Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC).
KEYNOTE-629 ...was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab.
Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 interquartile range (IQR), 12.6-17.2 months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% 95% confidence interval (CI), 36.1% to 63.9%, including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients.
The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.
•The phase II KEYNOTE-629 study assessed the efficacy and safety of pembrolizumab in cSCC.•Pembrolizumab showed rapid, robust, and durable antitumor activity in both LA and R/M cSCC.•Adverse events were generally consistent with the established safety profile of pembrolizumab.•Our data establish pembrolizumab as a promising treatment option for cSCC.
Introduction: Prediction models using logistic regression may perform poorly in external patient cohorts. However, there is a need to standardize and validate models for clinical use. The purpose of ...this project was to describe a method for validation of external NTCP models used for patient selection in the randomized trial of protons versus photons in head and neck cancer radiotherapy, DAHANCA 35.
Material and methods: Organs at risk of 588 patients treated primarily with IMRT in the randomized controlled DAHANCA19 trial were retrospectively contoured according to recent international recommendations. Dose metrics were extracted using MatLab and all clinical parameters were retrieved from the DAHANCA database. The model proposed by Christianen et al. to predict physician-rated dysphagia was validated through the closed testing, where change of the model intercept, slope and individual beta's were tested for significant prediction improvements.
Results: Six months prevalence of dysphagia in the validation cohort was 33%. The closed testing procedure for physician-rated dysphagia showed that the Christianen et al. model needed an intercept refitting for the best match for the Danish patients. The intercept update increased the risk of dysphagia for the validation cohort by 7.9 ± 2.5% point. For the raw model performance, the Brier score (mean squared residual) was 0.467, which improved significantly with a new intercept to 0.415.
Conclusions: The previously published Dutch dysphagia model needed an intercept update to match the Danish patient cohort. The implementation of a closed testing procedure on the current validation cohort allows quick and efficient validation of external NTCP models for patient selection in the future.
•MACH-NC second update with 107 randomized trials (19805 patients) investigating chemotherapy (CT) in non-metastatic HNSCC.•Overall Survival (OS) improved by CT, benefit superior for concomitant CT ...(HR 0.83 0.79; 0.86) over induction or adjuvant CT.•Direct comparison confirmed the superiority of concomitant over induction CT on OS.
The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.
Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.
For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI 0.79; 0.86; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 0.90; 1.01) or adjuvant CT (1.02 0.92; 1.13). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 0.74; 0.95, p = 0.005).
The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.
Diagnosis of SAV infections has traditionally been based upon clinical observations together with a set of histopathological findings in exocrine pancreas, heart and skeletal muscle, but recently, ...real-time RT-PCR assays have been developed as a supplement for the detection of SAV. The aim of this study was to determine tissue tropism of SAV1 and SAV3 in Atlantic salmon Salmo salar L. in order to identify the most suitable tissues for real-time RT-PCR diagnostic assays. The results indicated that the pseudobranch and the heart (ventricle) are the most useful tissues for such assays, regardless of disease status. The pyloric caecae with associated pancreatic tissue is unsuitable for diagnosis using this method. The use of real-time RT-PCR enabled viral RNA detection at all stages of the disease, including in surviving fish six months after infection. Considering the short production cycle of farmed salmonids, this suggests that surviving Atlantic salmon may become life-long asymptomatic carriers of SAV after an infection.
We investigated how changes in vegetation structure and prey resources following wildfire affected the winter ecology of hairy woodpeckers (Picoides villosus) in ponderosa pine (Pinus ponderosa) ...forests of northern Arizona, USA. Using point-counts, radiotelemetry, and focal bird observation, we assessed the relative abundance, home range size and composition, and habitat use by foraging hairy woodpeckers in 3 stands that had experienced wildfire in 1996, 2000, or 2002. Because we conducted the study over 2 years, we used the 1996 fire to represent 6 and 7 years after fire, while we used the 2000 fire to represent 2 and 3 years after fire in a space-for-time substitution chronosequence analysis. We also assessed bark beetle and woodborer density by x-raying bark samples collected from a subset of trees within burned areas. We detected significantly greater hairy woodpecker relative abundance in burned forests representing 1 and 2 years after fire, and bark beetle and woodborer density was highest in these stands as well. Woodpecker home range size increased across stands representing increasing time since fire. Within a burn, hairy woodpeckers used high-severity burned areas more than moderate-severity burned areas representing 2 and 3 years after fire, but not in areas representing 6 and 7 years after fire. Bark beetle and woodborer densities were also higher in high-severity burned stands representing 2 and 3 years after fire. Hairy woodpeckers used edges of high-severity burned areas more than the interior. We hypothesize that an initial increase in bark beetle and woodborer density following fire allowed for higher woodpecker abundance and smaller home ranges, but as burned forests aged, bark beetle and woodborer density within trees decreased, killed trees fell, and, in response, hairy woodpecker relative abundance decreased and home range size increased. These patterns suggest that high-severity burned areas provide important but ephemeral resources to this dominant primary cavity-nester. The higher bark beetle and woodborer densities and greater use of edges of high-severity burned areas by woodpeckers suggests that salvage logging of these areas could remove potential prey and preferred foraging areas for hairy woodpeckers, especially when trees are removed along severely burned edges.
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