The Gut Microbiome, Microsatellite Status and the Response to Immunotherapy in Colorectal Cancer.

There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with differences in immunotherapy responses in a range of non-gastrointestinal tract cancers. DNA mismatch repair-deficient (dMMR) colorectal cancer (CRC) is radically different to DNA mismatch repair-proficient (pMMR) CRC in clinical phenotype and in its very good responses to immunotherapy. While this has usually been thought to be due to the high mutational burden in dMMR CRC, the gut microbiome is radically different in dMMR and pMMR CRC in terms of both composition and diversity. It is probable that differences in the gut microbiota contribute to the varied responses to immunotherapy in dMMR versus pMMR CRC. Targeting the microbiome offers a way to boost the response and increase the selection of patients who might benefit from this therapy. This paper reviews the available literature on the role of the microbiome in the response to immunotherapy in dMMR and pMMR CRC, explores the potential causal relationship and discusses future directions for study in this exciting and rapidly changing field.

Patient Derived Organoids Confirm That PI3K/AKT Signalling Is an Escape Pathway for Radioresistance and a Target for Therapy in Rectal Cancer.

Objectives: Partial or total resistance to preoperative chemoradiotherapy occurs in more than half of locally advanced rectal cancer patients. Several novel or repurposed drugs have been trialled to improve cancer cell sensitivity to radiotherapy, with limited success. We aimed to understand the mechanisms of resistance to chemoradiotherapy in rectal cancer using patient derived organoid models. Design: To understand the mechanisms underlying this resistance, we compared the pre-treatment transcriptomes of patient-derived organoids (PDO) with measured radiotherapy sensitivity to identify biological pathways involved in radiation resistance coupled with single cell sequencing, genome wide CRISPR-Cas9 and targeted drug screens. Results: RNA sequencing enrichment analysis revealed upregulation of PI3K/AKT/mTOR and epithelial mesenchymal transition pathway genes in radioresistant PDOs. Single-cell sequencing of pre & post-irradiation PDOs showed mTORC1 and PI3K/AKT upregulation, which was confirmed by a genome-wide CRSIPR-Cas9 knockout screen using irradiated colorectal cancer (CRC) cell lines. We then tested the efficiency of dual PI3K/mTOR inhibitors in improving cancer cell sensitivity to radiotherapy. After irradiation, significant AKT phosphorylation was detected (p=0.027) which was abrogated with dual PI3K/mTOR inhibitors and lead to significant radiosensitisation of the HCT116 cell line and radiation resistant PDO lines. Conclusions: The PI3K/AKT/mTOR pathway upregulation contributes to radioresistance and its targeted pharmacological inhibition leads to significant radiosensitisation in CRC organoids, making it a potential target for clinical trials.

The impact of bariatric surgery on the resolution of obstructive sleep apnoea.

OBJECTIVE: Obesity is associated with a high incidence of obstructive sleep apnoea (OSA). Bariatric surgery is postulated to lead to OSA resolution, but there is inconclusive evidence on its efficacy. We used objective measurements to determine the rate of resolution or improvement of OSA in patients who had bariatric procedures in our unit. RESULTS: Data was analysed on all patients with OSA who underwent bariatric procedures [laparoscopic Roux-en-Y gastric bypass (LRYGB) and sleeve gastrectomy (LSG)] between June 2012 and September 2016 in our unit. 47 patients (26.7%) were diagnosed with OSA. Mean age was 48.5 years. 63.8% were female. 43 required nocturnal continuous positive airway pressure (CPAP) support. Procedures were LRYGB (n = 26) and LSG (n = 21). Mean excess weight loss was 56.1%. Mean start apnoea-hypopnoea index (AHI) on CPAP was 6.4 events/hr and end AHI was 1.4 events/h. 14 patients (32.6%) had complete OSA resolution and 12 (27.9%) showed improvement in pressure support requirements. We demonstrated that 55.3% of patients had resolution or improvement in OSA following bariatric surgery. However, there was a high rate of non-attendance of follow-up appointments. Future efforts will involve analysis of the reasons for this to ensure more robust monitoring.

Parasitic twin within spina bifida.

Spinal dysraphisms in association with accessory limbs are extremely rare congenital anomalies. The potential mechanisms of development and classification of these anomalies remain unclear. We report a unique case of a baby boy with an accessory foot and external genitalia in association with spina bifida.

Haematuria and the retro-aortic left renal vein.

The authors present the case of a 10-year-old boy with a 2-year history of intermittent macroscopic haematuria. After exclusion of other causes of haematuria through history, examination and a number of investigations, MRI revealed the finding of a retro-aortic left renal vein, which appeared to be compressed between the aorta and the L3 vertebral body. The retro-aortic left renal vein or 'posterior nutcracker syndrome" is a rare but important cause of haematuria and other manifestations of left renal vein hypertension. A discussion about the implications of this finding in children with symptoms consistent with left renal vein hypertension, and the potential options for management is undertaken.