Management of complex acute biliary disease for the general surgeon: A narrative review.

Acute gallbladder diseases are a common surgical emergency faced by General Surgeons that can sometimes be quite challenging. These complex biliary diseases require multifaceted and expeditious care, optimized based on hospital facility and operating room (OR) resources and the expertise of the surgical team. Effective management of biliary emergencies requires two foundational principles: achieving source control while mitigating the risk of injury to the biliary tree and its blood supply. This review article highlights salient literature on seven complex biliary diseases: acute cholecystitis, cholangitis, Mirizzi syndrome, gallstone ileus with cholecystoenteric fistula, gallstone pancreatitis, gall bladder cancer, and post-cholecystectomy bile leak.

Clinical consensus statement: Establishing the roles of locoregional and systemic therapies for the treatment of intermediate-stage hepatocellular carcinoma in Canada.

BACKGROUND: Hepatocellular carcinoma (HCC) a leading cause of cancer mortality worldwide and approximately one-third of patients present with intermediate-stage disease. The treatment landscape of intermediate-stage HCC is rapidly evolving due to developments in local, locoregional and systemic therapies. Treatment recommendations focused on this heterogenous disease stage and that take into account the Canadian reality are lacking. To address this gap, a pan-Canadian group of experts in hepatology, transplant, surgery, radiation therapy, nuclear medicine, interventional radiology, and medical oncology came together to develop consensus recommendations on management of intermediate-stage HCC relevant to the Canadian context. METHODS: A modified Delphi framework was used to develop consensus statements with strengths of recommendation and supporting levels of evidence graded using the AHA/ACC classification system. Tentative consensus statements were drafted based on a systematic search and expert input in a series of iterative feedback cycles and were then circulated via online survey to assess the level of agreement. RESULTS & CONCLUSION: The pre-defined ratification threshold of 80 % agreement was reached for all statements in the areas of multidisciplinary treatment (n = 4), intra-arterial therapy (n = 14), biologics (n = 5), radiation therapy (n = 3), surgical resection and transplantation (n = 7), and percutaneous ablative therapy (n = 4). These generally reflected an expansion in treatment options due to developments in previously established or emergent techniques, introduction of new and more active therapies and increased therapeutic flexibility. These developments have allowed for greater treatment tailoring and personalization as well as a paradigm shift toward strategies with curative intent in a wider range of disease settings.

Phlebotomy resulting in controlled hypovolemia to prevent blood loss in major hepatic resections (PRICE-2): study protocol for a phase 3 randomized controlled trial.

INTRODUCTION: Blood loss and red blood cell (RBC) transfusion in liver surgery are areas of concern for surgeons, anesthesiologists, and patients alike. While various methods are employed to reduce surgical blood loss, the evidence base surrounding each intervention is limited. Hypovolemic phlebotomy, the removal of whole blood from the patient without volume replacement during liver transection, has been strongly associated with decreased bleeding and RBC transfusion in observational studies. This trial aims to investigate whether hypovolemic phlebotomy is superior to usual care in reducing RBC transfusions in liver resection. METHODS: This study is a double-blind multicenter randomized controlled trial. Adult patients undergoing major hepatic resections for any indication will be randomly allocated in a 1:1 ratio to either hypovolemic phlebotomy and usual care or usual care alone. Exclusion criteria will be minor resections, preoperative hemoglobin <100g/L, renal insufficiency, and other contraindication to hypovolemic phlebotomy. The primary outcome will be the proportion of patients receiving at least one allogeneic RBC transfusion unit within 30 days of the onset of surgery. Secondary outcomes will include transfusion of other allogeneic blood products, blood loss, morbidity, mortality, and intraoperative physiologic parameters. The surgical team will be blinded to the intervention. Randomization will occur on the morning of surgery. The sample size will comprise 440 patients. Enrolment will occur at four Canadian academic liver surgery centers over a 4-year period. Ethics approval will be obtained at participating sites before enrolment. DISCUSSION: The results of this randomized control trial will provide high-quality evidence regarding the use of hypovolemic phlebotomy in major liver resection and its effects on RBC transfusion. If proven to be effective, this intervention could become standard of care in liver operations internationally and become incorporated within perioperative patient blood management programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03651154 . Registered on August 29 2018.

Outcomes of liver transplant recipients with high MELD scores: an experience from a Canadian centre.

BACKGROUND: The frequency with which patients with high Model for End-Stage Liver Disease (MELD) scores undergo liver transplantation has been increasing. Canadian literature regarding the outcomes of liver transplantation in recipients with high MELD scores is limited. The primary objective of this study was to assess patient and graft survival among recipients with high (> 35) and low (≤ 35) MELD scores. Secondary objectives were to potentially identify independent predictors of graft failure and patient mortality. METHODS: We conducted a retrospective chart review of patients undergoing liver transplantation at a single Canadian centre from 2012 to 2017. RESULTS: A total of 332 patients were included in the study: 280 patients had a MELD score of 35 or lower, and 52 had a MELD score above 35. Patients with high MELD scores had higher rates of pretransplant acute kidney injury and dialysis (p < 0.001), admission to the intensive care unit (ICU) or intubation (p < 0.001), intraoperative blood product transfusions (p < 0.001) and post-transplantation acute kidney injury and dialysis (p < 0.001), as well as longer ICU (p < 0.001) and hospital stays (p = 0.002). One- and 3-year patient survival in recipients with MELD scores of 35 or lower was 93.1% and 84.9% versus 85.0% and 80.0% in recipients with MELD scores above 35 (p = 0.37). One- and 3-year graft survival in recipients with MELD scores of 35 or lower was 91.7% and 90.9% versus 77.2% and 72.8% in recipients with MELD scores above 35 (p < 0.001). Prior liver transplant was an independent predictor of patient mortality, and no independent predictors of graft failure were identified. When MELD was replaced with D-MELD (donor age × recipient MELD), it predicted graft failure but not patient survival. CONCLUSION: No difference in patient mortality was found between MELD groups. Graft survival was significantly lower in recipients with MELD scores above 35. D-MELD may potentially be used as an adjunct in determining risk of graft failure in recipients with high MELD scores.

Pancreas tail adenocarcinoma tumor size is highly predictive of positive margins after a nonradical resection.

BACKGROUND: Radical resection (RAMPS) of left sided pancreatic ductal adenocarcinoma (PDAC) is effective in achieving R0 margins; however, not universally accepted due to lack of improved survival. We hypothesized that only larger tumors lead to R1 in non-RAMPS procedures. METHODS: A retrospective review of charts between 2008 and 2020 was performed. The primary outcome was evaluating R0 resection based on left-sided tumors' size and location, and secondary outcomes were OS and DFS. RESULTS: Sixty-eight percent had R0 resection. R1 groups' tumors were larger (5.5 cm vs. 3.8 cm, p = 0.004) and had higher LVI involvement (p = 0.003). OS and DFS did not differ on multivariate analysis. Tumor size above 4 cm in the tail was associated with R1 (p = 0.01). CONCLUSIONS: Larger tumors in the tail, but not body were associated with R1, but not worse survival. Perhaps larger tumors in the tail are a surrogate marker of poor disease biology.

Prevention of postoperative pancreatic fistula after pancreatectomy: results of a Canadian RAND/UCLA appropriateness expert panel.

BACKGROUND: We aimed to define the appropriateness of interventions for the prevention of postoperative pancreatic fistulas (POPF) after pancreatectomy, given the lack of consistent data on this topic. METHODS: Using the RAND/UCLA appropriateness method, we assembled an expert panel to rate clinical scenarios for interventions to prevent POPF after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). RESULTS: The following interventions were rated appropriate: individualized risk prediction for all patients; perioperative pasireotide administration for patients undergoing PD who have a soft pancreatic gland and a pancreatic duct size of less 3 mm and for patients undergoing DP; pancreaticogastrostomy for patients undergoing PD who have a soft pancreatic gland and pancreaticojejunostomy for PD for patients with a pancreatic duct size of 6 mm or greater regardless of pancreatic gland texture; duct-to-mucosa anastomosis for all patients undergoing PD and dunking anastomosis for patients undergoing PD who have a pancreatic duct size of less than 3 mm with a firm pancreatic gland; simple stapled and reinforced stapled transection for all DP; surgical drains for PD and DP in patients with a soft pancreatic gland; and open and minimally invasive surgery for DP and open surgery for PD. The following were rated inappropriate: gastrointestinal anastomosis for stump closure in all DP and omission of surgical drain in PD for patients with a pancreatic duct diameter less than 3 mm and a soft pancreatic gland. CONCLUSION: The expert panel identified appropriate and inappropriate scenarios for POPF prevention following pancreatectomy, to provide guidance to clinicians. However, the appropriateness of the interventions in the majority of the clinical scenarios was rated as uncertain, demonstrating equipoise.

The association between bacterobilia and the risk of postoperative complications following pancreaticoduodenectomy.

BACKGROUND: Pre-operative biliary bacterial colonisation (bacterobilia) is considered a risk factor for infectious complications after pancreaticoduodenectomy (PD). This study aimed to investigate the role of the PD biliary microbiome grown in the development of post-PD complications. METHODS: In a retrospective study of 162 consecutive patients undergoing PD (2008-2018), intra-operative bile cultures were analyzed and sensitivities compared to pre-anesthetic antibiotics and thirty-day post-surgery complications. RESULTS: Bacterobilia was present in 136 patients (84%). Most bile cultures grew bacteria resistant to pre-operative antibiotics (n = 112, 82%). Patients with bacterobilia had significantly higher rates of major complication than patients without (P = 0.017), as well as higher rates of surgical-site infections (SSI) (P = 0.010). Patients with negative bile cultures (n = 26) had significantly lower rates of major complication and SSI than those growing sensitive (n = 24) or non-sensitive (n = 112) bacteria (major complication P = 0.029 and SSI P = 0.011). CONCLUSION: Positive bile cultures were associated with a higher incidence of major complications and SSI. Patients with sterile bile cultures had the lowest risk of post-operative complications and efforts to reduce rates of bacterobilia, such as limitation of biliary instrumentation, should be considered. Sensitivity to antibiotics had no effect upon the rate of post-operative complications, but this may reflect low cohort numbers.

COVID-19 infection immediately post-transplant in an unvaccinated patient: Clinical observations and ethical implications.

We report the case of a 28-year-old woman who presented with acute liver failure from suspected drug-induced liver injury. She was not vaccinated against COVID-19 and expressed considerable reluctance to become vaccinated, prompting discussions within the transplant group regarding her candidacy. She received a liver transplant and acquired COVID-19 immediately post-operatively that was treated with sotrovimab. She recovered well and was discharged shortly following her transplant. This case suggests that unwillingness to receive COVID-19 vaccination pre-transplant should not represent an absolute contraindication to a life-saving liver transplantation.

End stage liver disease etiology & transplantation referral outcomes of major ethnic groups in British Columbia, Canada: A cohort study.

ABSTRACT: Liver disease etiology and transplantation outcomes may vary by ethnicity. We aimed to determine if disparities exist in our province.We reviewed the provincial database for liver transplant referrals. We stratified cohorts by ethnicity and analyzed disease etiology and outcomes.Four thousand nine hundred sixteen referrals included 220 South Asians, 413 Asians, 235 First Nations (Indigenous), and 2725 Caucasians. Predominant etiologies by ethnicity included alcohol (27.4%) and primary sclerosing cholangitis (PSC) (8.8%) in South Asians, hepatitis B (45.5%) and malignancy (13.9%) in Asians, primary biliary cholangitis (PBC) (33.2%) and autoimmune hepatitis (AIH) (10.8%) in First Nations, and hepatitis C (35.9%) in Caucasians. First Nations had lowest rate of transplantation (30.6%, P = .01) and highest rate of waitlist death (10.6%, P = .03). Median time from referral to transplantation (268 days) did not differ between ethnicities (P = .47). Likelihood of transplantation increased with lower body mass index (BMI) (hazard ratio [HR] 0.99, P = .03), higher model for end stage liver disease (MELD) (HR 1.02, P < .01), or fulminant liver failure (HR 9.47, P < .01). Median time from referral to ineligibility status was 170 days, and shorter time was associated with increased MELD (HR 1.01, P < .01), increased age (HR 1.01, P < .01), fulminant liver failure (HR 2.56, P < .01) or South Asian ethnicity (HR 2.54, P < .01). Competing risks analysis revealed no differences in time to transplant (P = .66) or time to ineligibility (P = .91) but confirmed increased waitlist death for First Nations (P = .04).We have noted emerging trends such as alcohol related liver disease and PSC in South Asians. First Nations have increased autoimmune liver disease, lower transplantation rates and higher waitlist deaths. These data have significance for designing ethnicity specific interventions.

The role of intraperitoneal chemotherapy in the surgical management of pancreatic ductal adenocarcinoma: a systematic review.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis, particularly for patients with metastatic disease. Treatment for oligometastatic presentation has been reported in recent literature, but the role of intraperitoneal chemotherapy for patients with peritoneal metastases (PM) remains unclear. We performed a systematic literature search of the PubMed, Cochrane and Embase databases in order to identify clinical trials and case-series reporting on the safety and efficacy of intraperitoneal chemotherapy in patients with PDAC-derived PM. Eight publications reporting on 85 patients were identified, using three different therapeutic strategies. First, 37 patients received cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for PDAC with PM. Grade 3 and 4 complications occurred in 37.8% of patients, without perioperative mortality. Median disease-free survival and overall survival (OS) rates varied from 4 to 36 months and 4 to 62 months, respectively. Secondly, 40 patients with resectable PDAC without PM received prophylactic HIPEC following pancreatic resection, with postoperative morbidity and mortality rates of 30% and 5%, and 5-year OS rates of 23-24%. Finally, eight patients with PDAC-derived peritoneal disease were converted to resectable disease after receiving neoadjuvant intraperitoneal chemotherapy and operated on with curative intent, achieving a median OS of 27.8 months. In conclusion, CRS with HIPEC for PDAC-derived PM appears to be safe, conferring the same postoperative morbidity and mortality as reported on non-pancreatic malignancies. In highly selected patients, it could be considered for short-term disease control. However, long-term survival remains poor. The addition of prophylactic HIPEC for resectable PDAC cannot be recommended.

Determining when endoscopic ultrasound changes management for patients with pancreatic cystic neoplasms.

INTRODUCTION: Pancreatic cystic neoplasms (PCNs) are being incidentally detected at an increased rate due to increased CT and MRI usage. EUS is an emerging tool that can differentiate between benign and malignant features of pancreatic cysts. We hoped to identify the specific cross-sectional imaging findings and patient characteristics that warrant EUS referral. METHODS: We conducted a retrospective case-control chart review, evaluating patients, who were diagnosed with pancreatic cysts and underwent EUS between January 1, 2010 and December 31, 2017. RESULTS: EUS was found to change management when CT imaging found cyst size > 4 cm (OR = 4.07, p < 0.01), cyst size > 3 cm (OR = 3.79, p < 0.001) and associated solid component to the cyst (OR = 5.95, p < 0.01). Additionally, patient characteristics, including age less than 50 years, male sex and 10-pack year smoking history were significantly associated with EUS change in management. DISCUSSION: Our findings suggest that EUS referral should be coordinated based on the findings of specific HRFs, with support from high risk patient characteristics, rather than the accumulation of multiple HRFs, as suggested by existing guidelines.

Minimally invasive hepatectomy is associated with decreased morbidity and resource utilization in the elderly.

BACKGROUND: The aim of this study was to evaluate whether elderly patients undergoing elective hepatectomy experience increased morbidity/mortality and whether these outcomes could be mitigated by minimally invasive hepatectomy (MIH). METHODS: 15,612 patients from 2014 to 2017 were identified in the Hepatectomy Targeted Procedure Participant Use File of the American College of Surgeons National Surgical Quality Improvement Program. Multivariable logistic regression models were constructed to examine the effect of elderly status (age ≥ 75 years, N = 1769) on outcomes with a subgroup analysis of elderly only patients by open (OH) versus MIH (robotic, laparoscopic, and hybrid, N = 4044). Propensity score matching was conducted comparing the effect of MIH to OH in elderly patients to ensure that results are not the artifact of imbalance in baseline characteristics. RESULTS: Overall, elderly patients had increased risk for 30-day mortality, major morbidity, prolonged length of hospital stay, and discharge to destination other than home. In the elderly subgroup, MIH was associated with decreased major morbidity (OR 0.71, P = 0.031), invasive intervention (OR 0.61, P = 0.032), liver failure (OR 0.15, P = 0.011), bleeding (OR 0.46, P < 0.001), and prolonged length of stay (OR 0.46, P < 0.001). Propensity score-matched analyses successfully matched 4021 pairs of patients treated by MIH vs. OH, and logistic regression analyses on this matched sample found that MIH was associated with decreased major complications (OR 0.69, P = 0.023), liver failure (OR 0.14, P = 0.010), bile leak (OR 0.46, P = 0.009), bleeding requiring transfusion (OR 0.46, P < 0.001), prolonged length of stay (OR 0.46, P < 0.001), and discharge to destination other than home (OR 0.691, P = 0.035) compared to OH. CONCLUSION: MIH is associated with decreased risk of major morbidity, liver failure, bile leak, bleeding, prolonged length of stay, and discharge to destination other than home among elderly patients in this retrospective study. However, MIH in elderly patients does not protect against postoperative mortality.

Impact of surgical wait times on oncologic outcomes in resectable pancreas adenocarcinoma.

BACKGROUND: Timely surgical resection in patients with suspected or diagnosed pancreas adenocarcinoma is an essential part of care. We hypothesized that longer surgical wait time was associated with worse oncologic outcomes. METHODS: A retrospective cohort of patients (N = 144) with resectable pancreas adenocarcinoma was divided into four wait time groups (<4, 4-8, 8-12, and >12 weeks), defined from the time of diagnosis on cross-sectional imaging. Overall and recurrence-free survival were analyzed using the Kaplan-Meier method and Cox proportional hazards regression. A higher rate of conversion to palliative bypass in patients waiting over 4 weeks was observed and further analyzed using post-hoc multivariate regression. RESULTS: On multivariable analysis, longer wait time was associated with improved overall (HR 0.49, 95% CI: 0.28-0.85) and recurrence-free survival (HR 0.29, 95% CI: 0.15-0.56) in >12 weeks compared to <4 weeks group. On post-hoc analysis, longer wait time over 8 weeks was positively associated with palliative bypass (OR 5.33, 95% CI: 1.32-27.88). CONCLUSION: Wait time over 8 weeks was associated with a higher rate of palliative bypass. There was an improvement in overall and recurrence-free survival in patients who waited over 12 weeks, likely due to selection bias.

Neoadjuvant therapy and major arterial resection for potentially reconstructable arterial involvement by stage 3 adenocarcinoma of the pancreas.

BACKGROUND: Stage 3 pancreatic ductal adenocarcinoma (PDAC) is defined by arterial involvement. This study objective was to evaluate outcomes for patients with stage 3 PDAC with potentially reconstructable arterial involvement, considered for neoadjuvant therapy (NAT) and pancreatic resection, and to compare outcomes following arterial (AR) and non-arterial resection (NAR). METHODS: This study included patients from 2009 to 2016 with biopsy-proven stage 3 PDAC who were offered NAT before surgical exploration. AR was performed if required to achieve R0 resection. Time to event outcomes were analysed from diagnosis date. RESULTS: 87/89 patients (97.8%) received NAT (chemotherapy 41.6%, chemotherapy/radiotherapy 56.2%). 46/89 (51.7%) underwent exploration; 31 underwent resection (AR n = 20, NAR n = 11). AR patients had longer operative time (681 vs. 563 min, p = 0.006) and more blood loss (1600 vs. 575 mL, p = 0.0004), with no difference for blood transfusion, pancreatic fistula, length of stay, reoperation, or mortality. R0 rate was 30/31. Post-resection 90-day mortality was 3.2%. Median overall survival was statistically comparable between the AR and NAR groups (19.7 vs. 28.4 months, p = 0.41). CONCLUSIONS: AR had comparable clinical and oncologic outcomes to NAR. Following careful selection and non-progression after NAT, major AR may cautiously be considered if required to obtain a negative resection margin.

BRM polymorphisms, pancreatic cancer risk and survival.

Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM-1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically.(1) Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk,(1-3) and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer. A provincial population-based case-control study was conducted with 623 histologically confirmed pancreatic adenocarcinoma cases and 1,192 age/gender distribution-matched controls.(4) Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Median age was 65 y; 52% were male; Stage I (8%), II (55%), III (14%), IV (23%); 53% after curative resection, 79% after chemotherapy; and 83% had died. In the risk analysis, adjusted odds ratios (aOR) were 1.01 (95% CI: 0.1-2.0) and 0.96 (95% CI: 0.7-1.3) for the homozygotes of BRM-741 and BRM-1321, respectively; aOR of double-homozygotes was 1.11 (95% CI: 0.80-1.53), compared to the double-wildtype. For the survival analysis, adjusted hazard ratios (aHR) were 2.19 (95% CI: 1.9-2.5) for BRM-741 and 1.94 (95% CI: 1.7-2.2) for BRM-1321, per unit increase in variant alleles. Compared with the double-wildtype, aHR for carrying no, one, and two double-homozygotes were 2.14 (95% CI: 1.6-2.8), 4.17 (95% CI: 3.0-5.7), 8.03 (95% CI: 5.7-11.4), respectively. In conclusion, two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.

Biliary and vascular anomalies in living liver donors: the role and accuracy of pre-operative radiological mapping.

BACKGROUND: The aim of the present study was to determine the utility of computed tomography (CT) and magnetic resonance imaging (MRI) anatomic mapping in the detection of biliary and vascular anomalies prior to a living liver donor (LLD) operation. METHODS: A retrospective study of all LLD patient charts, operative and radiology reports from 1 January 2002 to 1 January 2012 was conducted. Primary post-operative outcomes assessed included mortality, re-operation, readmission and need for endoscopic or percutaneous intervention. Sensitivity and specificity of MR and CT pre-operative screening was calculated against the gold standard of intra-operative findings. RESULTS: A total of 34 donors had an average age of 38 years (range: 22-58) with a body mass index (BMI) of 25.6 kg/m(2) (range: 19.8-32.5) and a length of stay (LOS) of 10.1 days (range: 5-41). There were no donor mortalities. Sensitivity and specificity of CT was 70.0% and 91.3%, and of MRI screening 23.1% and 100.0%, respectively. Patients with inaccurate pre-operative CT or MRI did not have an increased risk of complications. CONCLUSIONS: Even although it was specific, pre-operative MR screening missed up to 77.0% of biliary anomalies. An impeccable surgical technique remains the key in preventing biliary complications of a living donor hepatectomy where pre-operative MRI screening is false.