Comparison of three-weekly and six-weekly pembrolizumab United Kingdom prescribing practice for advanced and resected melanoma.

BACKGROUND: Pembrolizumab is approved for the treatment of advanced and resected melanoma and was originally licensed as a three-weekly infusion (Q3W). In April 2019, a six-weekly infusion schedule (Q6W) was also approved. We retrospectively reviewed pembrolizumab prescribing for patients with melanoma across multiple United Kingdom (UK) centres to compare the safety and efficacy of Q6W with Q3W in real-world clinical practice. METHODS: Case notes for melanoma patients treated with pembrolizumab between April 2019 and August 2020 at eight UK centres were reviewed. Prespecified baseline characteristics of the Q3W and Q6W cohorts were compared, as well as toxicity and efficacy outcomes. Prescribers were surveyed about their prescribing practice. RESULTS: Two hundred seventy-seven patients were included: 116 commenced Q3W and 161 commenced Q6W pembrolizumab. The proportion of Q6W prescriptions varied by the centre (range 32-88%). Patient factors associated with an increased likelihood of receiving Q3W over Q6W were preexisting autoimmune comorbidity (odds ratio [OR] 0.33; 95% confidence interval [CI] 0.12-0.82) and treatment for advanced (versus resected) disease (OR 0.54; 95%CI 0.33-0.90). Toxicity outcomes were broadly similar for Q6W and Q3W: 14.9% versus 15.5% ≥ grade 3 Common Terminology Criteria for Adverse Events. Estimated 12-month recurrence-free survival for adjuvantly treated patients was 78.9% for Q6W and 74.2% for Q3W (hazard ratio [HR] 0.93; 95%CI 0.50-1.73). Estimated 12-month progression-free survival for advanced patients was 41.8% for Q6W and 55.9% for Q3W (HR 1.21, 95%CI 0.67-2.18). CONCLUSIONS: Q6W is an appropriate option for administering pembrolizumab, given the opportunity to reduce the health service resource burden.

Clinical and biological markers predictive of treatment response associated with metastatic pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy for metastatic pancreatic adenocarcinoma (PDAC) offers limited benefits, but survival outcomes vary. Reliable predictive response biomarkers to guide patient management are lacking. METHODS: Patient performance status, tumour burden (determined by the presence or absence of liver metastases), plasma protein biomarkers (CA19-9, albumin, C-reactive protein and neutrophils) and circulating tumour DNA (ctDNA) were assessed in 146 patients with metastatic PDAC prior to starting either concomitant or sequential nab-paclitaxel + gemcitabine chemotherapy in the SIEGE randomised prospective clinical trial, as well as during the first 8 weeks of treatment. Correlations were made with objective response, death within 1 year and overall survival (OS). RESULTS: Initial poor patient performance status, presence of liver metastases and detectable mutKRAS ctDNA all correlated with worse OS after adjusting for the different biomarkers of interest. Objective response at 8 weeks also correlated with OS (P = 0.026). Plasma biomarkers measured during treatment and prior to the first response assessment identified ≥10% decrease in albumin at 4 weeks predicted for worse OS (HR 4.75, 95% CI 1.43-16.94, P = 0.012), while any association of longitudinal evaluation of mutKRAS ctDNA with OS was unclear (ß = 0.024, P = 0.057). CONCLUSIONS: Readily measurable patient variables can aid the prediction of outcomes from combination chemotherapy used to treat metastatic PDAC. The role of mutKRAS ctDNA as a tool to guide treatment warrants further exploration. CLINICAL TRIAL REGISTRATION: ISRCTN71070888; ClinialTrials.gov (NCT03529175).

Towards a Semi-Automatic Early Warning System for Vector-Borne Diseases.

The emergence and spread of vector-borne diseases (VBDs) is a function of biotic, abiotic and socio-economic drivers of disease while their economic and societal burden depends upon a number of time-varying factors. This work is concerned with the development of an early warning system that can act as a predictive tool for public health preparedness and response. We employ a host-vector model that combines entomological (mosquito data), social (immigration rate, demographic data), environmental (temperature) and geographical data (risk areas). The output consists of appropriate maps depicting suitable risk measures such as the basic reproduction number, R0, and the probability of getting infected by the disease. These tools consist of the backbone of a semi-automatic early warning system tool which can potentially aid the monitoring and control of VBDs in different settings. In addition, it can be used for optimizing the cost-effectiveness of distinct control measures and the integration of open geospatial and climatological data. The R code used to generate the risk indicators and the corresponding spatial maps along with the data is made available.

Point of Care Nucleic Acid Testing for SARS-CoV-2 in Hospitalized Patients: A Clinical Validation Trial and Implementation Study.

There is an urgent need for rapid SARS-CoV-2 testing in hospitals to limit nosocomial spread. We report an evaluation of point of care (POC) nucleic acid amplification testing (NAAT) in 149 participants with parallel combined nasal and throat swabbing for POC versus standard lab RT-PCR testing. Median time to result is 2.6 (IQR 2.3-4.8) versus 26.4 h (IQR 21.4-31.4, p < 0.001), with 32 (21.5%) positive and 117 (78.5%) negative. Cohen's κ correlation between tests is 0.96 (95% CI 0.91-1.00). When comparing nearly 1,000 tests pre- and post-implementation, the median time to definitive bed placement from admission is 23.4 (8.6-41.9) versus 17.1 h (9.0-28.8), p = 0.02. Mean length of stay on COVID-19 "holding" wards is 58.5 versus 29.9 h (p < 0.001). POC testing increases isolation room availability, avoids bed closures, allows discharge to care homes, and expedites access to hospital procedures. POC testing could mitigate the impact of COVID-19 on hospital systems.

Elucidating fitness components of the invasive dermestid beetle Trogoderma granarium combining deterministic and stochastic demography.

The invasive dermestid khapra beetle, Trogoderma granarium, is an important pest of stored products that is subject to strict phytosanitary measures. In this study, we conducted a demographic analysis of this species at 30, 35 and 40°C, combining deterministic and stochastic approaches. The net reproductive rate, the intrinsic rate of increase, the finite rate of increase and the doubling time did not differ significantly between 30 and 35°C, while at 40°C we detected negative values of the intrinsic rate of increase and the doubling time. The Briere model fit the data well with respect to the intrinsic rate of increase. Females of roughly 63, 42 and 21 days old reached their maximum reproductive potential at 30, 35 and 40°C, respectively. The stochastic models of this study allowed for checking model fit and the characterization of the most suitable distribution for each component of the process. We expect these results to have bearing on the management of T. granarium since they could be combined with models related to international trade and climatic change, alerting specialists towards early detection strategies against this species.

Does Mutual Interference Affect the Feeding Rate of Aphidophagous Coccinellids? A Modeling Perspective.

Mutual interference involves direct interactions between individuals of the same species that may alter their foraging success. Larvae of aphidophagous coccinellids typically stay within a patch during their lifetime, displaying remarkable aggregation to their prey. Thus, as larvae are exposed to each other, frequent encounters may affect their foraging success. A study was initiated in order to determine the effect of mutual interference in the coccinellids' feeding rate. One to four 4th larval instars of the fourteen-spotted ladybird beetle Propylea quatuordecimpunctata were exposed for 6 hours into plastic containers with different densities of the black bean aphid, Aphis fabae, on potted Vicia faba plants. The data were used to fit a purely prey-dependent Holling type II model and its alternatives which account for interference competition and have thus far been underutilized, i.e. the Beddington-DeAngelis, the Crowley-Martin and a modified Hassell-Varley model. The Crowley-Martin mechanistic model appeared to be slightly better among the competing models. The results showed that although the feeding rate became approximately independent of predator density at high prey density, some predator dependence in the coccinellid's functional response was observed at the low prey-high predator density combination. It appears that at low prey densities, digestion breaks are negligible so that the predators do waste time interfering with each other, whereas at high prey densities time loss during digestion breaks may fully accommodate the cost of interference, so that the time cost may be negligible.

Factors associated with IgG positivity to Crimean-Congo hemorrhagic fever virus in the area with the highest seroprevalence in Greece.

In order to gain insight into the factors playing a role for the high seroprevalence of Crimean-Congo hemorrhagic fever virus in the human population of Thesprotia prefecture, Greece, serum samples were collected from residents of the area together with a questionnaire about demographic and epidemiological factors. A 14.4% seroprevalence was detected, with increased age, agro-pastoral activities, slaughtering, and contact with animals (especially sheep) among the factors associated with seropositivity. The high seroprevalence with the absence of any clinical cases needs further investigation.