bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined analysis of randomized controlled trial (RCT) and patient-preference trial (PPT) evaluating second-line chemotherapy (SLC) in advanced gastric cancer (AGC).
Authors: Lee Soonil , Kang Jung Hun , Lim Do Hyoung , Park Keon-Woo , Oh Sung Yong , Hwang In Gyu , Lee Jeeyun , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki , Park Se Hoon 
Published: March 2020

4064 Background: While prolonged overall survival (OS) from SLC compared to best supportive care (BSC) has recently been demonstrated for AGC (Park et al, ASCO 2011), the prognosis of pretreated AGC remains poor. We assessed whether patient preference, willing to participate onto RCT, or other parameters contributed to this OS improvement. Methods: In the phase III trial, pretreated AGC patients (n=372) were first offered RCT. If a patient agreed to participate, randomly assigned 2:1 to SLC or BSC (n=202). If refused RCT, but agreed to receive treatment of their preference, they were offered SLC or BSC (PPT; n=170). OS of RCT participants was compared to that of whole patient population according to prognostic subgroups. In addition, analyses of OS unadjusted for multiple comparisons were conducted across predefined subgroups. Results: Median OS was 6.3 months among 254 patients treated with SLC and 3.3 months among 118 patients treated with BSC (HR, 0.507; 95% CI, 0.405 to 0.637; one-sided p<0.001). Compared to the RCT patients, younger age group, those with an ECOG performance status (PS) of 0, and with one prior chemotherapy were under-represented in the PPT patients. OS was comparable between RCT (5.0 months) and PPT (4.4 months) patients even after controlling for major prognostic factors (log-rank p=0.322). The OS benefit for SLC was preserved when analyzed according to baseline parameters. Parameters that were associated significantly with a prolonged OS included a PS of 0, the chemotherapy-free interval ≥3 months, and one prior chemotherapy. When the analysis was adjusted for these three parameters, patients who received SLC still had improved OS (HR, 0.554; 95% CI, 0.441 to 0.696; p<0.001). Conclusions: The 54% participation rate obtained in the current study represents the best achievable rate for this kind of phase III RCT involving BSC only arm. Even if we consider differences in the baseline characteristics between RCT and PPT patients, it is concluded that the RCT results can be generalized for the patient population and provided additional evidence supporting the use of SLC in patients with pretreated AGC.
Assessment of the 7th edition of the AJCC classification and a proposal of a new classification in patients with gastric cancer undergoing D2 gastrectomy.
Authors: Catalano Vincenzo , Sisti Valerio , Spada Daniele , Graziano Francesco , Cicetti Moreno , Giordani Paolo , Alessandroni Paolo , Baldelli Anna Maria , Casadei Virginia , Luzi Fedeli Stefano , Rossi David , D'Emidio Silvia , De Nictolis Michele , Testa Enrica , Fiorentini Giammaria , Zingaretti Costantino 
Published: March 2020

4084 Background: Studies on Asian, US, and German patients have moved some criticisms on the validity of the 7th edition of the AJCC classification to discriminate outcome of gastric cancer stages. We investigated the effect of this AJCC classification in a high-quality surgical populations of patients receiving D2 lymphadenectomy. Methods: From the prospective database at San Salvatore Hospital, Pesaro, we identified 515 patientswith gastroesophageal junction (Siewert II and III) or stomach adenocarcinoma who underwent gastrectomy with curative intent from 1998 to 2010. Lymphadenectomy extended to the 3rd level 12p/b nodes (D2/D3) was performed in all patients. Overall survival (OS) probabilities, calculated from the date of surgery to the date of death, from any cause, were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: 58% of patients were male,median age was 73 years (range 36-96). Median number of examined lymph nodes was 32 (range, 1-89), and only 8.9% of patients had less than 15 examined lymph nodes; 96 patients received adjuvant chemo- or chemoradiotherapy. As shown in the table, we proposed a revised staging system (Pesaro Staging System, PSS), which performs better than the 7th edition of AJCC classification in terms of survival differences between stages. Conclusions: This study confirms once again that the 7th edition of the AJCC classification does not discriminate adequately the outcome from stage to stage. In a European population of patients undergoing gastrectomy plus at least D2 lymphadenectomy, the revised staging system, PSS, better defines patient prognosis. [Table: see text]
Tolerability and efficacy of a biweekly docetaxel, fluorouracil, leucovorin, oxaliplatin regimen (TFOX) in previously advanced metastatic gastric and oesogastric junction (AGC) adenocarcinoma.
Authors: Pernot Simon , Mitry Emmanuel , Samalin Emmanuelle , Dahan Laetitia , Turki Hajer , Mazard Thibault , Ychou Marc , Seitz Jean Francois , Rougier Philippe , Taïeb Julien 
Published: March 2020

4087 Background: The DCF regimen is superior to 5-FU-Cisplatin in term of response rate (RR) and overall survival (OS) in advanced gastric cancer, but is also more toxic. Oxaliplatin is better tolerated and can effectively replace cisplatin in AGC patients (pts). We hypothesize that incorporating Docetaxel into a simplified FOLFOX regimen should be a tolerable and efficient option, and could facilitate the use of this drug in 1st line in AGC. Methods: TFOX regimen was given biweekly as follow: Docetaxel (50mg/m2), oxaliplatin (85mg/m2), leucoverin (400mg/m2) and 5FU continuous infusion 48h (2400mg/m2). Main inclusion criteria were: pts with histollogically proven metastatic or locally advanced gastric or oesogastric junction adenocarcinoma, previously untreated, PS≤2. Using Fleming design the primary end point was response rate, needing a sample size of 40 pts. Results: Between 02/2008 and 07/2011, 41 pts with AGC were enrolled (oesogastric junction: 17 pts, diffuse type: 22 pts, metastatic: 37 pts); mean age was 53.5 years (31-73), 26 pts were male. PS 0/1/2: 11/24/6 pts, 14 pts had a relapse after a R0 resection. The total number of cycles administered was 310 (mean 7.6 cycles/pts) and 90% of pts received at least 4 cycles. No toxic death occurred. Grade 3-4 toxicities were observed in 20 pts (48%). Grade 3-4 toxicities were neutropenia (29%) febrile neutropenia (7%), neurotoxicity (10%), asthenia (10%). ORR was 63% (n=26) [IC95% 48-78], with 2 complete responses. Disease control rate (CR+PR+SD) was 78% (n=32) [IC95% 65-90]. Median progression free survival and overall survival were 6.5 months [IC95% 5.02-10.85] and 12.1 months [IC95% 7.25-15.28], respectively. Conclusions: TFOX is effective with a manageable toxicity profile in first line treatment for AGC pts. Tolerability of this regimen compares favourably with DCF reported tolerability. TFOX may be an alternative option for intensive 1st line treatment and should now be evaluated in randomized trials.
Prognostic value of lemur tyrosine kinase-3 (LMTK3) polymorphism in Japanese (J) patients (PTS) with localized gastric adenocarcinoma (GAC).
Authors: Barzi Afsaneh , Wakatsuki Takeru , Zhang Wu , Yang Dongyun , Loupakis Fotios , Ning Yan , El-Khoueiry Rita , Labonte Melissa Janae , Azuma Mizutomo , Bohanes Pierre Oliver , Benhaim Leonor , Gerger Armin , Koizumi Wasaburo , Watanabe Masahiko , Stebbing Justin , Giamas Georgios , Lenz Heinz-Josef 
Published: March 2020

4088 Background: LMTK3 is an estrogen receptor α (ERα) regulator. Recent studies show that [rs808419(r8) and rs9989661(r9)] and LMTK3 expression are prognostic in breast and colon cancers. Our group demonstrated that r9AA is associated with shorter time to recurrence in Caucasian(C) and Hispanic(H) females(F) with GAC. We investigated the significance of LMTK3 polymorphism in J PTS with GAC. Methods: Blood or tissue samples of 169 J PTS who had surgery with/without adjuvant chemotherapy (ACT) were analyzed. Genomic DNA was extracted using the QIAmp kit; all samples were analyzed using PCR-based direct DNA-sequencing. The endpoints of the study were disease-free survival (DFS) and overall survival (OS). Kaplan-Meier curves and log-rank test were used for univariate analysis. Multivariate analysis was performed to test the interaction between polymorphism and gender adjusting for other variables. Results: 60 F and 109 males were enrolled in this study, 17% stage(s) IB, 31% s II, 36% s III, 17% s IV (AJCC-6). The median age was 67(31-88). 65% of PTS received S-1 based ACT. Median follow-up was 4 years(ys). Prognosis was worse in men with r9 AA than AG/GG, at 1 year 67% (95% CI 40-83%) with AA vs 99% (95% CI 91-99%) of AG/GG were alive (p= 0.039). Median survival was not reached in the AG/GG group; in the AA group median DFS and OS was 1yr (p= 0.03) and 2ys (p= 0.039) respectively. In the multivariate analysis adjusting for s, age, and ACT, males carrying AA had increased risk of disease recurrence (HR 3.84 95%CI 1.86-7.92, p< 0.001) and dying (HR 3.47 95%CI 1.58-7.62 p=0.002) compared to those with AG/GG (HR=1, reference). Conclusions: r9 AA was associated with significantly worse DFS and OS in J male with GAC. These results confirm our previous findings that LMTK3 is an independent prognostic factor for localized GAC; interestingly the relationship between gender and prognostic significance is the opposite in J vs. C/H. The gender disparity can be due to the differences in the etiology (histological subtypes), management strategies, allele frequency, and degree of estrogen exposure in the two populations. Additional studies are warranted to identify the underlying biological mechanism.
Two-year follow-up of a phase II study on catumaxomab as part of a multimodal approach in primarily resectable gastric cancer.
Authors: Bokemeyer Carsten , Ridwelski Karsten , Atanackovic Djordje , Arnold Dirk , Woell Ewald , Büchler Markus W. , Krueger Colin , Schuhmacher Christoph 
Published: March 2020

4095^ Background: Perioperative chemotherapy (CT) has demonstrated as survival benefit in locally advanced gastric cancer (GC) in randomized trials. However, the overall cure rate is 30-40% and a significant number of patients are not able to receive the postoperative part of their CT regimen. In Europe, the trifunctional antibody catumaxomab is approved for the treatment of malignant ascites based on a pivotal trial which also included GC patients. A new multimodal approach combining neoadjuvant CT, followed by gastrectomy and intraperitoneal (i.p.) immunotherapy with catumaxomab was assessed in a single-arm multicenter phase II study. We here report 2-year follow-up data. Methods: GC pts (T2/T3/T4, N+/–, M0) received 3 cycles of neoadjuvant fluoropyrimidin/platinum-based CT followed by ’en-bloc’ R0-gastrectomy. Catumaxomab was administered i.p. as intraoperative bolus (10 µg) followed by 4 consecutive 3-hour infusions of 10-150 µg. Primary safety endpoint was the rate of predefined postoperative complications observed during 30 days after surgery. Key efficacy endpoints included disease-free (DFS) and overall survival (OS). Results: The original study data presented at the WCGC in 2011 (Schuhmacher et al.,Ann Oncol (2011) 22(suppl. 5)) showed that the primary endpoint was met and the described application regimen is safe. At time of surgery, 27.8% of patients were stage I, 27,8% of patients were stage II, 22,3% of patients were stage III and 14,8% of patients were stage IV as assessed according to pTNM measures. At 24 months 39/54 (safety analysis set) patients were still alife,14/54 were dead, (one patient lost to follow-up), 24/37 had no progression, only 13/37 patients relapsed (for 2 patients disease status was not recorded). At the 2 year cut off DFS was 56.4% (95% CI: 41–69%), OS was 75% (95% CI: 60–85%). Conclusions: Catumaxomab as part of a multimodal therapy in primarily resectable GC is a feasible option. The 2-year follow up efficacy results show promising data for DFS and OS in a cohort of locally advanced gastric cancer pts.
A prospective cohort study using a Japanese nationwide survey to evaluate the therapeutic effects of surgery and percutaneous ablation for hepatocellular carcinoma.
Authors: Hasegawa Kiyoshi , Kokudo Norihiro , Makuuchi Masatoshi , Izumi Namiki , Ichida Takafumi , Kudo Masatoshi , Ku Yonson , Sakamoto Michiie , Nakashima Osamu , Matsui Osamu , Matsuyama Yutaka ,   Liver Cancer Study Group of Japan
Published: March 2020

4104 Background: Which is the best treatment for less advanced hepatocellular carcinoma (HCC) with good liver function remains one of the most important and unsolved problems. To solve this problem, we conducted this study and evaluated the therapeutic impacts of surgical resection (SUR), percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA) on long-term outcomes in patients with HCC. Methods: A large-scale database constructed by a Japanese nationwide survey was used for this study. Between 2000 and 2005, 28,510 patients with HCC were treated by SUR, PEI, or RFA, among whom we identify 12,968 patients with no more than 3 tumors (≤3cm) and liver damage of class A or B. The patients were divided into SUR group (n=5,361), RFA group (n=5,548), and PEI group (n=2,059). Rates of overall and recurrence-free survival were compared among them. Results: Median follow-up was 2.16 years. Overall survival rates at 3 and 5 years were respectively 85.3%/71.1% in the SUR group, 81.0%/61.1% in the RFA, and 78.9%/56.3% in the PEI. Recurrence-free survival rates at 3 and 5 years were 56.7%/36.2%, 42.8%/28.3%, and 35.7%/23.1%, respectively. On multivariate analysis, the hazard ratio for death was significantly lower in the SUR group than in the RFA (SUR vs. RFA:0.84, 95% confidence interval, 0.74-0.95; p=0.006) and the PEI (SUR vs. PEI:0.75, 0.64-0.86; p=0.0001). The hazard ratios for recurrence were also lower in the SUR group than in the RFA (SUR vs. RFA:0.74, 0.68-0.79; p=0.0001) and the PEI (SUR vs. PEI:0.59, 0.54-0.65; p=0.0001). Conclusions: Surgical resection would provide longer overall and recurrence-free survival than either RFA or PEI in patients with HCC.
Blood signatures for early liver cancer detection in patients with chronic hepatitis B.
Authors: Liew Choong-Chin , Omar Haniza , Lim Chun Ren , Bong Chin Wei , Ooi Edie Jian Jiek , Lee Michelle Mei Lin , Yu Choon Geok , Tan Soek Siam , Hassan Muhammad Radzi Abu , Menon Jarayam , Muthukaruppan Raman , Singh Mandeep , Abdullah Nik Azim Nik , Ooi Boon Phoe , Ding Robert Phooi Huat , Low Eng Joo , Tan Francis , Chao Samuel , Yang Hengxuan , Merican Ismail 
Published: March 2020

4106 Background: Some 20-30% of patients with chronic hepatitis B (CHB) eventually develop hepatocellular carcinoma (HCC), a disease with poor prognosis and high mortality unless detected early. Ultrasound and/or alpha-fetoprotein (AFP) are widely used for HCC surveillance. However these technologies are operator-dependent, have low sensitivity and are considered inadequate for screening. This study describes a blood-based gene-expression signature prognostic for HCC in CHB patients. Methods: PaxGene was used to extract RNA from whole blood samples taken from more than 1,000 Malaysian patients (matched HCC, CHB, healthy controls). Complementary DNA was generated from isolated RNA via reverse transcription and analyzed using Affymetrix U133Plus 2.0 with MAS 5.0 normalization. To minimize bias we developed a novel algorithm based on SentinelPair regression analysis to identify biomarker panels. A Monte Carlo search identified pair combinations that could differentiate between cancer and controls. Twelve genes were selected for qRT-PCR Cohort 1 verification (n=139). Six genes were then short-listed for qRT-PCR Cohort 2 verification using independent samples (n=150). Results: Multivariate quantitative microarray analysis of 147 samples (HCC=47; CHB=50; controls=50) identified 12 probe sets differentially expressed between HCC patients and controls and CHB (ROC AUC=0.90). These genes were evaluated using qRT-PCR on the same cohort (ROC AUC=0.86). Six genes were subsequently short listed for qRT-PCR Cohort 2 verification. The AUC of the 6-gene-combination of Cohort 2 (HCC=50; CHB=50; controls=50) was 0.80. Importantly, of the thirteen HCC with low AFP (<15ng/ml), 9 were predicted as “positive.” Conclusions: Blood RNA biomarkers identified in this study may form the basis of a test that can be used in patients with CHB for detection of early HCC, potentially improving prognosis for this cancer. This blood-based test would represent a significant clinical alternative to ultrasound and/or AFP.
Clinical, pharmacodynamic (PD), and pharmacokinetic (PK) evaluation of cediranib in advanced hepatocellular carcinoma (HCC): A phase II study (CTEP 7147).
Authors: Zhu Andrew X. , Ancukiewicz Marek , Supko Jeffrey G. , Blaszkowsky Lawrence Scott , Meyerhardt Jeffrey A. , Abrams Thomas Adam , McCleary Nadine Jackson , Bhargava Pankaj , Fuchs Charles S. , Ryan David P. , Jain Rakesh K. , Duda Dan G. 
Published: March 2020

4112 Background: Sorafenib remains the only approved systemic therapy in HCC. We performed a phase II study of cediranib (AZD2171)—a more potent and selective pan-VEGF receptor inhibitor—in advanced HCC patients (pts). Methods: Eligibility criteria included unresectable or metastatic measurable HCC, ECOG PS ≤2, CLIP score ≤3, and adequate organ function. Patients received cediranib at 30 mg po qd continuously (4-wk cycle). The primary endpoint was progression free survival (PFS). We also assessed overall survival (OS) and response rates, steady-state PK of cediranib, and blood circulating biomarkers. Results: Since 6/16/09, we have enrolled the targeted 17 pts required for the first stage of the planned study: ECOG 0/1/2=5/11/1, CLIP 1/2/3=6/4/7, Child A/B=14/3, BCLC C=17. Nine pts had prior sorafenib. The best response was stable disease in five pts (29%). The median PFS was 5.3 months (95% CI: 3.5-9.7). The median OS was 11.7 months (95% CI: 7.5-13.6). Grade 3 toxicities included hypertension (29%), hyponatremia (12%), elevated SGOT (12%) and one pt each (6%) in SGPT, fatigue, hyperbilirubinemia, cardiac ischemia, and proteinuria. Grade 4 pulmonary embolism and brainstem hemorrhage occurred in 1 pt each. Steady-state PK parameters (mean±SD) were, Cmin, 22±21 ng/mL; Cmax, 55±33 ng/mL; AUCτ, 887±503 ng*h/mL. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased significantly after cediranib treatment (p<0.05). PFS was inversely correlated with baseline levels of bFGF, sVEGFR2 and VEGF, and OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-alpha and CD34+CD133+ hematopoietic progenitor cells (p<0.05). Conclusions: Cediranib at 30 mg daily is associated with high frequency of grade 3 hypertension and shows preliminary evidence of antitumor activity in advanced HCC pts. Exploratory studies confirmed potential PD and response biomarkers of anti-VEGF therapy. Cediranib exhibits similar PK in HCC pts as in those with other tumor types and normal/near normal hepatic function. This study was stopped by AstraZeneca after discontinuation of cediranib development for unrelated factors.
Merkel cell polyomavirus in gastrointestinal neuroendocrine tumors.
Authors: Renne Salvatore Lorenzo , Fumagalli Caterina , Fazio Nicola , Viale Giuseppe , Barberis Massimo 
Published: March 2020

4120 Background: Cutaneous Merkel cell carcinoma (MCC) is a high grade neuroendocrine carcinoma potentially induced by Merkel Cell Polyomavirus (MCPyV), a clonally integrated host in the tumor cell genome. Integration of viral DNA and truncating mutations in the helicase domain of the large T (LT) antigen, a protein implicated in the viral life cycle, have been detected in all MCPyV associated MCCs. These results suggest a role of the virus in tumor pathogenesis according to a two step model: a necessary but not sufficient integration of viral DNA followed by LT antigen premature truncations. Gastrointestinal neuroendocrine tumors (GI-NETs) share common phenotypical features with MCCs, therefore we evaluated whether MCPyVs may be present in GI-NET. Methods: Formalin–fixed and paraffin-embedded samples from 14 cases of liver metastases of G2 GI-NETs, 9 small cell lung cancer (SCLCs) and 4 MCCs of the skin were screened for MCPyV-DNA positivity using two PCR primer sets mapping the LT antigen gene. Then to confirm the putative pathogenetic role of the virus, we seeked for premature truncation of LT antigen by sequencing the helicase portion using seven amplicons mapping 1356-2210 region of the MCPyV complete genome (RefSeq: NC_010277.1). Results: Viral DNA was detected in 7/14 GI-NETs, in 0/9 SCLCs and in 4/4 MCCs. We found a premature stop codon truncating the helicase domain in two GI-NETs. Both the patients had a rapid disease progression. We also found previously not reported alterations in MCCs: a single aminoacid deletion in 3 cases and a point mutation causing a single aminoacid substitution in another case. Conclusions: For the first time the potential tumorigenic signature of MCPyV has been detected in GI-NETs, suggesting a possible role in pathogenesis. The study is ongoing to confirm these observations that could support new diagnostic and therapeutical perspectives of a subset of GI NETs. Moreover we have shown that the clonal integration of MCPyV in MCCs produces different genetic alterations with unknown effects on cell biology.
A multi-institutional phase II open-label study of AMG 479 in advanced carcinoid and pancreatic neuroendocrine tumors.
Authors: Kulke Matthew , Chan Jennifer A. , Ryan David P. , Meyerhardt Jeffrey A. , Fuchs Charles S. , Abrams Thomas Adam , Regan Eileen , Brady Rachel , Weber Jill M. , Campos Tiffany , Kvols Larry , Strosberg Jonathan R. 
Published: March 2020

4125 Background: The IGF pathway is thought play an important role in neuroendocrine tumor progression. We therefore investigated AMG 479, a human monocolonal antibody against IGF1-R, in patients with metastatic progressive carcinoid and pancreatic neuroendocrine tumors (NETS). Methods: This open-label phase II study enrolled patients (≥18 yrs) with metastatic low and intermediate-grade carcinoid and pancreatic NETs. Key inclusion criteria included evidence of progressive disease (by RECIST) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160mg/dL. Prior treatments were allowed, and concurrent somatostatin analog therapy was permitted as long as patients remained on a stable dose. The primary endpoint was objective response rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: 60 patients (30 carcinoid, 30 pancreatic NET) were treated with AMG 479 18mg/kg every 3 weeks and 54 patients were evaluable for response. There were no objective responders by RECIST. When best response to therapy was evaluated, 10/27 (37%) evaluable carcinoid patients and 8/26 (31%) evaluable pancreatic NET patients experienced 1-29% tumor shrinkage, while 17/27 (63%) of the carcinoid patients and 15/26 (58%) of the pancreatic NET patients appeared to experience continued tumor growth. Median PFS was 6.3 months (95% CI 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients and 4.2 months for pancreatic NET patients. The OS rate at 12 months was 70% (55%-81%) for the entire cohort. Median OS has not been reached. Treatment related grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%) and infusion reaction (1%). Conclusions: While well-tolerated, single-agent AMG 479 was not found to result in major tumor responses among patients with metastatic low-intermediate grade carcinoid or pancreatic NET. Subgroup analysis to identify characteristics of patients who may have benefited from therapy with AMG 479 is ongoing.