Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Selective TLR4 Antagonism Prevents and Reverses Morphine-Induced Persistent Postoperative Cognitive Dysfunction, Dysregulation of Synaptic Elements, and Impaired BDNF Signaling in Aged Male Rats.

Perioperative neurocognitive disorders (PNDs) are characterized by confusion, difficulty with executive function, and episodic memory impairment in the hours to months following a surgical procedure. Postoperative cognitive dysfunction (POCD) represents such impairments that last beyond 30 d postsurgery and is associated with increased risk of comorbidities, progression to dementia, and higher mortality. While it is clear that neuroinflammation plays a key role in PND development, what factors underlie shorter self-resolving versus persistent PNDs remains unclear. We have previously shown that postoperative morphine treatment extends POCD from 4 d (without morphine) to at least 8 weeks (with morphine) in aged male rats, and that this effect is likely dependent on the proinflammatory capabilities of morphine via activation of toll-like receptor 4 (TLR4). Here, we extend these findings to show that TLR4 blockade, using the selective TLR4 antagonist lipopolysaccharide from the bacterium Rhodobacter sphaeroides (LPS-RS Ultrapure), ameliorates morphine-induced POCD in aged male rats. Using either a single central preoperative treatment or a 1 week postoperative central treatment regimen, we demonstrate that TLR4 antagonism (1) prevents and reverses the long-term memory impairment associated with surgery and morphine treatment, (2) ameliorates morphine-induced dysregulation of the postsynaptic proteins postsynaptic density 95 and synaptopodin, (3) mitigates reductions in mature BDNF, and (4) prevents decreased activation of the BDNF receptor TrkB (tropomyosin-related kinase B), all at 4 weeks postsurgery. We also reveal that LPS-RS Ultrapure likely exerts its beneficial effects by preventing endogenous danger signal HMGB1 (high-mobility group box 1) from activating TLR4, rather than by blocking continuous activation by morphine or its metabolites. These findings suggest TLR4 as a promising therapeutic target to prevent or treat PNDs.SIGNIFICANCE STATEMENT With humans living longer than ever, it is crucial that we identify mechanisms that contribute to aging-related vulnerability to cognitive impairment. Here, we show that the innate immune receptor toll-like receptor 4 (TLR4) is a key mediator of cognitive dysfunction in aged rodents following surgery and postoperative morphine treatment. Inhibition of TLR4 both prevented and reversed surgery plus morphine-associated memory impairment, dysregulation of synaptic elements, and reduced BDNF signaling. Together, these findings implicate TLR4 in the development of postoperative cognitive dysfunction, providing mechanistic insight and novel therapeutic targets for the treatment of cognitive impairments following immune challenges such as surgery in older individuals.

Outcomes of Neoadjuvant Chemotherapy for Invasive Intraductal Papillary Mucinous Neoplasm Compared with de Novo Pancreatic Adenocarcinoma.

BACKGROUND: The management of invasive intraductal papillary mucinous cystic neoplasm (I-IPMN) does not differ from de novo pancreatic ductal adenocarcinoma (PDAC); however, I-IPMNs are debated to have better prognosis. Despite being managed similarly to PDAC, no data are available on the response of I-IPMN to neoadjuvant chemotherapy. METHODS: All patients undergoing pancreatic resection for a pancreatic adenocarcinoma from 2011 to 2022 were included. The PDAC and I-IPMN cohorts were compared to evaluate response to neoadjuvant therapy (NAT) and overall survival (OS). RESULTS: This study included 1052 PDAC patients and 105 I-IPMN patients. NAT was performed in 25% of I-IPMN patients and 65% of PDAC patients. I-IPMN showed a similar pattern of pathological response to NAT compared with PDAC (p = 0.231). Furthermore, positron emission tomography (PET) response (71% vs. 61%; p = 0.447), CA19.9 normalization (85% vs. 76%, p = 0.290), and radiological response (32% vs. 37%, p = 0.628) were comparable between I-IPMN and PDAC. A significantly higher OS and disease-free survival (DFS) of I-IPMN was denoted by Kaplan-Meier analysis, with a p-value of < 0.001 in both plots. In a multivariate analysis, I-IPMN histology was independently associated with lower risk of recurrence and death. CONCLUSIONS: I-IPMN patients have a longer OS and DFS after surgical treatment when compared with PDAC patients. The more favorable oncologic outcome of I-IPMNs does not seem to be related to early detection, as I-IPMN histological subclass is independently associated with a lower risk of disease recurrence. Moreover, neoadjuvant effect on I-IPMN was non-inferior to PDAC in terms of pathological, CA19.9, PET, and radiological response and thus can be considered in selected patients.

Value of Surgical Cytoreduction in Patients with Small Intestinal Neuroendocrine Tumors Metastatic to the Liver and Peritoneum.

BACKGROUND: Cytoreductive hepatectomy can improve survival and symptoms of hormonal excess in patients with small intestinal neuroendocrine tumor (siNET) liver metastases, but whether to proceed when peritoneal metastases are encountered at the time of planned cytoreductive hepatectomy is controversial. METHODS: This was a retrospective review of patients who underwent surgical management of metastatic siNETs at Mayo Clinic between 2000 and 2020. Patients who underwent cytoreductive operation for isolated liver metastases or both liver and peritoneal metastases were compared. RESULTS: Of 261 patients who underwent cytoreductive operation for siNETs, 211 had isolated liver metastases and 50 had liver and peritoneal metastases. Complete cytoreduction was achieved in 78% of patients with isolated liver metastases and 56% of those with liver and peritoneal metastases (p = 0.002). After complete cytoreduction, median overall survival (OS) was 11.5 years for isolated liver metastases and 11.2 years for liver and peritoneal metastases (p = 0.10), and relief of carcinoid syndrome was ≥ 97% in both groups. After incomplete cytoreduction with debulking of > 90% of hepatic disease and/or closing Lyon score of 1-2, median OS was 6.4 years for isolated liver metastases and 7.1 years for liver and peritoneal metastases (p = 0.12). CONCLUSIONS: Patients with siNETs metastatic to both the liver and peritoneum have favorable outcomes after aggressive surgical cytoreduction, with the best outcomes observed after complete cytoreduction. Therefore, the presence of peritoneal metastases should not by itself preclude surgical cytoreduction in this population.

Neuroendocrine Tumors of Unknown Primary in the Setting of Cytoreductive Hepatectomy.

BACKGROUND: Surgical cytoreduction for neuroendocrine tumor liver metastasis (NETLM) consistently shows positive long-term outcomes. Despite reservations in guidelines for surgery when the primary tumor is unidentified (UP-NET), this study compared the surgical and oncologic long-term outcomes between patients with these rare cases undergoing cytoreductive surgery and patients who had liver resection for known primaries. METHODS: The study identified 32 unknown primary liver metastases (UP-NETLM) in 522 retrospectively evaluated patients who underwent resection of well-differentiated NETLM between January 2000 and December 2020. Tumor and patient characteristics were compared with those in 490 cases of liver metastasis from small intestinal (SI-NETLM) or pancreatic (pNETLM) primaries. Survival analysis was performed to highlight long-term outcome differences. Surgical outcomes were compared between liver resections alone and simultaneous primary resections to assess surgical risk distinctions. RESULTS: The UP-NET patients had fewer NETLMs (p = 0.004), which on the average were larger than SI-NETLMs or pNETLMs (p = 0.002). Expression of Ki-67 was balanced among the groups. Major hepatectomy was performed more often in the UP-NETLM group (p = 0.017). The 10-year survival rate of 53% for UP-NETLM was comparable with that for SI-NETML (58%; p = 0.463) and pNETLMs (47%; p = 0.497). The median hepatic progression-free survival was 26 months for the UP-NETLM patients and 25 months for the SI-NETLM patients compared to 12 months for the pNETLM patients (p < 0.001). Perioperative mortality was lower than 2%, and severe postoperative morbidity occurred in 21%, similarly distributed among all the groups. CONCLUSION: The surgical risk and long-term outcomes for the UP-NETLM patients were comparable with those for other NETLM cases, affirming the validity of equally aggressive surgical cytoreduction as a therapeutic option in carefully selected cases.

Supply and demand of hepatopancreatobiliary surgeons in the United States.

BACKGROUND: Hepatopancreatobiliary (HPB) surgery requires specialized training and adequate case volumes to maintain procedural proficiency and optimal outcomes. Studies of individual HPB surgeon supply related to annual HPB case demand are sparse. This study assesses the supply and demand of the HPB surgical workforce in the United States (US). METHODS: The National Inpatient Sample (NIS) was queried from 1998-2019 to estimate the number of HPB procedures performed. To approximate the number of HPB surgeons, models based on previous HPB workforce publications were employed. We then calculated the number of HPB surgeons needed to maintain volume-outcome thresholds at current reported levels of centralization. RESULTS: In 2019, approximately 37,335 patients underwent inpatient HPB procedures in the US, while an estimated 905-1191 HPB surgeons were practicing. Assuming 50% centralization and an optimal volume-outcome threshold of 24 HPB cases-per-year, only 778 HPB surgeons were needed. Without adjustment in centralization, by 2030 there will be a demand of fewer than 12 annual cases per HPB surgeon. CONCLUSION: The current supply of HPB surgeons may exceed demand in the United States. Without alteration in training pathways or improved care centralization, by 2030, there will be insufficient HPB case volume per surgeon to maintain published volume-outcome standards.

Early vs conventional onset pancreatic ductal adenocarcinoma: analysis of surgical and oncologic outcomes in patients undergoing curative intent resection.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) impacts patients in their 60s, but its incidence in younger patients is increasing. We hypothesize that younger patients may have worse oncologic outcomes. METHODS: Patients who underwent curative pancreatic resection for PDAC between January 2011 and December 2021 at a single institution were analyzed. Early-onset pancreatic cancer (EOPC) was defined as pancreatic cancer diagnosed in patients ≤50 years. Clinical and survival outcomes were compared between EOPC and Conventional Onset Pancreas Cancer (COPC). RESULTS: A total of 1133 patients were identified, 65 (5.7%) were EOPC. Preoperative patient characteristics including sex, smoking status, alcohol habitus, diabetes mellitus, CA 19-9, and neoadjuvant therapy were similar between EOPC and COPC (p > 0.05). EOPC patients were more likely non-white (p = 0.03), had lower ASA scores (p = 0.02) and larger median tumor size (33 vs 28 mm, p = 0.04), but had similar pathological stages and rate of R0 resections (p > 0.05). Postoperative outcomes were similar (p > 0.05). There was no statistically significant difference in overall (HR 0.93, CI 0.64, 1.33; p = 0.68) or recurrence free (HR 1.05, CI 0.75, 1.48; p = 0.77) survival between the EOPC and COPC after adjusting for significant factors. CONCLUSION: Patients with EOPC who underwent surgical resection had similar oncological outcomes compared to patients with COPC.

An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND: Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS: 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS: A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION: Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app.

Combining Surface-Induced Dissociation and Charge Detection Mass Spectrometry to Reveal the Native Topology of Heterogeneous Protein Complexes.

Charge detection mass spectrometry (CDMS) enables the direct mass measurement of heterogeneous samples on the megadalton scale, as the charge state for a single ion is determined simultaneously with the mass-to-charge ratio (m/z). Surface-induced dissociation (SID) is an effective activation method to dissociate non-intertwined, non-covalent protein complexes without extensive gas-phase restructuring, producing various subcomplexes reflective of the native protein topology. Here, we demonstrate that using CDMS after SID on an Orbitrap platform offers subunit connectivity, topology, proteoform information, and relative interfacial strengths of the intact macromolecular assemblies. SID dissects the capsids (∼3.7 MDa) of adeno-associated viruses (AAVs) into trimer-containing fragments (3mer, 6mer, 9mer, 15mer, etc.) that can be detected by the individual ion mass spectrometry (I2MS) approach on Orbitrap instruments. SID coupled to CDMS provides unique structural insights into heterogeneous assemblies that are not readily obtained by traditional MS measurements.

Dynamic risk profiling of HCC recurrence after curative intent liver resection.

BACKGROUND AND AIMS: Following liver resection (LR) for HCC, the likelihood of survival is dynamic, in that multiple recurrences and/or metastases are possible, each having variable impacts on outcomes. We sought to evaluate the natural progression, pattern, and timing of various disease states after LR for HCC using multistate modeling and to create a practical calculator to provide prognostic information for patients and clinicians. APPROACH AND RESULTS: Adult patients undergoing LR for HCC between January 2000 and December 2018 were retrospectively identified at a single center. Multistate analysis modeled post-LR tumor progression by describing transitions between distinct disease states. In this model, the states included surgery, intrahepatic recurrence (first, second, third, fourth, fifth), distant metastasis with or without intrahepatic recurrence, and death. Of the 486 patients included, 169 (34.8%) remained recurrence-free, 205 (42.2%) developed intrahepatic recurrence, 80 (16.5%) developed distant metastasis, and 32 (7%) died. For an average patient having undergone LR, there was a 33.1% chance of remaining disease-free, a 31.0% chance of at least one intrahepatic recurrence, a 16.3% chance of distant metastasis, and a 19.8% chance of death within the first 60 months post-LR. The transition probability from surgery to first intrahepatic recurrence, without a subsequent state transition, increased from 3% (3 months) to 17.4% (30 months) and 17.2% (60 months). Factors that could modify these probabilities included tumor size, satellite lesions, and microvascular invasion. The online multistate model calculator can be found on https://multistatehcc.shinyapps.io/home/. CONCLUSIONS: In contrast to standard single time-to-event estimates, multistate modeling provides more realistic prognostication of outcomes after LR for HCC by taking into account many postoperative disease states and transitions between them. Our multistate modeling calculator can provide meaningful data to guide the management of patients undergoing postoperative surveillance and therapy.

Oncologic Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Highly Selected Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Peritoneal metastases (PM) from pancreatic ductal adenocarcinoma (PDAC) are currently treated with palliative systemic chemotherapy alone, with unsatisfactory results. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may provide an oncologic benefit for highly selected patients. PATIENTS AND METHODS: Patients with PDAC and isolated PM who completed ≥ 6 months of systemic chemotherapy with objective response between 2017 and 2022 were retrospectively reviewed. All patients met the inclusion/exclusion criteria as per our previously published PDAC CRS/HIPEC protocol. Patients who underwent CRS/HIPEC were compared with matched patients who underwent systemic therapy alone. Overall survival (OS) from diagnosis of PM and progression-free survival (PFS) from CRS/HIPEC was evaluated. RESULTS: In total, 61 patients met the inclusion criteria: 38 underwent systemic therapy alone and 23 CRS/HIPEC. There were no differences in baseline prognostic factors, including age, sex, tumor size, tumor location, anatomic resectability, or serum cancer antigen (CA) 19-9 (p > 0.05). Median OS from PM diagnosis in patients who underwent systemic therapy alone was 19 months with 1, 2, and 3 year OS of 81%, 31%, and 8%, respectively. In contrast, median OS from PM diagnosis in patients who underwent CRS/HIPEC was 41 months with improved 1, 2, and 3 year OS of 91%, 66%, and 59%, respectively (p = 0.002). In the 21 patients who achieved complete cytoreduction (CC-0), no adjuvant therapy was administered and the median PFS was 17 months. CONCLUSIONS: CRS/HIPEC in highly selected patients with PDAC and PM results in promising oncologic outcomes that are unlikely to be achieved with systemic chemotherapy alone. Further investigation is warranted and ongoing (NCT04858009).

Cytoreduction with Hyperthermic Intraperitoneal Chemoperfusion for Pancreatic Cancer with Low-Volume Peritoneal Metastasis: Results from a Prospective Pilot Study.

INTRODUCTION: Resection of oligometastatic pancreatic ductal adenocarcinoma (PDAC) has historically been ineffective, however modern systemic chemotherapy has improved survival. Thus, re-evaluating safety and outcomes of surgical resection in selected patients with limited peritoneal metastasis (PM) warrants consideration. METHODS: From 2018 to 2021, patients with PDAC and positive cytology or limited PM without extraperitoneal metastasis and who had an objective response to ≥ 6 months of systemic chemotherapy were enrolled. Patients underwent laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin/mitomycin C. If amenable to a complete cytoreduction, patients went on to cytoreduction and HIPEC. RESULTS: Overall, 18 patients were enrolled and received a median of 14 (interquartile range [IQR] 12-17) cycles of chemotherapy; 16 (89%) patients received chemoradiation. Laparoscopic HIPEC was completed in 17 patients, with a median length of stay of 1 day, and no grade III complications or hematological toxicities were observed. All 18 patients subsequently underwent a complete cytoreduction (CC-0) along with definitive treatment of the primary tumor, with formal resection (7/18), irreversible electroporation (IRE; 10/18), or intraoperative radiation therapy (IORT; 1/18). Median PCI was 2 (IQR 0-4), median LOS was 7 days (IQR 6-8), and 7 (39%) patients were readmitted. Eight (44%) patients experienced grade 3 or higher complications, including one 30-day mortality. At a median follow-up of 16 months, the median progression-free survival was 20 months and the median overall survival was 26 months. CONCLUSION: Cytoreduction and HIPEC for selected patients with low-volume PM from PDAC is safe and feasible with favorable short-term outcomes. A phase II trial (NCT04858009) is now enrolling to further assess this multimodality approach in select patients.

Survival and Symptomatic Relief After Cytoreductive Hepatectomy for Neuroendocrine Tumor Liver Metastases: Long-Term Follow-up Evaluation of More Than 500 Patients.

BACKGROUND: Distant metastases are the strongest predictor of poor prognosis for patients with neuroendocrine tumors (NETs). Cytoreductive hepatectomy (CRH) can relieve symptoms of hormonal excess and prolong survival for patients with liver metastases (NETLMs), but long-term outcomes are poorly characterized. METHODS: This retrospective single-institution analysis analyzed patients who underwent CRH for well-differentiated NETLMs from 2000 to 2020. Kaplan-Meier analysis estimated symptom-free interval and overall and progression-free survival. Multivariable Cox regression analysis evaluated factors associated with survival. RESULTS: The inclusion criteria were met by 546 patients. The most common primary sites were the small intestine (n = 279) and the pancreas (n = 194). Simultaneous primary tumor resection was performed for 60 % of the cases. Major hepatectomy comprised 27% of the cases, but this rate decreased during the study period (p < 0.001). Major complications occurred in 20%, and the 90-day mortality rate was 1.6%. Functional disease was present in 37 %, and symptomatic relief was achieved in 96%. The median symptom-free interval was 41 months (62 months after complete cytoreduction and 21 months with gross residual disease) (p = 0.021). The median overall survival was 122 months, and progression-free survival was 17 months. In the multivariable analysis, worse overall survival was associated with age, pancreatic primary tumor, Ki-67, number and size of lesions, and extrahepatic metastases, with Ki-67 as the strongest predictor (odds ratio [OR], 1.90 for Ki-67 [3-20%; p = 0.018] and OR, 4.25 for Ki-67 [>20%; p < 0.001]). CONCLUSION: The study showed that CRH for NETLMs is associated with low perioperative morbidity and mortality and excellent overall survival, although the majority will experience recurrence/progression. For patients with functional tumors, CRH can provide durable symptomatic relief.

NEO-GAP: A Single-Arm, Phase II Feasibility Trial of Neoadjuvant Gemcitabine, Cisplatin, and Nab-Paclitaxel for Resectable, High-Risk Intrahepatic Cholangiocarcinoma.

PURPOSE: Most patients with intrahepatic cholangiocarcinoma (IHCC) develop recurrence after resection. Adjuvant capecitabine remains the standard of care for resected IHCC. A combination of gemcitabine, cisplatin, and nab-paclitaxel (GAP) was associated with a 45% response rate and 20% conversion rate among patients with unresectable biliary tract cancers. The aim of this study was to evaluate the feasibility of delivering GAP in the neoadjuvant setting for resectable, high-risk IHCC. METHODS: A multi-institutional, single-arm, phase II trial was conducted for patients with resectable, high-risk IHCC, defined as tumor size > 5 cm, multiple tumors, presence of radiographic major vascular invasion, or lymph node involvement. Patients received preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2, and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) for a total of 4 cycles prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of both preoperative chemotherapy and surgical resection. Secondary endpoints were adverse events, radiologic response, recurrence-free survival (RFS), and overall survival (OS). RESULTS: Thirty evaluable patients were enrolled. Median age was 60.5 years. Median follow-up for all patients was 17 months. Ten patients (33%) experienced grade ≥ 3 treatment-related adverse events, the most common being neutropenia and diarrhea; 50% required ≥ 1 dose reduction. The disease control rate was 90% (progressive disease: 10%, partial response: 23%, stable disease: 67%). There was zero treatment-related mortality. Twenty-two patients (73%, 90% CI 57-86; p = 0.008) completed all chemotherapy and surgery. Two patients (9%) who successfully underwent resection had minor postoperative complications. Median length of hospital stay was 4 days. Median RFS was 7.1 months. Median OS for the entire cohort was 24 months and was not reached in patients who underwent surgical resection. CONCLUSION: Neoadjuvant treatment with gemcitabine, cisplatin, and nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes.

Textbook outcomes and benchmarks of minimally invasive left lateral sectionectomy across North America.

BACKGROUND: Minimally invasive approach represents the gold standard for the resection of the left lateral section of the liver. Recently, the American Minimally Invasive Liver Resection (AMILES) registry has become available to track outcomes of laparoscopic and robotic liver resection in the Americas. The aim of the present study is to determine the benchmark performance of MILLS throughout the AMILES database. METHODS: The AMILES registry was interrogated for cases of minimally invasive left lateral sectionectomies (MILLS). Centers with best practices according to the achievement of textbook outcomes (TOs) were identified and were used to define benchmark performances. RESULTS: Seven institutions from US and Canada entered 1665 minimally invasive liver resections, encompassing 203 MILLS. Overall, 49% of cases of MILLS satisfied contemporarily all textbook outcomes. While all centers obtained TOs with different rates of success, the outcomes of the top-ranking centers were used for benchmarking. Benchmark performance metrics of MILLS across North America are: conversion rate ≤ 3.7%, blood loss ≤ 200 ml, OR time ≤ 199 min, transfusion rate ≤ 4.5%, complication rate ≤ 7.9%, LOS ≤ 4 days. CONCLUSION: Benchmark performances of MILLS have been defined on a large multi-institutional database in North America. As more institutions join the collaboration and more prospective cases accrue, benchmark for additional procedures and approaches will be defined.

Endoscopic ultrasound-guided versus percutaneous drainage for the management of post-operative fluid collections after distal pancreatectomy.

BACKGROUND: Post-operative pancreatic fluid collections (POPFCs) can be drained using percutaneous or endoscopic approaches. The primary aim of this study was to compare rates of clinical success between endoscopic ultrasound-guided drainage (EUSD) with percutaneous drainage (PTD) in the management of symptomatic POPFCs after distal pancreatectomy. Secondary outcomes included technical success, total number of interventions, time to resolution, rates of adverse events (AEs), and POPFC recurrence. METHODS: Adults who underwent distal pancreatectomy from January 2012 to August 2021 and developed symptomatic POPFC in the resection bed were retrospectively identified from a single academic center database. Demographic data, procedural data, and clinical outcomes were abstracted. Clinical success was defined as symptomatic improvement and radiographic resolution without requiring an alternate drainage modality. Quantitative variables were compared using a two-tailed t-test and categorical data were compared using Chi-squared or Fisher's exact tests. RESULTS: Of 1046 patients that underwent distal pancreatectomy, 217 met study inclusion criteria (median age 60 years, 51.2% female), of whom 106 underwent EUSD and 111 PTD. There were no significant differences in baseline pathology and POPFC size. PTD was generally performed earlier after surgery (10 vs. 27 days; p < 0.001) and more commonly in the inpatient setting (82.9% vs. 49.1%; p < 0.001). EUSD was associated with a significantly higher rate of clinical success (92.5% vs. 76.6%; p = 0.001), fewer median number of interventions (2 vs. 4; p < 0.001), and lower rate of POPFC recurrence (7.6% vs. 20.7%; p = 0.007). AEs were similar between EUSD (10.4%) and PTD (6.3%, p = 0.28), with approximately one-third of EUSD AEs due to stent migration. CONCLUSION: In patients with POPFCs after distal pancreatectomy, delayed drainage with EUSD was associated with higher rates of clinical success, fewer interventions, and lower rates of recurrence than earlier drainage with PTD.

Circumstances and implications of conversion from minimally invasive to open liver resection: a multi-center analysis from the AMILES registry.

BACKGROUND: Minimally invasive approaches to liver resection (MILR) are associated with favorable outcomes. The aim of this study was to determine the implications of conversion to an open procedure on perioperative outcomes. METHODS: Patients who underwent MILR at 10 North American institutions were identified from the Americas Minimally Invasive Liver Resection (AMILES) database. Outcomes of patients who required conversion were compared to those who did not. Additionally, outcomes after conversion due to unfavorable findings (poor visualization/access, lack of progress, disease extent) versus intraoperative events (bleeding, injury, cardiopulmonary instability) were compared. RESULTS: Of 1675 patients who underwent MILR, 102 (6.1%) required conversion. Conversion rate ranged from 4.4% for left lateral sectionectomy to 10% for right hepatectomy. The primary reason for conversion was unfavorable findings in 67 patients (66%) and intraoperative adverse events in 35 patients (34%). By multivariable analysis, major resection, cirrhosis, prior liver surgery, and tumor proximity to major vessels were identified as risk factors for conversion (p < 0.05). Patients who required conversion had higher blood loss, transfusion requirements, operative time, and length of stay, (p < 0.05). They also had higher major complication rates (23% vs. 5.2%, p < 0.001) and 30-day mortality (8.8% vs. 1.3%, p < 0.001). When compared to those who required conversion due to unfavorable findings, patients who required conversion due to intraoperative adverse events had significantly higher major complication rates (43% vs. 14%, p = 0.012) and 30-day mortality (20% vs. 3.0%, p = 0.007). CONCLUSIONS: Conversion from MILR to open surgery is associated with increased perioperative morbidity and mortality. Conversion due to intraoperative adverse events is rare but associated with significantly higher complication and mortality rates, while conversion due to unfavorable findings is associated with similar outcomes as planned open resection. High-risk patients may benefit from early conversion in a controlled fashion if difficulties are encountered or anticipated.

SAGES/AHPBA guidelines for the use of minimally invasive surgery for the surgical treatment of colorectal liver metastases (CRLM).

BACKGROUND: Colorectal liver metastases (CRLM) occur in roughly half of patients with colorectal cancer. Minimally invasive surgery (MIS) has become an increasingly acceptable and utilized technique for resection in these patients, but there is a lack of specific guidelines on the use of MIS hepatectomy in this setting. A multidisciplinary expert panel was convened to develop evidence-based recommendations regarding the decision between MIS and open techniques for the resection of CRLM. METHODS: Systematic review was conducted for two key questions (KQ) regarding the use of MIS versus open surgery for the resection of isolated liver metastases from colon and rectal cancer. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Additionally, the panel developed recommendations for future research. RESULTS: The panel addressed two KQs, which pertained to staged or simultaneous resection of resectable colon or rectal metastases. The panel made conditional recommendations for the use of MIS hepatectomy for both staged and simultaneous resection when deemed safe, feasible, and oncologically effective by the surgeon based on the individual patient characteristics. These recommendations were based on low and very low certainty of evidence. CONCLUSIONS: These evidence-based recommendations should provide guidance regarding surgical decision-making in the treatment of CRLM and highlight the importance of individual considerations of each case. Pursuing the identified research needs may help further refine the evidence and improve future versions of guidelines for the use of MIS techniques in the treatment of CRLM.

Laparoscopic versus open liver resections for intrahepatic cholangiocarcinoma and gallbladder cancer: the Mayo clinic experience.

BACKGROUND: Data regarding laparoscopic liver resections(LLRs) for Gallbladder cancer(GBC) and Intrahepatic Cholangiocarcinoma(iCCA) are sparse. This study compared LLRs with open liver resections(OLRs) in a high-volume center. METHODS: Data of patients who underwent LLR or OLR for GBC or iCCA at Mayo-Clinic between 01/2016 and 04/2021 were retrospectively compared. Proportional hazards models were used to compare the approach on survival. RESULTS: 32 and 52 patients underwent LLR and OLR during the study period, respectively. 64 and 20 patients had iCCA and GBC, respectively. LLR had lower median blood loss (250 mL vs. 475 mL, p = 0.001) and shorter median length of stay compared to OLR (3.0 days vs. 6.0 days, p = 0.001). LLR and OLR did not differ in post-operative major complication (25% vs. 32.7%, p = 0.62), negative margin (100% vs. 90.4%, p = 0.15) and completeness of lymphadenectomy rates (36.8% vs. 45.5%, p = 0.59). The median number of harvested lymph node was 4.0 and 5.0 for LLR and OLR, respectively (p = 0.347). There were no associations between approach and 3-year overall and disease-free survival between LLR and OLR (49.8% vs. 63.2% and 39.6% vs. 21.5%, p = 0.66 and p = 0.69). DISCUSSION: With appropriate patient selection and when compared to OLRs, LLRs for GBC and iCCA are feasible, safe and offer potential short-term benefits without compromising on oncological resection principals and long-term outcomes.

Segmental bile duct resection versus pancreatoduodenectomy for middle and distal third bile duct cancer. A systematic review and meta-analysis of comparative studies.

INTRODUCTION: Data regarding oncologic outcomes of segmental bile duct resection (SBDR) versus pancreatoduodenectomy (PD) for bile duct cancers (BDC) are conflicting. We compared SBDR and PD for BDC utilizing pooled data analysis. MATERIALS AND METHODS: A comprehensive PRISMA 2020 systematic review was performed. Studies comparing SBDR with PD for BDC were included. Pooled mean differences (MD), odds ratios (OR), and risk ratios (RR) with 95% confidence intervals (CI) were calculated. Subgroup analyses were performed. Study quality, bias, heterogeneity, and certainty were analyzed. RESULTS: Twelve studies from 2004 to 2021 were included, comprising 533 SBDR and 1,313 PD. SBDR was associated with positive proximal duct margins (OR 1.56; CI 1.11-2.18; P = .01), and distal duct margins (OR 43.25; CI 10.38-180.16; P < .01). SBDR yielded fewer lymph nodes (MD -6.93 nodes; CI -9.72-4.15; P < .01) and detected fewer nodal metastases (OR 0.72; CI 0.55-0.94; P = .01). SBDR portended less perioperative morbidity (OR 0.31; CI 0.21-0.46; P < .01), but not mortality (OR 0.52; CI 0.20-1.32; P = .17). SBDR was associated with locoregional recurrences (OR 1.88; CI 1.01-3.53; P = .02), and lymph node recurrences (OR 2.13; CI 1.42-3.2; P = .04). SBDR yielded decreased 5-year OS (OR 0.75; CI 0.65-0.85; P < .01). CONCLUSIONS: Despite decreased perioperative morbidity, SBDR appears to provide inferior oncologic control for BDC.