Five-year recurrence/survival after pancreatoduodenectomy for pancreatic adenocarcinoma: does pre-existing diabetes matter? Results from the Recurrence After Whipple's (RAW) study.

BACKGROUND: Diabetes mellitus (DM) has a complex relationship with pancreatic cancer. This study examines the impact of preoperative DM, both recent-onset and pre-existing, on long-term outcomes following pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study, a multi-centre cohort of PD for pancreatic head malignancy (2012-2015). Recurrence and five-year survival rates of patients with DM were compared to those without, and subgroup analysis performed to compare patients with recent-onset DM (less than one year) to patients with established DM. RESULTS: Out of 758 patients included, 187 (24.7%) had DM, of whom, 47 of the 187 (25.1%) had recent-onset DM. There was no difference in the rate of postoperative pancreatic fistula (DM: 5.9% vs no DM 9.8%; p = 0.11), five-year survival (DM: 24.1% vs no DM: 22.9%; p = 0.77) or five-year recurrence (DM: 71.7% vs no DM: 67.4%; p = 0.32). There was also no difference between patients with recent-onset DM and patients with established DM in postoperative outcomes, recurrence, or survival. CONCLUSION: We found no difference in five-year recurrence and survival between diabetic patients and those without diabetes. Patients with pre-existing DM should be evaluated for PD on a comparable basis to non-diabetic patients.

Patterns, timing and predictors of recurrence following pancreaticoduodenectomy for distal cholangiocarcinoma: An international multicentre retrospective cohort study.

INTRODUCTION: Patients undergoing pancreaticoduodenectomy for distal cholangiocarcinoma (dCCA) often develop cancer recurrence. Establishing timing, patterns and risk factors for recurrence may help inform surveillance protocol strategies or select patients who could benefit from additional systemic or locoregional therapies. This multicentre retrospective cohort study aimed to determine timing, patterns, and predictive factors of recurrence following pancreaticoduodenectomy for dCCA. MATERIALS AND METHODS: Patients who underwent pancreaticoduodenectomy for dCCA between June 2012 and May 2015 with five years of follow-up were included. The primary outcome was recurrence pattern (none, local-only, distant-only or mixed local/distant). Data were collected on comorbidities, investigations, operation details, complications, histology, adjuvant and palliative therapies, recurrence-free and overall survival. Univariable tests and regression analyses investigated factors associated with recurrence. RESULTS: In the cohort of 198 patients, 129 (65%) developed recurrence: 30 (15%) developed local-only recurrence, 44 (22%) developed distant-only recurrence and 55 (28%) developed mixed pattern recurrence. The most common recurrence sites were local (49%), liver (24%) and lung (11%). 94% of patients who developed recurrence did so within three years of surgery. Predictors of recurrence on univariable analysis were cancer stage, R1 resection, lymph node metastases, perineural invasion, microvascular invasion and lymphatic invasion. Predictors of recurrence on multivariable analysis were female sex, venous resection, advancing histological stage and lymphatic invasion. CONCLUSION: Two thirds of patients have cancer recurrence following pancreaticoduodenectomy for dCCA, and most recur within three years of surgery. The commonest sites of recurrence are the pancreatic bed, liver and lung. Multiple histological features are associated with recurrence.

Do some patients receive unnecessary parenteral nutrition after pancreatoduodenectomy? Results from an international multicentre study.

Backgrounds/Aims: After pancreatoduodenectomy (PD), an early oral diet is recommended; however, the postoperative nutritional management of PD patients is known to be highly variable, with some centers still routinely providing parenteral nutrition (PN). Some patients who receive PN experience clinically significant complications, underscoring its judicious use. Using a large cohort, this study aimed to determine the proportion of PD patients who received postoperative nutritional support (NS), describe the nature of this support, and investigate whether receiving PN correlated with adverse perioperative outcomes. Methods: Data were extracted from the Recurrence After Whipple's study, a retrospective multicenter study of PD outcomes. Results: In total, 1,323 patients (89%) had data on their postoperative NS status available. Of these, 45% received postoperative NS, which was "enteral only," "parenteral only," and "enteral and parenteral" in 44%, 35%, and 21% of cases, respectively. Body mass index < 18.5 kg/m2 (p = 0.03), absence of preoperative biliary stenting (p = 0.009), and serum albumin < 36 g/L (p = 0.009) all correlated with receiving postoperative NS. Among those who did not develop a serious postoperative complication, i.e., those who had a relatively uneventful recovery, 20% received PN. Conclusions: A considerable number of patients who had an uneventful recovery received PN. PN is not without risk, and should be reserved for those who are unable to take an oral diet. PD patients should undergo pre- and postoperative assessment by nutrition professionals to ensure they are managed appropriately, and to optimize perioperative outcomes.

Postoperative complications after pancreatoduodenectomy for malignancy: results from the Recurrence After Whipple's (RAW) study.

BACKGROUND: Pancreatoduodenectomy (PD) is associated with significant postoperative morbidity. Surgeons should have a sound understanding of the potential complications for consenting and benchmarking purposes. Furthermore, preoperative identification of high-risk patients can guide patient selection and potentially allow for targeted prehabilitation and/or individualized treatment regimens. Using a large multicentre cohort, this study aimed to calculate the incidence of all PD complications and identify risk factors. METHOD: Data were extracted from the Recurrence After Whipple's (RAW) study, a retrospective cohort study of PD outcomes (29 centres from 8 countries, 2012-2015). The incidence and severity of all complications was recorded and potential risk factors for morbidity, major morbidity (Clavien-Dindo grade > IIIa), postoperative pancreatic fistula (POPF), post-pancreatectomy haemorrhage (PPH) and 90-day mortality were investigated. RESULTS: Among the 1348 included patients, overall morbidity, major morbidity, POPF, PPH and perioperative death affected 53 per cent (n = 720), 17 per cent (n = 228), 8 per cent (n = 108), 6 per cent (n = 84) and 4 per cent (n = 53), respectively. Following multivariable tests, a high BMI (P = 0.007), an ASA grade > II (P < 0.0001) and a classic Whipple approach (P = 0.005) were all associated with increased overall morbidity. In addition, ASA grade > II patients were at increased risk of major morbidity (P < 0.0001), and a raised BMI correlated with a greater risk of POPF (P = 0.001). CONCLUSION: In this multicentre study of PD outcomes, an ASA grade > II was a risk factor for major morbidity and a high BMI was a risk factor for POPF. Patients who are preoperatively identified to be high risk may benefit from targeted prehabilitation or individualized treatment regimens.

Does an extensive diagnostic workup for upfront resectable pancreatic cancer result in a delay which affects survival? Results from an international multicentre study.

Backgrounds/Aims: Pancreatoduodenectomy (PD) is recommended in fit patients with a carcinoma (PDAC) of the pancreatic head, and a delayed resection may affect survival. This study aimed to correlate the time from staging to PD with long-term survival, and study the impact of preoperative investigations (if any) on the timing of surgery. Methods: Data were extracted from the Recurrence After Whipple's (RAW) study, a multicentre retrospective study of PD outcomes. Only PDAC patients who underwent an upfront resection were included. Patients who received neoadjuvant chemo-/radiotherapy were excluded. Group A (PD within 28 days of most recent preoperative computed tomography [CT]) was compared to group B (> 28 days). Results: A total of 595 patents were included. Compared to group A (median CT-PD time: 12.5 days, interquartile range: 6-21), group B (49 days, 39-64.5) had similar one-year survival (73% vs. 75%, p = 0.6), five-year survival (23% vs. 21%, p = 0.6) and median time-todeath (17 vs. 18 months, p = 0.8). Staging laparoscopy (43 vs. 29.5 days, p = 0.009) and preoperative biliary stenting (39 vs. 20 days, p < 0.001) were associated with a delay to PD, but magnetic resonance imaging (32 vs. 32 days, p = 0.5), positron emission tomography (40 vs. 31 days, p > 0.99) and endoscopic ultrasonography (28 vs. 32 days, p > 0.99) were not. Conclusions: Although a treatment delay may give rise to patient anxiety, our findings would suggest this does not correlate with worse survival. A delay may be necessary to obtain further information and minimize the number of PD patients diagnosed with early disease recurrence.

Serious complications of pancreatoduodenectomy correlate with lower rates of adjuvant chemotherapy: Results from the recurrence after Whipple's (RAW) study.

INTRODUCTION: Adjuvant chemotherapy (AC) can prolong overall survival (OS) after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, fitness for AC may be influenced by postoperative recovery. We aimed to investigate if serious (Clavien-Dindo grade ≥ IIIa) postoperative complications affected AC rates, disease recurrence and OS. MATERIALS AND METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study (n = 1484), a retrospective study of PD outcomes (29 centres from eight countries). Patients who died within 90-days of PD were excluded. The Kaplan-Meier method was used to compare OS in those receiving or not receiving AC, and those with and without serious postoperative complications. The groups were then compared using univariable and multivariable tests. RESULTS: Patients who commenced AC (vs no AC) had improved OS (median difference: (MD): 201 days), as did those who completed their planned course of AC (MD: 291 days, p < 0.0001). Those who commenced AC were younger (mean difference: 2.7 years, p = 0.0002), more often (preoperative) American Society of Anesthesiologists (ASA) grade I-II (74% vs 63%, p = 0.004) and had less often experienced a serious postoperative complication (10% vs 18%, p = 0.002). Patients who developed a serious postoperative complication were less often ASA grade I-II (52% vs 73%, p = 0.0004) and less often commenced AC (58% vs 74%, p = 0.002). CONCLUSION: In our multicentre study of PD outcomes, PDAC patients who received AC had improved OS, and those who experienced a serious postoperative complication commenced AC less frequently. Selected high-risk patients may benefit from targeted preoperative optimisation and/or neoadjuvant chemotherapy.

Predictors of actual five-year survival and recurrence after pancreatoduodenectomy for ampullary adenocarcinoma: results from an international multicentre retrospective cohort study.

BACKGROUND: Pancreatoduodenectomy (PD) is recommended in fit patients with a resectable ampullary adenocarcinoma (AA). We aimed to identify predictors of five-year recurrence/survival. METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study, a multicentre retrospective study of PD patients with a confirmed head of pancreas or periampullary malignancy (June 1st, 2012-May 31st, 2015). Patients with AA who developed recurrence/died within five-years were compared to those who did not. RESULTS: 394 patients were included and actual five-year survival was 54%. Recurrence affected 45% and the median time-to-recurrence was 14 months. Local only, local and distant, and distant only recurrence affected 34, 41 and 94 patients, respectively (site unknown: 7). Among those with recurrence, the most common sites were the liver (32%), local lymph nodes (14%) and lung/pleura (13%). Following multivariable tests, number of resected nodes, histological T stage > II, lymphatic invasion, perineural invasion (PNI), peripancreatic fat invasion (PPFI) and ≥1 positive resection margin correlated with increased recurrence and reduced survival. Furthermore, ≥1 positive margin, PPFI and PNI were all associated with reduced time-to-recurrence. CONCLUSIONS: This multicentre retrospective study of PD outcomes identified numerous histopathological predictors of AA recurrence. Patients with these high-risk features might benefit from adjuvant therapy.

Ultra-radical surgery for advanced ovarian cancer: a retrospective cohort study in a tertiary referral cancer center in the UK.

BACKGROUND: Ovarian cancer is the leading cause of death from gynecological cancer in the UK. The standard of care is a combination of surgery and chemotherapy. The aim of the treatment is the resection of all macroscopic disease. In selected cases of advanced ovarian cancer this is achieved with ultra-radical surgery. However, NICE encourages further research due to low quality evidence on the safety and efficacy of this extensive surgery. The aim of this study was to examine the morbidity and survival rates of ultra-radical surgery for advanced ovarian cancer performed in our unit and compare our findings with the current literature. METHODS: This is a retrospective study of 39 patients diagnosed with stage IIIA-IV ovarian and primary peritoneal cancer who underwent surgery in our unit between 2012 and 2020. The main outcome measures were the perioperative complications, the disease-free survival, the overall survival rate and the recurrence rate. RESULTS: The study enrolled 39 patients with stages IIIA-IV who were treated in our unit between 2012 and 2020. 21 patients were at stage III (53.8%) whereas 18 (46.1%) at stage IV. 14 patients underwent primary and 25 secondary debulking surgery. Major and minor complications occurred 17.9% and 56.4% of the patients, respectively. Complete cytoreduction following surgery was achieved in 24 cases (61.5%). The mean and the median survival time were 4.8 years and 5 years, respectively. The mean disease-free survival time was 2.9 years while median disease-free survival time was 2 years. Age (P=0.028) and complete cytoreduction (p=0.048) were found to be significantly associated with survival. Primary debulking surgery was significantly associated with lower probability of recurrence (P=0.049). CONCLUSIONS: Although the number of patients is relatively small, our study indicates that ultra-radical surgery in centers with high expertise may result in excellent survival rates with an acceptable rate of major complications. All patients in our cohort were operated by an accredited gynecological oncologist and a hepatobiliary general surgeon with a special interest in ovarian cancer. A few cases required input from a colorectal and a thoracic surgeon. We believe that the careful selection of the patients that can benefit from ultra-radical surgery and our model of joint surgery can explain our excellent results. Further research is essential to establish that ultra- radical surgery has an acceptable rate of morbidity for patients with advanced ovarian cancer.

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.

Thromboembolism in inflammatory bowel disease: an insidious association requiring a high degree of vigilance.

Venous and arterial thromboembolism are both serious extraintestinal manifestations of inflammatory bowel disease (IBD). Acquired risk factors seem to play a more prominent role than congenital in promoting thrombotic events. Prevention of thromboembolism is thus mainly aimed at minimizing the acquired/reversible risk factors (e.g., inflammation, immobility, hospitalization, steroid therapy, central intravenous catheters, smoking, oral contraceptives, and deficiency of B vitamins and folate). The diagnosis of venous and arterial thromboembolism is extremely challenging and requires a high degree of vigilance. Deep vein thrombosis and pulmonary embolism may be clinically silent or manifest with only few specific symptoms. Thrombosis of the portal vein system may occur with nonspecific symptoms such as abdominal pain, nausea/vomiting, abdominal tenderness, ascites, and fever. The diagnosis of arterial thromboembolism may also be challenging, particularly when the splanchnic region is involved. Indeed, arterial thrombosis of the splanchnic region tends to be overlooked and misinterpreted as a clinical exacerbation of IBD. Early diagnosis plays a central role in optimizing the therapeutic intervention and reducing the risk of short-term and long-term thrombosis-associated complications. The decision regarding the duration of systemic anticoagulation must take into account the individual risk of intestinal bleeding.

Single-centre comparative study of laparoscopic versus open right hepatectomy.

BACKGROUND: Expansion of laparoscopic major hepatectomy is still limited mainly due to the well-recognised technical difficulties compared to open surgery, and doubts regarding the oncological efficiency when major resections are required. METHODS: Patients undergoing open right hepatectomy (ORH) were matched with patients undergoing laparoscopic right hepatectomy (LRH) and compared for perioperative outcomes. RESULTS: Seventy patients were included: 36 patients underwent LRH and 34 ORH. Operative time was significantly longer for LRH (median, 300 min vs. 180 min for ORH; p < 0.0001). Intensive care unit (median, 2 days for LRH vs. 4 days for ORH; p < 0.0001) and postoperative length of stay (5 days for LRH vs. 9 days for ORH; p < 0.0001) were significantly shorter for LRH. Four laparoscopic cases were converted to open surgery. No significant difference in postoperative complications and mortality was observed between LRH and ORH. Among patients with colorectal carcinoma liver metastases, R0 resection was obtained in 20/21 (95%) cases after LRH, and in 20/25 (80%) after ORH (p = 0.198). Mid-term overall survival did not significantly differ between the laparoscopic and the open group. CONCLUSIONS: LRH can be a safe, effective, and oncologically efficient alternative to open resection in selected cases. Extensive experience in hepatic and laparoscopic surgery is required.

Ischemia as a possible effect of increased intra-abdominal pressure on central nervous system cytokines, lactate and perfusion pressures.

INTRODUCTION: The aims of our study were to evaluate the impact of increased intra-abdominal pressure (IAP) on central nervous system (CNS) cytokines (Interleukin 6 and tumor necrosis factor), lactate and perfusion pressures, testing the hypothesis that intra-abdominal hypertension (IAH) may possibly lead to CNS ischemia. METHODS: Fifteen pigs were studied. Helium pneumoperitoneum was established and IAP was increased initially at 20 mmHg and subsequently at 45 mmHg, which was finally followed by abdominal desufflation. Interleukin 6 (IL-6), tumor necrosis factor alpha (TNFa) and lactate were measured in the cerebrospinal fluid (CSF) and intracranial (ICP), intraspinal (ISP), cerebral perfusion (CPP) and spinal perfusion (SPP) pressures recorded. RESULTS: Increased IAP (20 mmHg) was followed by a statistically significant increase in IL-6 (p = 0.028), lactate (p = 0.017), ICP (p < 0.001) and ISP (p = 0.001) and a significant decrease in CPP (p = 0.013) and SPP (p = 0.002). However, further increase of IAP (45 mmHg) was accompanied by an increase in mean arterial pressure due to compensatory tachycardia, followed by an increase in CPP and SPP and a decrease of cytokines and lactate. CONCLUSIONS: IAH resulted in a decrease of CPP and SPP lower than 60 mmHg and an increase of all ischemic mediators, indicating CNS ischemia; on the other hand, restoration of perfusion pressures above this threshold decreased all ischemic indicators, irrespective of the level of IAH.