bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human phaseⅠstudy of JPH203 in patients with advanced solid tumors.
Authors: Okano Naohiro , Kawai Kirio , Yamauchi Yoshiya , Kobayashi Takaaki , Naruge Daisuke , Nagashima Fumio , Endou Hitoshi , Furuse Junji 
Published: January 2019

419 Background: Uptake of amino acids is essential for cancer growth. L-type amino acid transporter-1 (LAT-1) is overexpressed in various cancers, and uptake of LAT-1 substrate amino acids is known to have a critical role in cancer growth. JPH203 is a novel, selective, LAT-1 inhibitor. A first-in-human phase I study of JPH203 was designed to determine the safety, maximum-tolerated dose (MTD) and recommended dose. This study included evaluation of the anti-tumor effect, pharmacokinetics, and pharmacodynamics of JPH203 and analyzed plasma free amino acids. Methods: JPH203 was administered intravenously for 7 days followed by 21 days’ rest at planned doses ranging from 12 to 110 mg/m2 in patients with advanced solid tumors refractory to standard therapy. Before starting this schedule, we confirmed safety of a single dose of JPH203. Dose-limiting toxicity was evaluated during the first cycle, using a 3+3 design. Results: 17 patients were enrolled from January 2015 to August 2016. One patient was discontinued after a single dose of JPH203 because of tumor progression. Dosage was escalated up to 85 mg/m2. Grade 3 liver dysfunction occurred in 1 of 6 patients at 60 mg/m2 and in the first patient at 85 mg/m2. Therefore, it was determined that MTD was 60 mg/m2. Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension and fever of Grade 1 or 2. Partial response was achieved in a patient with biliary tract cancer (BTC) who continued JPH203 for two years without progression. Disease control (PR+SD) was observed in 3 of 5 patients with BTC and 2 of 6 with colorectal cancer. LAT-1 substrate amino acids and branched chain amino acids including LAT-1 substrate amino acids were higher in patients with BTC than in those with other cancers. All patients with disease control had a body mass index more than the median of 20.5 kg/m2. In exploratory analysis, longer survival was achieved in patients with high inhibition of uptake of LAT-1 substrate amino acids, compared with patients with low inhibition of uptake. Conclusions: JPH203 was well tolerated, resulting in promise against BTC. This phase I study suggested that LAT-1 could be targeted in treatment for advanced BTC, because LAT-1 substrate amino acids in plasma tended to remain high. Clinical trial information: UMIN000016546.
Volume reduction rate of the primary tumor as an objective clinical measure to evaluate efficacy of neoadjuvant chemotherapy for esophageal squamous cell carcinoma.
Authors: Nagasawa Shinsuke , Ogata Takashi , Hara Kentaro , Osakabe Hiroaki , Nakazono Masato , Kumazu Yuta , Hayashi Tsutomu , Yamada Takanobu , Rino Yasushi , Masuda Munetaka , Yoshikawa Takaki 
Published: January 2019

42 Background: Neoadjuvant chemotherapy (NAC) followed by surgery is a standard treatment for esophageal squamous cell carcinoma (ESCC) in Japan. Efficacy of NAC on the primary tumor is clinically evaluated during NAC and before surgery and is pathologically examined after surgery. Clinical evaluation of the primary tumor is sometimes difficult because primary tumor is nonmesurable lesion and is usually evaluated subjectively, while pathological finding is objective and a gold standard to evaluate efficacy of NAC. In the present study, we tried to evaluate clinicaly efficacy objectively by calcurating tumor volume by esophagography and concordance between volume reduction rate and pathological efficacy. Methods: This retrospective study examined 53 patients who fullfilled the following criteria; (1) thoracic ESCC, (2) underwent resection following NAC between January 2011 and February 2017, and (3) T2-3N0 before surgey. Clinically, volume of the primary tumor was calculated by multiplying length and thickness in the lateral view of esophagography. Pathological efficacy was examined by the proportion of the tumor disappearance of the primary tumor and was classified as Grade 0-1 when degeneration area was < 2/3, Grade 2 when those area was > 2/3 and < 3/3, and Grade 3 when there was no residual tumor. Volume reduction rate calculrated by the difference of pre- and post-NAC was compared by stratifying pathological grade. Results: T2/T3 was 23/30, respectively. Regimen of neoadjuvant chemotherapy was 5-FU/CDDP in 50 patients,docetaxel/5-FU/CDDP in 1,and 5-FU/CDDP and Radiotherapy in 2. Overall volume reduction rate was 58.9% in median (range -127-100%). Pathological response (Grade 0-1/2/3) was 28/18/4, respectively. Median volume reduction rate (range) was 38.5% (-127-100%) in Grade 0-1, 72.2% (21.7-100%) in Grade 2, and 91.1% (75.5-100%) in Grade 3, which was significantly different (p < 0.01). Conclusions: The volume reduction rate of the primary tumor was correlated with pathological efficacy, suggesting that volume reduction rate could be a objective measure to evaluate efficacy of neoadjuvant chemotherapy for ESCC.
Locally advanced gallbladder cancer: Contemporary outcomes for aggressive surgical management.
Authors: Ito Hiromichi , Takahashi Yu , Mise Yoshihiro , Inoue Yosuke , Ishizawa Takeaki , Saiura Akio 
Published: January 2019

420 Background: Patients with gallbladder cancer (GBCA) often present at advanced stages and their prognosis is dismal. Surgery for locally advanced (LA) disease has been controversial and the optimal indication for resection needs to be defined. Methods: Patients who underwent curative resection for GBCA of T1b or greater with curative intent at our institution from Jan. 2006 through Jun. 2017 were included. “Locally advanced disease” was defined as GBCA deemed to invade the hepatic hilum, or the extrahepatic organs either by the preoperative imaging. Perioperative management, operative procedures, and the short- and long-term for the patients with LA-GBCA were evaluated and compared with those for the patients with localized GBCA (L-GBCA). Results: Total 102 patients were identified and 35 patients were with LA-GBCA. Nineteen patients (54%) with LA-GBCA presented with jaundice, and all of them had biliary stent placed preoperatively. Preoperative portal embolization was performed for 22 patients (63%). Extended resections included hepatopancreaticoduodenectomy (n = 14, 40%), major hepatectomy (lobectomy or greater, n = 29, 83%), with partial duodenectomy (n = 7, 20%), with partial colectomy (n = 6, 17%), and with major vascular resection/reconstruction (n = 9, 26%). R0 resection was achieved in 87% of the patients with LA-GBCA by extended resection, while it was achieved in 91% of those with L-GBCA by standard radical cholecystectomy ( p= 0.13). The 5-year recurrence-free and overall survival (RFS and OS) rates for the patients with LA-GBCA were 19% and 26%, compared with 57% and 66% for those with L-GBCA ( p< 0.001 for RFS, and p < 0.001 for OS, respectively). In the multivariate analysis for all the patients with GBCA, T3 or greater, nodal metastasis and R1 resection remained as significant risk factors for both recurrence and death after resection with curative intent. Conclusions: Although extended resection for locally advanced cancer is safe and feasible, its long-term outcomes remained poor. Appropriate patient selection criteria needs be established to avoid aggressive operation without benefit for the patients with LA-GBCA.
Epidemiology and treatment of high-grade gastrointestinal neuroendocrine tumors (HG-GI-NETs).
Authors: Alese Olatunji B. , Jiang Renjian , Shaib Walid Labib , Wu Christina Sing-Ying , Akce Mehmet , Behera Madhusmita , El-Rayes Bassel F. 
Published: January 2019

421 Background: High grade neuroendocrine tumors of the gastrointestinal tract are rare tumors. Management strategies are modeled after small cell lung cancer (SCLC). Treatment patterns and outcomes have not been studied. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Univariate and multivariate testing was done to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between patient characteristics and survival. Results: A total of 1,861 patients were identified for the 10 years of the study. The mean age was 63 years (SD±13), with a male preponderance (53.3%). The vast majority of patients (78.1%) were non-Hispanic Whites. The most common primary sites were pancreas (PNET = 19.4%), large intestine (18.1%), esophagus (17.8%) and rectum (15.5%). About 27.9% of the cases were resectable at the time of diagnosis, and distribution across stages 1-IV was 6.6%, 10.5%, 18% and 64.6% consecutively. Liver was a common site of metastases (50.4%), followed by bone (11.3%) and lungs (10.8%). Only 3.5% of the patients had brain metastases. On univariable analysis, age < 65years (HR 0.72; 0.66-0.8; p < 0.001) and treatment at an academic center (HR 0.88; 0.79-0.99; p < 0.034) were associated with improved survival. Multivariable analysis confirmed prognostic advantage of treatment at an academic center. Patients treated with chemotherapy had a median overall survival (OS) of 11.2 months, compared with 1.7 months for those who did not. The median OS for high grade PNET was 6 months, compared to 9.9 months for other HG-GI-NETs. One year and 5-year survival rates were 27.5% vs. 41% and 4.5% vs. 12.3% respectively. Conclusions: This is the largest series of HG-GI-NET. Almost two-thirds of the cases present with metastatic disease. Pattern of metastasis differs from SCLC. Survival is short. Treatment at high volume academic center, younger age and use of chemotherapy are associated with improved survival.
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]