bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrast-enhanced intra-operative ultrasound as a clinical decision making tool during surgery for colorectal liver metastases: The ULIIS study.
Authors: Evrard Serge , Désolneux Grégoire , Isambert Milene , Mathoulin-Pélissier Simone , Dupré Aurélien , Rivoire Michel , Catena Vittorio , Palussière Jean , Dinart Derek , Bellera Carine A.
Published: January 2019

422

Background: In the era of parenchymal sparing surgery, detecting more colorectal liver metastases (CRLM) is essential to optimize the treatment. We evaluated the added-value of contrast enhanced intraoperative ultrasound (CE-IOUS) with a prospective design. Methods: We used an optimal 2-stage Simon’s design for this two-center study open for patients with operable CRLMs. Primary objective was the justified clinical utility of contrast-enhanced IOUS. Secondary objectives included detection rate of CRLMs, characterization rate of focal liver lesions, specific toxicity and detection of missing CRLMs. Results: Among the 58 eligible patients, 54 were eligible and assessable. Of these 54 patients, 36 were men (66.7%), median age was 63.6 years (range, 37-81), and 43 patients underwent pre-operative chemotherapy. The median number of CRLMs was 2 (range, 1-11). Pre-operative staging was performed using MRI in all 58 eligible patients, CT scan in 41 (70%) and PET-scan in 21 (36%). Compared to pre-operative staging, IOUS allowed identification of 40 new CRLMs in 11 (20.4%) patients. Furthermore, compared to IOUS, CE-IOUS allowed identification of 9 additional CRLMs in 8 (14.8%) patients. The correct detection rate based on pathological exams was 0.94. No additional missing CRLM was diagnosed. The surgical procedure was altered in 5 (9.26%) patients but was justified only in 4 patients (one lesion was ablated without previous biopsy), leading to a clinical utility rate of 7.70% (95 CI, [3.2, 18.6]). There was no specific toxicity reported. Conclusions: Despite the primary endpoint not met for one protocol violation,the Uliis study demonstrates an added-value for CE-IOUS for surgeons treating CRLMs, especially for advanced cases pre-treated by chemotherapy. Clinical trial information: NCT01880554.
Hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil with systemic pegylated interferonα-2B for unresectable advanced intrahepatic cholangiocarcinoma.
Authors: Sawara Kei , Oikawa Takayoshi , Kuroda Hidekatu , Kasai Kazuhiro , Takikawa Yasuhiro
Published: January 2019

428

Background: Cholangiocarcinoma is categorized into intrahepatic cholangiocarcinoma (ICC) and extrahepaticcholangiocarcinoma (ECC). The prognosis of ICC is far worse than that of ECC. In this study, the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) combined with subcutaneous administration of pegylated interferon (PEG-IFN) α-2b for patients with unresectable advanced ICC was evaluated. Methods: The subjects were 21 unresectable advanced ICC patients treated using subcutaneous PEG-IFN α-2b (50-100 μg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1-5 of every week, for 4 weeks). One treatment cycle lasted 4 weeks. Therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for ≥ 1 cycle. Results: The objective early response rate was 60.0 %. Cumulative survival rates were 71.6 % at 6 months, 53.7 % at 12 months, 28.6 % at 18 months, and 14.3 % at 24 months. Median survival time was 14.6 months. All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment related deaths were not observed. Conclusions: The combination therapy of PEG-IFN α-2b and 5-FU for unresectable advanced ICC seems to be better than the results of the previous studies. In addition, most adverse effects are transient and well tolerated. Although a larger prospective study involving a larger population of patients with advanced ICC is needed to evaluate this combination therapy, this combination therapy may be useful for patients with unresectable advanced ICC as one of the therapeutic option.
Analysis of DNA damage response (DDR) genes and tumor mutational burden (TMB) across 17,486 carcinomas of the tubular GI tract: Implications for therapy.
Authors: Parikh Aparna Raj , He Yuting , Hong Theodore S. , Corcoran Ryan Bruce , Clark Jeffrey W. , Ryan David P. , Catenacci Daniel V.T. , Chao Joseph , Fakih Marwan , Ross Jeffrey S. , Stephens Philip J. , Miller Vincent A. , Ali Siraj Mahamed , Schrock Alexa Betzig
Published: January 2019

43

Background: The DDR pathway is important in tumor biology, allowing cancer cells a mechanism to resist damage by chemotherapy and radiotherapy. BRCA1/2 are the most well described genes in the pathway, but several others ( ATM, ATR, PALB2, etc.) are involved with DDR and are mutated in many cancers. Tumors with a DDR defect are susceptible to PARP inhibition (PARPi) in some cases, but also potentially to immune checkpoint inhibitors (ICPIs), given immunomodulatory effects of PARPi and the hypermutated phenotype commonly associated with these genomic alterations (GA). We looked at the prevalence of select DDR defects in tubular GI cancers and the correlation between DDR and TMB. Methods: We prospectively analyzed samples from 17,486 unique patients with advanced colorectal (CRC), esophageal, gastric, or small bowel carcinomas using hybrid-capture based comprehensive genomic profiling. TMB (mutations/Mb) was calculated from 1.11 Mb of sequenced DNA. We looked at GA in 8 genes- ARID1A, ATM, ATR, BRCA1, BRCA2, CDK12, PALB2, RAD51 across these tumors types. Results: DDR GA were found in 16% of cases: gastric 464/1,750 (27%), small bowel 141/666 (21%), esophageal 441/2,501 (18%), and CRC 1,824/12,569 (15%). ARID1A (9.0%) and ATM (5%) were the most commonly altered DDR genes in this series, followed by BRCA2 (2.3%), BRCA1 (1.1%), ATR (0.8%), CDK12 (0.7%), PALB2 (0.6%), and RAD51 (0.1%), with 24% (675/2,870) of DDR-altered cases having GA in more than one DDR gene. Among DDR-altered cases, 21% had high TMB (≥20 mut/Mb) compared to just 1.4% high TMB in DDR-wild-type cases (p < 0.001). Microsatellite instability (MSI) status was available for a subset of cases and 19% (419/2,154) of those with a DDR GA were MSI high. CDK12 and ATR altered cases had the highest proportion of high TMB: CDK12 (55%, median TMB 31.5 mut/Mb) and ATR (55%, median TMB 35.1 mut/Mb), followed by cases with GA in BRCA2 (40%), BRCA1 (28%), ARID1A (27%), ATM (22%), and RAD51 (20%). Conclusions: DDR defects are relatively common across tubular GI tumor types and are associated with a hypermutated phenotype in over 20% of cases. This may be important to identify likely responders to both PARPi and ICPIs.
Single hepatocellular carcinoma (HCC) ineligible for surgical resection (SR): High tumor control rate with conformal radiotherapy + transarterial chemoembolization (CRT + TACE).
Authors: Merle Philippe , Rode Agnes , Manichon Anne-Frederique , Fares Nadim , Prevost Celia , Ducerf Christian , Lesurtel Mickael , Mabrut Jean-Yves , Mornex Francoise
Published: January 2019

433

Background: SR is a curative therapy of single HCC. CRT is efficient for small HCC (≤ 5 cm), whereas its combination to TACE (CRT+TACE) is needed for large ( > 5 cm) HCC. However, SR remains the gold-standard in guidelines for large HCC. This work aims to compare these approaches. Methods: Retrospective analysis of prospectively collected data, on patients (pts) included at Lyon North Hepatobiliary Centre, Child-Pugh-A, single HCC. CRT+TACE was decided at the HCC board by ineligibility for SR, radiofrequency or liver transplantation. Outcome of pts was compared between CRT+TACE and SR. Continuous variables were assessed by the t-Student test, and survival analysis by the Cox proportional-hazards regression. Results: 178 pts (68 CRT+TACE, 110 SR), males 78%, cirrhosis 52%, etiology (alcohol 46%, HCV 17%, HBV 13%, NASH 30%), 103 small, 75 large HCC, median age 66 ys, tumor size 50 mm, AFP 8 ng/mL, albuminemia (ALB) 39 g/L, platelets (PLAT) 166 Giga/L, follow-up 33 months. CRT+TACE complete response rate: 92% small / 80% large HCC. Small HCC comparison: CRT+TACE vs SR: age (67 vs 64, P= NS), cirrhosis (94% vs 47%, P< 0.0001), ALB (36 vs 40, P= 0.0001), PLAT (150 vs 201, P= 0.02), AFP (381 vs 300, P= NS). CRT-TACE was a poor outcome factor in univariate analysis for overall survival (OS) (HR 2.32; P= 0.01), progression-free survival (PFS) (HR 1.90; P= 0.007), but did not remain independent in multivariate analysis due to combined factors: age > 70, cirrhosis, ALB < 35, PLAT < 100. Large HCC comparison: CRT+TACE vs SR: age (73 vs 62, P= 0.0008), cirrhosis (70% vs 25%, P= 0.0004), ALB (38 vs 39, P= NS), PLAT (173 vs 240, P= 0.01), AFP (5616 vs 3456, P= NS). CRT-TACE was a poor outcome factor only for OS (HR 3.01; P= 0.0007) in univariate analysis. After adjustment to other factors (age > 70, cirrhosis, PLAT < 100), CRT-TACE was not independent in multivariate analysis for OS ( P= 0.19). Conclusions: CRT+TACE induced an encouraging tumor control rate in a population of older pts, more deteriorated chronic hepatopathy than pts treated by SR. Especially for large HCC, SR was not better than CRT+TACE on the outcome. Prospective randomized trials are warranted to confirm these data.
Outcomes and characteristics of patients receiving second-line therapy for advanced pancreatic cancer.
Authors: Tsang Erica S , Wong Hui-Li , Wang Ying , Renouf Daniel John , Cheung Winson Y. , Lim Howard John , Gill Sharlene , Loree Jonathan M. , Kennecke Hagen F.
Published: January 2019

435

Background: Recent trials have demonstrated improved outcomes in the 1st-line treatment of advanced pancreatic cancer (APC). However, there is limited randomized data to guide 2nd-line chemotherapy (CT) selection. We aimed to characterize predictors and outcomes of 2nd-line CT in patients (pts) with APC. Methods: We identified all pts with APC (locally advanced (LAPC) or metastatic (MPC)) who received ≥1 cycle of 1st-line CT between January 1, 2012 and December 31, 2015 across 6 centers in British Columbia, Canada. Baseline characteristics and survival outcomes were summarized. Results: Of 676 pts with APC (31% LAPC, 69% MPC) who received ≥1 cycle of CT, 164 (24%) received 2nd-line CT. These pts were younger (median 63.7 vs. 67.4 years; p= 0.01), had a lower ECOG (77% ECOG 0-1 vs. 51% ECOG ≥2; p< 0.001), and higher CA19-9 (median 1034 vs. 829; p= 0.01) compared to patients who did not receive 2nd-line CT. There were no differences in rates of 2nd-line CT between LAPC and MPC (28% vs. 23%; p= 0.18). On logistic regression, only 1st-line FOLFIRINOX (OR 5.90, p< 0.001) was associated with 2nd line CT. CT regimens are summarized by line (Table). Median duration of 2nd-line CT was 3 cycles (range 1-30). Median overall survival (mOS) from diagnosis of patients with 2nd-line CT was 16 months. mOS from 2nd-line CT was longer with 2nd-line gemcitabine/nab-paclitaxel than fluoropyrimidine or gemcitabine (7.9 vs. 5.1 vs. 4.3 months; p= 0.008). On multivariate analysis, longer OS from 2nd-line CT was associated with gemcitabine/nab-paclitaxel (vs. single agent CT), lower ECOG, LAPC (vs MPC), and lower CA 19-9 (HRs 0.49, 0.67, 0.58, 0.38, respectively). Conclusions: In this population-based cohort, pts treated with 2nd line CT were younger, have better ECOG, similar rates of LAPC vs. MPC, and achieved a median OS of 16 months. 1st-line FOLFIRINOX was the strongest predictor of 2nd-line CT. Gemcitabine/nab-paclitaxel was associated with superior 2nd line OS compared to gemcitabine/fluoropyrimidine. [Table: see text]
Early safety from a phase 1, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected into liver tumors.
Authors: Hecht J. Randolph , Pless Miklos , Cubillo Antonio , Calvo Aitana , Raman Steven , Liu Chunxu , Chan Emily , Chesney Jason Alan , Prat Aleix
Published: January 2019

438

Background: T-VEC is a genetically modified HSV-1 oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF, and stimulate anti-tumor immune responses. This study evaluates the safety of intrahepatic injection (inj) of T-VEC in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated dose. Eligible pts were ≥ 18 years (y) old, had progressive HCC or breast cancer (BC), colorectal cancer (CRC), gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer with liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 1) or 108 PFU/mL (cohort 2) every 21 (±3) days (Q21D), or up to 8 mL of the maximum tolerated concentration (MTC) Q21D (cohort 3). Inj volume was based on lesion size. Results: Results from cohorts 1 and 2 of group A are reported. 14 pts were treated; 12 (3 BC, 9 CRC) were DLT-evaluable: Median age was 65.5 y (range: 33, 73); median number of inj was 3; 1 pt received all 12 inj. MTC was 108 PFU/mL. There was 1 DLT, grade 3 aspartate aminotransferase (AST)/grade 2 bilirubin increase (inc), after 1 dose. In all treated pts, 4 (28.6%) had grade 3/4 treatment-related adverse events (TRAEs): anemia and inc gamma-glutamyltransferase, alanine aminotransferase (ALT), and AST. There were 2 deaths attributable to disease. Incidence of serious AEs (SAEs) is shown (Table). Conclusions: The MTC was 108 PFU/mL Q21D after initial inj at 106 PFU/mL. Repeated intrahepatic inj of T-VEC at the FDA-approved concentration for intralesional inj of melanoma was deemed tolerable and feasible in pts with liver mets. Additional investigation in combination with a PD-1 inhibitor is planned. Clinical trial information: NCT02509507. [Table: see text]
Acute and chronic deterioration in liver function after transarterial radioembolization (TARE) in US patients (pts) with hepatocellular carcinoma (HCC).
Authors: Miksad Rebecca A. , Piscaglia Fabio , Xia Fang , Fellous Marc Mardoche , Ogasawara Sadahisa
Published: January 2019

439

Background: TARE is available in several countries for the treatment of hepatic malignancies, including unresectable HCC. Liver function deterioration in pts treated with TARE has been reported in real-world practice but less is known about incidence at a national US level. To better understand the prevalence of liver function deterioration after TARE, a retrospective analysis was performed using a database of US HCC pts. Methods: HCC pts treated with index TARE between Jan 1, 2010 and Dec 31, 2015 were identified in Optum’s integrated database using standard codes. Eligible pts had at least one laboratory (lab) value at baseline ( < 30 days before TARE), acute period ( < 30 days post TARE), and chronic period (90–180 days post TARE) and did not undergo additional/repeat HCC treatment before any further lab test in the chronic period. Due to lack of universally accepted criteria for liver function deterioration, clinically meaningful lab parameter changes were predefined by experts (Table). Changes in liver function from baseline were assessed in the acute and chronic periods. Results: Of 790 Optum TARE pts, 78 (10%) were eligible. Majority of pts were excluded due to lack of lab data and due to additional HCC treatments prior to lab tests in the chronic period. 50 (64%) were male and median age was 66 yrs. At baseline, 20 pts (26%) had extrahepatic spread (EHS). The incidence of liver function deterioration varied by parameter (Table). Albumin was the parameter most likely to be changed in both the acute and chronic periods. Conclusions: Although anti-tumor effects are thought to be optimized about 3 months after TARE, this retrospective, post-hoc, real-world analysis demonstrated decreased liver function 90–180 days after TARE. TARE, a liver-directed therapy, was used in some pts with EHS. Limitations include missing data, small sample size, and difficulty establishing causation. These results suggest that chronic liver function deterioration 90–180 days after TARE may be observed in some HCC pts. [Table: see text]
Genomic alterations (GA) predicted to confer lack of benefit from trastuzumab in advanced esophagogastric cancers (EGC): Analysis of 527 HER2-amplified (HER2amp) cases.
Authors: Klempner Samuel Jacob , Chao Joseph , Bailey Mark , Kim Seung Tae , He Jie , Lipson Doron , Ali Siraj Mahamed , Miller Vincent A. , Ross Jeffrey S. , Lee Jeeyun , Schrock Alexa Betzig
Published: January 2019

44

Background: The addition of trastuzumab to chemotherapy improves survival in first line treatment of advanced HER2 overexpressing EGC. However, the response rate is under 50% in this molecularly heterogeneous group of cancers. Genomic alterations (GA) associated with lack of benefit from trastuzumab are understudied. Methods: We prospectively analyzed clinical samples from patients with EGC using hybrid-capture based comprehensive genomic profiling (CGP). Pre-specified literature review was used to determine GA associated with de-novo trastuzumab resistance. Results: From 2,245 gastroesophageal junction (GEJ) adenocarcinomas and 1,883 gastric adenocarcinomas (GC) we identified 395 HER 2-amplified GEJ (18%) and 132 HER 2-amplified (HER2amp) GC (7.0%) cases. Median HER 2 copy number was 19 in GEJ and 16 in GC samples. PIK3CA GA and METamp were observed in ~9% and ~5% of both HER 2amp and non- HER2amp EGC cases; however, co-amplification of cell-cycle mediators CDK6 and CCCNE1 were each significantly enriched in HER 2amp cases (Table). MYCamp and deleterious SMAD4 GA were also significantly enriched in cases with Her2amp. CDKN2A GA were common regardless of HER 2amp, particularly in GEJ . In cases with >100 estimated HER 2 copies, only PIK3CA GA were significantly less frequent than in those with 6-99 copies (2.3% vs. 9.8%, P =0.04). All HER 2amp cases were microsatellite stable. A clinically annotated HER 2amp cohort will be presented. Conclusions: GA predicted to decrease trastuzumab sensitivity exist in a significant portion of HER 2amp EGC, although not all are enriched relative to non- HER 2amp cases. CGP may provide additive information to traditional HER2 testing and identify patients less likely to benefit from therapy. Larger clinical datasets are needed to validate our observations. [Table: see text]
Changes in liver function following real-world transarterial chemoembolization (TACE) in US patients (pts) with hepatocellular carcinoma (HCC): The LiverT study.
Authors: Miksad Rebecca A. , Ogasawara Sadahisa , Xia Fang , Fellous Marc Mardoche , Piscaglia Fabio
Published: January 2019

441

Background: Acute elevations of serum transaminases and bilirubin after TACE are commonly observed in pts with HCC. However, real-world incidence of chronic liver damage after TACE is unclear. LiverT is a retrospective, observational study to assess potential chronic deterioration of liver function of HCC pts after a single TACE in US real-world practice. Methods: Eligible HCC pts underwent index TACE between Jan 1, 2010 and Mar 31, 2016 and did not undergo repeat/additional HCC treatment in the subsequent 90 days. Pts were identified from Optum’s integrated database using standard codes. At least one laboratory value was required within 30 days prior to index TACE (baseline = latest value within period) and 30–90 days after TACE (chronic period = latest value within period). Due to lack of universally accepted liver function deterioration criteria, clinically meaningful changes in laboratory parameters were predefined by experts (Table). Subgroup analyses explored the impact of HCC etiology, diabetes status, anticoagulation use, and presence of portal vein thrombosis. Results: Of 5142 Optum TACE pts, 572 (11%) were eligible; exclusions were primarily due to lack of HCC diagnostic code and laboratory availability; 411 (72%) were male and median age was 62 yrs. Although lower than acute liver deterioration (0–29 days post-TACE), 30–90 day chronic liver deterioration varied by parameter and ranged from 15% to 31% (Table). Overall, sub-groups showed similar patterns. Conclusions: We report real-world chronic deterioration of liver function 30–90 days after a single TACE in a cohort of HCC pts. Limitations include missing data, small sample size, and difficulty establishing causation. Subsequent HCC treatments may be limited by liver function; therefore, further characterization of post-TACE chronic deterioration of liver function for HCC is important. [Table: see text]
Stereotactic-body radiotherapy for portal vein tumor thrombosis in hepatocellular carcinoma patients.
Authors: Jeong Bae Kwon , Choi Hoon Sik , Kang Ki Mun , Jeong Hojin , Lee Yun Hee , Ha In Bong , Song Jin Ho
Published: January 2019

442

Background: Portal vein tumor thrombosis (PVTT) is commonly accompanied by hepatocellular carcinoma (HCC) patients, and in these cases the treatment options became limited and treatment outcome was poor. Stereotactic body radiotherapy (SBRT) is one of the possible treatment options, which can deliver higher doses with highly conformal target have conducted for treatment of PVTT. However, only few studies about the SBRT have reported, even treatment schedules were not consistent. In this study, we report our institutional experience of treating PVTT in HCC patients using SBRT. Methods: 24 HCC patients with PVTT were treated with SBRT at our institution. All patients had unresectable HCC with PVTT, baseline liver function of Child-Pugh class A or B. SBRT was performed by Cyberknife based on 4D-simulation and 4D-planning. The prescription dose was 45 Gy in 3 fractions in 17 (70.8%) patients, and was modified to 39 to 42 Gy in 3 to 4 fractions in 7 (29.2%) patients whose target was large or adjacent to the bowel. After SBRT, transarterial chemoembolization (TACE) was performed in 16 (66.7%) patients within 3 months. Results: There were 2 (8.3%) patients of PVTT showed complete response, and 11 (45.8%) patients showed partial response. Stable disease was found in 7 (29.2%) patients, and progression in 4 (16.7%) patients. The response rate was lower in patients with tumor thrombus at main portal vein than those at branch of portal vein (main, 30% vs. branch, 71.4%, p = 0.052). The 1- and 2-year overall survival (OS) was 67.5%, 48.2%, respectively, with median survival of 20.8 months. The combination SBRT followed by TACE, and presence of grade 3 hepatic toxicities impacted on survival. The 1-year OS was 71.4% in patients whom TACE was combined after SBRT, which was higher than that of 14.6% who were treated with SBRT alone (p < 0.001). The 1-year OS was 81.1% in patients who did not occur grade 3 hepatic toxicity, while 0% in patients who had grade 3 hepatic toxicity (p = 0.002). Conclusions: SBRT is a relatively effective treatment option for HCC patients of PVTT. Especially combined with TACE. Finding an optimal dose schedule which can reduce hepatic toxicity, while keeping the response seems important to increase the survival.
BCLC subclassification and tumour characteristics to provide prognostication of outcomes in an Asian population of locally advanced hepatocellular carcinoma treated using selective internal radiation therapy with Yttrium-90.
Authors: Mathew Eshani Nastassia , Nadkarni Nivedita , Choo Su-Pin , Toh Han Chong , Tai David Wai-Meng , Goh Brian , Chung Alexander , Chan Chung Yip , Ng David , Goh Anthony , Lo Richard , Venkatanarasimha Nanda , Gogna Apoorva , Too Chow Wei , Abdul Latiff Julianah Bee , Thng Choon Hua , Chow Pierce K. H.
Published: January 2019

443

Background: Selective internal radiation therapy (SIRT) with Yttrium-90 (Y90) is preferentially used in locally advanced hepatocellular carcinoma (HCC) patients in the Barcelona clinic liver cancer (BCLC) B or C cohort. However, the BCLC B cohort has a wide heterogeneity. To address this, Bolondi et al. proposed a BCLC B subclassification system. Additionally, the BCLC C cohort is also diverse in their Child-Pugh (CP) stage and extent of portal vein thrombosis (PVT). The effect of these subclassifications on survival outcomes has not been studied in HCC patients treated using SIRT. Methods: 392 HCC patients treated using SIRT from 1st January 2008 to 17th March 2017 were analyzed. These patients were classified according to the proposed subclassification system for the BCLC B cohort, and CP stage for the BCLC C cohort, and their survival outcomes reviewed. Results: 293 patients met the study’s inclusion criteria. For B1/B2/B3/B4/ C CP-A and C CP-B, the median OS was 48.3/28.7/14.4/13.7/12.8 and 6.6 months respectively. Overall comparison between the subgroups for median OS reached statistical significance (p < 0.001). The Cox proportional-hazards regression analysis found that tumour location defined as unilobar or bilobar disease significantly influenced median OS. In the BCLC C cohort, the extent of portal vein invasion significantly influenced median OS (p < 0.001). For the BCLC C CP-A group, median OS for segmental/sectoral branch invasion, right and/or left portal vein invasion and main portal vein trunk invasion was 24.1, 12.8 and 6.5 months respectively. Conclusions: Bolondi et al.’s subclassification system optimizes prognostic prediction by reducing the clinical heterogeneity in BCLC B HCC patients treated using SIRT. However tumour location, unaccounted for in the proposed subclassification, is also an important prognosticator. For the BCLC C cohort CP stage, extent of PVT, and tumour location were important predictors of treatment outcomes.
Safety and efficacy of the selective FGFR inhibitor debio 1347 in phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC).
Authors: Cleary James M. , Voss Martin Henner , Meric-Bernstam Funda , Hierro Cinta , Heist Rebecca Suk , Ishii Nobuya , Kirpicheva Yulia , Nicolas-Metral Valerie , Pokorska-Bocci Anna , Vaslin Anne , Venetz Werner , Zanna Claudio , Flaherty Keith , Tabernero Josep , Baselga Jose
Published: January 2019

447

Background: BTC are aggressive tumors with limited treatment options and poor overall survival. Aberrant FGFR signaling has been implicated in BTC carcinogenesis. Debio 1347 is an orally available selective FGFRi with potent antitumor effect in preclinical model bearing FGFR alterations. Debio 1347 showed encouraging preliminary clinical activity and manageable treatment-emergent adverse events (TEAE) in its first-in-human (FIH) ph1 study (NCT1948297) dose-escalating part. Here we report only results from the BTC pts of this study. Methods: This FIH study enrolled pts with advanced solid malignancies harboring defined activating alterations of FGFR 1, 2, or 3: amplifications (amp), mutations (mut) and translocations (trans). Pharmacokinetics (PK) and pharmacodynamics were serially evaluated in blood, skin and/or tumor tissue. A confirmatory post-hoc analysis was performed centrally for all available biopsies. Results: Eight pts, six with intrahepatic cholangiocarcinoma (iCCA) and two with gallbladder cancer (GBC), were treated with Debio 1347 at doses between 60 and 150 mg orally daily in 28-day cycles. Among the iCCA pts, one had an FGFR2mut, one had an FGFR2 activating deletion (del), and one had an FGFR3mut; the other three had FGFR2trans. One of the two GBC pts had an FGFR3trans, the other one an FGFR2mut. All pts had prior systemic therapy (mostly 2 or 3 lines). The most common TEAEs were hyperphosphatemia (8/8), nail changes (5/8), nausea (5/8), dry mouth (4/8) and stomatitis (3/8). No grade ≥ 3 related TEAE were reported except grade 3 hyperphosphatemia (4/8). PK was comparable to that in pts with other solid malignancies.A partial response lasting up to 48 weeks was observed in an iCCA pt (FGFR2 del exon 5); three additional iCCA pts (FGFR2trans: ROCK1; KIAA1217; DDX21) and one GBC pt (FGFR3-TACC3 trans) had target lesions regression < 30% and stayed on trial between 24 – 37 weeks. Overall disease control was 62.5%. Conclusions: These results suggest that BTC pts with genomic events leading to activation of FGFR2/3 may benefit from treatment with Debio 1347. Further study is ongoing in the expansion cohort of this trial. Clinical trial information: NCT1948297.
Second-line chemotherapy for gallbladder cancer.
Authors: Wongjarupong Nicha , Hassan Mohamed Abdelrahim Muddathir , Sanhueza Cristobal T. , Hartgers Mindy L. , Hassan Fatima , Roberts Lewis R. , Mahipal Amit
Published: January 2019

450

Background: The standard treatment for patients with gallbladder cancer is a combination of gemcitabine and cisplatin based on ABC-02 trial. However, there are no guidelines regarding treatment after first-line therapy. We retrospectively analyzed the efficacy and overall survival of different second-line regimens. Methods: We identified 203 patients with advanced gallbladder cancer who received palliative treatment between January 2000 and December 2015 at Mayo Clinic, Rochester. RECIST criteria was used to assess response. Results: 68 patients received second-line chemotherapy. Median age was 63 years (range: 32-86) and majority were males (60.6%). The median time from the diagnosis to the start of the second line chemotherapy was 8 (1-120) months. The most common used second-line chemotherapy were FOLFOX (14), gemcitabine alone (10), single agent fluoropyrimidine (11), gemcitabine with capecitabine (5), and capecitabine with oxaliplatin (4). There were 30 patients that received 5-fluorouracil based regimens, 20 patients received gemcitabine-based regimen, 3 patients received taxane-based regimen, and 15 patients received other types of chemotherapy. Median progression free survival and overall survival was 2.1 (1.8-2.7) and 16.7 (13.2-21.3) months respectively. There were 10 (52%), 11 (37%), 2 (67%), 5 (33%) with partial response and stable disease in 5-fluorouracil-based, gemcitabine-based, taxane-based, and others, respectively. There were no difference in PFS, with median PFS of 2.5, 2.0, 2.8 and 2.3 months, respectively (p=0.43). The overall survival were 15.7 (8.9-40.2), 15.0 (10.7-21.3), 40.3 (22.0-47.0), and 20.4 (9.2-30.7) months, respectively (p=0.83). There were 27 patients that received single agent chemotherapy and 41 patients that received combined regimen. There were 17 (42%) patients and 13 (48%) patients with partial response or stable disease in single and combined regimen. There were no differences in progression free survival and overall survival between single and multi agent chemotherapy. Conclusions: In this largest single institution study, second-line chemotherapy regimens for gallbladder cancer provided benefit in select patients and there is an urgent need to develop more active therapeutic regimens.
Pancreatic exocrine insufficiency (PI) secondary to chronic use of long-acting (LA) somatostatin analogues (SA) in patients (pts) with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Authors: Saif Wasif M. , Smith Melissa H , Romano Alicia , Patel Rachna , Relias Valerie
Published: January 2019

454

Background: SA are used in GEP-NETs and acromegaly. Side effects of SAs include biliary disorders, gastrointestinal disorders, injection-site pain and hyperglycemia. PI is often misdiagnosed as disease progression or failure to SA or diagnosed after a delay in pts receiving SA. We present our experience with PI developing in pts following chronic use of SA. Methods: Retrospective chart and pharmacy review of GEP-NETs pts (6/2009 - 6/2017) was completed. Data including demographics, dose/duration of long and short-acting SA, antidiarrheal, pancreatic enzyme replacement (PER), proton pump inhibitors (PPI), chromogranin A (CgA), urine 5-HIAA and quantitative fecal fat test (QFFT) was collected. Results: 110 GEP-NETs pts (Med. age: 56 yr) were identified. 104 pts received LA Octreotide acetate and 6 Somatuline Depot Injection. Of these, 23 received SA octreotide for worsening diarrhea, 96 had intensification of antidiarrheal and 1 got telotristat ethyl. 79 pts were evaluated by nutritionist and/or gastroenterology. QFFT was performed in 47 pts with worsening diarrhea despite stable or improved CgA/urine 5-HIAA. 19 had evidence of steattorrhea and received PER at a dose of 72,000 lipase units per meal. 13 received PPI concomitantly while 6 started when symptoms did not improve with PER. In addition, low fat diet was recommended. 14 of 19 had improvement in diarrhea within 4-8 weeks. 2 pts were non-compliant and 3 were found to have motility disorders. Deficiency of vitamins and trace elements was found in 11 of 19 pts, who received supplementation. Conclusions: Our experience constitutes first study addressing PI as a rare but serious complication of chronic use of SA. Although SA are used to treat diarrhea, paradoxically they can worsen diarrhea secondary to PI. It is believed that SA may inhibit secretion and release of hormones (amylase, trypsin, lipase, secretin, CCK, motilin, bile acid) leading to PI. Early recognition and diagnosis of this under-diagnosed and under-reported side effect of SA can improve not only diarrhea and weight in these pts but also can reduce cost of using short-acting SA and antidiarrheal.
SM-88 therapy in patients with advanced or metastatic pancreatic cancer.
Authors: Hoffman Steve , Stega Jeanetta , Zawisny Patricia , Gostout Zachary , Del Priore Giuseppe , Loushin Maria , Taylor Ben R
Published: January 2019

457

Background: SM-88 (tyrosine derivative, mTOR inhibitor, CYP3a4 inducer and oxidative stress catalyst) is a relatively non-toxic, targeted therapy that utilizes the Warburg Effect in combination with oxidative stress to cause tumor cell death. Previously reported results (Phase I and preliminary Phase II) showed safety and efficacy for SM-88 in metastatic and recurrent cancers. Pancreatic cancer continues to have a poor prognosis with toxic standard of care (SOC) therapies, associated serious adverse events (SAEs), and QOL degradation. SM-88 is being evaluated as a minimally toxic alternative treatment. Methods: Retrospective chart review between 2012-17 of 12 patients with advanced or metastatic pancreatic cancer treated with SM-88 through a Phase 1 study (3/12) or compassionate use (9/12) with 10/12 evaluable. Although treatment regimens specifics varied, all were provided SM-88 therapy five days a week, administered by clinicians, orally or through subcutaneous injection; 7/10 patients received SM-88 mono therapy; and 3/10 received combination therapy (5FU-based). Results: 40% (4/10) of patients achieved survival benefit of greater than one year (mean 12.2 mo) (see table). Monotherapy patients maintained or improved ECOG PS and did not experience drug-related SAEs during treatment. 2/10 patients achieved partial responses. One patient maintained rPFS for 13 months despite positive margins post-surgery and elevated CA19.9 levels. Conclusions: SM-88 appears well tolerated and demonstrated notable survival times in comparison to expected SOC therapies. In addition, several of the patients demonstrating benefit had baseline ECOG PSs of 2, for which current SOC is palliative care only. For further evaluation, a North American Phase II trial in recurrent pancreatic cancer has been initiated. [Table: see text]
Second-line treatment of modified FOLFIRINOX or nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma.
Authors: Ozaka Masato , Sasaki Takashi , Yamada Ikuhiro , Kanata Ryo , Akiyama Dai , Katagiri Tomoko , Takano Koichi , Matsuyama Masato , Sasahira Naoki
Published: January 2019

458

Background: Both FOLFIRINOX (FFX) and Nab-paclitaxel plus Gemcitabine(GnP) standard treatment in first-line treatment of metastatic pancreatic adenocarcinoma (MPA). It could be of interest to use them consecutively, knowing that there is currently no standard for second-line treatments for MPA. The aim of this study was to compare second-line modified FFX (mFFX) after GnP failure with second-line GnP after mFFX failure. Methods: From January 2015 to Jul 2017, medical records were retrospectively reviewed for consecutive patients receiving mFFX or GnP for a histologically proven MPA after failure of GnP or mFFX respectively. Patients were treated with mFFX (intravenous oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 h, no bolus 5-FU) or GnP (Gemcitabine 1000 mg/m2/, nab-paclitaxel 125mg/m2 d1,8 15) until disease progression, patient refusal or unacceptable toxicity. Results: Second-line mFFX was administered to 50 patients and GnP was 25 patients. At baseline of second-line treatment, there was no difference in patient’s characteristics between mFFX group and GnP group. No significant difference in the response rate (mFFX, 16.6% vs. GnP, 10.5%, P = 0.63) or the disease control rate (mFFX, 50% vs. GnP, 64%, P = 0.82) was seen between the two groups. Median Progression free survival of GnP/mFFx were 4.3 months/4.6 months (p=0.89) and median survival (OS) from the 2nd line treatment of GnP/mFFx were 10.4 months/10.8 months (p=0.65) and OS from the first-line treatment of GnP/mFFx were 20.6 months/16.5 months (p=0.34). No toxic death occurred in both groups. There was no difference in the incident of adverse event between mFFX group and GnP group. Conclusions: Second-line mFFX and GnP achieved similar disease control and survival in unresectable pancreatic cancer. The use of the FFX and GnP in sequence is an attractive option to maximize disease control and survival. We need the clinical trial to compare with mFFX and GnP in sequence to guide the selection of initial chemotherapy.
Nomogram for predicting overall survival (OS) in patients (pts) treated with liposomal irinotecan (nal-IRI) ± 5-fluorouracil/leucovorin (5-FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy in NAPOLI-1.
Authors: Wang-Gillam Andrea , Hubner Richard , Mirakhur Beloo , de Jong Floris A , Belanger Bruce , Chen Li-Tzong
Published: January 2019

459

Background: Results from NAPOLI-1 (NCT01494506), a phase 3 study in pts with mPDAC previously treated with gemcitabine-based therapy, demonstrated an improvement in OS (primary endpoint), progression-free survival, and objective response rate with nal-IRI+5-FU/LV vs 5-FU/LV. The MPACT study reported a nomogram to predict OS using baseline pt variables in previously untreated mPDAC. We conducted an exploratory post hoc analysis of NAPOLI-1 variables to develop a nomogram to predict OS in the post-gemcitabine setting. Methods: In NAPOLI-1, pts were randomized to receive nal-IRI 80 mg/m2 q2w + 5-FU/LV, nal-IRI 100 mg/m2 q3w, or 5-FU/LV. Univariate and multivariate analyses determined factors significantly predictive of OS. A multivariable Cox model was created using these factors to develop a nomogram that assigned points equal to the weighted sum of relative significance of each variable. Predictive accuracy of the nomogram as measured by the concordance index (c-index) was evaluated by internal bootstrap validation. Results: Data from the 417-pt univariate analysis and 399-pt multivariate analysis (18 pts excluded for missing baseline data) were used. Eight of 21 variables were retained in the multivariate analysis (p < 0.01 except BMI [p=0.08]). Conclusions: In NAPOLI-1, predictors of OS were nal-IRI+5-FU/LV treatment, KPS, NLR, albumin level, baseline CA19-9, stage 4 at diagnosis, BMI, and presence of liver metastasis. The nomogram, which will distinguish between risk groups and may aid in clinical decision making, will be presented in the poster. Clinical trial information: NCT01494506. [Table: see text]
Identification and validation of a novel drug target in an organoid model of esophageal cancer.
Authors: Shukla Navika , Salahudeen Ameen Abdulla , de la O Sean , Hart Daniel James , Taylor Gregory , Zhu Junjie , Yuki Kanako , Seoane Jose , Ma Zhicheng , Ding Jie , Han Kyuho , Morgens David , Bassik Michael , Curtis Christina , Kuo Calvin Jay
Published: January 2019

46

Background: Esophageal squamous cell carcinomas remains a particularly intractable disease due to limited therapeutic options as well as a lack of targeted therapies. The genetic landscape of esophageal squamous cell carcinoma is varied, but a common means of tumorigenesis in squamous cancers are alterations in copy number of putative oncogenic loci that result in upregulated mRNA. Within this subset of loci with copy number alterations, however, it has been difficult to distinguish between driver and passenger mutations using traditional in vitro models. Methods: We functionally screened a data set of amplified “outlier” candidates nominated through a bioinformatics pipeline that scored chromosomal amplifications with linked mRNA overexpression. Screening and validation was performed in a novel three-dimensional organoid model of esophageal squamous cell carcinoma that served as a tabula rasa by virtue of a single p53 null alteration. Results: Functional screening uncovered a novel oncogenic mechanism that serves to drive esophageal squamous cell cancer tumorigenesis both in vitro and in vivo when subcutaneously transplanted into immunodeficient mice. In addition, pharmacologic perturbation of this mechanism resulted in attenuation of the oncogenic phenotype in vitro. Conclusions: We have paired bioinformatics analysis of TCGA data with a p53 null organoid model to functionally validate a novel driver mechanism of esophageal squamous cell carcinoma. Studies are underway to translate these findings and hopefully generate additional therapeutic strategies for esophageal squamous cell carcinoma patients.
Subgroup analysis by measurable metastatic lesion (ML) number and selected lesion locations (LL) at baseline (BL) in NAPOLI-1: A phase III study of liposomal irinotecan (nal-IRI)±5-fluorouracil/leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy.
Authors: Siveke Jens T. , Hubner Richard , Macarulla Teresa Mercade , Wang-Gillam Andrea , Dean Andrew Peter , Blanc Jean-Frédéric , Cunningham David , Mirakhur Beloo , Belanger Bruce , de Jong Floris A , Chen Li-Tzong
Published: January 2019

460

Background: We report a post hoc, exploratory analysis of pts with BL ML number and LL data who received nal-IRI+5-FU/LV, nal-IRI or 5-FU/LV in NAPOLI-1, a pivotal, phase 3 trial (NCT01494506). nal-IRI+5-FU/LV increased median OS (mOS) vs 5-FU/LV (6.1 vs 4.2 mo [HR=0.67; p=0.012]). Methods: ML (1, 2, 3, >3) and LL were recorded (local investigator) at BL. Pts with >1 LL were counted for each location. Results: 354 of 417 ITT pts had measurable BL ML and 1,080 LL were recorded. There was no clear trend in the percentage of pts with KPS ≥80 in 1- >3 ML (range 87%-95%) or LL (range 89%-94%) subgroups. ML 1 (n=81), 2 (n=65) and 3 (n=24) subgroups were small. nal-IRI+5-FU/LV significantly improved mOS vs. 5-FU/LV in pts with 2/>3 ML (n=184/24); nal-IRI+5-FU/LV had numerically higher mOS vs. 5-FU/LV for all LL (Table). nal-IRI+5-FU/LV had favourable median PFS (mPFS) vs. 5-FU/LV in pts with 1–>3 ML (range 2.0-4.2 vs. 1.4-1.9 mo; HR range 0.35-0.88) and for all LL (range 2.8-4.2 vs. 1.4-2.0 mo; HR range 0.39-0.55). Conclusions: Low pt numbers across groups and repeat counting of pts in LL subgroups preclude firm conclusions on treatment efficacy, pending further analyses. Allowing for these limitations, we detected no clear prognostic effect on outcomes of higher BL ML number or LL in NAPOLI-1 ITT pts. nal-IRI+5-FU/LV improved mOS vs. 5-FU/LV in some ML groups and across LL groups; improvement in mPFS vs. 5-FU/LV in the ITT population was maintained in all subgroups. Clinical trial information: NCT01494506. [Table: see text]
Ampullary adenocarcinoma: A single center experience.
Authors: Henry Jason , Iyer Pritish , Garberich Ross , Davis Sarah Lindsey , Lieu Christopher Hanyoung , Meguid Cheryl Lauren , Edil Barish H. , Leong Stephen
Published: January 2019

462

Background: Ampullary adenocarcinoma (AC) is a rare clinical entity representing only 0.2% of gastrointestinal malignancies. While outcomes are superior compared to other hepatobiliary cancers, mortality remains high. There is limited data to guide clinical decisions regarding adjuvant therapy, largely extrapolated from other hepatobiliary cancers. We evaluated treatment strategies and variables associated with survival in patients with AC. Methods: We retrospectively reviewed 54 consecutive patients with pathologically proven AC between January 2012 and August of 2015. Demographic data, adverse prognostic features and adjuvant treatment patterns were examined using a cox univariate hazard model for predictors of overall survival (OS). There were 5 patients who had metastatic disease on presentation who were included for markers of poor prognosis but excluded from treatment analysis. Results: The average age was 64.7 years with 50% male. Treatment strategy included 40.8% surgery alone, 44.9% adjuvant chemotherapy (CT) and surgery, 14.2% chemoradiation (CRT) and surgery while only 1 patient did not have surgery. Open surgical whipple (n = 28) was most frequent followed by laparoscopic whipple (n = 18) and endoscopic resection (n = 2). The two most common chemotherapeutic agents were single agent gemcitabine (74%) and capecitabine plus oxaliplatin. (7%). At time of last follow-up, 20 (37%) patients had died with a median follow-up of 16.8 months (range 1.9 to 47.4). Older age (HR [95% CI]: 1.05 [1.02, 1.09]; p = 0.002), Stage III (6.75 [1.40, 32.53]; p = 0.017), Stage IV (32.44 [32.44, 216.92]; p < 0.001), N stage 1 (8.52 [2.44, 29.67]; p = 0.014), lymphovascular invasion (LVI) (4.80 [1.54, 15.00]; p = 0.007), and peri-neural invasion (PNI) (3.835 [1.197, 12.29]; p = 0.024) were all associated with poor OS. There was no difference in OS between histologic subtype, surgery type, adjuvant CT or CRT. Conclusions: There was no difference in OS between adjuvant CT or CRT, or between surgical modalities. Despite being administered more frequently in patients with adverse prognostic features including LVI, PNI and advanced stage, adjuvant CT or CRT was equivalent to no adjuvant therapy.
Significance of hypoxia inducible factor-1 expression in liver metastasis of colorectal cancer.
Authors: Wada Yuma , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Iwahashi Shuichi , Saito Yu , Teraoku Hiroki , Ohta Shogo , Higashijima Jun , Shimada Mitsuo
Published: January 2019

464

Background: In colorectal liver metastasis (CRLM), the difference of tumor malignancy between primary and metastatic lesion has been elucidated. Hypoxia inducible factor-1 (HIF-1) represent tumor malignancy including angiogenesis, tumor growth and epithelial mesenchymal transition (EMT). The aim of this study was to investigate the difference of tumor malignancy between metastatic and primary lesion of CRLM and its impact for patient’s prognosis. Methods: In an initial curative hepatectomy of 75 cases in CRLM, HIF-1 expression in primary and metastatic lesion was evaluated by immunostaining method (Sigma-Aldrich, HPA 001275). Staining score was classified as follows, staining intensity (0: negative, 1: low, 2: medium, 3: high) and staining area (0: 0%, 1: -25%, 2: 26-50%, 3: ≥ 51%), and defined more than 4 points as positive expression. We evaluated the clinicopathological features according to HIF-1 expression. Results: Regarding HIF-1 expression of metastatic site, we divided into the positive group (n = 54) and the negative group (n = 21). There was no difference between metastatic HIF-1 expression and clinicopathological factors. Nevertheless, in overall survival, multivariate analysis revealed that HIF-1 positive in metastasis (HR: 2.850, p = 0.042) and poor differentiation type of primary lesion (HR: 20.873, p = 0.001) were independent prognostic factors. HIF-1 positive and negative patients were 3 year survival of 95.2% and 58.6%, respectively. Also, in disease free survival, HIF-1 positive in metastasis (HR: 2.608, p = 0.004), Synchronous (HR: 1.794, p = 0.049), Grade BC (HR: 2.145, p = 0.008), and lymph node metastasis in primary lesion (HR: 2.070, p = 0.016) was identified. Regarding HIF-1 expression of primary site, we divided into 51 cases of positive group and 24 cases of negative group. There was no relationship to clinicopathological factors as well as HIF-1 expression in metastasis, besides HIF-1 expression of prognosis was not associated. Conclusions: In CRLM, HIF-1 expression in the metastatic lesion is not associated with the primary lesion and may be useful as prognostic marker.