The Molecular Pathogenesis of Cholangiocarcinoma

Introduction: Cholangiocarcinoma (CC) is a malignancy of the biliary tract. It has a dismal prognosis and complete surgical resection offers the only chance of cure. The aim of this study was to identify prognostic DNA/microRNA signatures, and to identify key targets and pathways in CC to improve treatment. Methods: We performed a retrospective study to assess the role of surgery and adjuvant therapy on the survival outcomes of patients with CC based on the experience of two institutions. We investigated the molecular pathogenesis of CC assessing DNA copy number alterations and differential miRNA expression. We used array comparative genomic hybridization (CGH) (1Mb BAC array-CGH, and 180K Oligonucleotide array-CGH) on 71 UK and 24 Thai cases CC. We performed microRNA-arrays (Agilent Human miRNA slides V3) on 34 CC and 10 normal cholangiocyte samples. Results: Survival analysis showed a statistically significant difference in survival between those resected and those receiving medical management only. Thai CC cases exhibited a lower proportion of CNA compared to UK cases. A common UK alteration was seen at 17q12, the region encoding ErbB-2. The copy number gain at 17q12 was validated using CISH and IHC for ErbB-2 expression, revealing heterogeneous expression. Copy number gain of chromosome 8q24.21-24.3 was significantly related to survival. Median survival was 14.4 months vs 28.3 months with and without the gain (p = 0.016). Thirty-eight miRNAs showed significantly different expression, including several microRNAs implicated in other malignancies, with predicted gene targets including the p53 signaling pathway and the TGF-beta signaling pathway. We identified a 4-microRNA signature that correlated with overall survival. With a median survival of 15.7 months vs 35.6 months: p = 0.00016. Conclusion: This study illustrates the genetic variability of CC, highlights several potential therapeutic targets, and identified a DNA and miRNA signature that correlated with prognosis

The Molecular Pathogenesis of Cholangiocarcinoma

Introduction: Cholangiocarcinoma (CC) is a malignancy of the biliary tract. It has a dismal prognosis and complete surgical resection offers the only chance of cure. The aim of this study was to identify prognostic DNA/microRNA signatures, and to identify key targets and pathways in CC to improve treatment. Methods: We performed a retrospective study to assess the role of surgery and adjuvant therapy on the survival outcomes of patients with CC based on the experience of two institutions. We investigated the molecular pathogenesis of CC assessing DNA copy number alterations and differential miRNA expression. We used array comparative genomic hybridization (CGH) (1Mb BAC array-CGH, and 180K Oligonucleotide array-CGH) on 71 UK and 24 Thai cases CC. We performed microRNA-arrays (Agilent Human miRNA slides V3) on 34 CC and 10 normal cholangiocyte samples. Results: Survival analysis showed a statistically significant difference in survival between those resected and those receiving medical management only. Thai CC cases exhibited a lower proportion of CNA compared to UK cases. A common UK alteration was seen at 17q12, the region encoding ErbB-2. The copy number gain at 17q12 was validated using CISH and IHC for ErbB-2 expression, revealing heterogeneous expression. Copy number gain of chromosome 8q24.21-24.3 was significantly related to survival. Median survival was 14.4 months vs 28.3 months with and without the gain (p = 0.016). Thirty-eight miRNAs showed significantly different expression, including several microRNAs implicated in other malignancies, with predicted gene targets including the p53 signaling pathway and the TGF-beta signaling pathway. We identified a 4-microRNA signature that correlated with overall survival. With a median survival of 15.7 months vs 35.6 months: p = 0.00016. Conclusion: This study illustrates the genetic variability of CC, highlights several potential therapeutic targets, and identified a DNA and miRNA signature that correlated with prognosis

Surgical management of non-metastatic pancreatic cancer in the United Kingdom: results of a nationwide survey on current practice

Background: It is presently unclear what clinical pathways are followed for patients with non-metastatic PDAC in specialised centres for pancreatic surgery across the United Kingdom (UK). Methods: Between August 2019 and August 2020 an electronic survey was conducted aiming at a national cohort of pancreatic surgeons in the UK. Participants replied to a list of standardised questions and clinical vignettes, and data were collected and analysed focusing on management preferences, resectability criteria, and contraindications to surgery. Results: Within the study period, 65 pancreatic surgeons from 27 specialist centres in the UK (96%) completed the survey. Multidisciplinary team meetings are utilised universally for the management of patients with PDAC, however, different staging systems for resectability classification are being applied. In borderline resectable PDAC, most surgeons were keen to proceed with surgical exploration post NAT, but differences were noted in preferred chemotherapy regimens. Surgeons from standard volume institutions performed fewer vein resections annually and were more likely to deem patients with locally advanced PDAC as unresectable. Intra-institutional variability in patient management was also present and ranging between 20-80%. Conclusions: Significant variability in the surgical management of non-metastatic PDAC was identified both on inter- and intra-institutional level

Rates of Bile Acid Diarrhoea After Cholecystectomy:A Multicentre Audit

Introduction: Bile acid diarrhoea (BAD) can occur due to disruption to the enterohepatic circulation, e.g. following cholecystectomy. Post-cholecystectomy diarrhoea has been reported in 2.1–57.2% of patients; however, this is not necessarily due to BAD. The aim of this study was to determine the rates of bile acid diarrhoea diagnosis after cholecystectomy and to consider investigation practices. Methods: A retrospective analysis of electronic databases from five large centres detailing patients who underwent laparoscopic cholecystectomy between 2013 and 2017 was cross-referenced with a list of patients who underwent 75SeHCAT testing. A 7-day retention time of <15% was deemed to be positive. Patient demographics and time from surgery to investigation were collected and compared for significance (p < 0.05). Results: A total of 9439 patients underwent a laparoscopic cholecystectomy between 1 January 2013 and 31 December 2017 in the five centres. In total, 202 patients (2.1%) underwent investigation for diarrhoea via 75SeHCAT, of which 64 patients (31.6%) had a 75SeHCAT test result of >15%, while 62.8% of those investigated were diagnosed with bile acid diarrhoea (BAD). In total, 133 (65.8%) patients also underwent endoscopy and 74 (36.6%) patients had a CT scan. Median time from surgery to 75SeHCAT test was 672 days (SD ± 482 days). Discussion/Conclusion: Only a small proportion of patients, post-cholecystectomy, were investigated for diarrhoea with significant time delay to diagnosis. The true prevalence of BAD after cholecystectomy may be much higher, and clinicians need to have an increased awareness of this condition due to its amenability to treatment. 75SeHCAT is a useful tool for diagnosis of bile acid diarrhoea

Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans.

BACKGROUND: The COVID-19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 weeks of peak disruption due to COVID-19. METHODS: A global expert response study was conducted to elicit projections for the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption. A Bayesian β-regression model was used to estimate 12-week cancellation rates for 190 countries. Elective surgical case-mix data, stratified by specialty and indication (surgery for cancer versus benign disease), were determined. This case mix was applied to country-level surgical volumes. The 12-week cancellation rates were then applied to these figures to calculate the total number of cancelled operations. RESULTS: The best estimate was that 28 404 603 operations would be cancelled or postponed during the peak 12 weeks of disruption due to COVID-19 (2 367 050 operations per week). Most would be operations for benign disease (90·2 per cent, 25 638 922 of 28 404 603). The overall 12-week cancellation rate would be 72·3 per cent. Globally, 81·7 per cent of operations for benign conditions (25 638 922 of 31 378 062), 37·7 per cent of cancer operations (2 324 070 of 6 162 311) and 25·4 per cent of elective caesarean sections (441 611 of 1 735 483) would be cancelled or postponed. If countries increased their normal surgical volume by 20 per cent after the pandemic, it would take a median of 45 weeks to clear the backlog of operations resulting from COVID-19 disruption. CONCLUSION: A very large number of operations will be cancelled or postponed owing to disruption caused by COVID-19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease