bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcome associated with neoadjuvant chemoradiation and orthotopic liver transplantation versus definitive chemoradiation in 49 patients with unresectable, hilar, or extrahepatic cholangiocarcinoma.
Authors: Laughlin Brady S. , Petersen Molly M. , Ashman Jonathan Ben , Rule William G. , Borad Mitesh J. , Aqel Bashar A. , Sonbol Mohamad Bassam , Bekaii-Saab Tanios S. , Ahn Daniel H. , Yu Nathan Y. , DeWees Todd , Sio Terence Tai Weng
Published: February 2020

494

Background: Our aim was to compare survival between patients receiving neoadjuvant chemoradiation and orthotopic liver transplantation (OLT group) versus definitive chemoradiation (CRT group) for extrahepatic or hilar cholangiocarcinoma. Methods: 49 patients (20 in OLT group vs. 29 in CRT group) with unresectable hilar/extrahepatic cholangiocarcinoma were treated at Mayo Clinic Arizona between Feb. 1998–Sep. 2019. Treatment included external beam radiation therapy (median 4500cGy) and boost (median 900cGy) with either continuous 5-flurouracil (dose range 180–225 mg/m2) or capecitabine (dose range 825–1000 mg/m2 BID) prior to or without OLT. Radiation boosts were delivered with EBRT or bile duct brachytherapy. Patients were between 27.9–84.3 years (median 64.3) at diagnosis. 18 patients had previous diagnosis of PSC. Results: Between Feb. 1998–Sep. 2019, 31(63%) of 49 patients died by the end of follow-up. Of patients treated with neoadjuvant therapy and OLT, 7(35%) of 20 patients died. 24(86%) of 28 patients treated with definitive therapy died. The OLT cohort were younger (mean age 56.5 vs. 69.0 years), more likely to have PSC and UC (65% vs. 17%), and had a lower CA 19-9 (median 43 vs. 535)(P < 0.003). From the end date of radiation, median overall survival was 76.8 months vs. 15.6 months for the OLT and CRT groups, respectively. Survival rates at 3 and 5 years were 78% and 69% in the OLT group compared to 19% and 6% in the CRT group (HR 7.73; 3.04-19.65:(P < 0.0001)). Progression-free survival (89% vs. 30% at 3 years), and distant metastasis-free survival (88% vs. 66% at 3 years) favored OLT versus CRT alone (HR 5.74;1.12-29.34:(P < 0.02)). Univariate analysis demonstrated that the method of treatment (OLT vs. CRT) was the only variable associated with better clinical outcomes. Conclusions: In patients with unresectable extrahepatic/hilar cholangiocarcinoma, survival was higher in those who underwent chemoradiation and OLT. Patients who received definitive chemoradiation in the absence of OLT were expected to have worse overall, progression-free, and metastasis-free survival.
Variations in surgical treatment of stage I gallbladder carcinoma impacts survival.
Authors: Scholer Anthony Joseph , Garland-Kledzik Mary , Wang Mansen , Khader Adam , Santamaria-Barria Juan , Jutric Zeljka , Wolf Ronald , Goldfarb Melanie
Published: February 2020

495

Background: Variations in surgical care for stage I gallbladder carcinoma (GBC) may be associated with inferior outcomes. The aim of this study was to identify the variations in surgical treatment of GBC. Methods: All patients diagnosed with stage I GBC by AJCC 8 criteria from 2004-2013 were identified in the NCDB. Surgical treatment was categorized as cholecystectomy (C), cholecystectomy with lymph node dissection (C+LND), or radical cholecystectomy (RC). Independent predictors of improved overall survival (OS) and extent of surgery were identified by multinomial regression analyses. Results: Of 1756 patients with stage I GBC, 26% were T1a, 56% T1b, and 18.5% T1NOS. The majority were White non-Hispanic (61.8%) and female (68.5%), with 55.1% > 70 years of age. Two-thirds of T1a tumors were treated with more aggressive surgery (28% C+LND, 4.2% RC), which did not differ by age. However, only 44.4% of patients with T1b tumors had more aggressive surgery, which was significantly less likely in patients > 70 years, even after controlling for other factors (C+LND (OR:0.60; CI:0.44-0.81), RC (OR:0.52; CI:0.29-0.91)). Five-year OS was 54.34% for T1a and 43.05% for T1b (p = 0.02). After controlling for other factors, both C+LND (HR:0.46, CI:0.26-0.81) and RC (HR:0.31, CI:0.16-0.62) significantly improved 5-year OS for T1b tumors, whereas RC also improved 5-year OS for all patients > 70 years old (p = 0.04). Conclusions: A majority of patients with T1b GBC had less than adequate surgery by the current AJCC staging, which significantly decreased survival in all patients. This was especially evident in older patients who were also the least likely to receive more aggressive surgery.
Utility of circulating tumor DNA (ctDNA) versus tumor tissue clinical sequencing for enrolling patients (Pts) with advanced gastrointestinal (GI) cancer to matched clinical trials: SCRUM-Japan GI-SCREEN and GOZILA Combined Analysis.
Authors: Nakamura Yoshiaki , Taniguchi Hiroya , Bando Hideaki , Kato Ken , Esaki Taito , Komatsu Yoshito , Takahashi Naoki , Ueno Makoto , Kagawa Yoshinori , Nishina Tomohiro , Kato Takeshi , Yamamoto Yoshiyuki , Furuse Junji , Denda Tadamichi , Kawakami Hisato , Oki Eiji , Sunakawa Yu , Satoh Taroh , Yoshino Takayuki , Ohtsu Atsushi
Published: February 2020

5

Background: Blood-based genomic profiling by ctDNA analysis has a promise to potentially identify actionable genomic alterations. However, utility of clinical sequencing with ctDNA compared with that with tumor tissue for enrolling cancer pts to matched clinical trials remains unclear. Herein we investigated the utility of ctDNA clinical sequencing by the SCRUM-Japan GI-SCREEN and GOZILA Combined Analysis. Methods: In the GI-SCREEN, tumor tissue samples of pts with advanced GI cancer were analyzed by a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay since Feb 2015. In the GOZILA, plasma samples of pts with advanced GI cancer were analyzed by an NGS-based ctDNA assay, Guardant360 since Feb 2018. Tests were performed centrally by CLIA-certified and CAP-accredited laboratories. Pts with actionable alterations were enrolled to matched company-sponsored or investigator-initiated clinical trials. Results: As of Apr 2019, test results were generated in 5,029 out of 5,743 pts (88%) in GI-SCREEN and 1,089 out of 1,103 pts (99%) in GOZILA ( P < 0.0001).Median turnaround time (TAT) was 35 days in GI-SCREEN and 12 days in GOZILA ( P < 0.0001). There were no differences in other baseline characteristics between GI-SCREEN and GOZILA. Proportion of enrolling matched clinical trials in GOZILA was significantly higher than that in GI-SCREEN (126 pts [2.2%] in GI-SCREEN vs. 60 pts [5.4%] in GOZILA, P < 0.0001). Median time from GI-SCREEN or GOZILA enrollment to clinical trial enrollment was 5.9 and 1.0 months (mo), respectively ( P < 0.0001). The objective response rate (ORR) and progression-free survival (PFS) were not significantly different (ORR: 17.5 vs. 16.7%, P = 1.00; median PFS: 2.8 vs. 2.0 mo, P = 0.24). Conclusions: Clinical sequencing with ctDNA having the advantage of the shorter TAT enrolled more pts with advanced GI cancer to matched clinical trials than those with tumor tissue, without compromising the efficacy. Clinical trial information: UMIN000029315.
Role of hepatologists in management of hepatocellular carcinoma in the new era of transplant oncology.
Authors: Ashat Divya , Karwal Mark , Sun Shiliang , Laroia Sandeep , Tanaka Tomohiro
Published: February 2020

501

Background: There have been global efforts to manage hepatobiliary malignancies such as hepatocellular carcinoma (HCC) in a multidisciplinary setting under the concept of transplant oncology. We published preliminary data of hepatology-directed treatment of HCC (Ann Hepatol 2019). However, the actual role of hepatologists in this setting is not well defined. Methods: We evaluated 107 patients with newly diagnosed HCC, undergoing locoregional therapy (LRT) as a first therapy (microwave ablation, TACE, TARE or SBRT) in our institution between 1/2017 to 2/2019 and being followed until 8/2019. Patients were divided into three groups based on referral pathways: outside referral directly to oncologists (O-group, n=24), internal referral from hepatologists to oncologists (H/O-group, n=62) and hepatologist directed HCC treatment (H-group, n=21). The hepatologist performed all microwave ablations in H-group; rest of the LRTs were performed by either interventional radiology or radiation oncology. Results: The baseline gender, etiology of liver disease, MELD score, Child-Pugh score, BCLC stage, CLIP score, AFP and proportion of patients within Milan criteria were similar between 3 groups ( p=n.s.). However, O-group included older patients (median 70 vs 63/62 y.o., p<0.01), and had larger HCC size (median diameter 41 vs 26/28mm, p<0.01). In H-group, there were more cases discussed in multidisciplinary tumor boards (77% vs 46%, p=0.012) and referrals for liver transplantation (71% versus 50%, p=0.046). Time between the diagnosis and the first procedure was shorter in H-group than others (median 53 vs 69 days, p=0.048). The rate of complete response/partial response per mRECIST criteria was highest in H-group (91 vs 66%, p=0.024). The 2-year cumulative survival was comparable among three groups (70, 74 and 76% in O-group, H/O-group and H-group, respectively, p=0.4). Conclusions: Hepatologists are often the first point of contact and can play a key (and even more direct) role in subsequent management of HCC. To further accomplish the concept of multidisciplinary approach and transplant oncology, primary/secondary care institutions might be a potential target for intervention for outreach.
Determination of quality of care for patients with hepatocellular carcinoma in Nova Scotia.
Authors: Ouellet Cathie , Ramjeesingh Ravi
Published: February 2020

506

Background: Hepatocellular carcinoma (HCC) is the most common primary malignancy found in the liver. Little is known about the outcomes of HCC patients in the province of Nova Scotia (NS). There is suggestion that closer proximity to tertiary cancer center provides better outcomes for HCC patients. We postulate that cancer care for HCC patients differs based on a patient’s accessibility to an academic cancer care center. Methods: A retrospective chart review of HCC patients diagnosed from 2015 to 2017, looking at referrals patterns, treatments and wait time was undertaken. Patients who live within the urban area of Halifax, NS (N = 97), where the academic cancer center is, was compared to patients who live outside Halifax (rural, N = 70). Results: 167 patients were identified with a diagnosis of HCC, which included 139 males and 28 females with median age of 68 years old at HCC diagnosis. During that period, only 35.3% of patients diagnosed with HCC had a tissue diagnosis and 67.7% had a baseline AFP (16% had an AFP > 400). Just over 76% were diagnosed based on clinical features. Surgical intervention occurred in 15.6% and local treatments including radiation and TACE occurred in 35.3% of patients .Referral rate to Medical Oncology (MO) was 37.7%, of which 34.1% of patients had seen a MO at the time of data cut off (09-15-2019). 22 patients were eligible for systemic therapy but only 14 patients received systemic treatment (sorafenib n = 14). Conclusions: Initial data suggests patients who live in Halifax appear to have better outcomes than those outside. Further analysis is required to identify what differs between the urban and rural centers accounting for the seen difference in survival.

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Clinical and genomic factors associated with outcome following ablative radiotherapy for oligometastatic and oligoprogressive liver tumors.
Authors: Bitterman Danielle Sara , Niemierko Andrzej , Van Seventer Emily E. , Kim Daniel W. , Qadan Motaz , Blaszkowsky Lawrence Scott , Clark Jeffrey William , Zhu Andrew X. , Goyal Lipika , Keane Florence , Eyler Christine Elissa , Parikh Aparna Raj , Corcoran Ryan Bruce , Wo Jennifer Yon-Li , Hong Theodore S.
Published: February 2020

515

Background: There is increasing use of ablative radiotherapy (RT) for oligometastatic and/or oligoprogressive cancer, but the population who may benefit from this more aggressive treatment remains poorly defined. We aimed to identify factors associated with improved outcomes following ablative RT for oligometastatic/oligoprogressive liver tumors. Methods: We retrospectively analyzed 106 patients who had tumor genomic profiling and received a 5, 6, or 15-fraction course of ablative RT for liver metastases from 2008-2019. The interval off systemic therapy post-RT was calculated for patients who did not continue treatment through RT. Overall survival (OS) was estimated using the Kaplan-Meier method. The association between clinical and genomic variables and OS were assessed using uni- and multivariable Cox regression. Results: Median follow-up was 12.6 months. Median age was 61.3 years and 57% were male. The most common primary site was colorectum (42%), followed by pancreas (25%) and non-small cell lung cancer (10%). 42% had colorectal adenocarcinoma, 46% had other adenocarcinoma, and 12% had other histology. A BRAF/RAS family mutation (KRAS, NRAS, and/or BRAF) was present in 41%, 69% had > 1 metastasis, and 38% had extra-hepatic disease. Median biological effective dose (α/β = 10) (BED) was 92 Gy. The RT field encompassed all liver metastases in 91%, and 11% received radiosensitizing chemotherapy. Median time off systemic agents was 5 months. Patients with 1 vs > 1 metastasis had a longer interval off systemic therapy (9 vs 4 months, p = 0.026). Median OS was 12.6 months. The table shows the multivariable Cox model for OS. Conclusions: Presence of a BRAF/RAS family mutation, extra-hepatic metastases, exclusion of liver metastases from RT fields, lower BED, and concurrent radiosensitizing chemotherapy were associated with worse OS. This may inform patient selection and RT delivery for aggressive local therapy for liver metastases.

[Table: see text]
Real-world treatment patterns and survival in patients (pts) with hepatocellular carcinoma in the United States.
Authors: Morse Michael , Meyer Anne-Marie , Lawrance Marcus , Pereira Marta , Mhatre Shivani K. , Gaillard Vincent , Dayyani Farshid
Published: February 2020

519

Background: Outcomes in pts with hepatocellular carcinoma (HCC) vary by epidemiology, degree of hepatic dysfunction and tx. We analyzed the relationship between tx patterns and outcomes to help characterize emerging clinical data in the context of contemporary disease management. Methods: Retrospective observational study of the Flatiron Health de-identified electronic health record–derived database to analyze the relationship between first recorded tx (1tx) and overall survival (OS) in pts diagnosed with HCC (any stage) Jan 2011 to Nov 2018. Tx categories included transplant, resection/SBRT/RFA, TACE/TARE/TAE, tyrosine kinase inhibitor (TKI), cancer immunotherapy (CIT), and others. Descriptive statistics were used to summarize tx distribution and pt characteristics; Kaplan-Meier method was used to estimate OS by tx category. Results: A total of 2134 pts with HCC were categorized by 1tx: transplant (n = 35), resection/SBRT/RFA (n = 408), TACE/TARE/TAE (n = 830), TKI (n = 751), and CIT (n = 20). Pt demographics were generally similar across txs (Table). Overall, pts with HCC had a median OS of 16.6 mo; varying from 71.5 mo in pts receiving transplant to 5.0 mo in pts treated with TKI. Conclusions: Pts receiving systemic tx for HCC have poor prognoses in clinical practice. Despite the limitations of data availability, this study showed a substantial unmet need for more effective HCC tx options.

[Table: see text]
RECIST v1.1 and irRECIST outcomes in advanced HCC treated with pembrolizumab (pembro).
Authors: Edeline Julien , Karwal Mark , Zhu Andrew X. , Finn Richard S. , Cattan Stéphane , Ogasawara Sadahisa , Verslype Chris , Dadduzio Vincenzo , Fartoux Laetitia , Vogel Arndt , Rosmorduc Olivier , Verset Gontran , Chan Stephen Lam , Knox Jennifer J. , Daniele Bruno , Cheng Ann-Lii , Goldmacher Gregory V. , Jensen Erin , Siegel Abby B. , Kudo Masatoshi
Published: February 2020

528

Background: IO can cause pseudoprogression (PP): apparent tumor growth followed by stability or favorable response. We assess PP in aHCC treated with pembro (KEYNOTE-224 [ph 2], NCT02702414; KEYNOTE-240 [ph 3], NCT02702401). Methods: aHCC pts with PD on/intolerance to sorafenib received pembro 200 mg IV Q3W until unacceptable toxicity, study withdrawal, 2 y of therapy, or RECIST v1.1 PD; if pt clinically stable at PD, physician could continue therapy and repeat scans to confirm PD per irRECIST. PP=RECIST v1.1 PD then irRECIST response other than PD. Data cutoff: Jan 02, 2019 (KEYNOTE-240); Feb 13, 2018 (KEYNOTE-224). Results: 245/382 pembro-treated pts had RECIST v1.1 PD: 138 irRECIST repeat scan; 105 PD; 33 (8.6%; 33/382) outcomes other than PD. Of 33 PP, 29 had SD, 3 PR, 1 CR (irRECIST; 29 had this at first irRECIST scan; 4 [2 SD, 2 PR] at subsequent scan). For initial RECIST v1.1 PD, 16/33 PP had PD at first postbaseline scan (pembro cycles 2-4); 17/33 PP had PD at pembro cycles 4-18. Median (range) time to RECIST v1.1 PD in the 33 PP was 80 (37-378) days. OS shown in Table. KEYNOTE-240 had 135 PBO-treated pts: 8 (5.9%) PP; small samples bar meaningful interpretation. Conclusions: PP in aHCC, per irRECIST, has a similar incidence to other cancers (eg, melanoma) and does not seem to correlate with OS. Data may help physicians assess when to continue pembro after PD. Clinical trial information: NCT02702414, NCT02702401.

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Patient-reported outcomes (PRO) before and after colorectal cancer (CRC) by race in a national survey.
Authors: Barzi Afsaneh , Jiao Xiayu , Farias Albert John
Published: February 2020

53

Background: There is significant disparities in the incidence, stage at diagnosis, and survival of CRC by race, however there is little evidence for disparities in patient reported health—an important quality of care metric. The SEER-CAHPS database (A linkage of Surveillance Epidemiology and End Results registry with Consumer Assessment of Healthcare Providers and Systems surveys) was used to explore the impact of CRC diagnosis on PRO. Methods: PRO was assessed by general health (GH) and mental health (MH). Responses of fair & poor to survey questions were classified as “modest”; and responses of excellent, very good, & good as “decent”. The responses were compared for surveys within 4 year window before or after CRC diagnosis. Logistic regression was used to identify variables associated with decline from decent to modest in the GH and MH. Results: The distribution of available surveys and outcome categories are presented in Table. CRC diagnosis was associated with a decline in MH (OR 1.42 95% CI 1.09 – 1.86 p-value < 0.05) and GH (OR 1.40 95% CI 1.17 – 1.67 p-value < 0.01). There was no association between race and decline in GH. However, compared to Whites, Blacks experienced lower odds of decline in MH (OR 0.396, 95% CI 0.185 - 0.848 p-value < 0.05). Hispanics had a trend for more pronounced decline in MH (OR 1.772, p value= 0.098). Tumor stage at diagnosis was a predictor of poorer GH (OR 1.75 95% CI 1.40 - 2.19 p-value < 0.01) and MH (OR 1.37 95% CI 1.00 - 1.87 p value = 0.048). Survey characteristics. Conclusions: Diagnosis of CRC is associated with decline in GH and MH across all racial groups, with worse MH and GH in patients with later stages of disease. Minorities experience gereater declines in MH.

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Respiratory-gated magnetic resonance image guided radiation therapy for hepatocellular carcinoma: A pilot study.
Authors: Kang Hyun-Cheol , Kim Jin Ho , Chie Eui Kyu
Published: February 2020

532

Background: Hypofractionated RT has shown encouraging results in hepatocellular carcinoma (HCC) patients. However, HCC adjacent to the gastrointestnal (GI) tract should be carefully treated using the high-precision irradiation technique due to risk of radiation damage. We evaluated the feasibility of a respiratory-gated magnetic resonance image guided radiation therapy (RgMRg-RT) for hepatocellular carcinoma (HCC). Methods: Thirty-three patients with HCC underwent RgMRg-RT in our hospital from 2015 to February 2019, including patients with Child-Pugh A/B7 cirrhosis and unresectable tumors near the gastrointestinal tract. The median radiation dose was 50 Gy (range, 25–60) and median fraction number was 5 (range, 4–15). Gating was performed based on real-time magnetic resonance image without an external surrogate. Results: The median follow-up period was 11.7 months (range, 3.6–37.9 months). The rates of local control of the target tumor at 6 months and 1 year were 90.2 and 86.9%, respectively. The overall survival rates at 6 months, 1, and 2 years were 84.3, 76.3, and 61%, respectively. The median distances from gross tumor to the esophagus, stomach, duodenum and colon were 6.1 (range, 1.9-14.3), 6.4 (0-13.4), 3.8 (0-13.5) and 4cm (0.3-13), respectively. A total of 15 tumors (45.5%) were located within 2 cm of the gastrointestinal tract and 9 tumors (27.3%) within 1cm. Grades 3 treatment‐related bleeding was observed in one patient and one patient had radiation‐induced liver disease. Conclusions: Hypofractionated RgMRg-RT was a safe and potentially ablative therapy for HCC. RgMRg-RT is a good alternative treatment for patients with HCCs that are unsuitable for surgical resection or local ablative therapy.
Role of para-aortic lymph node sampling for patients with potentially resectable biliary cancer.
Authors: Ito Hiromichi , Ono Yoshihiro , Sato Takafumi , Inoue Yosuke , Takahashi Yu
Published: February 2020

540

Background: While paraaortic lymph node (PALN) metastasis has been known as poor prognostic indicator for patients with biliary cancer and is regarded as distant metastasis in AJCC staging system. However, preoperative diagnosis of PALN metastasis by current imaging studies is not accurate and the incidence of PALN metastasis among patients with potentially resectable biliary cancer and its impact on their long-term outcomes remain unclear. Methods: The patients who underwent exploratory laparotomy with PALN sampling for potentially resectable biliary cancer at our institution from 2006 through 2018 were included. All patients were appropriately staged preoperatively with CT/MRI and patients with suspected PALN metastasis preoperatively were not considered resectable disease, and thus, such patients were not included. The incidence of PALN metastasis and long-term outcomes (recurrence-free and overall survivals [RFS, OS]) for patients with/without PALN metastasis were compared. Results: Total 383 patients with three types of biliary cancers (164 perihilar cholangiocarcinoma [PHCC], 115 distal cholangiocarcinoma [DCC] and 104 gallbladder cancer [GBCA]) were included. The median age was 71 years and 65% were man. Majority of them (362 patients [95%]) completed planned resection and 9 patients (2%) died of post-operative complications. PALN metastasis was confirmed on 33 patients (9%) among the entire cohort; the yield of positive PALN sampling was the highest in the patients with GBCA (14%), followed by 9% in those with PHCC and 4% in those with DCC. Among 33 patients with positive PALN, 20 underwent tumor resection. Median RFS and OS following resection for the patients with PALN metastasis were 11 months and 22 months, respectively, compared to 46 months and 56 months for those without, respectively ( p< 0.001 for both RFS and OS). There were no survivors beyond 5-years among those with PALN metastasis. Conclusions: The yield of routine intraoperative PALN sampling is not small even among patients with potentially resectable biliary cancer and positive PALN indicates poor long-term outcomes. This procedure can provide the opportunity to avoid morbid operation for patients who unlikely benefits.
Irreversible electroporation of the bile duct in swine: A pilot study.
Authors: Kim Sang Hyun , Lee Jae Min , Lee Kang Won , Kim Sang Hoon , Jang Se Hyun , Jeon Han Jo , Choi Seong Ji , Choi Hyuk Soon , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Chun Hoon Jai , Lee Hong Sik , Kim Chang Duck ,   Department of Gastroenterology, Korea University Anam Hospital
Published: February 2020

541

Background: Irreversible electroporation (IRE) is a relatively new ablative method. However, the application of IRE ablation has not been attempted for the treatment of biliary disease. Minimally invasive approach using endoscopic retrograde cholangio-pancreatography (ERCP) can be a novel therapeutic modality for IRE ablation. In this study, we investigated the feasibility and effect of endoscopic IRE for biliary tract in animal model. Methods: A new catheter electrode was developed for endoscopic IRE ablation of biliary tract. The electrode for IRE ablation has two band-shaped electrodes on catheter tip. We performed ERCP and endoscopic IRE ablations on normal common bile duct in 6 Yorkshire pigs. Experimental parameters of IRE were 500V/cm, 1000V/cm and 2000V/cm (under 50 pulses, 100 µs length). Animals were sacrificed after 24 hours and ablated bile duct were collected. H & E stain, immunohistochemistry and western blot were performed. Results: Well-demarcated focal color changes were observed on the mucosa of the common bile duct under all experimental parameters. After IRE ablation, bile duct epithelium was disappeared around ablated area and it showed fibrotic change in H&E stain. Depth of change after IRE was different between each experimental parameters. Apoptotic change of bile duct was localized around mucosa in 500V. Diffuse transmural fibrosis of bile duct was shown after IRE ablation with 2000V. TUNEL immunohistochemistry showed the cell death of bile duct mucosa and submucosa along the electrode. Within 24 hours, no complication was observed in pigs after endoscopic IRE ablation. Conclusions: Endoscopic IRE ablation using ERCP was successfully performed on common bile duct by using catheter-shaped electrode. It can be a potential therapeutic option as minimally invasive ablation for treatment of biliary tumors.
Comparative efficacy of second-line treatments for advanced hepatocellular carcinoma: A network meta-analysis.
Authors: Parikh Neehar , Marshall Alexander , Huff Keith D. , Savidge Rachel , Betts Keith A. , Song Jinlin , Zhao Jing , Yuan Muhan , Kim Richard D.
Published: February 2020

545

Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and is often advanced at the time of diagnosis. This study conducted a network meta-analysis (NMA) to assess the comparative efficacy of second-line (2L) immunotherapy and tyrosine kinase inhibitors (TKIs) without biomarker selection for advanced HCC (aHCC), including nivolumab (NIVO) + ipilimumab (IPI), cabozantinib (CABO), regorafenib (REG), and placebo (PBO). Methods: Randomized trials for CABO and REG (CELESTIAL and RESORCE) were identified through a literature review and included in the NMA. NIVO (1mg/kg) + IPI (3mg/kg) (from CHECKMATE-040) was linked into the evidence network through a matching-adjusted indirect comparison (MAIC) vs. the PBO arm of the CELESTIAL trial. The CELESTIAL trial was chosen due to the similar study design and patient population as the CHECKMATE-040 trial. Clinically relevant characteristics were matched, which included age, sex, Barcelona clinic liver cancer stage, Eastern Cooperative Oncology Group status, α-fetoprotein level, and prior treatments. The NMA included CELESTIAL, RESORCE, and the MAIC results. Investigator-assessed ORR and hazard ratio (HR) of overall survival (OS) were compared in the NMA. Results: After matching the baseline characteristics in the MAIC, the ORR of NIVO+IPI was 30.4% and the HR vs. PBO was 0.35. In the NMA, NIVO+IPI had significantly higher ORR (31.2%) compared to TKIs and PBO (REG: 4.8%; CABO: 4.2%; PBO: 1.0%, differences are presented in Table). In addition, NIVO+IPI was associated with significantly prolonged OS vs. TKIs and PBO (HR: NIVO+IPI vs. REG: 0.56; NIVO+IPI vs. CABO: 0.46; NIVO+IPI vs. PBO: 0.35). Conclusions: The NMA showed that NIVO+IPI was associated with significantly higher ORR and prolonged OS compared to TKIs as 2L treatments for aHCC.

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Hepatic and hematological toxicity associated with selective internal radiation therapy (SIRT): A meta-analysis of randomized clinical trials.
Authors: Manne Ashish , Behring Michael , Manne Upender , Jacob Rojymon , Paluri Ravi Kumar
Published: February 2020

546

Background: For advanced hepatocellular cancers (HCCs) and colorectal cancers (CRCs) with liver metastasis, the impact of selective internal radiation therapy(SIRT) with yttrium-90 on survival outcomes is not established. A meta-analysis of randomized clinical trials (RCT) was performed to determine the relative risk (RR) of hepatic and hematological toxicities with the use of SIRT, compared to therapies not including SIRT. For patients with advanced HCC or CRC, we assessed the RR of high grade (grades 3 and 4) hyperbilirubinemia, fatigue, leucopenia, thrombocytopenia and elevated liver enzymes (AST and ALT) with use of SIRT. Methods: Citations from PubMed/Medline, clinical trials.gov, package inserts, and abstracts from major conferences were reviewed to include RCTs comparing arms with or without SIRT. Potential publication bias was assessed using the Egger test for funnel plot asymmetry. There was no publication bias and the trials were of high quality per Jadad scoring. Patients in control arms received trans-arterial chemo-embolization (TACE) or sorafenib for HCC or FOLFOX for CRC. The proportion and 95% confidence intervals (CIs) for patients with adverse events were derived for each arm of each study and used to calculate the RR. For the meta-analysis, both the fixed-effects model and the random-effects model were considered; the method proposed by DerSimonian and Laird was used to estimate the random-effects model. Results: The RR of grade 3/4 leucopenia was consistently high across high with the use of SIRT across all the studies (RR 2.05, 95% CI (1.22-3.42), p-value 0.027). The risk of hepatic dysfunction and fatigue was higher with SIRT but not statistically significant. Conclusions: Since SIRT is associated with increased risk of high-grade leukopenia, caution is advised in selecting patients with HCC’s with underlying decompensated cirrhosis or with CRCs and on cytotoxic therapy. Proper selection of patients would reduce toxicities from SIRT alone or SIRT in combination with systemic chemotherapy.
Role of precision medicine for patients with advanced biliary tract cancers.
Authors: Hollebecque Antoine , Nabi Oumrou , Ducreux Michel , Boige Valerie , Scoazec Jean-Yves , Rouleau Etienne , Boileve Alice , Smolenschi Cristina , Verlingue Loic , Matias Margarida , Burtin Pascal , Prieux-Klotz Caroline , Massard Christophe , Malka David
Published: February 2020

552

Background: Biliary tract cancers (BTC) are rare and heterogeneous cancers with poor prognosis. Several actionable genomic targets have been described in BTC but data on the efficacy of targeted therapies remain limited. The main objectives of this retrospective study was to evaluate the frequency of actionable genomic alterations among BTC and the impact of targeted therapy. Methods: We performed a retrospective analysis on BTC patients seen at Gustave Roussy (IGR) from Dec 2011 to Jul 2019. All clinical and genomic reports were reviewed. Results: The study population included 212 patients with the main following characteristics: median age 61 years, female 51%, intrahepatic cholangiocarcinoma 57%, median of 2 previous lines. Of 212 BTC patients, 170 patients had a genomic profile based on archival tissue or a new tumor biopsy (IGR panel n = 120; Foundation One panel n = 92 ). 124 patients (73%) had at least one genomic alteration and 68 (40%) patients had genomic alteration considered as actionable. The most common actionable targets were FGFR2 rearrangement/mutation (n = 24, 35.3%), HER2/3 mutations (n = 9, 13.2%) and IDH1/2 mutations (n = 7, 10.3%). Of those 68 patients, 58 received the matched targeted therapy: FGFR inhibitor n = 24, HER2/3 inhibitors n = 9, Akt/PIK3CA/mTOR inhibitors n = 7, IDH1 inhibitor n = 6. In the treated population, the objective response rate was 36.2% and the disease control rate 85.1%. Progression-free survival (PFS) was 6.2 months compared to 2.8 months (p = 0.02) for patients who did not received targeted treatment. Overall survival (OS) was 17.7 months compared to 11.0 months (p = 0.03) for patients who did not received targeted treatment. Conclusions: Actionable genomic targets are frequent among BTC. Profiling-directed therapies resulted in a 36% response rate, a 85% tumor control rate and a 6.2 months PFS which compare favorably to second-line chemotherapy. A randomized trial is required to confirm the benefit of precision medicine in BTC.
Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: Experience of a tertiary Asian center.
Authors: Ng Kennedy , Wong Lawrence Wen Jun , Choo Su Pin , Tai David Wai-Meng , Tan Sze Huey , Ang Andrea Jing Shi , Lee Joycelyn Jie Xin
Published: February 2020

559

Background: Immune checkpoint inhibitor (ICI) use in advanced hepatocellular carcinoma (HCC) is increasing. Real-world data on efficacy and safety however is lacking, more so when used in patients who fall out of standard clinical trial criteria. Methods: We conducted a retrospective review of all patients with advanced HCC seen at our centre who received at least one dose of an ICI between May 2015 - June 2018. Data cutoff was 31 Dec 2018. Responses were evaluated using RECIST v1.1 criteria. Results: 114 patients fulfilled inclusion criteria. Median age was 66 years and 88.6% were male. 96.5% had an ECOG PS of 0 – 1. 64.9% received an ICI within a clinical trial setting. 62.3% received monotherapy ICI. 19.6% of patients had Child-Pugh B disease on initiation of ICI, and 69.3% had an ALBI Grade of 2. 50.0% were known to have hepatitis B and 11.4% had hepatitis C. Baseline HBV VL ranged from undetectable to 8210000 IU/mL. 30.7% received prior systemic treatment, most commonly sorafenib (82.9%). Over a median follow-up duration of 5.7 months (0.03 - 42.4), ORR was 18.4%, and disease control rate (DCR) was 51.8%. Median PFS was 2.6 months (1.7 - 3.9), and median OS was 13.9 months (7.0 - 16.2). 5 patients (23.8%) had response duration of more than 18 months. 35.1% received further systemic therapy after ICI. On multivariable analyses, age ≥ 65 years, higher albumin level and lower bilirubin level were associated with increased OS. 68.0% of patients experienced adverse events (AEs) of any grade, 12.0% of these being grade 3 - 4. No grade 5 adverse events were observed. Use of antiviral therapy was associated with a lower risk of hepatic AEs (p = 0.04) whilst high baseline HBV VL was not associated with an increased risk of reactivation or hepatic AEs. Conclusions: In the real-world setting, responses and adverse event profiles to ICI use are comparable to those observed in clinical trials despite a more heterogenous population base. The expansion of indications for ICI use in advanced HCC beyond current approvals warrants greater study.
Real-world data on treatment patterns of advanced CRC in third-line and beyond.
Authors: Flood William A. , Kozlovsky Vlad , Margolis Neil , Reddy Sandeep K.
Published: February 2020

56

Background: NCCN guidelines state “regorafenib (Stivarga) [REG], and Trifluridine+Tipiracil (Lonsurf) [LON] are treatment options for patients who have progressed through all available regimens”. Available clinical trial data has not established whether recycling of prior regimens (oxaliplatin/irinotecan/5FU) with exchange of biologics (bevacizumab, ziv-aflibercept, cetuximab, panitumumab) is superior to changing class of therapy with oral well tolerated agents such as REG and LON. Methods: Data from a pre-authorization platform used by multiple commercial insurance companies in the US (Eviti) was analyzed. 6325 treatment plans of advanced CRC patients were evaluated. Analysis for request for use of REG and LON was limited to third-line and later of therapy in patients with a diagnosis of advanced CRC patients. Results: Of 394 treatment plans beyond second-line of therapy, REG was preferred over LON (239 v 155). Excluding growth factors, anti-emetics, and leucovorin, REG and LON were the 9th and 13th most frequently requested drugs in this clinical setting. Irinotecan was the most commonly requested drug in this setting at >10x the frequency of REG. Ramucirumab was requested more often than REG, and Pembrolizumab, Nivolumab, and Ziv-aflibercept were more requested than LON. HEOR models that included expected supportive care drugs and medication complication management fees estimated the cost of REG at $62,515 per patient versus LON at $26,596 with similar duration of therapy. Conclusions: Therapeutic preferences exist in third-line and later treatment of advanced CRC patients which cannot be fully explained by clinical trial outcome differences, HEOR cost differences, or NCCN guideline preferences. Recycling of chemotherapy and biologics in the late line setting is common and occurs more frequently than switching to a drug regimen with an alternative mechanism of action.
Clinical outcomes of hepatocellular carcinoma patients with Child-Pugh class B treated with stereotactic body radiation therapy.
Authors: Baclay J Richelcyn , Toesca Diego Augusto Santos , von Eyben Rie , Minneci Madeline , Pollom Erqi L. , Chang Daniel Tandel
Published: February 2020

560

Background: Caution is usually employed in the treatment of patients with hepatocellular carcinoma (HCC) due to the inherent liver radiosensitivity, especially in patients with Child Pugh (CP) B and C classes. This study aims to review the outcomes of patients treated with SBRT for CP class B with HCC. Methods: Medical records of all patients with HCC and compromised liver function (CP class B) treated with SBRT between 2003 and 2018 were retrieved after institutional review board approval. Clinical, laboratory, and treatment-related data were collected and analyzed for their correlation to toxicity and survival. Liver function was assessed prior to SBRT and at 1, 3 and 6 months after treatment using the CP score classification. Patients were censored for toxicity after extensive tumor progression in the liver, new liver-directed therapies, or liver transplant. Time-to-events were calculated from date of SBRT. Results: A total of 22 patients were identified, but 3 were excluded for incomplete follow-up. Median follow-up time was 33 months (range: 11-95 months). At baseline, 13 (68%) patients had a CP score of 7, and 6 (32%) had a CP score of 8. The median PTV volume was 94 cc (range: 14-710 cc). The median prescribed dose was in 5 fractions (range: 35-45 Gy in 3-5 fractions). After SBRT, 8 (42%) patients presented with worsening in CP score, with a mean increase of 1.5 points (95% CI, 0.6-2.5; p = 0.005) at the first month of follow-up, but followed by recovery in liver function with change in CP score not statistically different from baseline at 3- or 6-month follow-up times (p = 0.35 and p = 0.13, respectively). Eight patients (42%) presented with acute hepatobiliary toxicity, with six of those presenting with ≥grade 2 toxicity. Patients with CP score change ≥2 points (n = 6) showed a significantly higher incidence of acute grade 2 or higher hepatobiliary toxicity (p = 0.001) with a trend toward worse overall survival (33 vs. 51 months, p = 0.45). Conclusions: In our cohort, SBRT demonstrated to be safe for patients with Child Pugh Class B liver function.
Proteomic features of HCC tumors reveal clinically distinct subtypes independent of somatic mutations.
Authors: Yim Sun Young , Shim Jaejun , Jeong Yun Seong , Sohn Bo Hwa , Kim Ji Hoon , Lee Ju-Seog
Published: February 2020

561

Background: Recent massive sequencing studies of HCC genomes revealed many new genetic alterations that might be accountable for HCC development and provided comprehensive view of malignant disease. However, genomic profiling of tumors is limited by a loose correlation between genetic alterations and their functional products such as proteins and metabolites. To overcome current limitation, we generated genomic and proteomic data together from HCC tumors and performed integrated analysis of both data sets. Methods: We analyzed proteomic data and genomic data such as somatic mutations, mRNA expression, miRNA expression, and copy number alterations from 300 HCC tumors to uncover most correlated genomic alterations with proteins. Clinical significance of identified key protein features were validated in multiple independent cohorts of HCC patients. Results: Analysis revealed three subtypes of HCC with substantial difference in proteomic patterns. Based on proteomic characteristics, three subtypes were named to mesenchymal (MES), metabolically active (MA), and kinase-active and genome stable (KAGS) subtypes. When assessed clinical relevance, the overall survival rate of patients in MES subtype was significantly worse than those in MA and KAGS subtype (P = 0.001). Poor clinical outcomes of mesenchymal subtype is validated in multiple independent cohorts (in total of >500 patients). Gene network analysis with integrated genomic and proteomic data further revealed association of subtypes with currently available treatments of HCC such as sorafenib and immunotherapy. In addition, multiple in-depth analysis of integrated data identified potential therapeutic target candidates for each subtype. Functional validation with cell lines demonstrated that some of candidates are essential for survival of HCC cells. Conclusions: HCC is classified into three subtypes by integrating genomic and proteomic data. These analyses has identified potential therapeutic targets as well as biomarkers associated with therapeutic targets. Our study demonstrated merit of integrated analysis of proteomic data with genomic data to uncover potential driver genes of HCC development.
Association of CXCR2+ granulocytic myeloid derived suppressor cells with the development of cholangiocarcinoma: A possible target for intervention.
Authors: Ullman Nicholas A. , Ruffolo Luis I. , Jackson Katherine M. , Chacon Alexander , Jewell Rachel , Georger Mary , Belt Brian A. , Linehan David
Published: February 2020

565

Background: Cholangiocarcinoma (CCA) is the second most common primary liver malignancy, with increasing incidence. Currently, surgical resection offers the only chance for cure, however the prognosis remains poor in part due to high rates of unresectability, recurrence, and poor response to conventional therapy. Thus, new systemic therapies represent an unmet medical need. Few preclinical models exist for identifying and testing new targeted or immune based therapies. Here we present our findings of the immune infiltrate in human CCA tumor microenvironment (TME) and a spontaneous murine model that faithfully recapitulates human disease. Methods: Histology and immunohistochemistry (IHC) staining was performed on human CCA and adjacent normal liver. Mice with targeted hepatic Kras activation and loss of p53 (KPPC) spontaneously develop CCA. KPPC hepatic tumors and normal livers from littermate controls underwent histological and gene expression studies. Flow cytometric analysis was performed on bone marrow, spleen, peripheral blood, CCA tumors and normal littermate livers. Results: Digital IHC quantification of archival human CCA specimens demonstrated elevated levels of CD15+CXCR2+ granulocytic myeloid derived suppressor cells (G-MDSC) compared to adjacent normal liver (p = < 0.05). In addition, the CXCR2 ligand, CXCL5, was significantly elevated in CCA tumors compared to adjacent normal liver. In KPPC mice, flow cytometric analysis of hepatic tumors showed an abundance of CD45+ leukocytes comprised of immunosuppressive G-MDSC vs normal littermate controls (p = 0.0007) which recapitulates human disease. qRT-PCR demonstrated significantly increased expression of G-csf, Csf1, Cxcl1, Cxcl2, and Cxcl5 (p = < 0.0001) in CCA KPPC tumors compared to normal livers. Accordingly, granulocytes in KPPC mice were elevated in both the bone marrow and blood compared to normal littermate controls. Conclusions: These data suggest CCA co-opts the ELR+ cytokine/CXCR2 axes to mobilize and recruit immunosuppressive G-MDSC to the TME. Targeted therapy against tumor infiltrating neutrophils can be tested in this pre-clinical model to inform clinical translation.
Survival outcomes according to the tumor mutation burden and PD-L1 expression in hepatobiliary tumors.
Authors: Sánchez-García Jorge , Lopez-Verdugo Fidel , Gagnon Andrew , Alonso Diane , Fujita Shiro , Rodriguez-Davalos Manuel , Lewis Mark Andrew , Gill David Michael , Gilroy Richard , Haslem Derrick S. , Yeatman Timothy Joseph , Krong Jake , Dong Li , Dow Sean , Zendejas-Ruiz Ivan R , Thota Ramya
Published: February 2020

566

Background: Hepatobiliary (HB) tumors are aggressive tumors with emerging evidence for increasing sensitivity to immune checkpoint inhibitors (ICI). Tumor mutation burden (TMB) was found to be a quantitative biomarker associated with production of neoantigens within the tumor and predict the sensitivity to immune therapy. Herein, we explore the TMB, microsatellite instability (MSI) and PD-L1 expression as a potential biomarker of response to immune therapy in HB tumors. Methods: We retrospectively assessed all patients with hepatobiliary malignancies who have undergone next generation sequencing (NGS) between October 2009 and June 2019. We then analysed the tumor mutation burden and PD-L1 of these tumors and also identified frequency of patients with no clinically actionable mutations. Results: In our total 61 patients with HB tumors predominantly were male (62.3%) with mean age of 63 years. Thirty-four patients had hepatocellular carcinoma, 22 patients had cholangiocarcinoma and 5 patients had gallbladder carcinoma. The most common risk factors were smoking status, cirrhosis, alcohol consumption and hepatitis C virus. The mean TMB reported was 3.2 (1.16 – 7.35). MSI was identified in 13 patients and one was indeterminate. Only 17 patients had PD-L1 positive. At least, 37 patients had one clinically actionable mutation while 24 patients had no clinically actionable mutations. Mean overall survival was 16.6 months, but no statistically significant difference was found by high PD-L1 (3 vs 3.7 months, p=0.3) expression. Conclusions: Our data suggests the TMB in HB tumors is low in general irrespective of their underlying risk factors. We also noted more than half had microsatellite stable tumors and PD-L1 expression. Future larger studies are needed to evaluate TMB, MSI and PD-L1 as a potential biomarker in hepatobiliary tumors to help select patients that will benefit from immune therapy.