Integrated genomics point to immune vulnerabilities in pleural mesothelioma.

Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled, double-blind, randomized trial.

PURPOSE: Fatigue is a distressing symptom occurring in more than 60% of patients with cancer. The CNS stimulants modafinil and methylphenidate are recommended for the treatment of cancer-related fatigue, despite a limited evidence base. We aimed to evaluate the efficacy and tolerability of modafinil in the management of fatigue in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Adults with advanced NSCLC and performance status of 0 to 2, who were not treated with chemotherapy or radiotherapy within the last 4 weeks, were randomly assigned to daily modafinil (100 mg on days 1 to 14; 200 mg on days 15 to 28) or matched placebo. The primary outcome was change in Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue score from baseline to 28 days, adjusted for baseline fatigue and performance status. Secondary outcomes included safety and patient-reported measures of depression, daytime sleepiness, and quality of life. RESULTS: A total of 208 patients were randomly assigned, and 160 patients (modafinil, n = 75; placebo, n = 85) completed questionnaires at both baseline and day 28 and were included in the modified intention-to-treat analysis. FACIT-Fatigue scores improved from baseline to day 28 (mean score change: modafinil, 5.29; 95% CI, 2.57 to 8.02; placebo, 5.09; 95% CI, 2.54 to 7.65), but there was no difference between treatments (0.20; 95% CI, -3.56 to 3.97). There was also no difference between treatments for the secondary outcomes; 47% of the modafinil group and 23% of the placebo group stated that the intervention was not helpful. CONCLUSION: Modafinil had no effect on cancer-related fatigue and should not be prescribed outside a clinical trial setting. Its use was associated with a clinically significant placebo effect.

A rare case of squamous cell carcinoma of the lung harbouring ALK and BRAF activating mutations.

The management of non-small cell lung cancer has significantly changed over the past few years through greater understanding of tumour biology. The identification of activating mutations has led to the development of targeted agents. Coexisting mutations in non-small cell lung cancer is uncommon, particularly in squamous cell carcinoma. Our case represents a late gentleman with squamous cell carcinoma of the lung with both a BRAF mutation and ALK rearrangement prior to treatment.

A review of in vitro and in vivo models of oesophageal and gastric cancer.

IMPORTANCE OF THE FIELD: Oesophageal and gastric cancers are leading causes of cancer-related mortality. In the era of targeted therapy and individualized treatment strategies, novel treatments for upper-gastrointestinal cancers are only just emerging compared to significant advances in other solid tumour types such as colorectal, breast and lung cancers. Clinical trials are investigating the value of established targeted agents for the treatment of oesophageal and gastric malignancies; however none are used in routine clinical practice. AREAS COVERED IN THIS REVIEW: In this review we have looked at current in vitro and in vivo models of oesophageal and gastric cancers which may improve our understanding of the biology of these tumours and lead to the development of new preventative, diagnostic and therapeutic approaches. WHAT THE READER WILL GAIN: We discuss the limitations of our current models and the challenges associated with research into these cancers. TAKE HOME MESSAGE: The lack of appropriate models for drug development in oesophageal and gastric cancers has hindered the progress of targeted therapy in this field.

Neuroendocrine tumour of the cystic duct: a case report and literature review.

This is a case report of a neuroendocrine tumour of the cystic duct which is extremely rare and was an incidental finding during laparoscopic surgery. A literature review of similar cases is also provided.