bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of a phase III randomized trial of comparison of three paclitaxel-based regimens concurrent with radiotherapy for patients with local advanced esophageal squamous cell carcinoma.
Authors: Ai Dashan , Ye Jinjun , Chen Yun , Liu Qi , Zheng Xiangpeng , Li Yunhai , Wei Shihong , Li Jiancheng , Lin Qin , Luo Hui , Cao Jianzhong , Zhou Jialiang , Huang Guang , Fan Min , Wu Kailiang , Yang Huanjun , Zhu Zhengfei , Zhao Weixin , Li Ling , Zhao Kuaile 
Published: May 2020

4564 Background: Paclitaxel (PTX) is effective in concurrent chemoradiation (CCR) against esophageal squamous cell carcinoma (ESCC). Which regimen, among cisplatin (DDP) (TP), carboplatin (CBP) (TC) or 5-Fu (TF) in combination with PTX concurrent with radiotherapy, provides best prognosis with minimum adverse events (AEs) is still unknown. Methods: The study compared two pairs of regimens: TF vs. TP and TF vs. TC concurrent with radiotherapy. Patients with histologically confirmed ESCC (clinical stage II, III or IVa) 20 were randomized into the three groups. Patients in TP group were treated with 2 cycles of CCR followed by 2 cycles of consolidation chemotherapy with TP (DDP 25 mg/m2/d, d1-3, PTX 175 mg/m2, d1, q28d). Patients in TF group were treated with 6 cycles of TF (5-Fu 300 mg/m2, civ 96h, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TF (5-FU 1800 mg/m2, civ 72h, PTX 175 mg/m2, d1, q28d) in consolidation chemotherapy. Patients in TC group were treated with 6 cycles of TC (CBP AUC = 2, d1, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TC (CBP AUC = 5, d1, PTX 175 mg/m2 d1, q28d) in consolidation chemotherapy. The radiotherapy dose in all groups was 61.2 Gy delivered in 34 fractions. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS) and adverse events. Results: Between July 2015 and January 2018, 321 ESCC patients in 11 centers were enrolled. Median follow-up of patients who survived was 36.3 months (IQR 27.9–45.2). The 3-yr OS was 58.2% in TF group and 59.5% in both TP and TC group. (TF vs. TP, HR 0.935, 95% CI 0.627-1.417; TF vs. TC, HR 0.881, 95% CI 0.578-1.342; P = 0.839). No significant differences were found in 3-yr PFS between TF, TP and TC groups [48.3% vs. 45.5%(TP) or 48.3% (TC). P = 0.820]. TP group had a significant higher incidence of acute Grade 3/4 neutropenia [60.7% vs. 16.8%(TF) or 32.7%(TC)], thrombocytopenia [13.1% vs. 2.8%(TF) or 4.7%(TC)], anemia [5.6% vs. 1.9%(TF) or 3.7% (TC)], fatigue [10.3% vs. 1.9%(TF) or 0.9%(TC)] and vomiting [5.6% vs. 0%(TF) or 0.9%(TC))]than other two groups ( P< 0.05). TF group had a significant higher incidence of Grade 3/4/5 esophagitis [11.2% vs. 0.9%(TP) or 4.7%(TC))]and pneumonitis [4.6% vs. 0%(TP) or 1.9% (TC)]than other two groups ( P< 0.05). Conclusions: No statistical differences were found in OS and PFS among TF, TP and TC groups. TC might be an option used in CCR in ESCC patients with mild of side effects compared with other two groups, although it did not significantly prolong OS. Clinical trial information: NCT02459457 .
Second primary malignancies in patients with clinical T1bN0 esophageal squamous cell carcinoma after definitive therapies: Supplementary analysis of the JCOG trial, JCOG0502.
Authors: Mitani Seiichiro , Kato Ken , Daiko Hiroyuki , Nozaki Isao , Kojima Takashi , Yano Masahiko , Nakagawa Satoru , Ueno Masaki , Watanabe Masaya , Tsunoda Shigeru , Abe Tetsuya , Kadowaki Shigenori , Kadota Tomohiro , Fukuda Haruhiko , Machida Ryunosuke , Kitagawa Yuko 
Published: May 2020

4565 Background: Esophageal squamous cell carcinoma (ESCC) is associated with synchronous or metachronous cancer at other primary sites. Previous studies have suggested that patients (pts) with ESCC are still at a high risk of second primary malignancies after definitive therapies. In particular, early-stage ESCCs result in good prognosis, which is associated with a higher risk of second primary malignancies. Methods: The JCOG0502 was a phase III trial, which included a randomized and a non-randomized part and compared esophagectomy with definitive chemoradiotherapy in clinical T1bN0 ESCC. We additionally reviewed data of all pts enrolled in the JCOG0502 for second primary malignancies. Lugol-voiding lesions (LVLs) were assessed in the noncancerous esophageal mucosa before the treatments. Results: Among 379 enrolled pts, 213 pts received esophagectomy and the remaining received chemoradiotherapy. Patient characteristics of overall cohort were as follows: male, 85%; median age, 63 (range, 41–75) years; upper- /middle- /lower thoracic esophagus, 11/63/27%; alcohol consumption history, 79%; smoking history, 66%; prevalence of no LVLs/several LVLs/many LVLs/unknown, 45/36/8/11%. With a median follow-up of 7.1 years, a total of 118 second malignancies were observed in 99 pts (26%). Cumulative incidences of second malignancies after 3, 5, 10 years were 9, 15, 36%, respectively. Most common primary tumor sites were head and neck (35%), followed by stomach (20%) and lung (14%). In multivariable analyses, several LVLs [hazard ratio (HR): 2.24, 95% confidential interval (CI): 1.32–3.81, vs. no LVLs] and many LVLs (HR: 2.88, 95% CI: 1.27–6.52, vs. no LVLs) were significantly associated with the development of second malignancies. Regarding the three most common types of cancers, 62 out of the 77 cancers (81%) were diagnosed in clinical stage 0–I. Seventeen pts died due to second primary malignancies. There were 4 and 3 deaths from head and neck and lung cancer, respectively. Whereas, mortality caused by stomach cancer was not observed. Conclusions: In the JCOG0502, the incidence of second malignancies was high, indicating that careful follow-up is required for ESCC pts even after treatment completion. The presence of LVLs in esophagus was identified as an independent predictive factor for second primary malignancies, which may be useful for surveillance strategies. Clinical trial information: UMIN000000551 .
Peripheral blood immune correlates associated with TGF-β inhibition (galunisertib) and stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Wattenberg Max Miller , Reiss Kim Anna , Giannone Michael , Damjanov Nevena , Prechtel Dunphy Elizabeth , DiCicco Lisa , Garcia-Marcano Luis , Karasic Thomas Benjamin , Furth Emma , Wojcieszynski Andrzej , Vonderheide Robert H. , Ben-Josef Edgar , Beatty Gregory Lawrence 
Published: May 2020

4575 Background: TGF-β is a pleiotropic cytokine with immunosuppressive activity. In mouse models, blockade of TGF-β signaling enhances the activity of radiation and invokes T cell dependent anti-tumor immunity. We previously reported preliminary safety and efficacy results from a pilot study combining galunisertib (LY2157299), an oral TGF-β inhibitor, with SBRT for the treatment of patients with advanced HCC. Here, we investigate immunological mechanisms and potential biomarkers associated with therapeutic activity. Methods: Patients with advanced HCC who had progressed on or refused sorafenib were treated with galunisertib (150 mg PO BID) on days 1-14 of each 28-day cycle. SBRT (18 Gy) was delivered in a single dose between days 15-28 of cycle 1. Blood was collected at baseline, following two weeks of galunisertib and following SBRT for high-dimensional analysis using a 37-marker CyTOF panel. Patients were dichotomized based on best response as either progressor (PD) or non-progressor (PR+SD). The frequency of immune subsets was compared between groups. Results: Fifteen patients were enrolled and treated. One patient was not evaluable. The most common adverse event was grade 1 or 2 fatigue in 53% of patients. The only possibly-related grade 3 event was achalasia in one patient which coincided with disease progression. Two patients achieved a PR and six patients had SD (DCR 57%) with a median progression-free survival of 3.7 months and a median overall survival of 9.0 months. For most patients, regardless of outcome, galunisertib treatment was associated with a decrease in activated Ki67+ Treg cells. However, pre-treatment immune composition within the blood of progressors and non-progressors was distinct. At baseline, progressors had an increased frequency of naive-like CD8+ T cells, whereas non-progressors had an increased frequency of non-classical monocytes. After combination therapy, only non-progressors showed a significant increase in CD8+PD1+TIGIT+ T cells. Conclusions: Galunisertib combined with SBRT was well-tolerated with modest efficacy. Immune profiling of the blood revealed distinct pre- and post-treatment signatures that differentiated patients with progression versus non-progression. These findings show that the combination of anti-TGF-β therapy with radiation can mediate disease control and identify potential correlates of efficacy. Clinical trial information: NCT02906397 .
Associating liver partition and portal vein ligation for staged hepatectomy versus portal vein embolization in staged hepatectomy for hepatocellular carcinoma: A randomized comparative study.
Authors: Huang Gang 
Published: May 2020

4578 Background: Both Portal Vein Embolization (PVE) and Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) have been used in patients with unresectable hepatocellular carcinoma (HCC) due to insufficient volumes in future liver remnant (FLR). But it remains unclear for which thetapy has better long-term overall survival. Methods: This study was a single-center, prospective randomized comparative study. Patients were randomly assigned in a 1:1 ratio to the 2 groups. The primary endpoints was three-year overall survival rates. Results: Between November 2014 to June 2016, 76 patients with unresectable HCC due to inadequate volume of FLR were randomly assigned to ALPPS groups (n = 38) and PVE groups (n = 38). Thirty-seven patients (97.4%) in the ALPPS Group compared with 25 patients (65.8%) in the PVE Group were able to undergo staged hepatectomy (risk ratio 1.48, 95% CI 1.17-1.87, p < 0.001). The three-year overall survival (OS) rate of the ALPPS group (65.8%) (95% CI 50.7-80.9) was significantly better than the PVE Group (42.1%) (95% CI 26.4-57.8), (HR 0.50, 95% CI 0.26-0.98, two-sided p = 0.036). Major postoperative complications rates after the stage-2 hepatectomy were 54.1% in the ALPPS group and 20.0% in the PVE group ((risk ratio 2.70, 95% CI 1.17-6.25, p = 0.007). Conclusions: ALPPS resulted in significantly better long-term overall survival outcomes, at the expenses of a significantly higher perioperative morbidity rate compared with PVE in patients who had initially unresectable HCC. Clinical trial information: ChiCTR-IOC-14005646 .
A randomized phase II feasibility study of individualized stereotactic body radiation therapy (SBRT) versus transarterial chemoembolization (TACE) with DEBDOX beads as a bridge to transplant in hepatocellular carcinoma (HCC).
Authors: Nugent Francis W. , Hunter Klaudia , Molgaard Chris , Qamar Amir , Gunturu Krishna , Stuart Keith E. , Gordon Frederic , Flacke Sebastian 
Published: May 2020

4586 Background: For HCC pts undergoing LT, loco-regional treatment as a "bridge" is standard. The best bridging modality is unclear. SBRT is safe and effective when used in pts with advanced HCC. We prospectively compared SBRT to TACE as a bridge for HCC pts undergoing LT. Methods: From 9/2014-10/2019, 60 pts within Milan Criteria with CTP Class A/B8 cirrhosis were consented. 54 pts were randomized to TACE vs. SBRT. TACE pts (n =30) were scheduled to receive 2 treatments one month apart utilizing DEBDOX beads. TACE pts were hospitalized after each TACE. Pts receiving SBRT (n =24) received a median total dose of 45Gy delivered over 5 fractions using fiducials. Mean liver dose, Veff, and NTCP determined prescription dose. Pts were assessed by using mRECIST criteria at 2 months and every 3 months thereafter until LT or death. Toxicity and QOL were assessed before treatment, during treatment, two weeks post-treatment, and then every three months using the PIQ-6 Pain Impact Questionnaire and the SF-36v2 Health Survey. The 1° endpoint was time to recurrent or residual dz. Secondary endpoints were toxicity, pathologic response, radiologic response, number of subsequent treatments, cost, and QOL. 50 pts are evaluable for review. Results: See table. Conclusions: For early stage HCC patients with CTP Class A/B liver cirrhosis, SBRT appears as effective as TACE at controlling HCC prior to LT, may engender less toxicity, and eliminates the need for hospitalization. A larger multi-center trial is ongoing. Clinical trial information: NCT02182687. [Table: see text]
Effect of pembrolizumab (pembro) on hepatitis B viral (HBV) load and aminotransferase (ALT) levels in patients (pts) with advanced hepatocellular carcinoma (aHCC) in KEYNOTE-224 and KEYNOTE-240.
Authors: Chan Stephen Lam , Zhu Andrew X. , Finn Richard S. , Edeline Julien , Ogasawara Sadahisa , Knox Jennifer J. , Daniele Bruno , Ryoo Baek-Yeol , Merle Philippe , Bouattour Mohamed , Lim Ho-Yeong , Chao Yee , Yau Thomas , Haber Barbara Anne , Malhotra Usha , Liu Chih-Chin , Kudo Masatoshi , Cheng Ann-Lii 
Published: May 2020

4587 Background: The effect of PD-1 inhibition on HBV infection is unclear, and pts with HBV are often excluded from trials. This analysis evaluated HBV viral load and liver function (ALT levels) in pts with HBV infection in 2 trials of pembro: KEYNOTE-224 and KEYNOTE-240. Methods: Eligible pts with aHCC post first-line sorafenib and controlled HBV received pembro 200 mg IV Q3W until progression. Pts with active HBV (HBsAg positive and/or HBV DNA detectable) and inactive HBV (anti-HBc positive, HBsAg negative, and HBV DNA not detectable) at baseline (BL) were included. Results: Of 104 pts in KEYNOTE-224 and 413 pts in KEYNOTE-240, 8 (7.7%) and 101 (24.5%) had active HBV and 13 (12.5%) and 102 (24.7%) had inactive HBV, respectively. All pts with HBV received nucleos(t)ide analogs. In KEYNOTE-240, 2 (2.8%) pts with active HBV in the pembro arm and 1 (3.4%) in placebo (pbo) had a > 1 log increase (incr) of HBV DNA and 1000 IU/mL over BL; none in the pembro arm were associated with ALT elevation. No pts with inactive HBV in KEYNOTE-240 and no pts in KEYNOTE-224 had a > 1 log incr and 1000 IU/mL over BL. No pts in KEYNOTE-224 and 28 (38.9%) with active HBV and 1 (1.4%) with inactive HBV in the pembro arm, and 8 (27.6%) with active HBV and 0 with inactive HBV in the pbo arm in KEYNOTE-240 had a > 1 log decrease (decr) in HBV DNA. Conclusions: Few pts with aHCC and HBV had viral load incr with pembro. In KEYNOTE-240 no clinically meaningful differences between pembro and pbo were observed. ALT elevation was not associated with viral load incr with pembro. These data suggest that pembro is unlikely to significantly affect underlying HBV infection in pts with aHCC receiving HBV antiviral therapy. Clinical trial information: KEYNOTE-224, NCT02702414; KEYNOTE-240, NCT02702401 . [Table: see text]
Comprehensive gene expression analysis of IDH1/2 mutant biliary cancers (BC).
Authors: Battaglin Francesca , Xiu Joanne , Baca Yasmine , Zeng Jia , Shields Anthony Frank , Goldberg Richard M. , Seeber Andreas , Habib Diane , Puccini Alberto , Tokunaga Ryuma , Arai Hiroyuki , Wang Jingyuan , Berger Martin D. , Astsaturov Igor A. , Lockhart Albert Craig , Zhang Wu , Marshall John , Korn Wolfgang Michael , Lenz Heinz-Josef , El-Khoueiry Anthony B. 
Published: May 2020

4598 Background: Isocitrate dehydrogenases (IDH) mutations (mut) identify a distinct subtype of BC that has yet to be fully characterized. We recently showed that IDH1/2 mutant (mIDH) BC harbor specific gene alterations involving chromatin remodeling and DNA repair, and a differential immune markers profile compared to other mIDH GI tumors. Here we aim to further dissect the molecular profile of mIDH BC through a comprehensive gene expression profiling analysis. Methods: 524 BC samples (303 intrahepatic cholangiocarcinoma, IHCC, 67 extrahepatic cholangiocarcinoma, EHCC, 141 gallbladder, 13 unspecified) collected between February to December of 2019 were included. Samples were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel), whole transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). EBseq was used to identify differentially expressed genes in mIDH vs wild type (WT) tumors with control for FDR ( Q < 0.2). Pathway and functional enrichment analysis was performed using g:Profiler and Enrichr. Results: mIDH frequency in our cohort was 11.4% (60/524), with higher prevalence of IDH1 mut (8.8%). IHCC showed the highest mut prevalence: IDH1 13.5%, IDH2 4.6%. mIDH was more common in females ( P = 0.0036). A total of 774 genes were significantly differentially expressed between mIDH and WT: 582 underexpressed (Fold change, FC: 0.025~0.699); 192 overexpressed (FC: 1.43~3.3). Pathway enrichment showed a significant decrease of gene expression in cytokine-cytokine receptor interaction ( Q = 0.002) and inflammatory response genes ( Q = 0.005) in mIDH. Interferon-γ- and PD1 signaling-related genes expression was significantly lower in mIDH vs WT ( Q = 0.02) including IFNG (FC 0.32), NKG7 (FC 0.36), CD8B (FC 0.37), BATF (FC 0.40), PD1 (FC 0.53), SLAMF6 (FC 0.55) and PD-L2 (FC 0.60). Wnt and cadherin signaling were also enriched for altered expression in several genes in mIDH BC ( Q = 3.86e-7 and < 0.00001, respectively). Conclusions: To our knowledge, this is the largest and most extensive gene expression profiling study focused on mIDH BC. Our data show for the first time a distinct gene expression profile characterizing mIDH tumors which display significant downregulation of inflammatory response pathways and immune-related genes. These findings contribute to further the understanding of mIDH BC and may inform the future development of rational combination therapies.
Final results of a randomized, open label, perioperative phase II study evaluating nivolumab alone or nivolumab plus ipilimumab in patients with resectable HCC.
Authors: Kaseb Ahmed Omar , Tran Cao Hop Sanderson , Mohamed Yehia I. , Qayyum Aliya , Vence Luis M. , Blando Jorge M. , Singh Shalini , Lee Sunyoung S. , Raghav Kanwal Pratap Singh , Altameemi Lina , Rashid Asif , Vauthey Jean-Nicolas , Carter Kristen , Tzeng Ching-Wei David , Chun Yun Shin , Yao James C. , Wolff Robert A. , Allison James Patrick , Sharma Padmanee ,   Kaseb's
Published: May 2020

4599 Background: In resectable hepatocellular carcinoma (HCC) surgical resection is associated with high recurrence rates. However, there is no approved neoadjuvant or adjuvant therapies yet. Neoadjuvant immunotherapy effect has never been reported in this setting in HCC. Methods: This is a randomized phase II trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as peri-operative treatment for patients (pts) with HCC who are eligible for surgical resection. Pts in Arm A are given nivolumab 240 mg iv, every 2 weeks (wks) for a total of 3 doses followed by surgery on week 6. Pts in Arm B are treated with nivolumab per same schedule as arm A plus concurrent ipilimumab 1 mg/kg on day 1. Adjuvant part of study starts 4 weeks after surgery, with Nivolumab at 480 mg iv every 4 weeks for 2 years in arm A. Pts in Arm B are treated with nivolumab per same schedule as arm A plus concurrent ipilimumab 1 mg/kg every 6 weeks times 4 doses after resection. The primary objective was the safety/tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, pathologic complete response (pCR) rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: 30 patients were enrolled, 2 patients withdrew consent, one patient was not eligible at time of therapy, and 27 randomized (13 to Arm A and 14 to Arm B). 21 patients proceeded with resection as planned and surgery was aborted for 6 patients; 1 for frozen abdomen due to old surgery, 2 for small residual volume, and 3 for progressive disease. Pts age ranged between 32-83 yo, 75 % were males, 7 pts had HCV, 7 had HBV and 7 had no hepatitis. Pathologic complete response (pCR) was observed in 5/21 pts (24% pCR rate) – 2 in Arm A and 3 Arm B, and 3/21 pts (16%) – 1 in Arm A, 2 in Arm B, achieved major pathologic response (necrosis effect of 50-99%). 5 patients in Arm B and 1 in Arm A experienced grade 3 or higher toxicity prior to surgery. No grade 4 or higher toxicity were observed and surgery was not delayed or cancelled due to oxicity. Conclusions: Our study reached its primary endpoint of safety. Importantly, we report a 40% pathologic response rate = pCR rate of 24%, and major necrosis rate of 16% for resectable HCC after preoperative immunotherapy in a randomized phase II pilot trial. After future validation, these promising results may contribute to a paradigm shift in the perioperative treatment of resectable HCC. Clinical trial information: NCT03222076 .
Risk of cancer-specific death for patients diagnosed with neuroendocrine tumors: A population-based analysis.
Authors: Hallet Julie , Law Calvin , Singh Simron , Mahar Alyson , Myrehaug Sten , Zuk Victoria , Zhao Haoyu , Assal Angela , Coburn Natalie 
Published: May 2020

4605 Background: While patients with neuroendocrine tumours (NETs) are known to experience prolonged overall survival, the contribution of cancer-specific and non-cancer deaths is undefined. We examined cancer-specific and non-cancer death after NET diagnosis. Methods: We conducted a population-based retrospective cohort study of adult patients with NETs from 2001-2015 by linking administrative healthcare datasets. Using competing-risks methods, we estimated the cumulative incidence of cancer-specific and non-cancer death and stratified by primary NET site and metastatic status. Sub-distribution hazard models examined prognostic factors. Results: Among 8,607 included patients, median follow-up was 42 months (interquartile range: 17-82). The risk of cancer-specific was higher than that of non-cancer death, with 27.3% (95%CI: 26.3-28.4%) and 5.6% (95%CI: 5.1-6.1%) at 5 years. Cancer-specific deaths largely exceeded non-cancer deaths in synchronous and metachronous metastatic NETs. Patterns varied by primary tumour site, with highest risks of cancer-specific death in broncho-pulmonary and pancreatic NETs. For non-metastatic gastric, small intestine, colonic, and rectal NETs, the risk of non-cancer death exceeded that of cancer-specific deaths. Advancing age, higher material deprivation, and metastases were independently associated with higher hazards, and female sex and high comorbidity burden with lower hazards of cancer-specific death. Conclusions: Among all NETs, the risk of dying from cancer is higher than that of dying from other causes. Heterogeneity exists by primary NET site. Some patients with non-metastatic NETs are more likely to die from non-cancer than from cancer causes. This information is important for counselling, decision-making, and design of future trials. Cancer-specific mortality should be included in outcomes when assessing treatment strategies.