Blood Vitamin C Levels of Patients Receiving Immunotherapy and Relationship to Monocyte Subtype and Epigenetic Modification.

The treatment of metastatic melanoma has been revolutionised by immunotherapy, yet a significant number of patients do not respond, and many experience autoimmune adverse events. Associations have been reported between patient outcome and monocyte subsets, whereas vitamin C (ascorbate) has been shown to mediate changes in cancer-stimulated monocytes in vitro. We therefore investigated the relationship of ascorbate with monocyte subsets and epigenetic modifications in patients with metastatic melanoma receiving immunotherapy. Patients receiving immunotherapy were compared to other cancer cohorts and age-matched healthy controls. Ascorbate levels in plasma and peripheral blood-derived mononuclear cells (PBMCs), monocyte subtype and epigenetic markers were measured, and adverse events, tumour response and survival were recorded. A quarter of the immunotherapy cohort had hypovitaminosis C, with plasma and PBMC ascorbate levels significantly lower than those from other cancer patients or healthy controls. PBMCs from the immunotherapy cohort contained similar frequencies of non-classical and classical monocytes. DNA methylation markers and intracellular ascorbate concentration were correlated with monocyte subset frequency in healthy controls, but correlation was lost in immunotherapy patients. No associations between ascorbate status and immune-related adverse events or tumour response or overall survival were apparent.

Textbook outcomes for liver resection: can a medium sized centre have acceptable outcomes?

BACKGROUND: Textbook outcome (TO) is an objective, composite measure of clinical outcomes in surgery. TO in liver surgery has been used in previous international studies to define and compare performance across centres. This study aimed to review TO rates following liver resection at a single institution. The secondary aim was to use a CuSum analysis to evaluate monitoring of performance quality over time for colorectal cancer liver metastases (CRCLM). METHODS: All patients undergoing liver resection for benign and malignant causes from Christchurch Hospital hepatobiliary unit between 2005 and 2022 were included. Textbook outcomes measures were the absence of; intraoperative incidents, Clavien-Dindo >3 complication, 90 day re-admission, 90 day mortality, R1 resection, and post-operative bile leak/liver failure. Sequential CuSum analysis was performed to review achievement of TO in liver resections for colorectal cancer liver metastases (CRCLM). RESULTS: Four hundred and seventy-eight patients were included in this study, 54 had resection for benign pathology, 290 for CRCLM and 134 for other malignancies. TO was achieved in 74% of cases overall, with rates for benign, CRCLM and other malignancy being 82%, 73% and 74% respectively (P = 0.405). CuSum analysis documented a deterioration in performance after patient 60, with return to baseline by end of study period. CONCLUSIONS: TO for liver resection in a medium sized centre in New Zealand are comparable to published rates. It is possible to use process control techniques like CuSum with the binary result of TO to monitor performance, providing opportunity for continuous improvement in surgical units.

Trauma Team Activation: improved care of major trauma patients.

AIM: To assess whether Trauma Team Activation (TTA) at Christchurch Hospital is associated with reduced mortality or improves in-hospital care for major trauma patients, and review differences in the two-tier activation system (Trauma Call versus Trauma Standby). METHODS: A retrospective observational study of major trauma patients presenting to Christchurch Emergency Department (ED) 2018-2019. Univariate analyses were undertaken followed by multivariate analyses controlling for age and injury severity score (ISS). RESULTS: Major trauma patients with a TTA had a higher mean ISS (p<0.001) compared to patients without TTA. After controlling for age and ISS, TTA was associated with decreased time to CT (p<0.001), and shorter ED length of stay (LOS) (p<0.001). Despite an increased rate of surgery (OR 1.9, 95%CI:1.2-3.0) and admission to ICU (OR 4.1, 95%CI:2.0-8.5), with longer total hospital LOS (p<0.001). When compared to those with a Trauma Standby, patients with a full Trauma Call had a higher mortality (OR 1.5, 95%CI:0.3-8.4), increased rates of surgery (OR 2.7, 95%CI:1.4-5.2) and ICU admission (OR 17.9, 95%CI:4.2-77.4), with a longer hospital LOS (p=0.006). CONCLUSION: TTA was associated with decreased time to diagnostic imaging and definitive management in major trauma patients. Whilst causation cannot be inferred, these trends were apparent after controlling for age and ISS.

Limited Association Between Ascorbate Concentrations and Vitamin C Transporters in Renal Cell Carcinoma Cells and Clinical Samples.

BACKGROUND/AIMS: Maintenance of whole-body ascorbate levels and distribution is mediated via sodium-dependent vitamin C transporters (SVCTs). The kidney is one of a few organs that express both SVCT1 and SVCT2. Recent evidence suggests that accumulation of ascorbate may be different in tumour compared to normal tissue, but data on SVCT levels in tumours is sparse. METHODS: The role of the two SVCT isoforms in ascorbate uptake in renal cell carcinoma (RCC) was investigated in vitro and in clinical samples. In three human RCC cell lines, we investigated SVCT protein levels and cellular location in response to ascorbate supplementation and withdrawal. In clinical RCC samples (n=114), SVCT patterns of staining and protein levels were analysed and compared to ascorbate levels. RESULTS: In cell culture, transporter levels and cellular location were not modified by ascorbate availability at any time up to 8h, although basal SVCT2 levels governed maximal ascorbate accumulation. In clinical samples, SVCT1 protein levels in papillary RCC (pRCC) were similar to matched normal renal cortex, but were increased in clear-cell RCC (ccRCC). Native SVCT2 (72 kDa) was significantly decreased in both pRCC and ccRCC tissues compared to cortex (p<0.01), whereas a modified form of SVCT2 (100 kDa) was significantly increased (p<0.001). There was no association between the transporters (SVCT1, native or modified SVCT2) and ascorbate concentrations in either normal or tumour tissues. SVCT1 and SVCT2 displayed diffuse cytoplasmic staining in both pRCC and ccRCC tumour cells, with cortex showing distinct membrane staining for SVCT1. CONCLUSION: We observed a re-distribution of ascorbate transporters in tumour tissue compared to normal cortex and a shift from native to modified SVCT2 in cell culture and clinical samples. Data presented here show that SVCT protein levels do not appear to predict intracellular ascorbate accumulation in RCC.

Low Vitamin C Status in Patients with Cancer Is Associated with Patient and Tumor Characteristics.

Vitamin C (ascorbate) acts as an antioxidant and enzyme cofactor, and plays a vital role in human health. Vitamin C status can be affected by illness, with low levels being associated with disease due to accelerated turnover. However, robust data on the ascorbate status of patients with cancer are sparse. This study aimed to accurately measure ascorbate concentrations in plasma from patients with cancer, and determine associations with patient or tumor characteristics. We recruited 150 fasting patients with cancer (of 199 total recruited) from two cohorts, either prior to cancer surgery or during cancer chemo- or immunotherapy. A significant number of patients with cancer had inadequate plasma ascorbate concentrations. Low plasma status was more prevalent in patients undergoing cancer therapy. Ascorbate status was higher in women than in men, and exercising patients had higher levels than sedentary patients. Our study may prompt increased vigilance of ascorbate status in cancer patients.