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BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is associated with poor long-term outcomes, and limited evidence exists on optimal resection margin width. This study used artificial intelligence to investigate long-term outcomes and optimal margin width in hepatectomy for ICC.METHODS: The study enrolled patients who underwent curative-intent resection for ICC between 1990 and 2020. The optimal survival tree (OST) was used to investigate overall (OS) and recurrence-free survival (RFS). An optimal policy tree (OPT) assigned treatment recommendations based on random forest (RF) counterfactual survival probabilities associated with each possible margin width between 0 and 20 mm.RESULTS: Among 600 patients, the median resection margin was 4 mm (interquartile range [IQR], 2-10). Overall, 379 (63.2 %) patients experienced recurrence with a 5-year RFS of 28.3 % and a 5-year OS of 38.7 %. The OST identified five subgroups of patients with different OS rates based on tumor size, a carbohydrate antigen 19-9 [CA19-9] level higher than 200 U/mL, nodal status, margin width, and age (area under the curve [AUC]: training, 0.81; testing, 0.69). The patients with tumors smaller than 4.8 cm and a margin width of 2.5 mm or greater had a relative increase in 5-year OS of 37 % compared with the entire cohort. The OST for RFS estimated a 46 % improvement in the 5-year RFS for the patients younger than 60 years who had small (CONCLUSIONS: Artificial intelligence OST identified subgroups within ICC relative to long-term outcomes. Although tumor biology dictated prognosis, the OPT suggested that different margin widths based on patient and disease characteristics may optimize ICC long-term survival.

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.

INTRODUCTION: While generally associated with poor prognosis, intrahepatic cholangiocarcinoma (ICC) can have a heterogeneous presentation and natural history. We sought to identify specific ICC subtypes that may be associated with varied long-term outcomes and patterns of recurrence after liver resection.METHODS: Patients who underwent curative-intent resection for ICC from 2000 to 2020 were identified from a multi-institutional database. Hierarchical cluster analysis characterized three ICC subtypes based on morphology (i.e., tumor burden score [TBS]) and biology (i.e., preoperative neutrophil-to-lymphocyte ratio [NLR] and CA19-9 levels).RESULTS: Among 598 patients, the cluster analysis identified three ICC subtypes: Common (n = 300, 50.2%) (median, TBS: 4.5; NLR: 2.4; CA19-9: 38.0 U/mL); Proliferative (n = 246, 41.1%) (median, TBS: 8.8; NLR: 2.9; CA19-9: 71.2 U/mL); Inflammatory (n = 52, 8.7%) (median, TBS: 5.4; NLR: 12.6; CA19-9: 26.7 U/mL). Median overall survival (OS) (Common: 72.0 months; Proliferative: 31.4 months; Inflammatory: 22.9 months) and recurrence-free survival (RFS) (Common: 21.5 months; Proliferative: 11.9 months; Inflammatory: 9.0 months) varied considerably among the different ICC subtypes (all p CONCLUSIONS: Cluster analysis identified three distinct subtypes of ICC based on TBS, NLR, and CA19-9. ICC subtype was associated with RFS and OS and predicted worse outcomes among patients. Despite more favorable T- and N-disease, the Inflammatory ICC subtype was associated with worse outcomes ICC subtype should be considered in the prognostic stratification of patients.

BACKGROUND: We sought to investigate whether the unique lateral patterns of lymphatic drainage impacted lymphadenectomy (LND), lymph node metastasis (LNM), and long-term survival of patients after curative hemi-hepatectomy for left- versus right-sided intrahepatic cholangiocarcinoma (ICC).METHODS: Data on patients who underwent curative hemi-hepatectomy for left- or right-sided ICC were collected from 15 high-volume centers worldwide, as well as from the Surveillance, Epidemiology, and End Results (SEER) registry. Primary outcomes included overall survival (OS) and disease-free survival (DFS).RESULTS: Among 697 patients identified from the multi-institutional database, patients who underwent hemi-hepatectomy for left-sided ICC (n = 363, 52.1%) were more likely to have an increased number of LND versus patients with right-sided ICC (n = 334, 47.9%) (median, left 5 versus right 3, p = 0.012), although the frequency (left 66.4% versus right 63.8%, p = 0.469) and station (beyond station no. 12, left 25.3% versus right 21.1%, p = 0.293) were similar. Consequently, left-sided ICC was associated with higher incidence of LNM (left 33.3% versus right 25.7%, p = 0.036), whereas the station and number of LNM were not different (both p > 0.1). There was no difference in OS (median, left 34.9 versus right 29.6 months, p = 0.130) or DFS (median, left 14.5 versus right 15.2 months, p = 0.771) among patients who underwent hemi-hepatectomy for left- versus right-sided ICC, which were also verified in the SEER dataset. LNM beyond station no. 12 was associated with even worse long-term survival versus LNM within station no. 12 among patients with either left- or right-sided ICC after curative-intent resection (all p < 0.05).CONCLUSIONS: The unique lateral patterns of lymphatic drainage were closely related to utilization of LND, as well as LNM of left- versus right-sided ICC.

Background: The aim of this study was to develop a predictive model to identify individuals most likely to derive overall survival (OS) benefit from adjuvant chemotherapy (AC) after hepatic resection of intrahepatic cholangiocarcinoma (ICC). Methods: Patients who underwent hepatic resection of ICC between 1990 and 2020 were identified from a multi-institutional database. Factors associated with worse OS were identified and incorporated into an online predictive model to identify patients most likely to benefit from AC. Results: Among 726 patients, 189 (26.0%) individuals received AC. Factors associated with OS on multivariable analysis included CA19-9 (Hazard Ratio [HR]1.17, 95%CI 1.04–1.31), tumor burden score (HR1.09, 95%CI 1.04–1.15), T-category (T2/3/4, HR1.73, 95%CI 1.73–2.64), nodal disease (N1, HR3.80, 95%CI 2.02–7.15), tumor grade (HR1.88, 95%CI 1.00–3.55), and morphological subtype (HR2.19, 95%CI 1.08–4.46). A weighted predictive score was devised and made available online (https://yutaka-endo.shinyapps.io/ICCrisk_model_for_AC/). Receipt of AC was associated with a survival benefit among patients at high/medium-risk (high: no AC, 0% vs. AC, 20.6%; medium: no AC, 36.4% vs. 40.8%; both p < 0.05) but not low-risk (low: no AC, 65.1% vs. AC, 65.1%; p = 0.73) tumors. Conclusion: An online predictive model based on tumor characteristics may help identify which patients may benefit the most from AC following resection of ICC.

This study aimed to enhance hepatocellular carcinoma (HCC) screening to achieve earlier diagnosis of patients with hepatitis C (HCV) cirrhosis in our Safety-Net population.Adherence to HCC screening guidelines at Safety-Net hospitals is poor. Only 23% of patients with HCC at our health system had a screening exam within 1-year of diagnosis and 46% presented with stage IV disease. HCV-induced cirrhosis remains the most common etiology of HCC (75%) in our patients.In the setting of an established HCV treatment clinic, an HCC screening quality improvement initiative was initiated for patients with stage 3 fibrosis or cirrhosis by transient elastography. The program consisted of semiannual imaging. Navigators scheduled imaging appointments and tracked compliance.From April 2018 to April 2021, 318 patients were enrolled (mean age 61 years, 81% Black race, 38% uninsured). Adherence to screening was higher than previously reported: 94%, 75%, and 74% of patients completed their first, second, and third imaging tests. Twenty-two patients (7%) were diagnosed with HCC; 55% stage I and 14% stage IV. All patients were referred and 13 (59%) received treatment. Median time to receipt of treatment was 77 days (range, 32-282). Median overall survival for treated patients was 32 months.Implementation of an HCC screening program at a safety-net hospital is feasible and facilitated earlier diagnosis in this study. Patient navigation and tracking completion of imaging tests were key components of the program's success. Next steps include expanding the program to additional at-risk populations.

The benefit of adjuvant therapy (AT) after curative resection of distal cholangiocarcinoma (DCC) remains unclear. The objective of the current study was to investigate the impact of AT on long-term survival of patients who underwent curative-intent resection for DCC.Patients who underwent curative-intent resection for DCC between 2000 and 2020 were identified from a multi-institutional database. The primary outcomes included overall (OS) and recurrence-free survival (RFS).Among 245 patients, 150 (61.2%) patients received AT (chemotherapy alone: n = 43; chemo- and radiotherapy: n = 107) after surgical resection, whereas 95 (38.8%) patients underwent surgery only. Patients who received AT were younger, and more likely to have an advanced tumor with the presence of perineural invasion (PNI), lymph node metastasis (LNM), lymph-vascular invasion, and higher T categories (all p 0.05). Overall, there was no difference in OS (median, surgery + AT 25.5 vs. surgery alone 24.5 months, p = 0.27) or RFS (median, surgery + AT 15.8 vs. surgery alone 18.9 months, p = 0.24) among patients who did versus did not receive AT. In contrast, AT was associated with improved long-term survival among patients with PNI (median OS, surgery + AT 25.9 vs. surgery alone 17.8 months, p = 0.03; median RFS, surgery + AT 15.9 vs. surgery alone 11.9 months, p = 0.04) and LNM (median, surgery + AT 20.0 vs. surgery alone 17.8 months, p = 0.03), but not among patients with no PNI or LNM (all p 0.1).AT was commonly utilized among patients with DCC. Patients with more advanced disease, including the presence of PNI or LNM, benefited the most from AT with improved long-term outcomes among this subset of patients.

Background The current study aimed to develop a dynamic prognostic model for patients undergoing curative-intent resection for intrahepatic cholangiocarcinoma (ICC) using landmark analysis. Methods Patients who underwent curative-intent surgery for ICC from 1999 to 2017 were selected from a multi-institutional international database. A landmark analysis to undertake dynamic overall survival (OS) prediction was performed. A multivariate Cox proportional hazard model was applied to measure the interaction of selected variables with time. The performance of the model was internally cross-validated via bootstrap resampling procedure. Discrimination was evaluated using the Harrell's Concordance Index. Accuracy was evaluated with calibration plots. Results Variables retained in the multivariable Cox regression OS model included age, tumor size, margin status, morphologic type, histologic grade, T and N category, and tumor recurrence. The effect of several variables on OS changed over time. Results were provided as a survival plot and the predicted probability of OS at the desired time in the future. For example, a 65-year-old patient with an intraductal, T1, grade 3 or 4 ICC measuring 3 cm who underwent an R0 resection had a calculated estimated 3-year OS of 76%. The OS estimate increased if the patient had already survived 1 year (79%). The discrimination ability of the final model was very good (C-index: 0.80). Conclusion The long-term outcome for patients undergoing curative-intent surgery for ICC should be adjusted based on follow-up time and intervening events. The model in this study showed excellent discriminative ability and performed well in the validation process.

Gallbladder cancer (GBC) is an aggressive malignancy associated with a high risk of recurrence and mortality. We used a machine-based learning approach to stratify patients into distinct prognostic groups using preperative variables.Patients undergoing curative-intent resection of GBC were identified using a multi-institutional database. A classification and regression tree (CART) was used to stratify patients relative to overall survival (OS) based on preoperative clinical factors.CART analysis identified tumor size, biliary drainage, carbohydrate antigen 19-9 (CA19-9) levels, and neutrophil-lymphocyte ratio (NLR) as the factors most strongly associated with OS. Machine learning cohorted patients into four prognostic groups: Group 1 (n = 109): NLR ≤1.5, CA19-9 ≤20, no drainage, tumor size5.0 cm; Group 2 (n = 88): NLR1.5, CA19-9 ≤20, no drainage, tumor size5.0 cm; Group 3 (n = 46): CA19-920, no drainage, tumor size5.0 cm; Group 4 (n = 77): tumor size5.0 cm with drainage OR tumor size ≥5.0 cm. Median OS decreased incrementally with CART group designation (59.5, 27.6, 20.6, and 12.1 months; p0.0001).A machine-based model was able to stratify GBC patients into four distinct prognostic groups based only on preoperative characteristics. Characterizing patient prognosis with machine learning tools may help physicians provide more patient-centered care.

Neoadjuvant chemoradiation therapy (NCRT, 5-fluorouracil and radiation) followed by resection and adjuvant chemotherapy (AC) is one of the standard treatment paradigms for locally advanced rectal adenocarcinoma. However, the utility of AC in patients with pathologic lymph node (pLN)-negative disease is unclear. Our aim is to assess the value of AC stratified by pLN status.The US Rectal Cancer Consortium database (2007-2017) was retrospectively reviewed for patients with clinical stage II and III rectal adenocarcinoma who received neoadjuvant chemoradiation (NACR) and curative-intent resection. Those who received neoadjuvant systemic chemotherapy or underwent local resection were excluded. Patients were categorized by pLN status. Primary outcome was overall survival (OS).Of 213 patients, 70% had pLN-negative disease and 30% pLN-positive disease. Median age was 57 years, 65% were male, and median follow-up was 31 months. Among patients with pLN-negative disease, 74% received AC. Receipt of AC was not associated with improved 5-year OS (82% versus 74%, respectively; p = 0.16). This finding persisted on multivariable analysis. Of patients with pLN-positive disease, 83% received AC. Patients with pLN-positive disease demonstrated improved 5-year OS with receipt of AC (72% compared with 0% with no adjuvant chemotherapy, p = 0.04).After receiving neoadjuvant chemoradiation, adjuvant chemotherapy for patients with pLN-negative disease does not appear to be associated with improved survival. Further validation and prospective studies are needed to evaluate the utility of adjuvant chemotherapy in this setting.

Purpose: Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC. Experimental Design: We examined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC. Results: At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progression-free survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively. Conclusions: This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.

Background: The therapeutic role of lymphadenectomy (LND) for intrahepatic cholangiocarcinoma (ICC) patients remains ill-defined. We sought to analyze the therapeutic value of LND relative to tumor location and preoperative lymph node metastasis (LNM) risk. Methods: Patients who underwent curative-intent hepatic resection of ICC between 1990 and 2020 were included from a multi-institutional database. Therapeutic LND (tLND) was defined as LND that harvested ≥3 lymph nodes. Results: Among 662 patients, 178 (26.9%) individuals received tLND. Patients were categorized into central type ICC (n = 156, 23.6%) and peripheral type ICC (n = 506, 76.4%). Central type harbored multiple adverse clinicopathologic factors and worse overall survival (OS) compared with peripheral type (5-year OS, central: 27.0% vs. peripheral: 47.2%, p < 0.001). After consideration of preoperative LNM risk, patients with central type and high-risk LNM who underwent tLND survived longer than individuals who did not (5-year OS, tLND: 27.9% vs. non-tLND: 9.0%, p = 0.001), whereas tLND was not associated with better survival among patients with peripheral type ICC or low-risk LNM. The therapeutic index of hepatoduodenal ligament (HDL) and other regions was higher in central type than in peripheral type, which was more pronounced among high-risk LNM patients. Conclusions: Central type ICC with high-risk LNM should undergo LND involving regions beyond the HDL.

Background: The high incidence of early recurrence after hepatectomy for intrahepatic cholangiocarcinoma (ICC) has a detrimental effect on overall survival (OS). Machine-learning models may improve the accuracy of outcome prediction for malignancies. Methods: Patients who underwent curative-intent hepatectomy for ICC were identified using an international database. Three machine-learning models were trained to predict early recurrence (< 12 months after hepatectomy) using 14 clinicopathologic characteristics. The area under the receiver operating curve (AUC) was used to assess their discrimination ability. Results: In this study, 536 patients were randomly assigned to training (n = 376, 70.1%) and testing (n = 160, 29.9%) cohorts. Overall, 270 (50.4%) patients experienced early recurrence (training: n = 150 [50.3%] vs testing: n = 81 [50.6%]), with a median tumor burden score (TBS) of 5.6 (training: 5.8 [interquartile range {IQR}, 4.1–8.1] vs testing: 5.5 [IQR, 3.7–7.9]) and metastatic/undetermined nodes (N1/NX) in the majority of the patients (training: n = 282 [75.0%] vs testing n = 118 [73.8%]). Among the three different machine-learning algorithms, random forest (RF) demonstrated the highest discrimination in the training/testing cohorts (RF [AUC, 0.904/0.779] vs support vector machine [AUC, 0.671/0.746] vs logistic regression [AUC, 0.668/0.745]). The five most influential variables in the final model were TBS, perineural invasion, microvascular invasion, CA 19-9 lower than 200 U/mL, and N1/NX disease. The RF model successfully stratified OS relative to the risk of early recurrence. Conclusions: Machine-learning prediction of early recurrence after ICC resection may inform tailored counseling, treatment, and recommendations. An easy-to-use calculator based on the RF model was developed and made available online.

Context.— The nature and associations of gallbladder (GB) “adenomyoma” (AM) remain controversial. Some studies have attributed up to 26% of GB carcinoma to AMs. Objective.— To examine the true frequency, clinicopathologic characteristics, and neoplastic changes in GB AM. Design.— Cholecystectomy cohorts analyzed were 1953 consecutive cases, prospectively with specific attention to AM; 2347 consecutive archival cases; 203 totally embedded GBs; 207 GBs with carcinoma; and archival search of institutions for all cases diagnosed as AM. Results.— Frequency of AM was 9.3% (19 of 203) in totally submitted cases but 3.3% (77 of 2347) in routinely sampled archival tissue. A total of 283 AMs were identified, with a female to male ratio = 1.9 (177:94) and mean size = 1.3 cm (range, 0.3–5.9). Most (96%, 203 of 210) were fundic, with formed nodular trabeculated submucosal thickening, and were difficult to appreciate from the mucosal surface. Four of 257 were multifocal (1.6%), and 3 of 257 (1.2%) were extensive (“adenomyomatosis”). Dilated glands (up to 14 mm), often radially converging to a point in the mucosa, were typical. Muscle was often minimal, confined to the upper segment. Nine of 225 (4%) revealed features of a duplication. No specific associations with inflammation, cholesterolosis, intestinal metaplasia, or thickening of the uninvolved GB wall were identified. Neoplastic change arising in AM was seen in 9.9% (28 of 283). Sixteen of 283 (5.6%) had mural intracholecystic neoplasm; 7 of 283 (2.5%) had flat-type high-grade dysplasia/carcinoma in situ. Thirteen of 283 cases had both AM and invasive carcinoma (4.6%), but in only 5 of 283 (1.8%), carcinoma was arising from AM (invasion was confined to AM, and dysplasia was predominantly in AM). Conclusions.— AMs have all the features of a malformative developmental lesion, and may not show a significant muscle component; (ie, the name “adeno-myoma” is partly a misnomer). While most are innocuous, some pathologies may arise in AMs, including intracholecystic neoplasms, flat-type high-grade dysplasia or carcinoma in situ and invasive carcinoma (1.8%, 5 of 283). It is recommended that gross examination of GBs include serial slicing of the fundus for AM detection and total submission if one is found.

Supplemental Figures S1-S7

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8+ and CD4+ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.

Supplementary Table from Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer

BACKGROUND: The interplay of carbohydrate antigen 19-9 (CA19-9) and tumor burden score (TBS) within intrahepatic cholangiocarcinoma remains ill-defined. We evaluated the roles of TBS and CA19-9 relative to overall survival (OS) and recurrence, as well as the predictive ability of the combined TBS and CA19-9 (CTC) grading system. STUDY DESIGN: Patients undergoing liver resection for intrahepatic cholangiocarcinoma between 2000 and 2020 were identified using a multi-institutional database. The impact of CA19-9 and TBS on 5-year OS and 3-year recurrence was assessed, along with the prognostic accuracy of the CTC grading system (ie the composite score of CA19-9 level and TBS). RESULTS: Among 831 patients, the median age was 58.2 years and 482 (58.0%) were male. The median [IQR] CA19-9 level was 49.7 [17.0, 221.0] U/mL and TBS was 6.1 [4.1, 8.3]. Median [IQR] and 5-year OS were 36.9 [32.3, 43.1] months and 38.9%, respectively; 3-year recurrence was 68.9%. Five-year survival varied relative to CA19-9 (low vs high, 49.0% vs 19.7%) and TBS (low vs high, 53.6% vs 26.9%) (p < 0.001 for both). On multivariable analysis, high CA19-9 (hazard ratio [HR] 2.02, 95% CI 1.64 to 2.49) and high TBS (HR 1.64, 95% CI 1.32 to 2.06) remained independently associated with OS. In turn, the CTC grading score stratified 5-year OS (low vs intermediate vs high CTC, 57.7% vs 39.9% vs 12.6%; p < 0.001) and remained an independent prognostic factor (referent, low CTC; [intermediate CTC] HR 1.54, 95% CI 1.18 to 2.01; [high CTC] HR 3.28, 95% CI 2.47 to 4.36). CONCLUSIONS: The interplay between tumor morphology and biology dictates long-term prognosis after liver resection for intrahepatic cholangiocarcinoma. Prognostic models such as the CTC grading system may inform discussions around prognosis, as well as help identify which patients with ICC may benefit more from neoadjuvant chemotherapy rather than up-front surgery.

Supplementary Figure from Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer

Purpose:Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC.Experimental Design:We examined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC.Results:At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progression-free survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively.Conclusions:This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.

To define surgical outcomes of patients with high-grade gastro-entero-pancreatic neuroendocrine neoplasm grade G3 (GEP-NEN G3).Patients who underwent surgical resection between 2000 and 2016 were identified. The overall survival (OS) and recurrence-free survival (RFS) of patients with gastro-entero-pancreatic neuroendocrine tumors grade G3 (GEP-NET G3) versus neuroendocrine carcinoma (NEC) were evaluated.Fifty-one out of 2182 (2.3%) patients who underwent surgical resection were diagnosed as GEP-NEN G3. The pancreas was the most common primary site (n = 3772.5%). A majority of patients had lymph node metastasis (n = 3262.7%); one in three (n = 1631.4%) had distant metastasis. The median OS and RFS of the entire cohort were 56.4 and 34.5 months, respectively. Perineural invasion was a strong prognostic factor associate with OS after surgical resection. Patients with NEC had a worse survival outcome versus patients with NET G3 (median OS: 33.1 months vs. not attained, p = 0.088). In contrast, among patients who underwent curative-intent resection, patients with NEC had comparable RFS versus patients with NET G3 (median RFS: 35.6 vs. 33.9 months, p = 0.774).Surgical resection provided acceptable short- and long-outcomes for well-selected patients with resectable GEP-NEN G3. NEC was associated with a worse OS versus NET G3.

BACKGROUND AND OBJECTIVES: Cholangiocarcinoma is a highly aggressive and heterogenous group of biliary malignancies arising from any site in the biliary tree, comprising 15% of all primary liver cancers. The nature of the disease and nonspecific presentation leads to late diagnosis and ultimately poor outcomes for patients. Combination gemcitabine and cisplatin has been the standard of care for cholangiocarcinoma (CCA) since 2010, with a median overall survival of 11.7 months. The five-year survival for CCA remains 5–10%, revealing a clear need for improved treatment options. METHODS: This targeted review highlights the role of next generation sequencing in CCA and the clinically relevant tumor biomarkers that have become the focus of therapeutic development. KEY CONTENT AND FINDINGS: These tumor biomarkers or actionable mutations hold the potential to enable earlier diagnosis, provide prognostic information, and guide treatment decisions for patients with CCA. Specifically, the FGFR2 fusion and IDH1 mutation have shown considerable promise in development of targeted therapies. Clinical trials with inhibitors targeting FGFR2 fusion and IDH1 mutation have created expectations that these drugs will soon enter clinical practice. Other biomarkers including KRAS and B-raf protooncogenes, Her2/neu genes, and BRCA1 and 2 tumor-suppressor genes have also been touted as potential targets for future therapies, with early data showing promise for new drug development. CONCLUSION: The discovery of these actionable mutations and identification of targeted therapies have challenged the notion of a “one-size fits all” for treatment of CCA, and generated optimism that these novel treatments will soon be available for patients with CCA.

PDF file - 981KB, Representative Immunohistochemistry for CHD7 Expression in Primary Tumor Tissue (S1). Network Analysis via MetaCore ExPlain Process Network Analysis for genes involved in CHK1, CDC25A, AURKB, PLK1, HUS1 pathway (S2). CHD7 Knockdown Causes Gemcitabine Sensitization (S3). Mice with Xenograft Tumors Showed No Significant Difference in Body Weight (S4). CHD7 Knockdown Effect on Cell Cycle (S5). Gemcitabine Does Not Significantly Change CHD7 Protein Levels in Cells (S6).

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XLS file - 675KB, Full Results of Primary Gemcitabine Sensitivity Screen (S1). Known DNA Damage Response Genes Identified as Hits in Gemcitabine Sensitivity Screen (S2). Dysregulation, Differential Expression, and Literature RNAi Cross-Reference for Known DDR Genes and Select Hits (S3). Selected Top 15% of Gemcitabine Sensitivity Genes Tested on Secondary Screen (S4).

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment. Cancer Res; 74(10); 2677–87. ©2014 AACR.

PurposeUsing a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; MethodsWe analyzed matched whole-transcriptome and DNA sequencing data from 2430 patient samples (YOPC, n=292; AOPC, n=2138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data was obtained from insurance claims (n=4928); Kaplan-Meier estimates were calculated for age-and molecularly-defined cohorts. Significance was determined as FDR-correctedP-values (Q)ResultsYOPC patients had higher proportions of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H),BRCA2-mutant, andPALB2-mutant tumors compared with AOPC patients, but fewerSMAD4-, RNF43-, CDKN2A-, andSF3B1-mutant tumors. Notably, YOPC patients demonstrated significantly lower incidence ofKRASmutations compared with AOPC patients (81.3% vs. 90.9%;Q=0.004). In theKRAS-wildtype subset (n=227), YOPC tumors demonstrated fewerTP53mutations and were more likely driven byNRG1andMETfusions, whileBRAFfusions were exclusively observed in AOPC patients. Immune deconvolution revealed significant enrichment of natural killer (NK) cells, CD8+T cells, monocytes, and M2 macrophages in YOPC patients relative to AOPC patients, which corresponded with lower rates ofHLA-DPA1homozygosity. There was an association with improved OS in YOPC patients compared with AOPC patients withKRAS-wildtype tumors (median 16.2 [YOPC-KRASWT] vs. 10.6 [AOPC-KRASWT] months;P=0.008) but notKRAS-mutant tumors (P=0.084).ConclusionIn this large, real-world multi-omic characterization of age-stratified molecular differences in PDAC, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

BACKGROUND: The prognostic role of tumor burden score (TBS) relative to albumin-bilirubin (ALBI) grade among patients undergoing curative-intent resection of ICC has not been examined.METHODS: We identified patients who underwent curative-intent resection for ICC between 1990 and 2017 from a multi-institutional database. Multivariable analysis was performed to assess the effect of TBS relative to ALBI grade on both short- and long-term outcomes.RESULTS: Among 724 patients, 360 (49.7%) patients had low TBS and low ALBI grade, 142 (19.6%) patients had low TBS and high ALBI grade, 138 (19.1%) patients had high TBS and low ALBI grade, and 84 patients (11.6%) had high TBS and high ALBI grade. Decreased tumor burden was associated with better long-term outcomes among patients with both low (5-year OS; low TBS vs. high TBS: 52.4% vs 21.4%; p 10 days) (OR 2.80, 95%CI 1.62-4.82; p CONCLUSION: Both TBS (i.e., tumor morphology) and ALBI grade (i.e., hepatic function reserve) were strong predictors of outcomes among patients undergoing ICC resection. There was an interplay between TBS and ALBI grade relative to patient prognosis after hepatic resection of ICC with high ALBI grade predicting worse outcomes among ICC patients with different TBS.

Simple ileocecectomy and right hemicolectomy are two potential operative approaches to treat patients with neuroendocrine neoplasm in the terminal ileum and/or cecum (IC-NENs). We sought to define the long-term outcome of patients undergoing ileocecectomy versus right hemicolectomy for IC-NENs, as well as characterize number of nodes evaluated and lymph node metastasis (LNM) associated with each procedure.Patients who underwent curative-intent resections for IC-NENs between 2000 and 2016 were identified from a multi-institutional database. The clinicopathologic characteristics, surgical procedures, and the overall (OS) and recurrence-free survival (RFS) were compared among patients who underwent formal right hemicolectomy versus ileocecectomy only.Among 127 patients with IC-NENs, median size of the largest tumor size was 2.0 (IQR 1.2-2.9) cm; 35 (27.6%) patients had multiple lesions. At the time of surgery, 93 (73.2%) patients underwent a right hemicolectomy, whereas 34 (26.8%) had ileocecectomy only. Every patient had a lymph node dissection (LND) with a median number of 16 (IQR 12-22) nodes evaluated. A majority (n = 110, 86.6%) of patients had LNM with a median number of 3 (IQR 2-5) LNM. Patients who underwent hemicolectomy had more lymph nodes evaluated versus patients who had an ileocecectomy only (median, 18 vs. 14, p = 0.004). Patients who underwent formal right hemicolectomy versus ileocecectomy had a similar OS (median OS, 101.9 vs. 144.5 months, p = 0.44) and RFS (median RFS, 70.3 vs. not attained, p = 0.80), respectively.Ileocecectomy had similar long-term outcomes versus right hemicolectomy in treatment of IC-NENs despite a difference in the lymph node harvest.

Pancreatic neuroendocrine tumor (PNET) survival outcomes differ by race. Current recommendations for surveillance of PNETs less than 2 cm in size are based on low malignant potential and low rates of lymph node metastases (LNM). We investigated whether these guidelines are universally applicable regardless of race.A multi-institutional analysis of patients with resected, nonfunctional, sporadic PNETs was performed initially using the US Neuroendocrine Study Group dataset with the National Cancer Database as a validation dataset. Patients with distant metastatic disease were excluded from analysis.A total of 453 (388 White and 65 Black) and 5,532 patients (4,772 White and 760 Black) were analyzed in the initial and validation datasets, respectively. White patients had a low incidence of LNM in tumors of less than 2 cm in both datasets (5% and 12%, respectively), which increased with tumor size. However, the incidence of LNM in Black patients was similar in the initial and validation datasets for tumors sized less than 2 cm (23% and 21%) and 2 to 3 cm (21% and 29%). Black patients had a significantly higher incidence of LNM in tumors less than 2 cm in size in the initial and validation datasets (p0.01) compared with White patients.The current recommendation for surveillance of PNETs of less than 2 cm in size is likely based on a low rate of LNM seen in a predominantly White population. The incidence of LNM in Black patients with tumors less than 2 cm in size is clinically relevant and concerning. Current guidelines may not be universally applicable, and a more aggressive approach to resection in Black patients with small PNETs may be warranted.

INTRODUCTION: Following resection of pancreatic acinar cell carcinoma (PACC) distant recurrence remains high. We utilized the national cancer database (NCDB) to evaluate the role of systemic therapy in early-stage resected PACC. METHODS: We queried the NCDB registry from 2004 to 2015 for patients with pathologic stage I-IIB PACC. For each stage, patients who underwent surgery alone (SA) were compared to patients who received systemic and/or radiation therapy in addition to surgery (surgery + therapy [S + T]). RESULTS: A total of 271 patients (101 pI, 81 pIIA, and 89 pIIB) were analyzed. Of all clinically node positive patients (n = 41), the majority (n = 32, 78%) had node-positive disease at resection (pIIB). SA was performed in 112 patients (41.3%), whereas 159 (58.7%) patients received S + T. There was no difference in overall survival (OS) between S + T and SA with respect to pI or pIIA disease. In pIIB disease, S + T was associated with improved OS compared to SA (34.9 vs. 16.9 months, p = 0.031). Single-agent chemotherapy was associated with improved OS for pIIB disease when compared to SA (hazard ratio: 0.38, 95% confidence interval: 0.16, 0.83). CONCLUSION: In resectable PACC, the survival benefit of adjuvant therapy is limited to pathologic stage IIB disease. This benefit is evident even in patients treated with single-agent chemotherapy.

The literature is highly conflicted on what percentage of pancreatic ductal adenocarcinomas (PDACs) arise in association with intraductal papillary mucinous neoplasms (IPMNs). Some studies have claimed that even small (Sendai-negative) IPMNs frequently lead to PDAC. Recently, more refined pathologic definitions for mucin-lined cysts were provided in consensus manuscripts, but so far there is no systematic analysis regarding the frequency and clinicopathologic characteristics of IPMN-mimickers, i.e., pseudo-IPMNs. In this study, as the first step in establishing frequency, we performed a systematic review of the pathologic findings in 501 consecutive ordinary PDACs, which disclosed that 10% of PDACs had associated cysts >= 1 cm. While 31 (6.2%) of these were IPMN or mucinous cystic neoplasm (MCN), 19 (3.8%) were other cyst types that mimicked IPMN (pseudo-IPMNs) per recent WHO/consensus criteria. As the second step of the study, we performed a comparative clinicopathologic analysis by also including our entire surgical pathology/consultation databases that was comprised of 60 IPMN-associated PDACs, 30 MCN-associated PDACs and 40 pseudo-IPMN-associated PDACs. We found that 84% of true IPMNs were pre-operatively recognized, whereas IPMN was considered in differential diagnosis of 33% of pseudo-IPMNs. Of the 40 pseudo-IPMNs, there were 15 secondary duct ectasias; 6 large-duct-type PDACs; 5 pseudocysts; 5 cystic tumor necrosis; 4 simple mucinous cysts; 3 groove pancreatitis-associated paraduodenal wall cysts; and 2 congenital cysts. Microscopically, pseudo-IPMNs had at least partial mucinous-lining mimicking IPMN but had smaller cystic (mean = 1.9 cm) and larger PDAC (mean = 3.8 cm) components compared to true IPMNs (cyst = 5.7 cm; PDAC = 2.0 cm). In summary, in this pathologically verified analysis that utilized refined criteria, 10% of PDACs were discovered to have cysts >= 1 cm, about two-thirds of which were IPMN/MCN but about one-third were pseudo-IPMNs. True IPMNs underlying the PDACs are often large and are already diagnosed pre-operatively as having an IPMN component, whereas only a third of the pseudo-IPMNs receive IPMN diagnosis by imaging and their cysts are smaller. At the histopathologic level, pseudo-IPMNs are highly prone to misdiagnosis as IPMN, which presumably accounts for much higher association of IPMNs with PDAC as reported in some studies. The subtle but salient characteristics of pseudo-IPMNs elucidated in this study should be combined with careful radiological/clinical correlation in order to exclude pseudo-IPMNs.

Resection of the primary (RP) in metastatic neuroendocrine tumor (NET) is controversial. The aim was to evaluate survival outcomes for RP in metastatic NET patients.Data were obtained from US hospitals at the National Cancer Database between 2004 and 2014. χ2, analysis of variance tests, univariate, and multivariate cox proportional hazards models were evaluated. Kaplan-Meier curves and log-rank tests conducted to compare the survival difference of patient characteristics.A total of 2361 patients were identified. The mean age was 62.1 years (standard deviation, 13 years), male-to-female ratio 1:1; 33% were small intestine, 26.3% pancreas, and 24.4% lung; 69.6% were well-differentiated; and 42.5% underwent RP. The 5-year overall survival (OS) was significantly improved for patients who underwent RP in small intestine (5-year OS, 63.9% vs 44.2%), lung (5-year OS, 65.4% vs 20.2%), and pancreas tumors (5-year OS, 75.6% vs 30.6%). On multivariate analysis, RP (hazard ratio, 0.46; 95% confidence interval, 0.29-0.73; P0.001), female, year of diagnosis 2010-2014, margin, Charlson-Deyo score less than 2, and age less than 51 years, were associated with better OS.Resection of the primary in metastatic well-differentiated NET is associated with improved OS compared with no RP.