapy into federally qualified health centers: real-world substance abuse treatment outcomes.

BACKGROUND: Few studies have examined real-world effectiveness of integrated buprenorphine maintenance treatment (BMT) programs in federally qualified health centers (FQHCs). METHODS: Opioid dependent patients (N=266) inducted on buprenorphine between July 2007 and December 2008 were retrospectively assessed at Connecticut's largest FQHC network. Six-month BMT retention and opioid-free time were collected longitudinally from electronic health records; 136 (51.1%) of patients were followed for at least 12 months. RESULTS: Participants had a mean age of 40.1 years, were primarily male (69.2%) and treated by family practitioners (70.3%). Co-morbidity included HCV infection (59.8%), mood disorders (71.8%) and concomitant cocaine use (59%). Retention on BMT was 56.8% at 6 months and 61.6% at 12 months for the subset observed over 1 year. Not being retained on BMT at 12 months was associated with cocaine use (AOR=2.18; 95% CI=1.35-3.50) while prescription of psychiatric medication (AOR=0.36; 95% CI 0.20-0.62) and receiving on-site substance abuse counseling (AOR=0.34; 95% CI 0.19, 0.59) improved retention. Two thirds of the participants experienced at least one BMT gap of 2 or more weeks with a mean gap length of 116.4 days. CONCLUSIONS: Integrating BMT in this large FQHC network resulted in retention rates similarly reported in clinical trials and emphasizes the need for providing substance abuse counseling and screening for and treating psychiatric comorbidity.

Advances in therapies for acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML), results from the arrest of the maturation of hematopoietic progenitors at the promyelocyte stage. It has been shown that APL is associated with a reciprocal chromosomal translocation, involving chromosomes 15 and 17, which fuses the gene encoding the retinoic acid receptor α (RARα) and the promyelocytic leukemia (PML) gene. The resultant PML-RARα fusion protein plays a critical role in the pathogenesis of APL. Although there are many subtypes of AML, all are typically managed using a standard chemotherapy regimen of an anthracycline plus cytarabine arabinoside (CA). Despite high rates of complete remission following standard chemotherapy, most patients relapse and long-term disease-free survival is only 30-40%. The introduction of drugs such as all-trans retinoic acid (ATRA) that promote progenitor differentiation by directly inhibiting the PML-RARα fusion protein has changed the treatment paradigm for APL and markedly improved patient survival. The purposes of the present review are to provide the latest results and future directions of clinical research into APL and to illustrate how new therapies, such as ATRA plus anthracycline-based induction and consolidation therapy, risk-adapted therapy, salvage therapy containing arsenic trioxide-based regimens, and hematopoietic stem cell transplantation, have improved the treatment outcomes for APL patients.