Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial.

Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier NCT03772899 .

Real-World Experience of Vismodegib in Advanced Basal Cell Carcinoma at a Canadian Cancer Center.

BACKGROUND: Vismodegib is a novel Hedgehog pathway inhibitor that has revolutionized the treatment of patients with advanced basal cell carcinoma (BCC) who are poor candidates for surgery or radiation. Few studies have explored the use of vismodegib to facilitate further surgery or radiotherapy, and the optimal treatment duration to balance outcomes with adverse effects. OBJECTIVES: To characterize the disease response, progression, and recurrence outcomes of BCC patients, and to report the impact of subsequent therapies. METHODS: We performed a retrospective study of 46 adult patients with advanced basal cell carcinoma (aBCC), including both locally advanced (laBCC) and metastatic (mBCC) disease, treated with vismodegib at a single center from 2012 to 2019. RESULTS: Thirty-six had laBCC, and 10 had mBCC. Treatment was given over a mean of 21.9 months. Twenty-three (50%) had a complete response (CR), and 19 (41.3%) achieved partial response (PR). Median time to maximal response was 5.3 months. Eleven (23.9%) had resected disease at median 17.2 months, and 11 patients (23.9%) received radiotherapy. Thirty-two (69.6%) experienced progressive disease after achievement of CR or PR. Among 17 CR patients, who stopped treatment, 14 (82.3%) experienced subsequent relapse; 6 (85%) attained a repeat response. Twenty (43.5%) discontinued treatment at least once due to adverse effects. CONCLUSIONS: With a response rate of 91%, London Regional Cancer Center's (LRCP)'s experience with vismodegib supports its effectiveness in treatment of aBCC. Moreover, a significant number of patients treated with vismodegib became amenable to surgery or radiotherapy. Toxicity remained an important factor that limited treatment duration.

A Marijuana Consequences Checklist for Young Adults with Implications for Brief Motivational Intervention Research.

Measures assessing marijuana-related consequences or problems experienced by young adults have typically been adapted from measures assessing alcohol consequences. These measures may not fully reflect the specific unwanted or perceived "not so good" effects of marijuana that are experienced by young adults. Thus, using these measures may present a gap, which needs to be addressed, given that reports of consequences are often utilized in brief motivational personalized feedback interventions. Data from three different studies of young adults were used to (1) examine self-reported "not so good" effects or consequences of marijuana use among frequent marijuana-using college students (Study 1), (2) create a new version of a marijuana consequences list and compare it to an existing marijuana consequences measure (Study 2), and (3) assess convergent and divergent validity between a finalized Marijuana Consequences Checklist (MCC, 26-items) and marijuana use and risk for cannabis use disorder (Study 3). The most frequently endorsed self-reported effects of marijuana included the impact on eating (the "munchies"), dry mouth, trouble concentrating, and acting foolish or goofy. Higher scores on the MCC were associated with more frequent use and a higher probability of meeting criteria for cannabis use disorder. The MCC represents a range of negative consequences of marijuana use derived from frequent users' own accounts and includes consequences not assessed by other measures. The MCC captures marijuana-specific negative consequences relevant for young adults, which can be incorporated in brief motivational personalized feedback interventions.

Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients.

PURPOSE: Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer. METHODS: One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia. RESULTS: More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia. CONCLUSIONS: Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.

Integrating addiction medicine into rural primary care: Strategies and initial outcomes.

OBJECTIVE: This retrospective study describes the role of behavioral health in an addiction medicine program integrated in a primary care clinic, and evaluates retention, substance use, and mental health symptoms for patients in a rural underserved community. METHOD: Data were abstracted from records of patients referred for buprenorphine treatment of opioid use disorder (N = 101; 45% female, 23% Native Hawaiian or Pacific Islander, Mage = 42.5, SD = 12.75). Among patients prescribed buprenorphine (n = 61), most had comorbid substance-related diagnoses (72% with tobacco use, 75% with at least one other substance use disorder) and non-substance-related mental health diagnoses (77%), most commonly depression and anxiety. Integrated sessions with a behavioral health provider and a buprenorphine-waivered prescriber occurred weekly to monthly. Participants completed depression and anxiety questionnaires (Patient Health Questionnaire-9 and Generalized Anxiety Disorder Scale-7) and provided urine samples at each visit. RESULTS: Most patients (72%) were retained for at least 3 months, with early dropout associated with higher initial depression and anxiety scores. Inconsistent urine drug tests (i.e., those positive for illicit/nonprescribed substances) were significantly more common at treatment initiation (74%) than during the most recent visit (43%, p < .001), and were associated with baseline substance and other mental health factors, as well as shorter treatment duration. Generalized estimating equations models suggested time-based improvements in depression and anxiety symptoms, especially for patients retained for at least 3 months. CONCLUSIONS: Integrating wraparound addiction treatment within a rural primary care setting is feasible and associated with improved mental health and retention outcomes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Transition From Hospital to Home: The Role of the Nurse Case Manager in Promoting Medication Adherence in the Medicare Population.

Lack of adherence to medication plans is a factor in costly hospital readmissions. Adherence to medication plans in the home care setting in relation to hospital readmission is a major issue among the Medicare population. Nurse case managers are in a key position to provide care after hospital discharge to promote medication adherence and thus reduce the chance of hospital readmission. This article discusses barriers to taking medications as prescribed and directed, the importance of ongoing medication reconciliation at home, and strategies to promote adherence to medication plans.

Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer.

PURPOSE: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia. METHODS: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms. RESULTS: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline. CONCLUSIONS: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

Taxanes as first-line therapy for advanced non-small cell lung cancer: a systematic review and practice guideline.

UNLABELLED: This evidence-based practice guideline on the use of paclitaxel (Taxol) or docetaxel (Taxotere) as first-line treatment for patients with advanced non-small cell lung cancer who are candidates for palliative first-line chemotherapy is based on a systematic search and review of literature published in full or in abstract form between 1985 and April 2005. Forty-five randomized trials, including 11 abstracts, were reviewed and clinicians in the province of Ontario, Canada, provided feedback on a draft version of the guideline. Two phase III trials detected a statistically significant survival advantage for a taxane (paclitaxel or docetaxel) with best supportive care versus best supportive care alone. Among the nine fully published phase III trials comparing platinum-based chemotherapies, taxane-platinum combinations achieved higher response rates compared with older chemotherapy combinations, although significantly longer survival was observed only for docetaxel-cisplatin compared with vindesine-cisplatin. Response rates and survival were generally not significantly different for taxane-platinum combinations compared with other current chemotherapy combinations, although the toxicity profile of the regimens varied. However, in one large trial, improved tumor response and modest survival and quality of life benefits were associated with docetaxel-cisplatin compared with vinorelbine-cisplatin. No statistically significant survival differences were detected in the three fully published phase III trials comparing a taxane-gemcitabine combination with a taxane-platinum regimen. RECOMMENDATIONS: (i) paclitaxel or docetaxel combined with cisplatin is recommended as one of a number of chemotherapy options for the first-line treatment of advanced non-small cell lung cancer in patients with a good performance status; (ii) carboplatin may be combined with a taxane if a patient is unable or unwilling to take cisplatin; (iii) a taxane-gemcitabine combination may be considered for patients with a contraindication to cisplatin and carboplatin; (iv) no firm recommendation can be made on the optimal dose and schedule of taxane-based chemotherapy; however, commonly used regimens include cisplatin 75 mg/m2 combined with either docetaxel 75 mg/m2 or paclitaxel 135 mg/m2 (24-h infusion) and carboplatin AUC 6 combined with paclitaxel 225 mg/m2 (3-h infusion); (v) a single-agent taxane may be used if combination chemotherapy is considered inappropriate.

Practice guideline for the role of combination chemotherapy in the initial management of limited-stage small-cell lung cancer.

UNLABELLED: An evidence-based practice guideline was developed to identify the optimal combination chemotherapy regimen, schedule of administration, and duration of therapy for the first-line treatment of adults with limited-stage small-cell lung cancer. The guideline is based on a systematic search and review of literature published between 1985 and December 2002. Three reviewers selected studies for inclusion in the guideline according to pre-defined criteria. Fifty randomized controlled trials, five in abstract form, were included in the review, and feedback on a draft version of the guideline was obtained from medical oncologists in the province of Ontario, Canada. The most commonly used regimens in clinical trials are cyclophosphamide-doxorubicin(Adriamycin)-vincristine, and etoposide-cisplatin. No combination chemotherapeutic regimen has been conclusively shown to be superior to either of these regimens. Most studies comparing chemoradiation regimens used sequential rather than concurrent thoracic radiotherapy. When treating for cure with chemoradiation, there is evidence from one randomized controlled trial to support the use of etoposide-cisplatin over an anthracycline-containing regimen. There is conflicting evidence concerning a survival advantage for a regimen that alternates cyclophosphamide-doxorubicin-vincristine with etoposide-cisplatin compared with either regimen alone. If bolus etoposide-cisplatin is the treatment of choice, evidence from one randomized trial suggests that the optimal sequence of administration is cisplatin followed by etoposide. The use of maintenance chemotherapy is not indicated. There is insufficient evidence to support the routine use of dose-intensive regimens outside a clinical trial, to determine the optimal duration of chemotherapy, or to support the routine substitution of carboplatin for cisplatin in combination chemotherapy regimens in this patient population. RECOMMENDATIONS: Etoposide-cisplatin is the preferred chemotherapy regimen for patients with limited-stage small-cell lung cancer when concurrent thoracic radiotherapy is used. It is reasonable to offer the alternation of etoposide-cisplatin with cyclophosphamide-doxorubicin-vincristine, provided the administration of radiotherapy concurrent with an anthracycline is avoided.