Centralization of Pancreaticoduodenectomy: A Systematic Review and Spline Regression Analysis to Recommend Minimum Volume for a Specialist Pancreas Service.

OBJECTIVE: Through a systematic review and spline curve analysis, to better define the minimum volume threshold for hospitals to perform (pancreaticoduodenectomy) and the high-volume center. BACKGROUND: The pancreaticoduodenectomy (PD) is a resource-intensive procedure, with high morbidity and long hospital stays resulting in centralization towards high-volume hospitals; the published definition of high volume remains variable. MATERIALS AND METHODS: Following a systematic review of studies comparing PD outcomes across volume groups, semiparametric regression modeling of morbidity (%), mortality (%), length of stay (days), lymph node harvest (number of nodes), and cost ($USD) as continuous variables were performed and fitted as a smoothed function of splines. If this showed a nonlinear association, then a "zero-crossing" technique was used, which produced "first and second derivatives" to identify volume thresholds. RESULTS: Our analysis of 33 cohort studies (198,377 patients) showed 55 PDs/year and 43 PDs/year were the threshold value required to achieve the lowest morbidity and highest lymph node harvest, with model estimated df 5.154 ( P <0.001) and 8.254 ( P <0.001), respectively. The threshold value for mortality was ~45 PDs/year (model 9.219 ( P <0.001)), with the lowest mortality value (the optimum value) at ~70 PDs/year (ie, a high-volume center). No significant association was observed for cost ( edf =2, P =0.989) and length of stay ( edf =2.04, P =0.099). CONCLUSIONS: There is a significant benefit from the centralization of PD, with 55 PDs/year and 43 PDs/year as the threshold value required to achieve the lowest morbidity and highest lymph node harvest, respectively. To achieve mortality benefit, the minimum procedure threshold is 45 PDs/year, with the lowest and optimum mortality value (ie, a high-volume center) at approximately 70 PDs/year.

Evaluation of post-operative surveillance strategies and surgeon perceptions and beliefs of surveillance for pancreatic ductal adenocarcinoma in the UK.

BACKGROUND: Despite high rates of recurrence after surgery for pancreatic ductal adenocarcinoma (PDAC) there is lack of standardised surveillance practices. We aimed to identify UK surveillance practice and interrogate surgeon beliefs around surveillance. METHODS: A web-based survey was sent to all UK pancreatic units to assess surveillance practice for resected PDAC, factors influencing surveillance protocols, and perceptions and beliefs surrounding on current postoperative surveillance. RESULTS: There was wide variation in reported practice between 40 consultant surgeons from 28 pancreatic units (100% unit response rate). 26% had standardised surveillance compared to 18% with no standardised practice. 16% individualised surveillance to the patient, and 40% reported differing practices between surgeons within units despite local surveillance protocols. 66% felt surveillance should be tailored to patient factors, and 58% to patient preference. There was a broad belief regarding a lack of robust evidence supporting surveillance making a trial necessary. Thematic analysis identified surveillance barriers, considerations for trial design, necessity for patient engagement and potential benefits of surveillance. DISCUSSION: Wide variation in surveillance practice exists within and between units. A surveillance trial was deemed beneficial, however identified barriers potentially preclude a trial. Future work should assess acceptability for patients including impact on anxiety and quality-of-life.

The impact of the COVID-19 pandemic upon pancreatic cancer treatment (CONTACT Study): a UK national observational cohort study.

INTRODUCTION: CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: The treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic ('COVID' cohort, 16/03/2020-10/05/2020), with 12-month follow-up. RESULTS: Among 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, p = 0.004) or received palliative anti-cancer therapy (20.5% vs. 26.5%, p = 0.045). Ultimately, fewer patients in the COVID cohort underwent surgical resection (6.4% vs. 9.3%, p = 0.036), whilst more patients received no anti-cancer treatment (69.3% vs. 59.2% p = 0.009). Despite these differences, there was no difference in median overall survival between the COVID and pre-COVID cohorts, (3.5 (IQR 2.8-4.1) vs. 4.4 (IQR 3.6-5.2) months, p = 0.093). CONCLUSION: Pathways for patients with PDAC were significantly disrupted during the first wave of the COVID-19 pandemic, with fewer patients receiving standard treatments. However, no significant impact on survival was discerned.

Ursodeoxycholic acid in the management of symptomatic gallstone disease: systematic review and clinician survey.

BACKGROUND: Symptomatic gallstones are common. Ursodeoxycholic acid (UDCA) is a bile acid that dissolves gallstones. There is increasing interest in UDCA for symptomatic gallstones, particularly in those unfit for surgery. METHOD: A UK clinician survey of use and opinions about UDCA in symptomatic gallstones was performed, assessing clinicians' beliefs and perceptions of UDCA effectiveness. A systematic review was performed in accordance with the PRISMA guidelines. PubMed, MEDLINE, and Embase databases were searched for studies of UDCA for symptomatic gallstones (key terms included 'ursodeoxycholic acid'; 'UDCA'; 'biliary pain'; and 'biliary colic'). Information was assessed by two authors, including bias assessment, with independent review of conflicts. RESULTS: Overall, 102 clinicians completed the survey, and 42 per cent had previous experience of using UDCA. Survey responses demonstrated clinical equipoise surrounding the benefit of UDCA for the management of symptomatic gallstones, with no clear consensus for benefit or non-benefit; however, 95 per cent would start using UDCA if there was a randomized clinical trial (RCT) demonstrating a benefit. Eight studies were included in the review: four RCTs, three prospective studies, and one retrospective study. Seven of eight studies were favourable of UDCA for biliary pain. Outcomes and follow-up times were heterogenous, as well as comparator type, with only four of eight studies comparing with placebo. CONCLUSION: Evidence for UDCA in symptomatic gallstones is scarce and heterogenous. Clinicians currently managing symptomatic gallstone disease are largely unaware of the benefit of UDCA, and there is clinical equipoise surrounding the benefit of UDCA. Level 1 evidence is required by clinicians to support UDCA use in the future.

Outcomes of patients undergoing elective liver and pancreas cancer surgery during the SARS-CoV-2 pandemic: an international, multicentre, prospective cohort study.

BACKGROUND: The effect of SARS-CoV-2 infection upon HPB cancer surgery perioperative outcomes is unclear. Establishing risk is key to individualising treatment pathways. We aimed to identify the mortality rate and complications risk for HPB cancer elective surgery during the pandemic. METHODS: International, prospective, multicentre study of consecutive adult patients undergoing elective HPB cancer operations during the initial SARS-CoV-2 pandemic. Primary outcome was 30-day perioperative mortality. Secondary outcomes included major and surgery-specific 30-day complications. Multilevel cox proportional hazards and logistic regression models estimated association of SARS-CoV-2 and postoperative outcomes. RESULTS: Among 2038 patients (259 hospitals, 49 countries; liver n = 1080; pancreas n = 958) some 6.2%, n = 127, contracted perioperative SARS-CoV-2. Perioperative mortality (9.4%, 12/127 vs 2.6%, 49/1911) and major complications (29.1%, 37/127 vs 13.2%, 253/1911) were higher with SARS-CoV-2 infection, persisting when age, sex and comorbidity were accounted for (HR survival 4.15, 95% CI 1.64 to 10.49; OR major complications 3.41, 95% CI 1.72 to 6.75). SARS-CoV-2 was associated with late postoperative bleeding (11.0% vs 4.2%) and grade B/C postoperative pancreatic fistula (17.9% vs 8.6%). CONCLUSION: SARS-CoV-2 infection was associated with significantly higher perioperative morbidity and mortality. Patients without SARS-CoV-2 had acceptable morbidity and mortality rates, highlighting the need to protect patients to enable safe ongoing surgery.

Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience.

INTRODUCTION: The SARS-CoV-2 pandemic presented healthcare providers with an extreme challenge to provide cancer services. The impact upon the diagnostic and treatment capacity to treat pancreatic cancer is unclear. This study aimed to identify national variation in treatment pathways during the pandemic. METHODS: A survey was distributed to all United Kingdom pancreatic specialist centres, to assess diagnostic, therapeutic and interventional services availability, and alterations in treatment pathways. A repeating methodology enabled assessment over time as the pandemic evolved. RESULTS: Responses were received from all 29 centres. Over the first six weeks of the pandemic, less than a quarter of centres had normal availability of diagnostic pathways and a fifth of centres had no capacity whatsoever to undertake surgery. As the pandemic progressed services have gradually improved though most centres remain constrained to some degree. One third of centres changed their standard resectable pathway from surgery-first to neoadjuvant chemotherapy. Elderly patients, and those with COPD were less likely to be offered treatment during the pandemic. CONCLUSION: The COVID-19 pandemic has affected the capacity of the NHS to provide diagnostic and staging investigations for pancreatic cancer. The impact of revised treatment pathways has yet to be realised.

Health-related quality of life, uncertainty and coping strategies in solid organ transplant recipients during shielding for the COVID-19 pandemic.

Strict isolation of vulnerable individuals has been a strategy implemented by authorities to protect people from COVID-19. Our objective was to investigate health-related quality of life (HRQoL), uncertainty and coping behaviours in solid organ transplant (SOT) recipients during the COVID-19 pandemic. A cross-sectional survey of adult SOT recipients undergoing follow-up at our institution was performed. Perceived health status, uncertainty and coping strategies were assessed using the EQ-5D-5L, Short-form Mishel Uncertainty in Illness Scale (SF-MUIS) and Brief Cope, respectively. Interactions with COVID-19 risk perception, access to health care, demographic and clinical variables were assessed. The survey was completed by 826 of 3839 (21.5%) invited participants. Overall, low levels of uncertainty in illness were reported, and acceptance was the major coping strategy (92%). Coping by acceptance, feeling protected, self-perceived susceptibility to COVID-19 were associated with lower levels of uncertainty. Health status index scores were significantly lower for those with mental health illness, compromised access to health care, a perceived high risk of severe COVID-19 infection and higher levels of uncertainty. A history of mental health illness, risk perceptions, restricted healthcare access, uncertainty and coping strategies was associated with poorer HRQoL in SOT recipients during strict isolation. These findings may allow identification of strategies to improve HRQoL in SOT recipients during the pandemic.

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks.

Mechanical factors in the prediction of integrity of the gastrojejunal anastomosis in ex-vivo RYGB models.

BACKGROUND: Surgical staplers represent one of the important instruments in modern surgery. Laparoscopic Roux-en-Y gastric bypass is one of the most commonly performed bariatric procedures. Various techniques have been described for performing gastrojejunal (GJ) anastomosis, including linear stapled anastomosis (LSA), circular stapled anastomosis (CSA) and hand-sewn anastomosis (HSA). OBJECTIVES: An ex-vivo porcine-based experiment was designed to compare the mechanical integrity of the GJ anastomosis among the 3 different techniques by measuring burst pressure (BP). SETTING: Laboratory-based study conducted at the clinical skills laboratory at Birmingham Heartlands Hospitals, Birmingham, United Kingdom. METHODS: Porcine stomachs and small bowels were used to create a GJ model. Four GJ anastomosis models each were created using circular stapler (CSA group) and hand-sewn techniques (HSA group). Stomach and small bowel thickness were recorded. BP was measured by sequential injections of methylene-blue diluted saline until a leak was detected. Total volume until leak is recorded. Compliance (C) was calculated using the formula C = ΔP/ΔV. RESULTS: Results from our previous experiment for the LSA group are included. One model was excluded from the CSA and the HSA groups due to technical errors. Results were presented as mean ± standard deviation. Total volume in LSA, CSA, and HSA groups was 60 ± 4.08 mL, 73.67 ± 3.22 mL, and 51.67 ± 20.21 mL, respectively. BP in LSA, CSA, and HSA groups was 18 ± 4.69 mm Hg, 20.33 ± 5.77 mm Hg, and 9.67 ± 3.79 mm Hg, respectively. There was a statistically significant difference in BP among the 3 groups (P = .033; Kruskal-Wallis test). C in LSA, CSA, and HSA were 3.50 ± .88 mm Hg/mL, 3.78 ± .85 mm Hg/mL, and 5.39 ± 1.34 mm Hg/mL, respectively (P = .064). CONCLUSION: BP was higher in CSA and LSA groups compared with the HSA group, suggesting a mechanically stronger anastomosis. Despite the lack of statistical significance, higher BP recorded in the CSA group than in the LSA group suggests better anastomotic integrity.

Polymorphisms in Natural Killer Cell Receptor Protein 2D (NKG2D) as a Risk Factor for Cholangiocarcinoma.

BACKGROUND AND AIMS: Understanding of the significant genetic risk factors for Cholangiocarcinoma (CC) remains limited. Polymorphisms in the natural killer cell receptor G2D (NKG2D) gene have been shown to increase risk of CC transformation in patients with Primary Sclerosing Cholangitis (PSC). We present a validation study of NKG2D polymorphisms in CC patients without PSC. METHODS: Seven common Single Nucleotide Polymorphisms (SNPs) of the NKG2D gene were genotyped in 164 non-PSC related CC subjects and 257 controls with HaploView. The two SNPs that were positively identified in the previous Scandinavian study, rs11053781 and rs2617167, were included. RESULTS: The seven genotyped SNPs were not associated with risk of CC. Furthermore, haplotype analysis revealed that there was no evidence to suggest that any haplotype differs in frequency between cases and controls (P > 0.1). CONCLUSION: The common genetic variation in NKG2D does not correlate significantly with sporadic CC risk. This is in contrast to the previous positive findings in the Scandinavian study with PSC-patients. The failure to reproduce the association may reflect an important difference between the pathogenesis of sporadic CC and that of PSC-related CC. Given that genetic susceptibility is likely to be multifaceted and complex, further validation studies that include both sporadic and PSC-related CC are required.

RNA and microRNA Stability in PAXgene-Fixed Paraffin-Embedded Tissue Blocks After Seven Years' Storage.

OBJECTIVES: To evaluate the stability of RNA and microRNA (miRNA) in PAXgene-fixed paraffin-embedded tissue blocks after 7 years' storage. METHODS: RNA and miRNA were extracted from PAXgene-fixed paraffin-embedded (PFPE) blocks in 2009 then stored at -80°C. Seven years later, RNA and miRNA were again extracted from the same blocks. RNA and miRNA integrity in the 2009 and 2016 extractions were compared using RNA integrity number (RIN), paraffin-embedded RNA metric (PERM), reverse transcription polymerase chain reaction (RT-PCR) for different amplicon lengths, and quantitative RT-PCR (qRT-PCR) for three mRNA and three miRNA targets. RESULTS: In PFPE blocks, mRNA was poorer in 2016 extractions compared to the 2009 extractions in all blocks and all assays applied, with transcripts degrading at different rates in the same blocks. For miRNA, qRT-PCR showed no statistically significant differences between 2009 and 2016 extractions. CONCLUSIONS: mRNA in PFPE tissue blocks degrades at room temperature storage over 7 years.

A Critical Evaluation of the PAXgene Tissue Fixation System: Morphology, Immunohistochemistry, Molecular Biology, and Proteomics.

OBJECTIVES: To evaluate the PAXgene tissue fixation system. METHODS: Clinical biospecimens (n = 46) were divided into PAXgene-fixed paraffin-embedded (PFPE), formalin-fixed paraffin-embedded (FFPE), and fresh-frozen (FF) blocks. PFPE and FFPE sections were compared for histology (H&E staining) and immunohistochemistry (14 antibodies) using tissue microarrays. PFPE, FFPE, and FF samples were compared in terms of RNA quality (RNA integrity number, polymerase chain reaction [PCR] amplicon length, and quantitative reverse transcription PCR), DNA quality (gel electrophoresis and methylation profiling) and protein quality (liquid chromatography-mass spectrometry [LC-MS/MS]). RESULTS: PFPE protocol optimization was required in most cases and is described. RNA extracted from PFPE sections was considerably less degraded than that from FFPE sections but more degraded than that from FF blocks. Genomic-length DNA was extracted from PFPE and FF biospecimens, and methylation profiling showed PFPE and FF biospecimens to be almost indistinguishable. Only degraded DNA was extracted from FFPE biospecimens. PFPE sections yielded peptides that were slightly less amenable to LC-MS/MS analysis than FFPE sections, but FF gave slightly better results. CONCLUSIONS: While it cannot be envisaged that PAXgene will replace formalin in a routine clinical setting, for specific projects or immunodiagnostics involving biospecimens destined for immunohistochemical or histologic staining and DNA or RNA analyses, PAXgene is a viable option.

Genetic factors in the pathogenesis of cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CC) is increasing in incidence, but its pathogenesis remains poorly understood. Chronic inflammation of the bile duct and cholestasis are major risk factors, but most cases in the West are sporadic. Genetic polymorphisms in biliary transporter proteins have been implicated in benign biliary disease and, in the case of progressive familial cholestasis, have been associated with childhood onset of CC. In the current study, five biologically plausible candidate genes were investigated: ABCB11 (BSEP), ABCB4 (MDR3), ABCC2 (MRP2), ATP8B1 (FIC1) and NR1H4 (FXR). METHODS: DNA was collected from 172 Caucasian individuals with confirmed CC. A control cohort of healthy Caucasians was formed. Seventy-three SNPs were selected using the HapMap database to capture genetic variation around the five candidate loci. Genotyping was undertaken with a competitive PCR-based system. Confirmation of Hardy-Weinberg equilibrium and Cochran-Armitage trend testing were performed using PLINK. Haplotype frequencies were compared using haplo.stats. RESULTS: All 73 SNPs were in Hardy-Weinberg equilibrium. Four SNPs in ABCB11 were associated with altered susceptibility to CC, including the V444A polymorphism, but these associations did not retain statistical significance after Bonferroni correction for multiple testing. Haplotype analysis of the genotyped SNPs in ATP8B1 identified significant differences in frequencies between cases and controls (global p value of 0.005). CONCLUSION: Haplotypes in ATP8B1 demonstrated a significant difference between CC and control groups. There was a trend towards significant association of V444A with CC. Given the biological plausibility of polymorphisms in ABCB11 and ATP8B1 as risk modifiers for CC, further study in a validation cohort is required.

Array comparative genomic hybridization identifies novel potential therapeutic targets in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CC) is a rare tumour with a dismal prognosis. As conventional medical management offers minimal survival benefit, surgery currently represents the only chance of cure. We evaluated DNA copy number (CN) alterations in CC to identify novel therapeutic targets. METHODS: DNA was extracted from 32 CC samples. Bacterial artificial chromosome (BAC) array comparative genomic hybridization was performed using microarray slides containing 3400 BAC clones covering the whole human genome at distances of 1 Mb. Data were analysed within the R statistical environment. RESULTS: DNA CN gains (89 regions) occurred more frequently than DNA CN losses (55 regions). Six regions of gain were identified in all cases on chromosomes 16, 17, 19 and 22. Twenty regions were frequently gained on chromosomes 1, 5, 7, 9, 11, 12, 16, 17, 19, 20 and 21. The BAC clones covering ERBB2, MEK2 and PDGFB genes were gained in all cases. Regions covering MTOR, VEGFR 3, PDGFA, RAF1, VEGFA and EGFR genes were frequently gained. CONCLUSIONS: We identified CN gains in the region of 11 useful molecular targets. Findings of variable gains in some regions in this and other studies support the argument for molecular stratification before treatment for CC so that treatment can be tailored to the individual patient.