Biomarkers for tyrosine kinase inhibitors in renal cell cancer

Renal cell carcinoma (RCC) is a common malignancy. In 2012, in the USA, there were 65,000 new cases and 13,500 disease-specific deaths. In the same year it was the 6th most common new cancer diagnosed. During the last 50 years, despite an increase in incidence, the mortality has fallen, a possible result of earlier detection and improvements in therapy

IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

Investigation of differentially expressed genes that contribute to therapeutic effects of bevacizumab in BRAF mutant melanoma

Malignant melanoma is a highly aggressive and often lethal disease. In 2012, patient outcomes were poor after resection of high-risk stage II and III melanoma, and vascular endothelial growth factor (VEGF) has been implicated in melanoma progression. The phase III AVAST-M clinical trial (recruiting between 2007-2012) randomized patients with high risk melanoma to 1 year of adjuvant bevacizumab (anti-VEGF antibody) or observation. Patients treated with bevacizumab experienced superior disease-free survival (DFS), and BRAFV600E mutation was unexpectedly predictive of benefit. The aim in this project was to investigate this novel association between BRAFV600E and VEGF, based on the hypothesis that BRAFV600E melanomas are dependent on VEGF and more sensitive to its inhibition. VEGF and CD31 expression were quantified in tissue microarrays (TMAs) and whole mount sections of AVAST-M melanomas. Although no differences were identified between BRAFV600E and wildtype (WT) tumours from TMAs, there was a trend towards higher VEGF and CD31 expression in BRAFV600E whole mounts. In three independent transcriptomic datasets including NanoString analysis of melanomas from the AVAST-M clinical trial, VEGF itself was not differentially expressed, but all identified receptor kinase ROR2 as overexpressed in BRAFV600E melanomas. Differential ROR2 expression was confirmed in a BRAFV600E/WT isogenic melanoma model. ROR2 expression decreased with pharmacological MEK inhibition, supporting regulation by MAPK signalling. In vitro, ROR2 expression associated with invasive and proliferative phenotypes, with novel evidence that ROR2 regulates VEGF secretion in BRAFV600E mutant melanoma cells. The putative ROR2 ligand Wnt5a was also identified as regulated by MAPK signalling, and MEK inhibition of BRAFV600E mutant ROR2-overexpressing cells was shown to suppress Wnt5a expression and VEGF secretion. An exploratory transcriptomic analysis of bevacizumab treated BRAFV600E/WT isogenic melanoma xenografts identified gene expression changes in the tumour and stroma, that were mutually exclusive between BRAFV600E and WT tumours, both basally and after bevacizumab treatment, and included upregulation of ROR2 in the tumours and Wnt5a in the stroma of BRAFV600E xenografts. Finally, as a predictive biomarker in AVAST-M patient samples, patients with melanomas containing high ROR2 expression trended towards a prolonged DFS after treatment with bevacizumab. In summary, this work identifies Wnt5a-ROR2 signalling as upregulated in BRAF mutant melanomas, contributing to increased VEGF secretion and potentially also to bevacizumab response

Accurate Simulation of Both Sensitivity and Variability for Amazonian Photosynthesis: Is It Too Much to Ask?

Estimates of Amazon rainforest gross primary productivity (GPP) differ by a factor of 2 across a suite of three statistical and 18 process models. This wide spread contributes uncertainty to predictions of future climate. We compare the mean and variance of GPP from these models to that of GPP at six eddy covariance (EC) towers. Only one model\u27s mean GPP across all sites falls within a 99% confidence interval for EC GPP, and only one model matches EC variance. The strength of model response to climate drivers is related to model ability to match the seasonal pattern of the EC GPP. Models with stronger seasonal swings in GPP have stronger responses to rain, light, and temperature than does EC GPP. The model to data comparison illustrates a trade-off inherent to deterministic models between accurate simulation of a mean (average) and accurate responsiveness to drivers. The trade-off exists because all deterministic models simplify processes and lack at least some consequential driver or interaction. If a model\u27s sensitivities to included drivers and their interactions are accurate, then deterministically predicted outcomes have less variability than is realistic. If a GPP model has stronger responses to climate drivers than found in data, model predictions may match the observed variance and seasonal pattern but are likely to overpredict GPP response to climate change. High or realistic variability of model estimates relative to reference data indicate that the model is hypersensitive to one or more drivers

Metabolic information on staging FDG-PET-CT as a prognostic tool in the evaluation of 97 patients with gastric cancer

Background and objective: Gastric cancer remains a leading cause of malignancy-related mortality. Many patients with locally advanced disease succumb despite peri-operative chemotherapy and the survival benefit of chemotherapy for advanced disease is modest, suggesting that current staging is imperfect. The role of fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in the staging of gastric cancer remains to be determined. This study aimed to determine, and compare with computerized tomography (CT), the association between FDG-PET uptake in the primary tumour and regional lymph nodes, and overall survival in patients with all stage gastric cancer. Methods: Patients with histologically confirmed gastric cancer (any stage) who, at diagnosis, had received a staging FDG-PET-CT at our institution between 2006 and 2011 were included. Records were retrospectively analysed. Patients with >50 % of tumour above the gastro-oesophageal junction or an active second malignancy were excluded. Results: 97 patients were included in the analysis. Surgery with curative intent was performed in 68 patients. In univariate analysis, an association with overall survival was seen in patients who had FDG-PET-positive primary tumours (hazard ratio (HR) for death 3.33, 95 % confidence interval (95 % CI) 1.63-6.80, p = 0.001). FDG-PET lymph node positive (vs node negativity) was associated with inferior overall survival (HR 8.66, 95 % CI 4.59-16.37, p < 0.0001), and remained an independent predictor in the multivariate analysis. In contrast, positive lymphadenopathy identified on CT was not associated with overall survival (HR 1.34, 95 % CI 0.79-2.29, p = 0.82). Conclusion: FDG-PET-positive tumours are associated with an inferior overall survival. In contrast to CT, FDG-PET-positive lymphadenopathy is associated with a decreased overall survival

Serial imaging using [18F]fluorodeoxyglucose positron emission tomography and histopathologic assessment in predicting survival in a population of surgically resectable distal oesophageal and gastric adenocarcinoma following neoadjuvant therapy

Background and objectives: We retrospectively evaluated the value of PET/CT in predicting survival and histopathological tumour-response in patients with distal oesophageal and gastric adenocarcinoma following neoadjuvant treatment. Methods: Twenty-one patients with resectable distal oesophageal adenocarcinoma and 14 with gastric adenocarcinoma between January 2002 and December 2011, who had undergone serial PET before and after neoadjuvant therapy followed by surgery, were enrolled. Maximum standard uptake value (SUVmax) and metabolic tumour volume were measured and correlated with tumour regression grade and survival. Results: Histopathological tumour response (PR) is a stronger predictor of overall and disease-free survival compared to metabolic response. ∆%SUVmax ≥70% was the only PET metric that predicted PR (82.4% sensitivity, 61.5% specificity, p = 0.047). Histopathological non-responders had a higher risk of death (HR 8.461, p = 0.001) and recurrence (HR 6.385, p = 0.002) and similarly in metabolic non-responders for death (HR 2.956, p = 0.063) and recurrence (HR 3.614, p = 0.028). Ordinalised ∆%SUVmax showed a predictive trend for OS and DFS, but failed to achieve statistical significance. Conclusions: PR was a stronger predictor of survival than metabolic response. ∆%SUVmax ≥70% was the best biomarker on PET that predicted PR and survival in oesophageal and gastric adenocarcinoma. Ordinalisation of ∆%SUVmax was not helpful in predicting primary outcomes