An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis.

Hepatocyte nuclear factor 4α (HNF4α) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4α initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that, once this circuit is activated, it maintains suppression of HNF4α and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4α circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.

A Prognostic Model To Predict Survival After Recurrence Among Patients With Recurrent Hepatocellular Carcinoma.

OBJECTIVE: We sought to develop and validate a preoperative model to predict survival after recurrence (SAR) in hepatocellular carcinoma (HCC). BACKGROUND: Although HCC is characterized by recurrence as high as 60%, models to predict outcomes after recurrence remain relatively unexplored. METHODS: Patients who developed recurrent HCC between 2000 and 2020 were identified from an international multi-institutional database. Clinicopathologic data on primary disease and laboratory and radiologic imaging data on recurrent disease were collected. Multivariable Cox regression analysis and internal bootstrap validation (5000 repetitions) were used to develop and validate the SARScore. Optimal Survival Tree analysis was used to characterize SAR among patients treated with various treatment modalities. RESULTS: Among 497 patients who developed recurrent HCC, median SAR was 41.2 months (95% CI 38.1-52.0). The presence of cirrhosis, number of primary tumors, primary macrovascular invasion, primary R1 resection margin, AFP>400 ng/mL on the diagnosis of recurrent disease, radiologic extrahepatic recurrence, radiologic size and number of recurrent lesions, radiologic recurrent bilobar disease, and early recurrence (≤24 months) were included in the model. The SARScore successfully stratified 1-, 3- and 5-year SAR and demonstrated strong discriminatory ability (3-year AUC: 0.75, 95% CI 0.70-0.79). While a subset of patients benefitted from resection/ablation, Optimal Survival Tree analysis revealed that patients with high SARScore disease had the worst outcomes (5-year AUC; training: 0.79 vs. testing: 0.71). The SARScore model was made available online for ease of use and clinical applicability ( https://yutaka-endo.shinyapps.io/SARScore/ ). CONCLUSION: The SARScore demonstrated strong discriminatory ability and may be a clinically useful tool to help stratify risk and guide treatment for patients with recurrent HCC.

Perioperative Changes in Serum Transaminase Levels: Impact on Postoperative Morbidity Following Liver Resection of Hepatocellular Carcinoma.

OBJECTIVES: To define how dynamic changes in pre- versus post-operative serum aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) levels may impact postoperative morbidity after curative-intent resection of hepatocellular carcinoma (HCC). BACKGROUND: Hepatic ischemia/reperfusion can occur at the time of liver resection and may be associated with adverse outcomes following liver resection. METHODS: Patients who underwent curative resection for HCC between 2010-2020 were identified from an international multi-institutional database. Changes in AST and ALT (CAA) on postoperative day (POD) 3 versus preoperative values () were calculated using the formula: based on a fusion index via Euclidean norm, which was examined relative to the comprehensive complication index (CCI). The impact of CAA on CCI was assessed by the restricted cubic spline regression and Random Forest analyses. RESULTS: A total of 759 patients were included in the analytic cohort. Median CAA was 1.7 (range, 0.9 to 3.25); 431 (56.8%) patients had a CAA<2, 215 (28.3%) patients with CAA 2-5, and 113 (14.9%) patients had CAA ≥5. The incidence of post-operative complications was 65.0% (n=493) with a median CCI of 20.9 (IQR, 20.9-33.5). Spline regression analysis demonstrated a non-linear incremental association between CAA and CCI. The optimal cutoff value of CAA=5 was identified by the recursive partitioning technique. After adjusting for other competing risk factors, CAA≥5 remained strongly associated with risk of post-operative complications (Ref. CAA<5, OR 1.63, 95%CI 1.05-2.55, P=0.03). In fact, the use of CAA to predict post-operative complications was very good in both the derivative (AUC 0.88) and external (ACU 0.86) cohorts (n=1137). CONCLUSIONS: CAA was an independent predictor of CCI after liver resection for HCC. Use of routine labs such as AST and ALT can help identify patients at highest risk of post-operative complications following HCC resection.

Great Debate: Chemoradiation Should be Added to Chemotherapy as a Neoadjuvant Treatment Strategy for Resectable Gastric Adenocarcinoma.

BACKGROUND: Most patients with resectable gastric cancer present with locally advanced disease and warrant neoadjuvant chemotherapy based on level 1 evidence. However, the incremental benefit of adding radiation to chemotherapy as a neoadjuvant treatment strategy for these patients is less clear. METHODS: While awaiting the results of two ongoing randomized clinical trials attempting to specifically address this question (TOPGEAR and CRITICS-II), this article presents the debate between two gastric cancer surgery experts supporting each side of the argument on the use or omission of neoadjuvant radiation in this setting. RESULTS: On the one hand, neoadjuvant radiation may be better tolerated compared with modern triplet chemotherapy and may be associated with higher rates of major pathologic response. Additionally, there is evidence to suggest that radiation may offer a survival benefit when the tumor is located at the gastroesophageal junction or there is concern for a margin-positive resection. However, in the setting of adequate surgery, no survival benefit has been demonstrated by adding radiation to modern chemotherapy, likely reflecting the fact that death from gastric cancer is a result of distant recurrence, which is not addressed by local treatment such as radiotherapy. CONCLUSION: While awaiting the results of the TOPGEAR and CRITICS-II trials, this discussion of current evidence can facilitate the refinement of an optimal neoadjuvant therapy strategy in patients with resectable gastric cancer.

Patterns of Recurrence After Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation.

BACKGROUND: Improved treatment strategies are needed for patients with locally advanced gastric cancer with poor response to neoadjuvant chemotherapy. We aimed to describe patterns of failure for patients with no or partial response (NR, PR) to preoperative chemotherapy. PATIENTS AND METHODS: We analyzed patients with locally advanced gastric cancer treated from 2008 to 2022 with preoperative chemotherapy followed by surgery with D2 resection. We excluded patients who received radiation. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated. For patients with recurrent abdominal disease, hypothetical radiation clinical treatment volumes (CTV) were contoured on postoperative scans and compared with patterns of recurrence. RESULTS: A total of 60 patients were identified. The most used preoperative chemotherapy was FLOT (38.6%), followed by FOLFOX (30%) and ECF/ECX/EOX (23.3%). Four (6.7%), 40 (66.7%), and 9 patients (15%) had a complete pathologic response (CR), PR, and NR to neoadjuvant therapy, respectively. Among patients without a CR, 3-year overall and progression-free survival rates were 62.3% (95% CI 48-76.6%) and 51.3% (95% CI 36.9-65.7%), respectively. Three-year cumulative incidence of LRF and DM were 8.4% (95% CI 0.4-16.4%) and 41.0% (95% CI 26.3-55.4%), respectively. Absolute rates of patients having the first site of recurrence encompassed by a postoperative radiation CTV was 2.0% for patients without a CR and 0% for patients with NR. CONCLUSIONS: Patients with locally advanced gastric cancer with less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival.

Accuracy and Prognostic Impact of Nodal Status on Preoperative Imaging for Management of Pancreatic Neuroendocrine Tumors: A Multi-Institutional Study.

BACKGROUND: We sought to define the accuracy of preoperative imaging to detect lymph node metastasis (LNM) among patients with pancreatic neuroendocrine tumors (pNETs), as well as characterize the impact of preoperative imaging nodal status on survival. METHODS: Patients who underwent curative-intent resection for pNETs between 2000 and 2020 were identified from eight centers. Sensitivity and specificity of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and OctreoScan for LNM were evaluated. The impact of preoperative lymph node status on lymphadenectomy (LND), as well as overall and recurrence-free survival was defined. RESULTS: Among 852 patients, 235 (27.6%) individuals had LNM on final histologic examination (hN1). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 12.4%, 98.1%, 71.8%, and 74.4% for CT, 6.3%, 100%, 100%, and 80.1% for MRI, 9.5%, 100%, 100%, and 58.7% for PET, 11.3%, 97.5%, 66.7%, and 70.8% for OctreoScan, respectively. Among patients with any combination of these imaging modalities, overall sensitivity, specificity, PPV, and NPV was 14.9%, 97.9%, 72.9%, and 75.1%, respectively. Preoperative N1 on imaging (iN1) was associated with a higher number of LND (iN1 13 vs. iN0 9, p = 0.003) and a higher frequency of final hN1 versus preoperative iN0 (iN1 72.9% vs. iN0 24.9%, p < 0.001). Preoperative iN1 was associated with a higher risk of recurrence versus preoperative iN0 (median recurrence-free survival, iN1→hN1 47.5 vs. iN0→hN1 92.7 months, p = 0.05). CONCLUSIONS: Only 4% of patients with LNM on final pathologic examine had preoperative imaging that was suspicious for LNM. Traditional imaging modalities had low sensitivity to determine nodal status among patients with pNETs.

Classification of Intrahepatic Cholangiocarcinoma into Perihilar Versus Peripheral Subtype.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) constitutes a group of heterogeneous malignancies within the liver. We sought to subtype ICC based on anatomical origin of tumors, as well as propose modifications of the current classification system. METHODS: Patients undergoing curative-intent resection for ICC, hilar cholangiocarcinoma (CCA), or hepatocellular carcinoma (HCC) were identified from three international multi-institutional consortia of databases. Clinicopathological characteristics and survival outcomes were assessed. RESULTS: Among 1264 patients with ICC, 1066 (84.3%) were classified as ICC-peripheral subtype, whereas 198 (15.7%) were categorized as ICC-perihilar subtype. Compared with ICC-peripheral subtype, ICC-perihilar subtype was more often associated with aggressive tumor characteristics, including a higher incidence of nodal metastasis, macro- and microvascular invasion, perineural invasion, as well as worse overall survival (OS) (median: ICC-perihilar 19.8 vs. ICC-peripheral 37.1 months; p < 0.001) and disease-free survival (DFS) (median: ICC-perihilar 12.8 vs. ICC-peripheral 15.2 months; p = 0.019). ICC-perihilar subtype and hilar CCA had comparable OS (19.8 vs. 21.4 months; p = 0.581) and DFS (12.8 vs. 16.8 months; p = 0.140). ICC-peripheral subtype tumors were associated with more advanced tumor features, as well as worse survival outcomes versus HCC (OS, median: ICC-peripheral 37.1 vs. HCC 74.3 months; p < 0.001; DFS, median: ICC-peripheral 15.2 vs. HCC 45.5 months; p < 0.001). CONCLUSIONS: ICC should be classified as ICC-perihilar and ICC-peripheral subtype based on distinct clinicopathological features and survival outcomes. ICC-perihilar subtype behaved more like carcinoma of the bile duct (i.e., hilar CCA), whereas ICC-peripheral subtype had features and a prognosis more akin to a primary liver malignancy.

Recurrent Intrahepatic Cholangiocarcinoma: A 10-Point Score to Predict Post-Recurrence Survival and Guide Treatment of Recurrence.

INTRODUCTION: Although up to 50-70% of patients with intrahepatic cholangiocarcinoma (ICC) recur following resection, data to predict post-recurrence survival (PRS) and guide treatment of recurrence are limited. METHODS: Patients who underwent resection of ICC between 2000 and 2020 were identified from an international, multi-institutional database. Data on primary disease as well as laboratory and radiologic data on recurrent disease were collected. Factors associated with PRS were examined and a novel scoring system to predict PRS (PRS score) was developed and internally validated. RESULTS: Among 986 individuals who underwent resection for ICC, 588 (59.6%) patients developed recurrence at a median follow up of 20.3 months. Among patients who experienced a recurrence, 97 (16.5%) underwent re-resection/ablation for recurrent ICC; 88 (15.0%) and 403 (68.5%) patients received intra-arterial treatment or systemic chemotherapy/supportive therapy, respectively. Patient American Society of Anesthesiologists (ASA) class > 2 (1 point), primary tumor N1/Nx status (1 point), primary R1 resection margin (1 point), primary tumor G3/G4 grade (1 point), carbohydrate antigen (CA) 19-9 > 37 UI/mL (2 points) at recurrence and carcinoembryonic antigen (CEA) > 5 ng/mL (2 points) at recurrence, as well as recurrent bilateral disease (1 point) and early recurrence (1 point) were included in the PRS score. The PRS score successfully stratified patients relative to PRS and demonstrated strong discriminatory ability (C-index 0.70, 95% confidence interval 0.68-0.72). While a PRS score of 0-3 was associated with a 3-year PRS of 62.5% following resection/ablation for recurrent ICC, a PRS score > 3 was associated with a low 3-year PRS of 35.5% (p = 0.03). CONCLUSIONS: The PRS score demonstrated strong discriminatory ability to predict PRS among patients who had developed recurrence following initial resection of ICC. The PRS score may be a useful tool to guide treatment among patients with recurrent ICC.

Perioperative Lymphopenia is Associated with Increased Risk of Recurrence and Worse Survival Following Hepatectomy for Hepatocellular Carcinoma.

INTRODUCTION: Immune dysregulation may be associated with cancer progression. We sought to investigate the prognostic value of perioperative lymphopenia on short- and long-term outcomes among patients undergoing resection of hepatocellular carcinoma (HCC). METHODS: Patients undergoing resection of HCC between 2000 and 2020 were identified using an international database. The incidence and impact of perioperative lymphopenia [preoperative, postoperative day (POD) 1/3/5], defined as absolute lymphocyte count (ALC) <1000/µL, on short- and long-term outcomes was assessed. RESULTS: Among 1448 patients, median preoperative ALC was 1593/µL [interquartile range (IQR) 1208-2006]. The incidence of preoperative lymphopenia was 14.0%, and 50.2%, 45.1% and 35.6% on POD1, POD3 and POD5, respectively. Preoperative lymphopenia predicted 5-year overall survival (OS) [lymphopenia vs. no lymphopenia: 49.1% vs. 66.1%] and 5-year disease-free survival (DFS) [25.0% vs. 41.5%] (both p < 0.05). Lymphopenia on POD1 (5-year OS: 57.1% vs. 71.2%; 5-year DFS: 30.0% vs. 41.1%), POD3 (5-year OS: 57.3% vs. 68.9%; 5-year DFS: 35.4% vs. 42.7%), and POD5 (5-year OS: 53.1% vs. 66.1%; 5-year DFS: 32.8% vs. 42.3%) was associated with worse long-term outcomes (all p < 0.05). Patients with severe lymphopenia (ALC <500/µL) on POD5 had worse 5-year OS and DFS (5-year OS: 44.7% vs. 54.3% vs. 66.1%; 5-year DFS: 27.8% vs. 33.3% vs. 42.3%) [both p < 0.05], as well as higher incidence of overall (45.5% vs. 25.3% vs. 30.9%; p = 0.013) and major complications (18.2% vs. 3.4% vs. 4.5%; p < 0.001) versus individuals with moderate (ALC 500-1000/µL) or no lymphopenia following hepatectomy for HCC. After adjusting for competing risk factors, prolonged lymphopenia was independently associated with higher hazards of death [hazard ratio (HR) 1.38, 95% CI 1.11-1.72] and recurrence (HR 1.22, 95% CI 1.02-1.45). CONCLUSION: Perioperative lymphopenia had short- and long-term prognostic implications among individuals undergoing hepatectomy for HCC.

Benchmarks in Liver Resection for Intrahepatic Cholangiocarcinoma.

INTRODUCTION: Benchmarking in surgery has been proposed as a means to compare results across institutions to establish best practices. We sought to define benchmark values for hepatectomy for intrahepatic cholangiocarcinoma (ICC) across an international population. METHODS: Patients who underwent liver resection for ICC between 1990 and 2020 were identified from an international database, including 14 Eastern and Western institutions. Patients operated on at high-volume centers who had no preoperative jaundice, ASA class <3, body mass index <35 km/m2, without need for bile duct or vascular resection were chosen as the benchmark group. RESULTS: Among 1193 patients who underwent curative-intent hepatectomy for ICC, 600 (50.3%) were included in the benchmark group. Among benchmark patients, median age was 58.0 years (interquartile range [IQR] 49.0-67.0), only 28 (4.7%) patients received neoadjuvant therapy, and most patients had a minor resection (n = 499, 83.2%). Benchmark values included ≥3 lymph nodes retrieved when lymphadenectomy was performed, blood loss ≤600 mL, perioperative blood transfusion rate ≤42.9%, and operative time ≤339 min. The postoperative benchmark values included TOO achievement ≥59.3%, positive resection margin ≤27.5%, 30-day readmission ≤3.6%, Clavien-Dindo III or more complications ≤14.3%, and 90-day mortality ≤4.8%, as well as hospital stay ≤14 days. CONCLUSIONS: Benchmark cutoffs targeting short-term perioperative outcomes can help to facilitate comparisons across hospitals performing liver resection for ICC, assess inter-institutional variation, and identify the highest-performing centers to improve surgical and oncologic outcomes.

Early Onset Intrahepatic Cholangiocarcinoma: Clinical Characteristics, Oncological Outcomes, and Genomic/Transcriptomic Features.

INTRODUCTION: Data on clinical characteristics and disease-specific prognosis among patients with early onset intrahepatic cholangiocarcinoma (ICC) are currently limited. METHODS: Patients undergoing hepatectomy for ICC between 2000 and 2020 were identified by using a multi-institutional database. The association of early (≤50 years) versus typical onset (>50 years) ICC with recurrence-free (RFS) and disease-specific survival (DSS) was assessed in the multi-institutional database and validated in an external cohort. The genomic and transcriptomic profiles of early versus late onset ICC were analyzed by using the Total Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center databases. RESULTS: Among 971 patients undergoing resection for ICC, 22.7% (n = 220) had early-onset ICC. Patients with early-onset ICC had worse 5-year RFS (24.1% vs. 29.7%, p < 0.05) and DSS (36.5% vs. 48.9%, p = 0.03) compared with patients with typical onset ICC despite having earlier T-stage tumors and lower rates of microvascular invasion. In the validation cohort, patients with early-onset ICC had worse 5-year RFS (7.4% vs. 20.5%, p = 0.002) compared with individuals with typical onset ICC. Using the TCGA cohort, 652 and 266 genes were found to be upregulated (including ATP8A2) and downregulated (including UTY and KDM5D) in early versus typical onset ICC, respectively. Genes frequently implicated as oncogenic drivers, including CDKN2A, IDH1, BRAF, and FGFR2 were infrequently mutated in the early-onset ICC patients. CONCLUSIONS: Early-onset ICC has distinct clinical and genomic/transcriptomic features. Morphologic and clinicopathologic characteristics were unable to fully explain differences in outcomes among early versus typical onset ICC patients. The current study offers a preliminary landscape of the molecular features of early-onset ICC.

Low Prognostic Nutritional Index Is Common and Associated with Poor Outcomes following Curative-Intent Resection for Gastro-Entero-Pancreatic Neuroendocrine Tumors.

INTRODUCTION: To investigate the impact of prognostic nutritional index (PNI) on short- and long-term outcomes of patients who underwent curative-intent resection for gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). METHODS: Patients with GET-NETs who underwent curative-intent resection were identified from a multi-center database. The prognostic impact of clinicopathological factors including PNI on post-operative outcomes were evaluated. A novel nomogram was developed and externally validated. RESULTS: A total of 2,099 patients with GEP-NETs were included in the training cohort; 255 patients were in the external validation cohort. Median PNI (n = 973) was 47.4 (IQR 43.1-52.4). At the time of presentation, 1,299 (61.9%) patients presented with some type of clinical symptom. Low-PNI (≤42.2) was associated with gastrointestinal symptoms, as well as nodal metastasis and distant metastasis (all p < 0.05). Patients with a low PNI had a higher incidence of severe (≥Clavien-Dindo grade IIIa: low PNI 24.9% vs. high PNI 15.4%, p = 0.001) and multiple (≥3 types of complications: low PNI 14.5% vs. high PNI 9.2%, p = 0.024) complications, as well as a worse overall survival (OS)(5-year OS, low PNI 73.7% vs. high PNI 88.5%, p < 0.001), and RFS (5-year RFS, low PNI 68.5% vs. high PNI 79.8%, p = 0.008) versus patients with high PNI (>42.2). A nomogram based on PNI, tumor grade and metastatic disease demonstrated excellent discrimination and calibration to predict OS in both the training (C-index 0.748) and two external validation (C-index 0.827, 0.745) cohorts. CONCLUSIONS: Low PNI was common and associated with worse short- and long-term outcomes among patients with GEP-NETs.

Long-term survivors after curative-intent resection for intrahepatic cholangiocarcinoma.

OBJECTIVES: The objective of the current study was to characterize prognostic factors related to long-term recurrence-free survival after curative-intent resection of intrahepatic cholangiocarcinoma (ICC). METHODS: Data on patients who underwent curative-intent resection for ICC between 2000 and 2020 were collected from an international multi-institutional database. Prognostic factors were investigated among patients who recurred within 5 years versus long-term survivors who survived more than 5 years with no recurrence. RESULTS: Among 635 patients who underwent curative-intent resection for ICC, 104 (16.4%) patients were long-term survivors with no recurrence beyond 5 years after surgery. Patients who survived for more than 5 years with no recurrence were more likely to have less aggressive tumor features, as well as have undergone an R0 resection versus patients who recurred within 5 years after resection. On multivariable analysis, tumor size (>5 cm) (HR: 1.535, 95% CI: 1.254-1.879), satellite lesions (HR: 1.253, 95% CI: 1.003-1.564), and lymph node metastasis (HR: 1.733, 95% CI: 1.349-2.227) were independently associated with recurrence within 5 years. Patients who recurred beyond 5 years (n = 23), 2-5 years (n = 60), and within 2 years (n = 471) had an incrementally worse post-recurrence survival (PRS, 28.0 vs. 20.0 vs. 12.0 months, p = 0.032). Among patients with N0 status, tumor size (>5 cm) (HR: 1.612, 95% CI: 1.087-2.390) and perineural invasion (PNI) (HR: 1.562,95% CI: 1.081-2.255) were risk factors associated with recurrence. Among patients with N1 disease, only a minority (5/128, 3.9%) of patients survived with no recurrence to 5 years. CONCLUSION: Roughly 1 in 6 patients survived for more than 5 years with no recurrence following curative-intent resection of ICC. Among N0 patients, tumor recurrence was associated with tumor size and PNI. Only a small subset of N1 patients experienced long-term survival.

Natural history of undifferentiated pleomorphic sarcoma: Experience from the US Sarcoma Collaborative.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS. METHODS: From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at seven academic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR), time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed. RESULTS: Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLR recurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation. CONCLUSION: For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.

Postoperative outcomes and costs of laparoscopic versus robotic distal pancreatectomy: a propensity-matched analysis.

BACKGROUND: Minimally invasive distal pancreatectomy (MIDP) has established advantages over the open approach. The costs associated with robotic DP (RDP) versus laparoscopic DP (LDP) make the robotic approach controversial. We sought to compare outcomes and cost of LDP and RDP using propensity matching analysis at our institution. METHODS: Patients undergoing LDP or RDP between 2000 and 2021 were retrospectively identified. Patients were optimally matched using age, gender, American Society of Anesthesiologists status, body mass index, and tumor size. Between-group differences were analyzed using the Wilcoxon signed-rank test for continuous data, and the McNemar's test for categorical data. Outcomes included operative duration, conversion to open surgery, postoperative length of stay, pancreatic fistula rate, pseudocyst requiring intervention, and costs. RESULTS: 298 patients underwent MIDP, 180 (60%) were laparoscopic and 118 (40%) were robotic. All RDPs were matched 1:1 to a laparoscopic case with absolute standardized mean differences for all matching covariates below 0.10, except for tumor type (0.16). RDP had longer operative times (268 vs 178 min, p < 0.01), shorter length of stay (2 vs 4 days, p < 0.01), fewer biochemical pancreatic leaks (11.9% vs 34.7%, p < 0.01), and fewer interventional radiological drainage (0% vs 5.9%, p = 0.01). The number of pancreatic fistulas (11.9% vs 5.1%, p = 0.12), collections requiring antibiotics or intervention (11.9% vs 5.1%, p = 0.12), and conversion rates (3.4% vs 5.1%, p = 0.72) were comparable between the two groups. The total direct index admission costs for RDP were 1.01 times higher than for LDP for FY16-19 (p = 0.372), and 1.33 times higher for FY20-22 (p = 0.031). CONCLUSIONS: Although RDP required longer operative times than LDP, postoperative stays were shorter. The procedure cost of RDP was modestly more expensive than LDP, though this was partially offset by reduced hospital stay and reintervention rate.

Prognostic significance of postoperative complications for patients with hepatocellular carcinoma relative to alpha-feto protein and tumor burden score.

BACKGROUND: We sought to elucidate the impact of postoperative complications on patient outcomes relative to differences in alpha-fetoprotein-tumor burden score (ATS) among patients with hepatocellular carcinoma (HCC). METHODS: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. Moderate/severe complications were defined using the optimal cut-off value of the comprehensive complication index (CCI) based on the log-rank test. RESULTS: A total of 1124 patients was included. CCI cut-off value of 16.6 was identified as the optimal prognostic threshold. Patients who experienced moderate/severe complications were more likely to have worse recurrence free survival [RFS] versus individuals who had no/mild complications (2-year RFS; no/mild complication: 55.9% vs. moderate/severe complication: 38.1% p < 0.001). Of note, low and medium ATS patients who experienced moderate/severe complications had a higher risk of recurrence (2-year RFS; no/mild complication: postoperative complications 70.0% vs. moderate/severe complication: 51.1%, p = 0.006; medium: no/mild complication: 50.8% vs moderate/severe complication: 56.7%, p = 0.01); however, postoperative complications were not associated with worse outcomes among patients with high ATS (no/mild complication: 39.1% vs. moderate/severe complication: 29.2%, p = 0.20). CONCLUSION: These data serve to emphasize how reduction in postoperative complications may be crucial to improve prognosis, particularly among patients with favorable HCC characteristics.

The aMAP score predicts long-term outcomes after resection of hepatocellular carcinoma: a multi-institutional analysis.

BACKGROUND: The aMAP score is a proposed model to predict the development of hepatocellular carcinoma (HCC) among high-risk patients with chronic hepatitis. The role of the aMAP score to predict long-term survival among patients following resection of HCC has not been determined. METHODS: Patients undergoing resection for HCC between 2000 and 2020 were identified using a multi-institutional database. The impact of the aMAP score on long-term outcomes following HCC resection was assessed. RESULTS: Among 1377 patients undergoing resection for HCC, a total of 972 (70.6 %) patients had a low aMAP score (≤63), whereas 405 (29.4 %) individuals had a high aMAP score (≥64). aMAP score was associated with 5-year OS in the entire cohort (low vs high aMAP score:66.5 % vs. 54.3 %, p < 0.001). aMAP score predicted 5-year OS following resection among patients with HBV-HCC (low vs. high aMAP:68.8 % vs. 55.6 %, p = 0.01) and NASH/other-HCC (64.7 % vs. 53.7, p = 0.04). aMAP score could sub-stratify 5-year OS among patients undergoing HCC resection within (low vs. high aMAP:81.5 % vs. 67.4 %, p < 0.001) and beyond (55.9 % vs. 38.8 %, p < 0.001) Milan criteria. DISCUSSION: The aMAP score predicted postoperative outcomes following resection of HCC within and beyond Milan criteria. Apart from a surveillance tool, the aMAP score can also be used as a prognostic tool among patients undergoing resection of HCC.

Impact of an artificial intelligence based model to predict non-transplantable recurrence among patients with hepatocellular carcinoma.

OBJECTIVE: We sought to develop Artificial Intelligence (AI) based models to predict non-transplantable recurrence (NTR) of hepatocellular carcinoma (HCC) following hepatic resection (HR). METHODS: HCC patients who underwent HR between 2000-2020 were identified from a multi-institutional database. NTR was defined as recurrence beyond Milan Criteria. Different machine learning (ML) and deep learning (DL) techniques were used to develop and validate two prediction models for NTR, one using only preoperative factors and a second using both preoperative and postoperative factors. RESULTS: Overall, 1763 HCC patients were included. Among 877 patients with recurrence, 364 (41.5%) patients developed NTR. An ensemble AI model demonstrated the highest area under ROC curves (AUC) of 0.751 (95% CI: 0.719-0.782) and 0.717 (95% CI:0.653-0.782) in the training and testing cohorts, respectively which improved to 0.858 (95% CI: 0.835-0.884) and 0.764 (95% CI: 0.704-0.826), respectively after incorporation of postoperative pathologic factors. Radiologic tumor burden score and pathological microvascular invasion were the most important preoperative and postoperative factors, respectively to predict NTR. Patients predicted to develop NTR had overall 1- and 5-year survival of 75.6% and 28.2%, versus 93.4% and 55.9%, respectively, among patients predicted to not develop NTR (p < 0.0001). CONCLUSION: The AI preoperative model may help inform decision of HR versus LT for HCC, while the combined AI model can frame individualized postoperative care (https://altaf-pawlik-hcc-ntr-calculator.streamlit.app/).

Demystifying BRAF Mutation Status in Colorectal Liver Metastases : A Multi-institutional, Collaborative Approach to 6 Open Clinical Questions.

OBJECTIVE: To investigate the clinical implications of BRAF -mutated (mut BRAF ) colorectal liver metastases (CRLMs). BACKGROUND: The clinical implications of mut BRAF status in CRLMs are largely unknown. METHODS: Patients undergoing resection for mut BRAF CRLM were identified from prospectively maintained registries of the collaborating institutions. Overall survival (OS) and recurrence-free survival (RFS) were compared among patients with V600E versus non-V600E mutations, KRAS/BRAF comutation versus mut BRAF alone, microsatellite stability status (Microsatellite Stable (MSS) vs instable (MSI-high)), upfront resectable versus converted tumors, extrahepatic versus liver-limited disease, and intrahepatic recurrence treated with repeat hepatectomy versus nonoperative management. RESULTS: A total of 240 patients harboring BRAF -mutated tumors were included. BRAF V600E mutation was associated with shorter OS (30.6 vs 144 mo, P =0.004), but not RFS compared with non-V600E mutations. KRAS/BRAF comutation did not affect outcomes. MSS tumors were associated with shorter RFS (9.1 vs 26 mo, P <0.001) but not OS (33.5 vs 41 mo, P =0.3) compared with MSI-high tumors, whereas patients with resected converted disease had slightly worse RFS (8 vs 11 mo, P =0.01) and similar OS (30 vs 40 mo, P =0.4) compared with those with upfront resectable disease. Patients with extrahepatic disease had worse OS compared with those with liver-limited disease (8.8 vs 40 mo, P <0.001). Repeat hepatectomy after intrahepatic recurrence was associated with improved OS compared with nonoperative management (41 vs 18.7 mo, P =0.004). All results continued to hold true in the multivariable OS analysis. CONCLUSIONS: Although surgery may be futile in patients with BRAF -mutated CRLM and concurrent extrahepatic disease, resection of converted disease resulted in encouraging survival in the absence of extrahepatic spread. Importantly, second hepatectomy in select patients with recurrence was associated with improved outcomes. Finally, MSI-high status identifies a better prognostic group, with regard to RFS while patients with non-V600E mutations have excellent prognosis.

Higher Tumor Burden Status Dictates the Impact of Surgical Margin Status on Overall Survival in Patients Undergoing Resection of Intrahepatic Cholangiocarcinoma.

BACKGROUND: The present study aimed to examine the prognostic significance of margin status following hepatectomy of intrahepatic cholangiocarcinoma (ICC) relative to overall tumor burden and nodal status. METHOD: Patients who underwent curative-intent surgery for ICC between 1990 and 2017 were included from a multi-institutional database. The impact of margin status and width on overall survival (OS) was examined relative to TBS and preoperative nodal status. RESULTS: Among 1105 patients with ICC who underwent resection, median tumor burden score (TBS) was 6.1 (IQR 4.2-8.8) and 218 (19.7%) patients had N1 disease. More than one in eight patients had an R1 surgical margin (n = 154, 13.9%). Among patients with low or medium TBS, an increasing margin width was associated with an incrementally improved 5-year OS (R1 31.9% vs. 1-3 mm 38.5% vs. 3-10 mm 48.0% vs. ≥ 10 mm 52.3%). In contrast, among patients with a high TBS, margin width was not associated with better survival (R1 28.9% vs. 1-3 mm 22.8% vs. 3-10 mm 29.6% vs. ≥ 10 mm 13.7%). In addition, surgical margin status did not impact survival with cutoffs of TBS 7 or greater. Furthermore, patients with low or medium TBS and preoperative negative lymph nodes derived a survival benefit from an R0 resection (R1 resection, HR 2.15, 95% CI 1.35-3.44, p = 0.001). In contrast, margin status was not associated with prognosis among patients with a high TBS and preoperative positive/suspicious lymph nodes (R1 resection, HR 1.34, 95% CI 0.58-3.11, p = 0.50). CONCLUSION: R0 resection and wider margin resection resulted in improved outcomes in patients with low tumor burden; however, the survival benefit of negative margin status disappeared in patients with underlying poor tumor biology.