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Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6–13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9–43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Merck KGaA, Darmstadt, Germany.

Background No validated disease-specific questionnaires exist to capture health-related quality of life (HRQoL) in patients with Merkel cell carcinoma (MCC). The Functional Assessment of Cancer Therapy – Melanoma (FACT-M) is validated in patients with melanoma, which shares many similarities with MCC. This paper reports the psychometric properties of the FACT-M in the metastatic MCC population. Methods Data were collected as part of a single-arm, open-label, multicenter trial involving patients with metastatic MCC who had failed at least one previous line of chemotherapy. FACT-M and EQ-5D were administered at baseline, Week 7, Week 13, and Week 25. An optional interview was administered at the same time points. MCC-specific FACT-M scores were derived following a combined quantitative and qualitative approach. Reliability and construct validity of original and additional MCC-specific FACT-M scores were assessed at baseline. Capacity to detect change in tumor size was assessed from baseline to Week 7. Minimally important differences (MIDs) were computed using distribution and anchor-based methods. Results Baseline assessments were available in 70 patients (mean age: 70 years; 74.3% male); 19 patients were interviewed at baseline. Additional MCC-specific scores were as follows: Physical Function score (six items), Psychological Impact score (six items), and MCC summary score (12 items). FACT-M original and additional MCC-specific scores both demonstrated acceptable psychometric properties: high reliability (Cronbach’s alpha: 0.81–0.96), good convergent validity (correlations above 0.4 observed for 88% of items of the Melanoma surgery scale, 75% of items of the Melanoma scale, and 100% of items of the other FACT-M domains). Some evidence of floor/ceiling effects and poor discriminant ability was found. Higher scores (better HRQoL) on all FACT-M domains were observed in patients with better functioning (assessed by ECOG performance score), supporting clinical validity. Despite the small sample for responsiveness analysis ( n  = 37), the majority of FACT-M scores showed sensitivity to changes in tumor size at Week 7 with small to moderate effect sizes. MIDs were consistent with previously reported values in the literature for FACT-M domains. Conclusions FACT-M is suitable to capture HRQoL in patients with metastatic MCC, thus making it a potential candidate for assessing HRQoL in MCC trials. Trial registration This study is a post-hoc analysis conducted on data collected in Part A of the JAVELIN Merkel 200 trial. This trial was registered on 2 June 2014 with ClinicalTrials.gov as NCT02155647 .

Health and Quality of Life Outcomes (2017) 15:247 https://doi.org/10.1186/s12955-017-0815-5 Unfortunately, the original version of this article [1] contained one error around the EQ-5D visual analogue scale (VAS) scores affecting a few patients. Table 1 Internal consistency reliability and clinical and concurrent validity of the FACT-M and MCC-specific scores in the mMCC population FACT-M Subscales and Summary scores # items Cronbach’s alpha[a] Scale structure ECOG PS (mean [SD]) EQ-5D VAS EQ-5D index Range of item-subscale correlations[b] Convergent[c]/Divergent[d] validity (% of items) 0 (n = 39) 1 (N = 31) p-value[e] Correlation[b] Correlation [b] FACT-G subscales Physical well-being (PWB) 7 0.86 0.49–0.81 100/ 57 23.21 (5.02) 20.10 (6.08) 0.0221 0.59 0.75 Social/Family well-being (SWB) 7 0.81 0.41–0.86 100/ 71 23.03 (4.78) 21.49 (5.30) 0.2065 0.19 0.24 Emotional well-being (EWB) 6 0.83 0.53–0.75 100/ 67 17.97 (4.22) 16.87 (4.95) 0.3179 0.36 0.53 Functional well-being (FWB) 7 0.87 0.49–0.82 100/ 71 17.41 (6.68) 15.48 (5.90) 0.2113 0.44 0.63 Melanoma-specific subscales Melanoma Subscale (MS) 16 0.85 0.24–0.85 75 / 31 51.64 (8.93) 49.10 (9.02) 0.2427 0.55 0.75 Melanoma surgery Scale (MSS) 8 0.84 0.15–0.81 88 / 63 26.51 (6.19) 25.58 (6.03) 0.5290 0.26 0.51 Summary scales FACT-M TOI 30 0.94 – – 92.26 (18.75) 84.68 (19.40) 0.1026 0.58 0.78 FACT-G total score 27 0.94 – – 81.62 (17.25) 73.95 (17.62) 0.0713 0.50 0.67 FACT-M total score 43 0.96 – – 133.26 (24.66) 123.04 (25.21) 0.0926 0.55 0.74 MCC-Specific scores Physical function score (PF) 6 0.88 – – 16.38 (5.67) 13.71 (5.54) 0.0519 0.52 0.72 Psychological impact score (PI) 6 0.85 – – 17.82 (4.40) 16.87 (5.18) 0.4101 0.36 0.52 MCC summary score 12 0.91 – – 34.21 (8.99) 30.58 (9.94) 0.1145 0.49 0.69 # number, ECOG PS Eastern Cooperative Oncology Group performance score, MCC Merkel cell carcinoma, PAS PRO analysis set, SD Standard deviation, TOI Trial Outcome Index [a] Recommended threshold α > 0.7; [b] Pearson correlation coefficients; [c] % of items correlated with its own dimension ≥0.4; [d] % of items correlated with its own dimension higher that the correlation with any other dimension; [e] p-value from t-test of score between the two ECOG performance status groups at baseline Internal consistency reliability and clinical validity were assessed in the PAS (N = 70) ECOG PS: 0 = Fully active; 1 = Restricted in physically strenuous activity Notes The original article can be found online at https://doi.org/10.1186/s12955-017-0815-5 Declarations Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Psychometric properties of the FACT-M questionnaire in patients with Merkel cell carcinoma.

This retrospective study of patients in the USA with metastatic Merkel cell carcinoma (mMCC) aimed to assess patient responses to second-line and later (2L+) and first-line (1L) chemotherapy. Out of 686 patients with MCC identified in The US Oncology Network, 20 and 67 patients with mMCC qualified for the 2L+ and 1L study, respectively; the primary analysis population was restricted to immunocompetent patients. In the 2L+ primary analysis population, objective response rate (ORR) was 28.6%, median duration of response (DOR) was 1.7 months and median progression-free survival was 2.2 months. In the 1L primary analysis population, ORR was 29.4%, median DOR was 6.7 months and median progression-free survival was 4.6 months. The low ORR and brief DOR underscore the need for novel therapies.

Merkel cell carcinoma (MCC) is a rare neuroendocrine, cutaneous malignancy with poor prognosis once metastasized. The aim of this study was to conduct a systematic literature review to assess clinical outcomes associated with chemotherapy regimens in metastatic MCC. Embase , MEDLINE , MEDLINE -In-Process and CENTRAL were searched for studies published in January 2016. Overall, the literature on chemotherapy in patients with metastatic MCC is sparse, with most studies being case series/reports. Across all studies, response rates ranged from 20 to 61%, with higher response rates in first-line setting (53-61%) versus second-line setting (23-45%). Among responders, duration of response was short (≤8 months) in both first- and second-line settings. There is a need for novel agents that can induce durable responses in metastatic MCC.

Background Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with limited treatment options at advanced stages. There is a paucity of data available regarding the impact of MCC and its management on patients’ lives. This study aimed to address this gap by interviewing patients with metastatic MCC entering a trial of an immunotherapy (avelumab). Methods In a single-arm, open-label, international, phase 2 trial in patients with stage IV, chemotherapy-refractory, histologically confirmed MCC, patients were invited to participate in semi-structured phone interviews. These were conducted before avelumab administration. Interview transcripts were analysed qualitatively to identify concepts important to patients relating to their experience of metastatic MCC and its management. Results Nineteen patients were interviewed. Most reported MCC to be painless and asymptomatic. They reported being often misdiagnosed and described a long process before receiving the correct diagnosis. They also reported a feeling of “shock” after being informed of the severity and seriousness of their cancer. Overall, patients did not report impaired physical and cognitive capacities or impact on daily lives, either before or after diagnosis. However, patients and their relatives reported feelings of “worry” and “fear” about the unknown outcome of the disease. Chemotherapy and radiotherapy negatively affected patients physically and psychologically in their everyday lives. Conclusions MCC disease was not perceived by the interviewed patients to result in severe functional limitations or to severely impact everyday activities, but was associated with substantial negative psychological impact. In contrast, chemotherapy and radiotherapy for MCC are highly debilitating and disrupt patients’ lives. ClinicalTrials.gov identifier NCT02155647.

Synaptic neurotransmission imposes high demands on membrane turnover, metabolism, and the remodeling of presynaptic molecular composition. While the impact of autophagy on neurotransmission has been firmly established, evidence for activity-dependent synaptic induction of autophagy remains surprisingly limited. Here, we demonstrate that amphisomes containing BDNF/TrkB are formed at presynaptic boutons following sustained synaptic activation. Activity-dependent bulk endocytosis serves as a membrane source for amphisome biogenesis, while key autophagy proteins are recruited to the active zone, and autophagy initiation is triggered locally by the energy-sensing kinase AMPK. BDNF/TrkB-containing amphisomes contribute to the turnover of key presynaptic cytoskeletal proteins involved in synaptic vesicle clustering. The formation of amphisomes following sustained synaptic activity facilitates both the degradation of these proteins and their replenishment through local translation of their mRNAs at presynaptic boutons. We propose that activity-induced synaptic autophagy largely reflects amphisome formation, which in turn is required for the replacement of proteins within the local presynaptic cytomatrix.