Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Safety of Selective Operative Drainage After Pancreatic Resection: A Retrospective Analysis of 2,607 Patients.

OBJECTIVE: To assess whether selective omission of operative drains after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) is associated with adverse perioperative outcomes. BACKGROUND: The routine use of operative drains after pancreatectomy is widely practiced; however, prospective randomized clinical trials and retrospective analyses have shown mixed results. METHODS: Patients who underwent PD or DP between November 2009 and May 2021 were reviewed and stratified by operative drain placement. Patient demographics, morbidity, the need for additional procedures, and mortality were compared between patients who did or did not develop a clinically relevant post-operative pancreatic fistula (CR-POPF). RESULTS: In total, 1,855 PD and 752 DP cases were analyzed. Among PD patients with a CR-POPF (N=259, 14%), 160 (62%) had an operative drain placed, of whom 141 (88%) required at least 1 additional procedure. Within this subgroup, grade ≥ 4 complications (7.5% vs. 11.1%, P=0.37), 90-day mortality (3.8% vs. 6.1%, P=0.54), length of stay (LOS) (median 12 vs. 13 d, P=0.19) and readmission rates (63.1% vs. 54.6%, P=0.19) were similar between drained and non-drained patients. Of note, drained PD patients without a CR-POPF had a longer hospital stay (8 vs. 7 d, respectively, P=0.004) and more thromboembolic events (2.4% vs. 1.1%, respectively, P=0.04) Among DP patients with a CR-POPF (n=129), 44 had an operative drain, with 37 (84%) requiring an additional procedure. Within this subgroup, grade ≥ 4 complications (4.6% vs. 5.9%, P>0.95), 90-day mortality (0%), LOS (median 7 d for both, P=0.88) and readmission rates (72.7% vs. 80%, P=0.38) were similar in drained and non-drained patients. CONCLUSION: This study confirms that selective omission of operative drains does not compromise perioperative outcomes, as initially reported in our prospective randomized trial.

Early-Onset Pancreatic Neuroendocrine Tumors: Clinical Presentation, Pathology Features, and Oncological Outcomes.

BACKGROUND: Early-Onset (EO) pancreatic neuroendocrine tumor (PanNET) is a rare disease, but whether it is clinically different from late-onset (LO) PanNET is unknown. Our study aimed to evaluate clinical differences and disease outcomes between EO-PanNET and LO-PanNET and to compare sporadic EO-PanNET with those with a hereditary syndrome. METHODS: Patients with localized PanNET who underwent pancreatectomy at Memorial Sloan Kettering between 2000 and 2017 were identified. Those with metastatic disease and poorly differentiated tumors were excluded. EO-PanNET was defined as <50 and LO-PanNET >50 years of age at the time of diagnosis. Family history and clinical and pathology characteristics were recorded. RESULTS: Overall 383 patients were included, 107 (27.9%) with EO-PanNET. Compared with LO-PanNET, EO-PanNET were more likely to have a hereditary syndrome (2.2% vs. 16%, P <0.001) but had similar pathology features such as tumor grade ( P =0.6), size (2.2 Vs. 2.3 cm, P =0.5) and stageof disease ( P =0.8). Among patients with EO-PanNET, those with hereditary syndrome had more frequently a multifocal disease (65% vs. 3.3%, P <0.001). With a median follow-up of 70 months (range 0-238), the 5-year cumulative incidence of recurrence after curative surgery was 19% (95% CI 12%-28%) and 17% (95% CI 13%-23%), in EO-PanNET and LO-PanNET ( P =0.3). Five-year disease-specific survival was 99% (95% CI 98%-100%) with no difference with respect to PanNET onset time ( P =0.26). CONCLUSIONS: In this surgical cohort, we found that EO-PanNET is associated with hereditary syndromes but has pathologic characteristics and oncological outcomes similar to LO-PanNET. These findings suggest that patients with EO-PanNET can be managed similarly to those with LO-PanNET.

Risk Factors for Progression in Patients Undergoing Surveillance for Pancreatic Cysts.

OBJECTIVE: To identify risk factors associated with the progression of pancreatic cysts in patients undergoing surveillance. BACKGROUND: Previous studies of intraductal papillary mucinous neoplasms (IPMNs) rely on surgical series to determine malignancy risk and have inconsistently identified characteristics associated with IPMN progression. METHODS: We conducted a retrospective review of 2197 patients presenting with imaging concerning for IPMN from 2010 to 2019 at a single institution. Cyst progression was defined as resection or pancreatic cancer development. RESULTS: The median follow-up time was 84 months from the presentation. The median age was 66 years, and 62% were female. Ten percent had a first-degree relative with pancreatic cancer, and 3.2% had a germline mutation or genetic syndrome associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). Cumulative incidence of progression was 17.8% and 20.0% at 12 and 60 months postpresentation, respectively. Surgical pathology for 417 resected cases showed noninvasive IPMN in 39% of cases and PDAC with or without associated IPMN in 20%. Only 18 patients developed PDAC after 6 months of surveillance (0.8%). On multivariable analysis, symptomatic disease [hazard ratio (HR)=1.58; 95% CI: 1.25-2.01], current smoker status (HR=1.58; 95% CI: 1.16-2.15), cyst size (HR=1.26; 95% CI: 1.20-1.33), main duct dilation (HR=3.17; 95% CI: 2.44-4.11), and solid components (HR=1.89; 95% CI: 1.34-2.66) were associated with progression. CONCLUSIONS: Worrisome features on imaging at presentation, current smoker status, and symptomatic presentation are associated with IPMN progression. Most patients progressed within the first year of presentation to Memorial Sloan Kettering Cancer Center (MSKCC). Further investigation is necessary to develop personalized cyst surveillance strategies.

Has Management of Intrahepatic Cholangiocarcinoma Evolved with the Evidence? Trends and Practice Patterns from the National Cancer Database.

BACKGROUND: Management of intrahepatic cholangiocarcinoma (IHC) has advanced in recent decades, including randomized trial evidence supporting systemic therapy in the palliative and adjuvant setting. Mounting observational evidence suggests resection of IHC with multifocal disease (IHC-MF) or lymph node metastasis (IHC-LNM) should be limited. It is unknown how real-world practice has evolved in light of research advances. This study characterizes trends in management and outcomes of IHC without distant metastasis. METHODS: We queried the National Cancer Database (NCDB) for patients treated for IHC without distant metastasis (M0) and identified subgroups with lymph node (cN1) or multifocal hepatic involvement (cT2b). Two-sided Cochran-Armitage tests evaluated trends in initial treating modality and perioperative chemotherapy. Logistic regression evaluated associations with choice of initial treating modality. Overall survival (OS) was evaluated by using Kaplan-Meier methods. RESULTS: Between 2004 and 2020, 11,368 patients were treated for IHC without extrahepatic metastasis. Forty-three percent underwent resection. Initial management shifted from resection towards radiation or systemic therapy in IHC-MF and IHC-LNM. Use of perioperative chemotherapy increased from 39% pre-2010 to 70% in 2018-2020 (p < 0.001), most often delivered postoperatively. Across the entire cohort, median OS improved from 16 (95% confidence interval [CI] 15-18) to 27 months (95% CI 26-29). More modest improvements were observed in IHC-MF and IHC-LNM. CONCLUSIONS: Use of perioperative chemotherapy has been widely adopted, predating randomized trial evidence in the adjuvant setting. Initial management of IHC-MF and IHC-LNM has shifted from resection to systemic and/or radiation therapy. While OS has improved overall, outcomes of IHC-MF and IHC-LNM remain poor, warranting further investigation.

Gemcitabine with Cisplatin Versus Hepatic Arterial Infusion Pump Chemotherapy for Liver-Confined Unresectable Intrahepatic Cholangiocarcinoma.

BACKGROUND: A post-hoc analysis of ABC trials included 34 patients with liver-confined unresectable intrahepatic cholangiocarcinoma (iCCA) who received systemic chemotherapy with gemcitabine and cisplatin (gem-cis). The median overall survival (OS) was 16.7 months and the 3-year OS was 2.8%. The aim of this study was to compare patients treated with systemic gem-cis versus hepatic arterial infusion pump (HAIP) chemotherapy for liver-confined unresectable iCCA. METHODS: We retrospectively collected consecutive patients with liver-confined unresectable iCCA who received gem-cis in two centers in the Netherlands to compare with consecutive patients who received HAIP chemotherapy with or without systemic chemotherapy in Memorial Sloan Kettering Cancer Center. RESULTS: In total, 268 patients with liver-confined unresectable iCCA were included; 76 received gem-cis and 192 received HAIP chemotherapy. In the gem-cis group 42 patients (55.3%) had multifocal disease compared with 141 patients (73.4%) in the HAIP group (p = 0.023). Median OS for gem-cis was 11.8 months versus 27.7 months for HAIP chemotherapy (p < 0.001). OS at 3 years was 3.5% (95% confidence interval [CI] 0.0-13.6%) in the gem-cis group versus 34.3% (95% CI 28.1-41.8%) in the HAIP chemotherapy group. After adjusting for male gender, performance status, baseline hepatobiliary disease, and multifocal disease, the hazard ratio (HR) for HAIP chemotherapy was 0.27 (95% CI 0.19-0.39). CONCLUSIONS: This study confirmed the results from the ABC trials that survival beyond 3 years is rare for patients with liver-confined unresectable iCCA treated with palliative gem-cis alone. With HAIP chemotherapy, one in three patients was alive at 3 years.

Initiation of a robotic pancreatoduodenectomy program using virtual collaboration.

BACKGROUND: Adoption of robotic pancreatoduodenectomy (RPD) is growing, although there are challenges for safe introduction of this technique, including limitations in on-site expert proctoring. We developed and implemented a structured approach for safe introduction of a new RPD program using virtual collaboration. METHODS: A structured framework for introducing a RPD program was designed; key steps included obtaining additional training, identifying required resources, establishing a dedicated team, and patient safety considerations. Virtual collaboration with a proctor for bidirectional communication was utilized for remote operative guidance. In the initial cohort, perioperative data and postoperative outcomes were extracted from a prospectively maintained database. RESULTS: From August 2020 to December 2023, 68 patients underwent RPD. The median operative time was 407 min with an estimated blood loss of 150 mL. Median length of stay was 8 days. Negative margins were obtained in 90% of resections. Operative time was significantly shorter in the second half of cases compared to the first (380min vs 441min, p < 0.01) and rate of conversion decreased (6% vs 21%). CONCLUSION: The safe initiation of a structured RPD program is feasible through virtual expert collaboration. With careful consideration and an appropriate environment, excellent perioperative outcomes are achievable even for initial cases.

Risk Perceptions and Risk Thresholds Among Surgeons in the Management of Intraductal Papillary Mucinous Neoplasms.

OBJECTIVES: We aimed to determine whether surgeon variation in management of intraductal papillary mucinous neoplasm (IPMN) is driven by differences in risk perception and quantify surgeons' risk threshold for changing their recommendations. BACKGROUND: Surgeons vary widely in management of IPMN. METHODS: We conducted a survey of members of the Americas HepatoPancreatoBiliary Association, presented participants with 2 detailed clinical vignettes and asked them to choose between surgical resection and surveillance. We also asked them to judge the likelihood that the IPMN harbors cancer and that the patient would have a serious complication if surgery was performed. Finally, we asked surgeons to rate the level of cancer risk at which they would change their treatment recommendation. We examined the association between surgeons' treatment recommendations and their risk perception and risk threshold. RESULTS: One hundred fifty surgeons participated in the study. Surgeons varied in their recommendations for surgery [19% for vignette 1 (V1) and 12% for V2] and in their perception of the cancer risk (interquartile range: 2%-10% for V1 and V2) and risk of surgical complications (V1 interquartile range: 10%-20%, V2 20-30%). After adjusting for surgeon characteristics, surgeons who were above the median in cancer risk perception were 22 percentage points (27% vs 5%) more likely to recommend resection than those who were below the median (95% CI: 11%-4%; P <0.001). The median risk threshold at which surgeons would change their recommendation was 15% (V1 and V2). Surgeons who recommended surgery had a lower risk threshold for changing their recommendation than those who recommended surveillance (V1: 10.0 vs 15.0, P =0.06; V2: 7.0 vs 15.0, P =0.05). CONCLUSIONS: The treatment that patients receive for IPMNs depends greatly on how their surgeons perceive the risk of cancer in the lesion. Efforts to improve cancer risk prediction for IPMNs may lead to decreased variations in care.

The Influence of Patient Preference on Surgeons' Treatment Recommendations in the Management of Intraductal Papillary Mucinous Neoplasms.

OBJECTIVE: We aimed to determine whether surgeon variation in management of intraductal papillary mucinous neoplasms (IPMN) is driven by differences in risk perception and quantify surgeons' risk threshold for changing their recommendations. BACKGROUND: Surgeons vary widely in management of IPMN. METHODS: We conducted a survey of members of the Americas HepatoPancreatoBiliary Association, presented participants with 2 detailed clinical vignettes and asked them to choose between surgical resection and surveillance. We also asked them to judge the likelihood that the IPMN harbors cancer and that the patient would have a serious complication if surgery was performed. Finally, we asked surgeons to rate the level of cancer risk at which they would change their treatment recommendation. We examined the association between surgeons' treatment recommendations and their risk perception and risk threshold. RESULTS: One hundred and fifty surgeons participated in the study. Surgeons varied in their recommendations for surgery [19% for vignette 1 (V1) and 12% for V2] and in their perception of the cancer risk (interquartile range: 2%-10% for V1 and V2) and risk of surgical complications (V1 interquartile range: 10%-20%, V2 20%-30%). After adjusting for surgeon characteristics, surgeons who were above the median in cancer risk perception were 22 percentage points (27% vs. 5%) more likely to recommend resection than those who were below the median (95% CI: 11.34%; P <0.001). The median risk threshold at which surgeons would change their recommendation was 15% (V1 and V2). Surgeons who recommended surgery had a lower risk threshold for changing their recommendation than those who recommended surveillance (V1: 10.0 vs. 15.0, P =0.06; V2: 7.0 vs. 15.0, P =0.05). CONCLUSIONS: The treatment that patients receive for IPMNs depends greatly on how their surgeons perceive the risk of cancer in the lesion. Efforts to improve cancer risk prediction for IPMNs may lead to decreased variations in care.

Segmental Versus Diffuse Main Duct Intraductal Papillary Mucinous Neoplasm: Examination of Main Pancreatic Duct Morphology and Implications for Malignancy Risk and Extent of Surgical Resection.

OBJECTIVE: To determine whether the morphologic features of the main pancreatic duct (MPD) of main-duct-involved-intraductal papillary mucinous neoplasm (IPMN) (ie, main duct or mixed main duct/side branch) have implications for the risk of malignancy and extent of resection. BACKGROUND: International consensus guidelines acknowledge the presence of various MPD morphologies (ie, diffuse vs segmental main-duct-involved-IPMN) without a precise definition of each entity and with limited data to guide treatment strategy. METHODS: All consecutive main-duct-involved-IPMN patients (2005-2019) with a MPD diameter ≥5 mm by cross-sectional imaging were reviewed from a prospective institutional database. Morphologic features of the MPD were correlated with the identification of high-grade dysplasia or pancreatic ductal adenocarcinoma (HGD/PDAC) by logistic regression modeling. In patients who underwent partial pancreatectomy, preoperative MPD morphologic features were correlated with the future development of HGD/PDAC in the pancreatic remnant by Cox hazards modeling. RESULTS: In a cohort of 214 main-duct-involved-IPMN patients, the overall rate of HGD/PDAC was 54.2%. MPD morphologic characteristics associated with HGD/PDAC included: maximal MPD diameter (5-10 mm: 29.8%; 10-14 mm: 59.0%; 15-19 mm: 78.6%; ≥20 mm: 95.8%; P <0.001), segmental extent of maximal dilation (<25%: 28.2%; 25%-49%: 54.9%; 50%-74%: 63.1%; ≥75%: 67.9%; P =0.002), and nonsegmental MPD diameter (<5 mm: 21.5% vs ≥5 mm: 78.5%, P <0.001). Diffuse MPD dilation involving ≥90% extent was rare (5.6%). After a median follow-up of 50 months, 7 (7.2%) patients who underwent partial pancreatectomy for IPMN without associated PDAC developed HGD/PDAC in the pancreatic remnant. Maximal MPD diameter, segmental extent of maximal dilation, or nonsegmental MPD diameter were not associated with the development of HGD/PDAC in the pancreatic remnant. However, a mural nodule on preoperative imaging was associated with the development of HGD/PDAC in the pancreatic remnant. CONCLUSIONS: "Diffuse" involvement with homogenous dilation of the MPD was rare. For the majority of patients with segmental main-duct-involved-IPMN, the MPD morphology conferred malignancy risk. Duct morphology was not predictive for the development of HGD or invasive disease in the pancreatic remnant, implying the safety of limited pancreatic resection for initial surgical management.

Surgical Margin of Resected Colorectal Liver Metastases:: How Accurate is Surgeon Prediction?

OBJECTIVE: The aim of this study was to describe the surgeon's ability to accurately predict the margin following resection of colorectal liver metastases (CRLM). SUMMARY BACKGROUND DATA: The decision to resect CRLM is based on the surgeon's ability to predict tumor free resection margins. However, to date, no study has evaluated the accuracy of surgeon margin prediction. METHODS: In this single-institution prospective study, the operating attending and fellow independently completed a preoperative and postoperative questionnaire describing their expected resection margin in 100 consecutive cases (200 assessments) of colorectal liver metastasis resections. In cases with multiple metastases, the closest margin was assessed as the margin of interest for the primary outcome. Surgeon assessments were compared to the gold-standard histopathologic assessment. RESULTS: After excluding aborted cases, 190 preoperative and 190 postoperative assessments from 95 cases were included in the analysis. The pathologic margin was noted to be wide (≥1 cm), 1 mm to 1 cm, narrow (<1 mm), and positive in 28 (29.5%), 55 (57.9%), 5 (5.3%), and 7 (7.4%) cases, respectively. The 88 cases with negative margins were all predicted to be negative. None of the cases with positive margins were predicted to be positive. Ninety-one (48%) preoperative and 104 (55%) postoperative predictions were accurate. The sensitivity of predicting a margin <1 mm was 8.3% preoperatively and 16.7% postoperatively. The positive predictive value for preoperative and postoperative predictions of margin <1 mm was 18.2% and 26.7%, respectively. CONCLUSIONS: Surgeons are inaccurate at predicting positive and close surgical margins following resection of CRLM. A predicted close margin should not necessarily preclude resection.

A Model to Predict Treatment Failure in Patients Undergoing Upfront Surgery for Resectable Colorectal Liver Metastases.

INTRODUCTION: Patients who recur in the first year after resection of colorectal liver metastases (CRLM) do poorly. The aim of our study was to predict treatment failure in patients undergoing upfront resection with a nomogram. METHODS: Data from patients resected between 1991 and 2019 were randomly split (70:30) into two cohorts. Treatment failure was defined as any recurrence or death within 12 months. A nomogram was constructed using multivariable logistic regression on the training cohort and validated using the testing cohort. RESULTS: Overall, 783 patients were included. Primary tumor characteristics included 50% left-sided: 75.2% T3/4 and 56.5% node-positive. The median disease-free interval was 10 months, median number of metastases was 1 (1-50), and with a median size of 3.6 cm (0.2-22); 222 (28.3%) patients recurred within 1 year. Recurrence was mostly extrahepatic with or without liver involvement (150/222, 67.6%). Curative-intent treatment was possible in 37.8% of these patients. Primary location, T-stage and node status, disease-free interval, and number and size of metastases were associated with treatment failure. The area under the curve from the validation of the model was 0.6 (95% confidence interval 0.52-0.68). Patients with a high-risk of treatment failure (≥40%) had a worse survival from the landmark time of 12 months from surgery compared with those with low-risk (2-years: 82% vs. 70%; p = 0.0002). CONCLUSIONS: Primary location, T stage, node status, disease-free interval, and number and size of metastases are associated with treatment failure. The survival of patients with a probability of treatment failure ≥40% is unfavorable. Future trials investigating the role of neoadjuvant therapy in these high-risk patients are warranted.

Combined Hepatic Arterial Infusion Pump and Systemic Chemotherapy in the Modern Era for Chemotherapy-Naive Patients with Unresectable Colorectal Liver Metastases.

PURPOSE: Chemotherapy-naive patients with unresectable colorectal liver metastases (CRLM) have been the best responders to hepatic arterial infusion (HAI) therapy. The current treatment paradigm has drifted away from HAI in the first-line setting. We aimed to analyze outcomes of combined first-line systemic therapy with HAI therapy (HAI+SYS) in the modern era. METHODS: We conducted a retrospective study of consecutive chemotherapy-naive patients with unresectable CRLM who received HAI+SYS between 2003 and 2019. Patients were selected from a prospectively maintained database. Outcomes included radiological response rate, conversion to resection (CTR) rate, and overall survival (OS). RESULTS: Fifty-eight chemotherapy-naive patients were identified out of 546 patients with unresectable CRLM managed with HAI. After induction treatment, 4 patients (7%) had a complete radiological response, including two durable responses. In total, 32 patients (55%) underwent CTR. CTR or complete response without resection was achieved after seven cycles of systemic therapy and four cycles of HAI therapy. Median OS for the whole cohort was 53.0 months (95% confidence interval 23.0-82.9). Three- and 5-year OS in patients who achieved CTR or complete response versus patients who did not was 88% and 72% versus 27% and 0% respectively. Of patients who underwent CTR, complete and major pathological response (no and <10% viable tumor cells, respectively) was observed in 7 (22%) and 12 patients (38%). CONCLUSIONS: Combined HAI+SYS in chemotherapy-naive patients resulted in durable and substantial response in a large proportion of patients. Nearly two-thirds of patients achieved a complete response or proceeded to conversion surgery, which was associated with prolonged survival.

Rates and Patterns of Recurrence After Microwave Ablation of Colorectal Liver Metastases: A Per Lesion Analysis of 416 Tumors in the Era of 2.45 GHz Generators.

BACKGROUND: For some patients with colorectal liver metastases (CRLMs), surgical resection of all visible disease can lead to long-term survival and even cure. When complete resection is not feasible, microwave ablation (MWA) can help achieve hepatic disease control. As modern 2.45-GHz MWA generators gain popularity, the characteristics of tumors most likely to benefit from this method remain unclear. This study aimed to evaluate local recurrence (LR) rates, patterns of recurrence, and factors contributing to treatment failure after 2.45-GHz MWA of CRLM. METHODS: Patients with CRLM who underwent operative 2.45-GHz MWA between 2011 and 2019 were identified in a prospectively maintained single-institution database. Recurrence outcomes were ascertained for each lesion by imaging review. Factors associated with LR were analyzed. RESULTS: The study enrolled 184 patients bearing 416 ablated tumors. Most of the patients (65.8%) had high clinical risk scores (3-5), and 165 (90%) underwent concurrent liver resection. The median tumor size was 10 mm. After a median follow-up period of 28.8 months, LR was observed in 45 tumors, and the cumulative incidence of LR at 24 months was 10.9% (95% confidence interval [CI], 8.0-14.3%]. In 7%, LR was the first recurrence site, often combined with recurrence elsewhere. The cumulative incidence of LR at 24 months was 6.8% (95% CI 3.8-11.0%) for tumors 10 mm in size or smaller, 12.4% (95% CI 7.8-18.1%) for tumors 11 to 20 mm in size, and 30.2% (95% CI 14.2-48.0%) for tumors larger than 20 mm. In the multivariable analysis, tumors larger than 20 mm with a subcapsular location were significantly associated with increased LR risk. CONCLUSIONS: Treatment of CRLM with 2.45-GHz MWA offers excellent local control at 2 years and is most successful for small tumors deep within the parenchyma.

Recurrence-free survival versus overall survival as a primary endpoint for studies of resected colorectal liver metastasis: a retrospective study and meta-analysis.

BACKGROUND: Recurrence-free survival has been used as a surrogate endpoint for overall survival in trials involving patients with resected colorectal liver metastases. We aimed to assess the correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases to determine the adequacy of this surrogate endpoint. METHODS: In this retrospective study and meta-analysis, we compiled an institutional cohort of consecutive patients who had complete resection of colorectal liver metastases from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) prospective database. Patients were eligible for inclusion if they were aged 18 years or older, and underwent hepatectomy, with or without operative ablation, between Jan 1, 1991, and April 30, 2019. We estimated overall survival and recurrence-free survival probabilities at various timepoints using the Kaplan-Meier method, and we assessed pairwise associations between these endpoints using Spearman's rank correlation. We also did a meta-analysis of adjuvant phase 3 clinical trials for colorectal liver metastases to assess the correlation between hazard ratios (HRs) for recurrence-free survival and overall survival. We searched MEDLINE for articles of phase 3 randomised controlled trials analysing adjuvant treatment strategies for resected colorectal metastases from database inception to Jan 1, 2022. The titles and abstracts of identified studies were screened before full-text screening and summary data were either recalculated or extracted manually from the published Kaplan-Meier curves (depending on data availability). FINDINGS: Data were available for 3299 patients in the institutional database, of whom 2983 were eligible for inclusion in our cohort. Median follow-up was 8·4 years (95% CI 7·9-9·1) , during which time there were 1995 (67%) disease recurrences and 1684 (56%) deaths. Median recurrence-free survival was 1·3 years (95% CI 1·3-1·4) and median overall survival was 5·2 years (95% CI 5·0-5·5). 1428 (85%) of 1684 deaths were preceded by recurrence, and median time from recurrence to death was 2·0 years (IQR 1·0-3·4). Pairwise correlations between recurrence-free survival and overall survival were low to moderate, with a correlation estimate ranging from 0·30 (SD 0·17) to 0·56 (0·13). In the meta-analysis of adjuvant clinical trials, the Spearman's correlation coefficient between recurrence-free survival HR and overall survival HR was r=0·20 (p=0·71). INTERPRETATION: We found a minimal correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases. Recurrence-free survival is an inadequate surrogate endpoint for overall survival in this disease setting. FUNDING: US National Cancer Institute.

Genomic Stratification of Resectable Colorectal Liver Metastasis Patients and Implications for Adjuvant Therapy and Survival.

OBJECTIVE: To determine whether genomic risk groups identified by somatic mutation testing of colorectal liver metastasis (CRLM) can be used for "molecularly-guided" selection for adjuvant systemic chemotherapy and hepatic artery infusion of FUDR (SYS+HAI-FUDR). BACKGROUND: Several genomic biomarkers have been associated with clinical phenotype and survival for patients with resectable CRLM. It is unknown whether prognostication afforded by genomic stratification translates into enhanced patient selection for adjuvant hepatic artery infusion therapy. METHODS: Consecutive patients with resected CRLM and available mutational characterization via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets were reviewed from a prospective institutional database. Patients were stratified into three genomic risk groups based on previously defined alterations in SMAD4, EGFR and the RAS/RAF pathway. The association between SYS+HAI-FUDR and overall survival, relative to adjuvant chemotherapy alone (SYS), was evaluated in each genomic risk group by Cox proportional hazard regression and propensity score matched analyses. RESULTS: A total of 334 patients (SYS+HAI-FUDR 204; SYS 130) were identified; the rates of RAS/RAF alterations and SMAD4 inactivation were 47.4% and 11.7%, respectively. After a median follow-up of 58 months, adjuvant SYS+HAI-FUDR was independently associated with a reduced risk of death (HR 0.50, 95%CI 0.26-0.98, P = 0.045) in the low-risk genomic group, but not in the moderate-risk (HR 1.07, 95%CI 0.5-2.07, P = 0.749) or high-risk (HR 1.62, 95%CI 0.29-9.12, P = 0.537) cohorts. Following propensity score matching, adjuvant SYS+HAI-FUDR remained associated with significant improvements in long-term survival selectively in the low-risk genomic cohort (5-year actuarial survival: 89% vs. 68%, P = 0.019). CONCLUSIONS: Genomic alterations in RAS/RAF, SMAD4, and EGFR may be useful to guide treatment selection in resectable CRLM patients and warrant external validation and integration in future clinical trial design.

Distinct Genomic Profiles are Associated With Conversion to Resection and Survival in Patients With Initially Unresectable Colorectal Liver Metastases Treated With Systemic and Hepatic Artery Chemotherapy.

OBJECTIVE: To examine genomic correlates of conversion to resection (CTR and overall survival (OS) in patients with initially unresectable colorectal liver metastasis (IU-CRLM) treated with combination systemic and hepatic artery infusion (HAI) chemotherapy. BACKGROUND: In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored. METHODS: Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation. RESULTS: Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range: 3-35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23,95% CI: 0.12-0.46, P < 0.001). The most frequently altered genes were APC (81%), TP53 (77%), and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations, any RAS pathway alterations, and co-altered RAS/RAF-TP53 mutations wereassociated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52, 95% CI: 1.37-4.64, P = 0.003) after controlling for CTR, number of liver metastases, and preoperative extrahepatic disease. CONCLUSIONS: Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9, BRAF , and co-altered RAS/RAF- TP53 mutations are promising biomarkers that, when validated in larger datasets, may impact treatment of IU-CRLM patients.

Multiinstitutional Validation Study of Cyst Fluid Protein Biomarkers in Patients With Cystic Lesions of the Pancreas.

OBJECTIVE: Prospective evaluation of 2 clinical-molecular models in patients with unknown pathology who underwent endoscopic ultrasound with fine-needle aspiration (EUS-FNA) for a cystic lesion of the pancreas. SUMMARY OF BACKGROUND DATA: Preoperative prediction of histologic subtype (mucinous vs nonmucinous) and grade of dysplasia in patients with pancreatic cystic neoplasms is challenging. Our group has previously published 2 clinical-molecular nomograms for intraductal papillary mucinous neoplasms (IPMN) that incorporated both clinical/radiographic features and cyst fluid protein markers (sFASL, CA72-4, MMP9, IL-4). METHODS: This multiinstitutional study enrolled patients who underwent EUS-FNA for a cystic lesion of the pancreas. Treatment recommendations regarding resection were based on standard clinical, radiographic, and endoscopic features. Predicted probabilities of high-risk IPMN (high-grade dysplasia/invasive cancer) were calculated using the previously developed clinical-molecular nomograms. RESULTS: Cyst fluid was obtained from 100 patients who underwent diagnostic EUS-FNA. Within this group there were 35 patients who underwent resection, and 65 were monitored radiographically. Within the group that underwent resection, 26 had low-risk IPMN or benign non-IPMN lesions, and 9 had high-risk IPMN. Within the surveillance group, no patient progressed to resection or developed cancer after a median follow-up of 12months (range: 0.5-38). Using the clinical/radiographic nomogram alone, 2 out of 9 patients with high-risk IPMN had a predicted probability >0.5. In the clinical-molecular models, 6 of 9 patients in model 1, and 6 of 9 in model 2, had scores >0.5. CONCLUSIONS: This prospective study of patients with unknown cyst pathology further demonstrates the importance of cyst fluid protein analysis in the preoperative identification of patients with high-risk IPMN. Longer follow-up is necessary to determine if this model will be useful in clinical practice.

Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIM: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS: This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.