bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of efficacy and safety of second-line palliative chemotherapy with paclitaxel plus raltitrexed and paclitaxel alone in patients with metastatic gastric adenocarcinoma: A randomized phase II trial.
Authors: Zhao Xiaoying , Guo Weijian , Chen Zhiyu , Zhang Xiaowei , Zhu Xiaodong , Zhang Wen , Yang Lei , Qiu Lixin , Wang Chenchen , Huang Mingzhu , Yu Hui , Li Jin , Zhang Zhe , Li Wenhua 
Published: May 2019

4054 Background: Paclitaxel is a microtubule stabilizing agent that has been the standard second line chemotherapy in the treatment of advanced gastric cancer. This study was designed to find out the clinical outcome of paclitaxel plus raltitrexed regimen as second line treatment in MGC patients. Methods: In an open, randomized, multi centers phase II clinical trial , 148 patients were randomly assigned and treated with either RP (raltitrexed 3 mg/m2 d1 and paclitaxel 135mg/m2 d1,3w) or P (paclitaxel 135mg/m2 d1,3w) as second-line palliative chemotherapy. The primary endpoint is PFS, secondary endpoint is ORR, OS and safety. Results: In 148 randomly assigned and treated patients (RP = 73; P = 75), the majority of patients were males (94 vs. 54). Progression free survival has a tendency to be prolonged with RP versus P (2.7m vs. 1.7m, p = 0.148). Overall survival also has a tendency to be prolonged with RP versus P (10.2m vs. 6.1m, p = 0.140). Overall response rate was equal with RP versus P (6.8% vs.4.0%, p = 0.72). DCR in the RP group was 56.2%, P group was 36.0%. Grade 3 to 4 treatment-related adverse events occurred in 36.2% (RP) v 28.2% (P) of patients. Frequent grade 3 to 4 toxicities for RP v P were: neutropenia (11.0% v 4.0%), anemia (1.4% v 4.0%), thrombocytopenia (1.4% v 5.3%), and all grade peripheral neurotoxicity (12.3% v 17.3%),all grade elevated aminotransferase (27.4% v 14.1%). Subgroup analysis shows if the disease combined with ascites or peritoneal involved , OS of RP regimen is more longer (p = 0.05). Conclusions: Second-line palliative chemotherapy with paclitaxel plus raltitrexed provides a tendency to prolong PFS and OS, and the patients with ascites or peritoneal involved may get benifits from combined chemotherapy, which needs to be confirmed by larger sample studies. Clinical trial information: NCT02072317.
Phase I trial of hyperthermic intraperitoneal chemoperfusion (HIPEC) with cisplatin, mitomycin, and paclitaxel in patients with gastric adenocarcinoma and carcinomatosis or positive cytology.
Authors: Badgwell Brian D. , Blum Mariela A. , Ikoma Naruhiko , Wang Xuemei , Estrella Jeannelyn , Roy-Chowdhuri Sinchita , Das Prajnan , Minsky Bruce D. , Song Shumei , Mansfield Paul F. , Ajani Jaffer A. 
Published: May 2019

4056 Background: This phase I trial evaluated the safety and toxicity of laparoscopic hyperthermic intraperitoneal perfusion with chemotherapy (HIPEC) combining mitomycin, cisplatin, and paclitaxel for patients with gastric cancer metastatic to the peritoneum. Methods: A Bayesian optimal interval design was used to identify the maximum tolerated dose (MTD) of escalating doses of paclitaxel (starting dose of 20 mg/m2 to maximum dose of 60 mg/m2) in combination with flat doses of mitomycin (30 mg) and cisplatin (200 mg) during laparoscopic HIPEC for patients with gastric adenocarcinoma metastatic to the peritoneum. The primary endpoint was MTD. Secondary endpoints included surgical complications and overall survival (OS). Results: A total of 27 patients were treated from November 2017 through November 2018. No dose-limiting toxicities were found. Treatment-related grade 1-2 side effects were leukopenia (11%), oral dysesthesia (4%), arthralgia (4%), and diarrhea (4%). Treatment-related grade 3-4 side effects included leukopenia (4%) and neutropenia (4%). The MTD was 60 mg/m2. Clavien-Dindo surgical complications were grade I (all representing electrolyte deficiencies requiring replacement) in 96% of patients, grade II in 4%, grade III in 0%, grade IV in 0%, and grade V in 4%. At a median follow-up of 15 months, the median OS from diagnosis of metastatic disease and the date of surgery has not been reached. One- and 2-year OS rates from the date of metastatic disease were 74% and 58%, respectively. The 1-year OS rate from the date of HIPEC was 51%. Conclusions: Laparoscopic HIPEC with mitomycin, cisplatin, and paclitaxel appears safe at intraperitoneal doses of 30 mg, 200 mg, and 60 mg/m2, respectively. Although electrolyte abnormalities are common, systemic toxicity of this therapy is modest. Survival rates are promising, supporting further research into intraperitoneal therapy for stage IV gastric cancer. Clinical trial information: NCT03330028.
Prospective evaluation of metabolic intratumoral heterogeneity using 18F-FDG-PET-CT in patients with advanced gastric cancer receiving palliative chemotherapy.
Authors: Yoo Shin Hye , Kang Seo Young , Cheon Gi Jeong , Oh Do-Youn , Bang Yung-Jue 
Published: May 2019

4059 Background: Metabolic intratumoral heterogeneity (ITH) gives important information on treatment response and prognosis. However, temporal changes in metabolic ITH and their associations with treatment outcome have not been reported yet in gastric cancer (GC). We aimed to evaluate the early changes in metabolic ITH and their predictive roles in advanced GC patients receiving palliative chemotherapy. Methods: Unresectable locally advanced or metastatic GC patients were prospectively enrolled before the first-line palliative chemotherapy and underwent 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET-CT) at baseline (T1) and at the first response evaluation follow-up (T2). SUVs (Standardized uptake values), volumetric parameters, and textural features including entropyHisto and contrastGLCM were extracted from the primary gastric tumor at T1, T2, and ΔT (T2-T1) was evaluated. Associations of these parameters with treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed. Results: 87 patients were analyzed. Of 86 evaluable patients, 44 obtained partial response, 33 stable disease, and 8 progressed. The objective response rate was 51.8% (95% confidence interval [CI], 40.7% to 62.7%). The median PFS and OS were 7.3 months (95% CI, 5.4 to 8.2 months) and 11.5 months (95% CI, 10.1 to 14.3 months), respectively. From T1 to T2, metabolic ITH was significantly reduced ( P < 0.01), and the degree of decrease was greater in responders than in non-responders ( P < 0.01). By multiple Cox regression analyses adjusted for clinical variables, low entropyHisto at T2 ( P= 0.001), larger decreases in coefficient of variance ( P= 0.003) and contrastGLCM ( P= 0.017) were associated with better PFS. Low SUVpeak at T2 ( P= 0.001), larger decreases in coefficient of variance ( P= 0.032) and being a responder were associated with better OS. Conclusions: Early reduction in metabolic ITH is useful to predict response to palliative chemotherapy, PFS and OS in advanced GC patients.
A digital pathology demonstration of an "immune hot" ICOS+/CD45RO+ immunephenotype and the impact on survival in patients with esophageal adenocarcinoma.
Authors: Humphries Matthew Philip , Fisher Natalie , Kacprzyk Rafal , Craig Stephanie G , Bingham Victoria , McQuaid Stephen , Turkington Richard C. , Murray Graeme I , James Jacqueline , Salto-Tellez Manuel 
Published: May 2019

4062 Background: Therapies targeting immune checkpoints are changing our understanding of the biology and treatment of cancer. Analysing the immune landscape in esophageal adenocarcinoma (EA) may help future prognostication and therapeutic decision-making. Methods: We assembled 310 EA cases in a tissue microarray format with associated clinicopathological information, including a discovery cohort of 156 EA from Northern Ireland and a 154 EA validation cohort from Aberdeen. We carried out validated immunohistochemistry (IHC), stained for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS and IDO-1). Slides were digitised and assessed using QuPath image analysis software program to quantify their expression and correlate them with outcome. Results: In the discovery cohort we identified a group of patients highly expressing several immune biomarkers, conferring a significant positive survival advantage (p = 0.022). CD3, CD4, CD8, CD45RO, and ICOS were individually prognostic for better overall survival (Log rank p = 0.0003; p = 0.0292; p = 0.0015; p = 0.0008; p = 0.0051 and p = 0.0264 respectively). Multivariate and correlation analysis identified a subgroup of CD45RO+/ICOS+ patients with significantly improved overall survival (p = 0.0002). The co-expression of CD45RO+/ICOS+ immunophenotype was investigated in the validation cohort and a confirmed survival advantage was seen (p = 0.042). Additionally, the Opal Multiplex IHC technology revealed the much higher frequency of single-cell, dual labelling of CD45RO+/ICOS+ in immune hot cases. Conclusions: These data demonstrate the advantage of immune markers other than the traditional CD3/CD4/CD8 in EA prognostication. The fact that one of these biomarkers is an immune checkpoint inhibitor may have therapeutic implications.
The impact of postoperative complications on survival outcomes in patients with cT3/4a gastric cancer.
Authors: Tokunaga Masanori , Kurokawa Yukinori , Doki Yuichiro , Machida Ryunosuke , Takiguchi Shuji , Sato Yuya , Katai Hitoshi , Fukushima Norimasa , Nishida Yasunori , Cho Haruhiko , Yamada Takanobu , Kaji Masahide , Fujita Junya , Boku Narikazu , Yoshikawa Takaki , Terashima Masanori 
Published: May 2019

4067 Background: Recently, the negative impact of postoperative complications on long-term survival outcomes has been reported in patients with gastric cancer. However, most are single center, retrospective studies with different definitions of postoperative complications. The objective of this study was to evaluate the impact of postoperative complications on long-term outcomes using the data of a multicenter randomized controlled trial (JCOG1001). Methods: This study included 1191 out of all 1204 patients enrolled in JCOG1001 which was aimed to confirm the superiority of bursectomy for patients with cT3/4a locally advanced gastric cancer. Complications were graded by Clavien-Dindo classification. The relationships between the grade (≥grade II or ≥grade III) or type (all or intraabdominal infectious (pancreatic fistula, anastomotic leakage, and intra-abdominal abscess.)) of complications and survival outcomes were evaluated. Results: The incidences of ≥grade II and ≥grade III all complications were 23.0% and 9.7%, and those of ≥grade II and ≥grade III intraabdominal infectious complications were 13.4% and 6.9%, respectively. The hazard ratios for overall survival (OS) of patients with ≥grade II and ≥grade III all complications and those of patients with ≥grade II and ≥grade III intraabdominal infectious complications were shown in Table. With whichever definition we adopted, postoperative complications were significantly associated with OS in both univariable and multivariable analysis. Conclusions: Postoperative complication was identified as an independent prognostic factor in patients with cT3/4a gastric cancer. Hazard ratios for overall survival by univariable and multivariable Cox proportional hazard model. Clinical trial information: UMIN000003688. [Table: see text]
Prognostic significance of sarcopenia in metastatic esophageal squamous cell carcinoma.
Authors: Taylor Kirsty , Espin-Garcia Osvaldo , Romagnuolo Tina , Allison Frances , Ma Lucy Xiaolu , McInnis Micheal , Fares Aline Fusco , Liu Geoffrey , Darling Gail Elizabeth , Wong Rebecca , Chen Eric Xueyu , Veit-Haibach Patrick , Jang Raymond Woo-Jun , Rozenberg Dmitry , Elimova Elena 
Published: May 2019

4068 Background: Sarcopenia is defined as low skeletal muscle mass and represents a quantifiable marker of frailty. Disease related symptoms of anorexia, nausea and dysphagia, in addition to reduced physical activity contribute to muscle wasting in metastatic esophageal squamous cell cancer (MESCC) patients. This study set out to evaluate the prognostic utility of sarcopenia and its association with nutritional indices. Methods: MESCC patients (pts) with available abdominal CT imaging, attending Princess Margaret Cancer Centre between 2011 and 2016, were identified from the institutional database. Skeletal muscle index (SMI), normalized by height, was calculated at the third lumbar (L3) vertebra using SliceOMatic software. SMI cutoffs for sarcopenia were 34.4cm2/m2 in females and 45.4cm2/m2 in males based on previously established consensus. Nutritional risk index (NRI) was calculated using weight and albumin with malnutrition defined as < 97.5. Results: Of the 58 pts analyzed, 26 presented with de novo MESCC, median age was 64 (range 48-85), 30 pts were ECOG PS ≤1 and 45% received systemic therapy. 93% of pts experienced weight loss > 5% in the 3 months preceding diagnosis and median BMI was 20.4 (range 16.3-34.9). Twenty-four (41%) pts were sarcopenic (SP) with differences in BMI and NRI (p < 0.05) compared to non-sarcopenic (NSP) pts. Median BMI in SP pts was 18.9 (16.3-25.6), 46% had a BMI < 18.5 and none were obese (BMI ≥ 30). By NRI, 58% of SP pts were malnourished. Males comprised 71% of SP pts (p = 0.03) but no difference from NSP MESCC pts was identified with age, race, ECOG PS or smoking status with univariate analysis. Median overall survival (OS) was 6 months; 4.2 in SP pts and 6.2 in NSP pts. Significant difference was identified with NRI (p = .0.009) but not sarcopenia (p = 0.247) or BMI (p = 0.393). With a multi-variate Cox model for NRI and sarcopenia, including age, sex, race, and ECOG PS, only ECOG PS was a significant predictor of mortality, HR for 2-3 vs 0-1 of 5.4 (2.5-11.9) p < 0.001. Conclusions: Sarcopenia at diagnosis was not associated with OS. NRI was superior to BMI alone with respect to discriminating pt outcomes, however ECOG PS was the only measure significantly associated with survival.
First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100).
Authors: Kudo Masatoshi , Motomura Kenta , Wada Yoshiyuki , Inaba Yoshitaka , Sakamoto Yasunari , Kurosaki Masayuki , Umeyama Yoshiko , Kamei Yoichi , Yoshimitsu Junichiro , Fujii Yosuke , Aizawa Mana , Robbins Paul B. , Furuse Junji 
Published: May 2019

4072 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of advanced/metastatic (a/m) hepatocellular carcinoma (HCC). Avelumab is a human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a tyrosine kinase inhibitor selective for VEGF receptors 1/2/3. VEGF Liver 100 (NCT03289533) is a phase 1b study evaluating safety and efficacy of avelumab + axitinib in treatment-naive patients (pts) with HCC; interim results are reported here. Methods: Eligible pts had confirmed a/m HCC, ≥1 measurable lesion, a fresh or archival tumor specimen, ECOG PS ≤1, and Child-Pugh class A. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and objective response (RECIST v1.1; modified [m] RECIST for HCC). Results: Interim assessment was performed after a minimum follow up of 6 months based on the released study data set (clinical cut-off date: Aug 1, 2018). As of the cut-off date, 22 pts (median age: 68.5 y) were treated with avelumab (median: 20.0 wk) and axitinib (median: 19.9 wk). The most common grade 3 treatment-related adverse events (TRAEs) (≥10% of patients) were hypertension (50.0%) and hand-foot syndrome (22.7%); no grade 4/5 TRAEs were reported. Immune-related AEs (irAEs) (≥10% of pts) were hypothyroidism (31.8%) and hyperthyroidism (13.6%). No grade ≥3 irAEs were reported; no pts discontinued treatment due to TRAEs or irAEs. Based on Waterfall plot calculations, tumor shrinkage was observed in 15 (68.2%) and 16 (72.7%) pts by RECIST and mRECIST, respectively. ORR was 13.6% (95% CI, 2.9%-34.9%) and 31.8% (95% CI, 13.9%-54.9%) by RECIST and mRECIST, respectively. OS data were immature at data cutoff. Conclusions: The preliminary safety of avelumab + axitinib in HCC is manageable and consistent with the known safety profiles of avelumab and axitinib when administered as monotherapies. This study demonstrates antitumor activity of the combination in HCC. Follow-up is ongoing. Clinical trial information: NCT03289533. [Table: see text]
DNA damage repair (DDR) gene alterations as a predictive biomarker for response to platinum-containing chemotherapy in advanced biliary tract cancer (BTC).
Authors: Chae Heejung , Yoo Changhoon , Kim Deokhoon , Jeong Jae Ho , Chang Heung-Moon , Kim Kyu-Pyo , Ryoo Baek-Yeol 
Published: May 2019

4078 Background: Although many studies using whole-exome sequencing or targeted sequencing have reported the molecular profile of BTC, its clinical implications remains unclear. In this study, we assessed a predictive role of DDR gene mutations in advanced BTC patients treated with platinum-containing regimen. Methods: Eighty-eight patients with pathologically-confirmed BTC who received first-line gemcitabine-cisplatin combination (n = 69) or fluoropyrimidine-oxaliplatin combination (n = 19) were included in this analysis. Targeted exome sequencing was performed using Foundation Medicine T7 assay or in-house OncoPanel AMC. Germline or somatic mutations in ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, GEN1, MLH1, MSH2, MSH6, MRE11A, NBN, PALB2, PMS2, RAD50, RAD51, RAD51C, RAD51D, and XRCC2 were classified as DDR gene mutations. Data regarding baseline characteristics and treatment outcomes were retrospectively obtained from medical records. Results: The median age was 62 years (range, 25-78), with male comprising 64.8% (n = 57). By primary tumor site, 21 patients with GBC (23.9%), 44 with ICC (50.0%) and 23 with ECC (26.1%) were included. Most patients received palliative chemotherapy for their initially metastatic (50.0%) or recurred (44.3%) disease; the rest 5.7% had locally advanced disease. The median PFS and OS of overall patients were 7.1 and 16.1 months, respectively with median follow-up duration of 20.2 months. DDR gene mutations were found in 63.5% of patients. BRCA2 (18.2%) was most frequently mutated, followed by ATM (13.6%), and ATR (8.0%). DDR gene mutations were significantly associated with prolonged PFS (presence vs. absence; median, 6.9 vs. 5.7 months; P = 0.013) and OS (median, 21.0 vs. 13.3 months, P = 0.009). The impact of DDR gene mutations remained significant in multivariate analyses for PFS that included other prognostic factors (hazard ratio, 0.51; P = 0.009), but not for OS. Conclusions: The presence of DDR gene mutations might be a promising predictive biomarker for response to platinum-based chemotherapies in advanced BTC. Future investigation using novel agents targeting DDR gene alteration in BTC are warranted.
CT-based radiogenomic signature to identify isocitrate dehydrogenase (IDH)1/2 mutations in advanced intrahepatic cholangiocarcinoma.
Authors: Idris Tagwa , Barghash Maggie , Kotrotsou Aikaterini , Huang Helen J , Subbiah Vivek , Kaseb Ahmed Omar , Piha-Paul Sarina Anne , Hong David S. , Meric-Bernstam Funda , Javle Milind M. , Janku Filip , Colen Rivka R. 
Published: May 2019

4081 Background: IDH1/2 mutations have a high prevalence (20%) in intrahepatic cholangiocarcinoma (iCCA) and can be associated with therapeutic benefit from IDH inhibitors. Radiomics, a developing field within imaging, has shown its ability to discriminate between tumors of distinct genomic profiles and mutational status. Methods: We developed a radiogenomic signature to robustly predict IDH1/2 mutation status (mutated versus wild-type [WT]) in 22 patients with iCCA using the pretreatment CT scans. The triphasic hepatic CT scan was used to segment the lesion. After semiautomatic segmentation of the tumor, the extracted volume of interest (VOI) was imported into our in-house radiomic pipeline and 610 radiomic features were extracted. The least absolute shrinkage and selection operator regression (LASSO) and minimum redundancy and maximum relevance (mRMR) were used for feature selection. Selected features were used to build a classification model for prediction of IDH1/2 mutation status (XGboost). The performance of the radiomics model was assessed using leave-one-out cross-validation (LOOCV). Results: Of 22 patients, 16 patients (male, 6; female, 10; average age, 55.5 years) had IDH1 (N = 14) or IDH2 (N = 2) mutations and 6 patients (male, 4; female, 2; average age = 55.5 years) had IDH1/2 WT.The CT-derived radiomic signature robustly predicted presence of IDH1/2 mutations versus WT with an area under the curve (AUC), sensitivity and specificity of 98.4%, 83.3% and 93.8%, respectively ( P = 0.037) and in a subgroup analysis presence of IDH1 mutation versus WT with an AUC, sensitivity and specificity of 98.2%, 83.3% and 92.8%, respectively ( P = 0.035). Conclusions: To our knowledge, this is the first study investigating the ability of radiogenomics as a potential method to predict the IDH1/2 mutation status in iCCA patients. Our data suggest that radiogenomic signature may correlate with IDH1/2 mutations and represent a promising non-invasive tool to stratify the patients based on molecular alterations.
Association of adverse events (AEs) with efficacy outcomes for cabozantinib (C) in patients (pts) with advanced hepatocellular carcinoma (aHCC) in the phase III CELESTIAL trial.
Authors: Abou-Alfa Ghassan K. , Meyer Tim , Cheng Ann-Lii , Cicin Irfan , Bolondi Luigi , Klümpen Heinz Josef , Chan Stephen Lam , Dadduzio Vincenzo , Milwee Steven , Dubey Sarita , Kelley Robin Kate , El-Khoueiry Anthony B. 
Published: May 2019

4088 Background: Class-specific AEs occurring with tyrosine kinase inhibitors have been associated with improved efficacy outcomes in several tumor types including aHCC. In the phase 3 CELESTIAL trial (NCT01908426), C, an inhibitor of VEGFR, MET, and AXL, improved overall survival (OS) and progression-free survival (PFS) vs placebo (P) in pts with previously treated aHCC. Here, we retrospectively evaluate the association of palmar-plantar erythrodysaesthesia (PPE) and hypertension (HTN) with OS and PFS for C in the CELESTIAL trial. Methods: 707 pts with aHCC were randomized 2:1 to receive 60 mg C or P once daily. Eligible pts had Child-Pugh score A, ECOG PS ≤1, must have received prior sorafenib, and could have received up to two prior regimens of systemic therapy for HCC. OS and PFS with C were evaluated for pts with any grade PPE or grade ≥3 HTN within the first 8 weeks of study treatment. Results: Overall, 374 (80%) pts in the C arm and 179 (76%) pts in the P arm completed ≥8 weeks of treatment. In the first 8 weeks, 188 (40%) of C-treated pts developed any grade PPE vs 11 (5%) of P-treated pts, and 61 (13%) of C-treated pts developed grade ≥3 HTN vs 3 (1%) of P-treated pts. Median OS with C was 14.4 mo for pts with any grade PPE vs 8.4 mo for pts without PPE (HR 0.59, 95% CI 0.47-0.74), and median PFS with C was 6.5 mo vs 3.7 mo, respectively (HR 0.63, 95% CI 0.51-0.78). Median OS with C was 16.1 mo for pts with grade ≥3 HTN vs 9.5 mo for pts without grade ≥3 HTN (HR 0.56, 95% CI 0.39-0.80), and median PFS with C was 7.4 mo vs 4.4 mo, respectively (HR 0.59, 95% CI 0.43-0.82). Some imbalances in baseline characteristics were present. Pts with PPE had better ECOG PS (60% vs 47% ECOG 0), better liver function (48% vs 34% ALBI grade 1), and less macrovascular invasion (24% vs 30%) than those without. Likewise, pts with grade ≥3 HTN had better ECOG PS (61% vs 51% ECOG 0), better liver function (56% vs 37% ALBI grade 1), and less macrovascular invasion (20% vs 29%) than those without. Conclusions: The development of PPE or grade ≥3 HTN with C was associated with prolonged OS and PFS in pts with previously treated aHCC although some imbalances in baseline characteristics between comparator groups were present. Clinical trial information: NCT01908426.