Cleary, Sean P.

4097 Background: Given a high recurrence rate, surgical resection for localized intrahepatic cholangiocarcinoma (IHCC) is curative in only 30-35% of patients. BILCAP has established a standard of care for adjuvant therapy with monotherapy capecitabine. Gemcitabine, cisplatin and nab-paclitaxel combination chemotherapy (GAP) was associated with a response rate of 45% in biliary cancer and 20% of patients who were previously inoperable underwent margin negative resection. Based on these data, we conducted a neoadjuvant study of GAP for resectable but high-risk IHCC. Methods: A multi-institutional prospective single-arm phase II trial was conducted for patients with resectable high-risk disease, as defined by tumor size > 5cm, multiple tumors, presence of radiographic major vascular invasion, and lymph node involvement. Patients were administered 4 cycles (3 months) of preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2 and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of all therapy, including both preoperative chemotherapy and resection. Secondary endpoints were toxicity, radiologic response according to Response Evaluation Criteria in Solid Tumor (RECIST) criteria, RFS, and OS. Thirty evaluable patients provided 73% power to reject a null therapy completion rate of 50%, with a target completion rate of 70% using a one-sided exact test with a Type I error of 0.05. Results: Thirty-seven patients were screened and 30 evaluable patients were enrolled. The trial was sequentially activated at each of the 4 sites from 09/18-02/21 and the final patient was enrolled in 09/21. Median age was 60.5 years and 40% were female. Twenty-three patients (77%, 90% CI: 60.6-88.5%; p = 0.0026) completed all preoperative chemotherapy and underwent surgical resection. Ten patients (33%) experienced grade 3-4 treatment-related adverse events, the most common being neutropenia and diarrhea; 47% required at least one dose reduction. Partial response rate was 23% and disease control rate was 90% (PD: 10%, PR: 23%, SD: 67%). Of the 23 patients who successfully underwent surgical resection, 2 (9%) had minor postoperative complications. Median size of largest tumor was 5.5cm, median number of tumors was 3, and 39% were lymph node positive. Median length of hospital stay was 4 days. There was zero treatment related mortality. Conclusions: This study met its primary endpoint and demonstrated that neoadjuvant gemcitabine/cisplatin/nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes. Continued follow-up for RFS and OS with this treatment strategy is underway and larger validation studies are planned. Clinical trial information: NCT03579771.

Introduction Despite use of operative and non-operative interventions to reduce blood loss during liver resection, 20%–40% of patients receive a perioperative blood transfusion. Extensive intraoperative blood loss is a major risk factor for postoperative morbidity and mortality and receipt of blood transfusion is associated with serious risks including an association with long-term cancer recurrence and overall survival. In addition, blood products are scarce and associated with appreciable expense; decreasing blood transfusion requirements would therefore have health system benefits. Tranexamic acid (TXA), an antifibrinolytic, has been shown to reduce the probability of receiving a blood transfusion by one-third for patients undergoing cardiac or orthopaedic surgery. However, its applicability in liver resection has not been widely researched. Methods and analysis This protocol describes a prospective, blinded, randomised controlled trial being conducted at 10 sites in Canada and 1 in the USA. 1230 eligible and consenting participants will be randomised to one of two parallel groups: experimental (2 g of intravenous TXA) or placebo (saline) administered intraoperatively. The primary endpoint is receipt of blood transfusion within 7 days of surgery. Secondary outcomes include blood loss, postoperative complications, quality of life and 5-year disease-free and overall survival. Ethics and dissemination This trial has been approved by the research ethics boards at participating centres and Health Canada (parent control number 177992) and is currently enrolling participants. All participants will provide written informed consent. Results will be distributed widely through local and international meetings, presentation, publication and ClinicalTrials.gov. Trial registration number NCT02261415 .

Abstract Background Pancreatic neuroendocrine tumors (pNETs) are rare cancers with outcomes determined by multiple factors including grade, stage, and clinical presentation. In this study, we aimed to determine the prognosis of patients with pNETs using a large population-based database. Materials and Methods In this population-based study, we identified patients with pNETs from the SEER 18 registry (2000-2016) using a combination of ICD-O-3 and histology codes. We calculated age-adjusted incidence rates using SEER*Stat 8.3.5. In addition, we analyzed overall survival (OS) using the Kaplan-Meier method, and investigated prognostic factors using a multivariable Cox proportional hazards model. Results A total of 8944 pNETs patients were identified. Annual incidence rates increased from 0.27 to 1.00 per 100 000. This was largely explained by an increase in number of patients diagnosed with localized disease in more recent years (2012-2016). Median OS was 68 months (95% CI [64, 73]) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for patients diagnosed between 2009 and 2016 (median OS 85 months) compared with those diagnosed between 2000 and 2008 (median OS 46 months) (HR 0.66; 95% CI [0.62, 0.70]). This improvement in OS was consistent across all stages. Conclusions and Relevance This study shows a steady increase pNETs incidence with notable stage migration to earlier stages in recent years. This increase in incidence is accompanied by a significant improvement in survival across different disease stages.

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

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10‐5) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10‐6). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68Ga‐PSMA‐11 standardized uptake value: SUVmax (median [range] 9.2 [4.9‐28.4]), SUVmean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

Abstract Background and Objectives Pancreatic neuroendocrine tumors (pNETs) in patients with hereditary cancer syndromes are typically multifocal. In contrast, sporadic pNETs are usually unifocal and the incidence of multifocal sporadic pNETs is unknown. The primary aim of this study was to investigate the incidence of multifocality in sporadic pNETs and any associated effect on recurrence risk and survival. Methods Patients who underwent resection of pNETs at Mayo Clinic from 2000 to 2019 were identified and clinical data were obtained from medical records. Syndromic disease was defined as pNETs arising in the setting of a hereditary cancer syndrome. Statistical comparisons were made using χ 2 , Fisher's exact, and Kruskal–Wallis tests and survival was assessed using the Kaplan–Meier method. Results Six hundred and sixty‐one patients with sporadic pNETs and fifty‐nine with syndromic pNETs were identified. Multifocal disease was present in 4.8% of sporadic patients and 84.7% of syndromic patients ( p < .001). Within patients with sporadic pNETs, clinicopathologic features and recurrence‐free and overall survival were similar between patients with unifocal and multifocal disease. Conclusions Multifocal sporadic pNETs are rare and multifocality is not associated with worse survival or increased recurrence risk. Patients with multifocal sporadic pNETs can likely be safely managed with a combination of resection and observation as indicated for each tumor.

AbstractIntroductionAlthough surgical resection is necessary, it is not sufficient for long‐term survival in pancreatic ductal adenocarcinoma (PDAC). We sought to evaluate survival after up‐front surgery (UFS) in anatomically resectable PDAC in the context of three critical factors: (A) margin status; (B) CA19‐9; and (C) receipt of adjuvant chemotherapy.MethodsThe National Cancer Data Base (2010–2015) was reviewed for clinically resectable (stage 0/I/II) PDAC patients. Surgical margins, pre‐operative CA19‐9, and receipt of adjuvant chemotherapy were evaluated. Patient overall survival was stratified based on these factors and their respective combinations. Outcomes after UFS were compared to equivalently staged patients after neoadjuvant chemotherapy on an intention‐to‐treat (ITT) basis.ResultsTwelve thousand and eighty‐nine patients were included (n = 9197 UFS, n = 2892 ITT neoadjuvant). In the UFS cohort, only 20.4% had all three factors (median OS = 31.2 months). Nearly 1/3rd (32.7%) of UFS patients had none or only one factor with concomitant worst survival (median OS = 14.7 months). Survival after UFS decreased with each failing factor (two factors: 23 months, one factor: 15.5 months, no factors: 7.9 months) and this persisted after adjustment. Overall survival was superior in the ITT‐neoadjuvant cohort (27.9 vs. 22 months) to UFS.ConclusionDespite the perceived benefit of UFS, only 1‐in‐5 UFS patients actually realize maximal survival when known factors highly associated with outcomes are assessed. Patients are proportionally more likely to do worst, rather than best after UFS treatment. Similarly staged patients undergoing ITT‐neoadjuvant therapy achieve survival superior to the majority of UFS patients. Patients and providers should be aware of the false perception of ‘optimal’ survival benefit with UFS in anatomically resectable PDAC.

Abstract Background: Mixed acinar neuroendocrine carcinoma (MANEC) of the pancreas is an extremely rare histopathologic subtype. MANEC is an amphicrine malignancy composed of at least 25% of acinar cell carcinoma (PACC) and neuroendocrine carcinoma (pNET). No standard systemic treatment is available for MANEC and current recommendations are derived from standard of care for PACC or pNET. Platinum based regimens have been approved for PACC while targeted agents (sunitinib and everolimus) are approved for pNET. This study aimed to investigate the antitumor effect and toxicities of both platinum based and targeted agents on a successfully first described patient derived xenograft (PDX) of metastatic MANEC of the pancreas. Methods: Several generations of PDX from a surgically resected metastatic MANEC of the pancreas was histologically validated. PDX-MANEC tumors were heterotopically implanted into NOD/SCID mice and randomized into 6 groups (4 mice each) as in table 1. The study continued for 3 weeks. Antitumor efficacy was determined based on change in the tumor volume. Toxicity was assessed change in mice weights. Results: Table 1 shows the changes in tumor volume and mouse weight in all study arms compared to controls end point. Only FOLFIRINOX and gemcitabine/cisplatin arms revealed overall decrease in tumor volume lower than starting volume in controls. All arms other than sunitinib, led to decrease in overall tumor volume compared to control tumor volumes over time. All treatment arms led to lower trending mouse weights (toxicities) except sunitinib, however only the everolimus arm had statistical significance. Conclusion: Both platinum-based regimens and everolimus revealed significant tumor control. No synergistic effect observed in sunitinib/everolimus. Preclinical studies are undergoing to investigate other effective and less toxic therapeutics for MANEC. Table 1.Delta in tumor volumes of PDX-MANEC-P after multiple platinum-based chemotherapy regimens and targeted therapeutics from the standard of care for other pancreatic cancer subtypes including PACC and pNET.ControlFOLFIRINOXGemcitabine and CisplatinSunitinibEverolimusSunitinib and EverolimusDelta in tumor volume in mm3 at the study end (mean ± standard deviation)3225 ± 2054-609.3 ± 351.8-654.7 ± 92.561583 ± 950.3-178.1 ± 61.58-160.8 ± 86.55P value (column group vs. control)&lt;0.0010.0030.0950.0010.001Delta in mice weight in grams at the study end (mean ± standard deviation)0.84 ± 1.68-1.26 ± 0.84-8.5 ± 1.630.86 ± 1.22-2.2 ± 1.61-1.42 ± 1.27P value (column group vs. control)0.058&lt;0.0010.9810.0070.050 Citation Format: Amro M. Abdelrahman, Jennifer A. Yonkus, Roberto Alva-Ruiz, Jennifer L. Leiting, Nellie A. Campbell, Lewis R. Roberts, Michael L. Kendrick, David M. Nagorney, Sean P. Cleary, Travis E. Grotz, Gregory J. Gores, Jun Yin, Rondell P. Graham, Thorvardur R. Halfdanarson, Rory L. Smoot, Mark J. Truty. Preclinical efficacy of platinum based chemotherapy regimens and targeted therapeutics in the first successful described patient derived xenograft model of mixed acinar neuroendocrine carcinoma of the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 413.

Abstract Background Aspartate aminotransferase/platelet ratio index (APRI) and albumin–bilirubin grade (ALBI) are validated prognostic indices implicated as predictors of postoperative liver dysfunction after hepatic resection. The aim of this study was to evaluate the relevance of the combined APRI/ALBI score for postoperative clinically meaningful outcomes. Methods Patients undergoing hepatectomy were included from the American College of Surgeons National Surgical Quality Improvement Program database. The association between APRI/ALBI score and postoperative grade C liver dysfunction, liver dysfunction-associated and overall 30-day mortality was assessed. Results A total of 12 055 patients undergoing hepatic resection from 2014 to 2017 with preoperative blood values and detailed 30-day postoperative outcomes were included (exploration cohort: January 2014 to December 2016; validation cohort: 2017). In the exploration cohort (8538 patients), the combination of both scores (APRI/ALBI) was significantly associated with postoperative grade C liver dysfunction, 30-day mortality, and liver dysfunction-associated 30-day mortality, and was superior to either score alone. The association with postoperative 30-day mortality was confirmed in multivariable analysis. A predictive model was generated using the exploration cohort. The predicted incidence of events closely followed the observed incidence in the validation cohort (3517 patients). Subgroup analyses of tumour types were used to generate disease-specific risk models to assess risk in different clinical scenarios. These findings informed development of a smartphone application (https://tellaprialbi.37binary.com). Conclusion The predictive potential of the combined APRI/ALBI score for clinically relevant outcomes such as mortality was demonstrated. An evidence-based smartphone application will allow clinical translation and facilitation of risk assessment before hepatic resection using routine laboratory parameters.

Objective: The aim of this work is to formulate recommendations based on global expert consensus to guide the surgical community on the safe resumption of surgical and endoscopic activities. Background: The COVID-19 pandemic has caused marked disruptions in the delivery of surgical care worldwide. A thoughtful, structured approach to resuming surgical services is necessary as the impact of COVID-19 becomes better controlled. The Coronavirus Global Surgical Collaborative sought to formulate, through rigorous scientific methodology, consensus-based recommendations in collaboration with a multidisciplinary group of international experts and policymakers. Methods: Recommendations were developed following a Delphi process. Domain topics were formulated and subsequently subdivided into questions pertinent to different aspects of surgical care in the COVID-19 crisis. Forty-four experts from 15 countries across 4 continents drafted statements based on the specific questions. Anonymous Delphi voting on the statements was performed in 2 rounds, as well as in a telepresence meeting. Results: One hundred statements were formulated across 10 domains. The statements addressed terminology, impact on procedural services, patient/staff safety, managing a backlog of surgeries, methods to restart and sustain surgical services, education, and research. Eighty-three of the statements were approved during the first round of Delphi voting, and 11 during the second round. A final telepresence meeting and discussion yielded acceptance of 5 other statements. Conclusions: The Delphi process resulted in 99 recommendations. These consensus statements provide expert guidance, based on scientific methodology, for the safe resumption of surgical activities during the COVID-19 pandemic.