Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma.

Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.

SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy. METHODS: This retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC. RESULTS: 412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC < 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC < 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC < 50%, 10.0 months, P = 0.39, respectively). CONCLUSIONS: PD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies. Trial registration ClinicalTrials.gov, NCT02543476. Registered September 4, 2015.

Efficacy, Safety, and Tolerability of RBP-7000 Once-Monthly Risperidone for the Treatment of Acute Schizophrenia: An 8-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 3 Study.

RBP-7000 is a sustained-release formulation of risperidone for the treatment of schizophrenia, designed to be administered by once-monthly subcutaneous injection using the ATRIGEL delivery system. This study assessed the efficacy, safety, and tolerability of RBP-7000 compared with placebo in subjects with acute exacerbation of schizophrenia. Inpatients were randomly assigned to 8 weeks of double-blind treatment with subcutaneous 90 or 120 mg of RBP-7000 or placebo. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline (the last nonmissing value before the first dose of RBP-7000 or placebo on day 1) to end of the study in Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure) and Clinical Global Impression-Severity score (secondary efficacy measure). The least-squares means from the repeated-measures analysis for the change from baseline in the PANSS total scores for placebo was -9.219 (SE, 1.2162). RBP-7000 produced statistically and clinically significant differences in mean reductions from baseline in PANSS total scores (90-mg RBP-7000 compared with placebo, -6.148 [-9.982 to -2.314], P = 0.0004; 120-mg RBP-7000 compared with placebo, -7.237 [-11.045 to -3.429], P < 0.0001) and significantly improved Clinical Global Impression-Severity scores (90-mg RBP-7000 compared with placebo, -0.350 [-0.557 to -0.143], P = 0.0002; 120-mg RBP-7000 compared with placebo, -0.396 [-0.602 to -0.190], P < 0.0001). Both RBP-7000 dosages were generally well tolerated. The most frequently reported treatment-emergent adverse events in RBP-7000 groups compared with placebo were somnolence, weight gain, and akathisia. The overall incidence of extrapyramidal syndrome-related effects was low and similar across groups. RBP-7000 may provide a new, long-acting alternative treatment for use in adults with acute schizophrenia.

Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder.

A major goal for the treatment of opioid use disorder is to reduce or eliminate the use of illicit opioids. Buprenorphine, a µ-opioid receptor partial agonist and kappa opioid receptor antagonist, is now being developed as a monthly, sustained-release formulation (RBP-6000). The objective of this study was to demonstrate that RBP-6000 blocks the subjective effects and reinforcing efficacy of the µ-opioid receptor agonist hydromorphone (intramuscularly administered) in subjects with moderate or severe opioid use disorder. Subjects were first inducted and dose stabilized on sublingual buprenorphine/naloxone (8-24 mg daily; dose expressed as the buprenorphine component), then received two subcutaneous injections of RBP-6000 (300 mg) on Day 1 and Day 29. Hydromorphone challenges (6 mg, 18 mg or placebo administered in randomized order) occurred on 3 consecutive days of each study week before and after receiving RBP-6000. Subjects reported their responses to each challenge on various 100-mm Visual Analogue Scales (VAS). Subjects also completed a choice task to assess the reinforcing efficacy of each hydromorphone dose relative to money. At baseline, mean "drug liking" VAS scores for hydromorphone 18 mg and 6 mg versus placebo were 61 mm (95% confidence interval, 52.3-68.9) and 45 mm (95% confidence interval, 37.2-53.6), respectively. After 300 mg RBP-6000 was administered, mean VAS score differences from placebo were less than 10 mm through week 12. The reinforcing efficacy of hydromorphone decreased in a parallel manner. This study demonstrated that RBP-6000 at a 300 mg dose provides durable and potent blockade of the subjective effects and reinforcing efficacy of hydromorphone in subjects with moderate or severe opioid use disorder.

Predictors of guideline treatment nonadherence and the impact on survival in patients with colorectal cancer.

BACKGROUND: This study investigated the effect of comorbidity, age, health insurance payer status, and race on the risk of patient nonadherence to NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon and Rectal Cancers. In addition, the prognostic impact of NCCN treatment nonadherence on overall survival was assessed. PATIENTS AND METHODS: Patients with CRC who received primary treatment at Memorial University Medical Center from 2003 to 2010 were eligible for this study. Modified Poisson regression was used to obtain risk ratios for the outcome of nonadherence with NCCN Guidelines. Hazard ratios (HRs) for the relative risk of death from all causes were obtained through Cox regression. RESULTS: Guideline-adherent treatment was received by 82.7% of patients. Moderate/severe comorbidity, being uninsured, having rectal cancer, older age, and increasing tumor stage were associated with increased risks of receiving nonadherent treatment. Treatment nonadherence was associated with 3.6 times the risk of death (HR, 3.55; 95% CI, 2.16-5.85) in the first year after diagnosis and an 80% increased risk of death (HR, 1.80; 95% CI, 1.14-2.83) in years 2 to 5. The detrimental effect of nonadherence declined with increasing comorbidity and varied according to age. CONCLUSIONS: Although medically justifiable reasons exist for deviating from NCCN Guidelines when treating patients with colorectal cancer (CRC), those who received nonadherent treatment had much higher risks of death, especially in the first year after diagnosis. This study's results highlight the importance of cancer health services research to drive quality improvement efforts in cancer care for patients with CRC.

An analysis of the distress thermometer problem list and distress in patients with cancer.

PURPOSE: Patients with a cancer diagnosis experience complex issues that can cause distress. The purpose of this study is to identify factors associated with overall distress for a diverse population of cancer survivors. METHODS: Researchers conducted a secondary data analysis of distress ratings (n = 1205) for people receiving outpatient care at a Midwestern US cancer center from 2005 to 2009 to describe the relationships between distress factors and need for assessment of distress. The screening tool was based on the distress thermometer (DT) scale and a modified problem list. Odds ratios and 95 % confidence intervals from this multivariable model were computed. RESULTS: Statistical analysis revealed that the items on the problem list that most contribute to being at risk for distress include financial, worry, nervousness, getting around, and sleep. The most highly associated risk factor for distress was worry. Those that were at risk for high distress were 5.57 times more likely to endorse problems related to worry. CONCLUSIONS: This research identifies which factors may be especially salient to the patient's perception of distress and help guide clinicians in developing targeted screening strategies and specific interventions based on patient response to the DT. It also points to the need for future research to more clearly characterize distress from the patient perspective and determine when interventions may be indicated.

Characteristics associated with breastfeeding behaviors among urban versus rural women enrolled in the Kansas WIC program.

The Special Supplemental Nutrition Program for Women, Infants and Children (WIC) is a public nutritional assistance program for low-income women and their children up to age five. This study provides insight into maternal characteristics associated with breastfeeding among urban versus rural women. A secondary analysis was conducted using the Pregnancy Nutrition Surveillance System dataset of women enrolled in the Kansas WIC program in 2011. Geographic residency status was obtained through application of the Census tract-based rural-urban commuting area codes. Descriptive variables included maternal demographics, health, and lifestyle behaviors. A multivariable binary logistic regression was used to obtain adjusted odds ratios with 95 % confidence intervals. The outcome variable was initiation of breastfeeding. A P value of ≤0.05 was considered statistically significant. The total sample size was 17,067 women. Statistically significant differences regarding socio-demographics, program participation, and health behaviors for urban and rural WIC participants were observed. About 74 % of all WIC mothers initiated breastfeeding. Urban women who were Hispanic, aged 18-19, high school graduates, household income >$10,000/year, and started early prenatal care were more likely to breastfeed. Urban and rural women who were non-Hispanic black with some high school education were less likely to breastfeed. Increased breastfeeding initiation rates are the result of a collaborative effort between WIC and community organizations. Availability of prenatal services to rural women is critical in the success of breastfeeding promotion. Findings help inform WIC program administrators and assist in enhancing breastfeeding services to the Kansas WIC population.

A pooled analysis of outcomes according to cytogenetic abnormalities in patients receiving ixazomib- vs placebo-based therapy for multiple myeloma.

Some cytogenetic abnormalities (CAs) are associated with poorer prognosis in multiple myeloma (MM); proteasome inhibitors appear to benefit patients with high-risk CAs. We evaluated 2247 MM patients from the TOURMALINE-MM1/-MM2/-MM3/-MM4 trials to assess the PFS benefit of ixazomib plus lenalidomide-dexamethasone (Rd) vs placebo-Rd (TOURMALINE-MM1/-MM2) or ixazomib vs placebo (TOURMALINE-MM3/-MM4) in specific high-risk CAs. After a pooled median follow-up of 25.6 months, the hazard ratio (HR) for PFS with ixazomib- vs placebo-based therapy for high-risk patients was 0.74 (95% confidence interval [CI]: 0.59-0.93; median PFS [mPFS] 17.8 vs 13.2 months), and 0.70 (95% CI: 0.62-0.80; mPFS 26.3 vs 17.6 months) for complementary standard-risk patients. The HR for expanded high-risk patients was 0.75 (95% CI: 0.64-0.87; mPFS 18.1 vs 14.1 months), and 0.71 (95% CI: 0.59-0.85; mPFS 36.1 vs 21.4 months) for complementary standard-risk patients. The HR for PFS with ixazomib- vs placebo-based therapy was 0.68 in patients with t(4;14) (95% CI: 0.48-0.96; mPFS 22.4 vs 13.2 months), and 0.77 for patients with amp1q21 (95% CI: 0.63-0.93; mPFS 18.8 vs 14.5 months). A PFS benefit was demonstrated with ixazomib- vs placebo-based therapy regardless of cytogenetic status, with greatest benefit observed in patients with t(4;14) and amp1q21.

Late versus early response and depth of response are associated with improved outcomes in patients with newly diagnosed multiple myeloma enrolled in the TOURMALINE-MM2 trial.

Deeper responses are associated with longer survival in multiple myeloma (MM); however, limited data exist on the impact of response kinetics on outcomes. We investigated progression-free survival (PFS) and duration of response (DOR) by response depth and in early (best confirmed response 0-4 months; n = 424) versus late responders (best confirmed response >4 months; n = 281). Newly diagnosed patients enrolled in TOURMALINE-MM2 receiving ixazomib-lenalidomide-dexamethasone (IRd) (n = 351) or placebo-Rd (n = 354) were evaluated post hoc. Deeper responses were associated with longer PFS (complete response [CR] not reached [NR], very good partial response [VGPR] 37.2 months, partial response [PR] 16.4 months) and DOR (CR NR, VGPR 42.6 months, PR 15.4 months). Among patients with a PFS (n = 511) or DOR (n = 484) of ≥6 months who achieved ≥PR, median PFS was prolonged among late versus early responders receiving IRd (59.7 vs. 17.9 months) or placebo-Rd (56.6 vs. 12.4 months), as was median DOR (IRd, NR vs. 20.9 months; placebo-Rd, 58.2 vs. 11.7 months). While the treatment paradigm for newly diagnosed MM is treatment to progression, our findings suggest slowness of response to a proteasome inhibitor-immunomodulatory drug-steroid combination is not a negative predictor of outcome.

Systematic review and meta-analysis on the use of honey to protect from the effects of radiation-induced oral mucositis.

Recently, 4 separate human controlled trials reported that honey appeared to protect from the effects of radiation-induced oral mucositis formation, a complication of radiation therapy that is responsible for pain and overall reduction in quality of life. In this systematic review and meta-analysis, the authors examined 3 of these controlled trials (n = 120) that met the inclusion and exclusion criteria to determine whether honey had protective effects against radiation-induced oral mucositis. The meta-analysis demonstrated an overall relative risk reduction of 80% in the honey treatment group compared with the control. Although favorable, the data must be approached with caution because of lack of description of the method of randomization and potential bias in all 3 of the individual studies included in the meta-analysis. The results are promising, and further studies are needed to strengthen the current evidence prior to a firm clinical recommendation being given.

Glioblastoma and Increased Survival with Longer Chemotherapy Duration.

INTRODUCTION: The five-year survival rate for patients with glioblastoma (GBM) is low at approximately 4.7%. Radiotherapy plus concomitant and adjuvant temozolomide (TMZ) remains the standard of care. The optimal duration of therapy with TMZ is unknown. This study sought to evaluate the survival benefit of two years of treatment. METHODS: This was a retrospective chart review of all patients diagnosed with GBM and treated with TMZ for up to two years between January 1, 2002 and December 31, 2011. The Kaplan-Meier method with log-rank test was used to estimate the progression-free survival (PFS) and the overall survival (OS). The results were compared to historical controls and data from previous clinical trials of patients treated up to one year. RESULTS: Data from 56 patients with confirmed GBM were evaluated. The OS probability was 54% (SE = 0.068) at one year, 28.3% (SE = 0.064) at two years, 17.8% (SE = 0.059) at three years, and 4% (SE = 0.041) at five years. Seven patients (12.5%) were treated with TMZ for two years. Their median time-to-progression was 28 months (95% CI = 5.0 - 28.0), and they had an increased survival probability at three years compared to other patients (log-rank test χ2 (1, N = 56) = 19.2, p < 0.0001). CONCLUSIONS: There may be an advantage for a longer duration of TMZ therapy among patients with GBM, but the sample size was too small for generalization. A multicenter prospective study is needed to identify optimal duration of TMZ therapy.

A walking intervention to reduce inflammation in patients with diabetes and peripheral arterial/artery disease: A pilot study.

OBJECTIVES: In this pilot study, we sought to determine whether walking reduces inflammation in patients with diabetes mellitus and peripheral arterial/artery disease. METHODS: We obtained blood samples from patients with diabetes mellitus and peripheral arterial/artery disease. Intervention participants were advised to walk for 50 min 3 days per week for 6 months. Participants completed assessments of comorbidities and walking ability. Difference-in-difference analyses were used to assess the relationship between group assignment and each biomarker over time. RESULTS: We randomized 55 participants (control = 25 and intervention = 30). At 6 months and based on p values of <0.20, vascular cellular adhesion molecule, beta-2 microglobulin, total cholesterol, and triglycerides demonstrated a greater decrease among participants randomized to the intervention compared to the control. CONCLUSIONS: Walking may reduce inflammation in persons with diabetes mellitus and peripheral arterial/artery disease. Further research is needed to determine the impact of walking on inflammation in persons with vascular disease.

Reliable Digit Span: a systematic review and cross-validation study.

Reliable Digit Span (RDS) is a heavily researched symptom validity test with a recent literature review yielding more than 20 studies ranging in dates from 1994 to 2011. Unfortunately, limitations within some of the research minimize clinical generalizability. This systematic review and cross-validation study was conducted to address these limitations, thus increasing the measure's clinical utility. Sensitivity and specificity rates were calculated for the ≤6 and ≤7 cutoffs when data were globally combined and divided by clinical groups. The cross-validation of specific diagnostic groups was consistent with the data reported in the literature. Overall, caution should be used when utilizing the ≤7 cutoff in all clinical groups and when utilizing the ≤6 cutoff in the following groups: cerebrovascular accident, severe memory disorders, mental retardation, borderline intellectual functioning, and English as a second language. Additional limitations and cautions are provided.

A longitudinal evaluation of religiosity and psychosocial determinants of suicidal behaviors among a population-based sample in the United States.

BACKGROUND: Relationships among religiosity and other psychosocial factors in determining suicidal behaviors in adolescence and in emerging adulthood have been inconclusive. We sought to investigate prospective relationships among religiosity, psychosocial factors and suicidal behaviors using a nationally representative sample of adolescents emerging into adulthood. METHOD: Analysis was based on 9412 respondents from four waves of National Longitudinal Study of Adolescent Health. A Generalized Estimating Equation (GEE) procedure was used to fit a series of models on the response variable (suicidal behaviors) and a set of psychosocial and religiosity predictors taking into account the correlated structure of the datasets. RESULTS: Analyses showed that adolescent suicidality and religious activity participation showed significant declines over time. Using multinomial logistic regression we found that females showed statistically significant risks of suicidal behaviors, but this effect declined in adulthood. In adjusted models, baseline attendance of a church weekly was associated with 42% reduction (95% Confidence Interval: 0.35-0.98) of suicide ideation in Wave III. Across all waves, low support from fathers (compared with mothers) consistently explained variability in suicidal behaviors among genders emerging into adulthood. LIMITATIONS: Accurate measurement of religiosity is psychometrically challenging. CONCLUSIONS: The findings of the study indicate that religious activity participation is associated with reduced suicidal behaviors among adolescents but this effect declines during emerging adulthood. Psychosocial supports particularly from fathers' have an enduring impact on reduced suicidal behaviors among adolescents and emerging adults. Prevention, identification and evaluation of disorders of suicidality need a careful assessment of underlying mental pain (psyache) to reduce the likelihood of aggravated suicide.

Preliminary benefits of information therapy.

UNLABELLED: Information therapy (ie, information prescriptions) is a potential new tool for primary care physicians that could improve patient knowledge, decision making, and communication between physicians and patients. Although patients have access to numerous health-related articles online, the availability of this health information does not ensure improved knowledge or better health decisions by patients. Communication between patients and physicians is often limited and messages are commonly misunderstood. Information therapy offers a potential solution for the primary care environment. METHOD: Two employers, in different geographical locations of the Midwest, offered the MedEncentive program to employees and their dependents as a part of their health plans. This program also offers primary care physicians the opportunity to prescribe information to patients during office visits. Patients were then eligible to participate in this information therapy (Ix) through a Web-based platform. Both primary care physicians and patients were financially incentivized for participation. Physicians received a monetary stipend for prescribing evidence-based information therapy and patients were refunded part or all of their copayment for reading their condition-specific Ix and answering questions about knowledge, compliance, health status, and satisfaction with the care they received compared to the evidence from the Ix. RESULTS: Patients received information therapy from their primary care physicians and reported a high level of satisfaction with care, improved health status, and compliance with pharmaceutical prescriptions. DISCUSSION: This case study had a number of limitations and as such the results should be interpreted with caution. However, there is a need for an immediate solution as patient satisfaction with their care and compliance with pharmaceutical prescriptions continue to decrease, despite the amounts of widely available health information. These preliminary findings suggest that information therapy through a Web-based platform, augmented by doctor-patient mutual accountability, could be part of the solution for the current ambulatory health care environment.

Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10.

PURPOSE Adjuvant cisplatin-based chemotherapy (ACT) is now an accepted standard for completely resected stage II and III A non-small-cell lung cancer (NSCLC). Long-term follow-up is important to document persistent benefit and late toxicity. We report here updated overall survival (OS) and disease-specific survival (DSS) data. PATIENTS AND METHODS Patients with completely resected stage IB (T2N0, n = 219) or II (T1-2N1, n = 263) NSCLC were randomly assigned to receive 4 cycles of vinorelbine/cisplatin or observation. All efficacy analyses were performed on an intention-to-treat basis. Results Median follow-up was 9.3 years (range, 5.8 to 13.8; 33 lost to follow-up); there were 271 deaths in 482 randomly assigned patients. ACT continues to show a benefit (hazard ratio [HR], 0.78; 95% CI, 0.61 to 0.99; P = .04). There was a trend for interaction with disease stage (P = .09; HR for stage II, 0.68; 95% CI, 0.5 to 0.92; P = .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P = .87). ACT resulted in significantly prolonged DSS (HR, 0.73; 95% CI, 0.55 to 0.97; P = .03). Observation was associated with significantly higher risk of death from lung cancer (P = .02), with no difference in rates of death from other causes or second primary malignancies between the arms. CONCLUSION Prolonged follow-up of patients from the JBR.10 trial continues to show a benefit in survival for adjuvant chemotherapy. This benefit appears to be confined to N1 patients. There was no increase in death from other causes in the chemotherapy arm.