bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and prognostic factor analysis in second-line chemotherapy for elderly patients with metastatic gastric cancer.
Authors: Shoji Ayaka , Hasegawa Hiroko , Kato Seiya , Kiyota Ryosuke , Shinkai Kazuma , Tashiro Taku , Ishihara Akio , Iwasaki Tetsuya , Tanaka Satoshi , Akasaka Tomofumi , Sakakibara Yuko , Nakazuru Shoichi , Ishida Hisashi , Hirao Motohiro , Mita Eiji 
Published: January 2019

143 Background: Recently, the proportion of elderly patients (pts) with advanced gastric cancer has increased in Japan. Survival benefits of second-line chemotherapy (CTX) such as weekly paclitaxel (PTX)±Ramucirumab (RAM) or irinotecan (CPT) were shown in several phase 3 trials for metastatic gastric cancer (mGC). However, efficacy and prognostic factors in the second line CTX for elderly pts are not well studied. Methods: We retrospectively reviewed for mGC pts aged ≥ 70 years who underwent PTX+RAM, PTX or CPT as second-line CTX. Eligibility criteria were as follows: PS 0-2, refractory to an S-1containing CTX. Response rate (RR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were evaluated. Univariate and multivariate analyses were performed to determine prognostic factors of survival. Results: There were 250 pts with mGC treated at our institution between April 2007 and March 2017. Of all, total of 85 pts were eligible. Median age was 75 years (71-85). The RR was 28.0% in the PTX+RAM group (n=28), 17.2% in the PTX group (n=29) and 18.5% in the CPT group (n=28). Median PFS was 5.1 months(M) and MST was 12.2 M in the PTX+RAM group, compared with 4.1 M and 9.7 M in the PTX group, or 3.3M and 9.8M in the CPT group. The ORR, PFS and OS were better in the PTX+RAM group though differences between groups were not statistically significant. Grade 3 or higher non-hematological AEs such as fatigue or diarrhea were more frequent in the CPT group on the other hand, hematological AEs were more frequent in the PTX+RAM group. On multivariate analysis, PS (HR,3.13; 95%CI, 1.60-5.77), LDH (HR,3.19; 95%CI, 1.80-5.57), and CEA (HR,2.35; 95%CI, 1.30-4.16) were found to be significant prognostic factors for elderly pts with mGC who underwent second-line CTX. Conclusions: PTX+RAM therapy seemed to be more effective than the other regimens. Furthermore, this analysis for prognostic factors may help clinicians to better select elderly pts who may benefit from a second-line CTX.
Relationship between human epidermal growth factor receptor 2 (HER2) status and central nervous system metastases in gastroesophageal cancer.
Authors: Ma Lucy Xiaolu , Lim Charles Henry , Sun Peiran , Jiang Maria , Sim Hao-Wen , Natori Akina , Chan Bryan Anthony , Yokom Daniel , Moignard Stephanie , Le Lisa W , Chen Eric Xueyu , Liu Geoffrey , Swallow Carol Jane , Darling Gail Elizabeth , Kongkham Paul N. , Shultz David , Hafezi-Bakhtiari Sara , Conner James , Elimova Elena , Jang Raymond Woo-Jun 
Published: January 2019

145 Background: Central nervous system (CNS) metastases (mets) in gastroesophageal (GE) cancers are rare. There have only been limited studies examining the role of HER2 status in CNS mets in GE cancers. Methods: A retrospective analysis was performed for patients (pts) treated for GE cancers at the Princess Margaret Cancer Centre from 2011-2016. Quantitative and qualitative data were collected for all pts with CNS mets. Kaplan-Meier method was used to calculate overall survival (OS) and CNS progression free survival (PFS) for CNS mets pts. Results: Of 34 GE cancer pts diagnosed with CNS mets, 11 were HER2+, 11 HER2- and 12 had unknown HER2 status. Median time from initial cancer diagnosis to CNS mets was 10.3 months (13.4 in HER2+, 5.8 in HER2-, 11.7 in HER2 unknown). Characteristics at CNS mets diagnosis included: median age 63; 85% male; 74% had extracranial systemic mets; performance status ECOG 0-1 (64%), 2 (12%), 3-4 (24%). Treatment for CNS mets is shown in Table 1. Median OS from diagnosis of CNS mets was 6.1 months (95%CI 3.2-16.4) for all pts, 17.1 (95%CI 9.9-NA) in HER2+, 1.8 (95%CI 0.6-NA) in HER2-, 6.0 (95%CI 1.9-NA) in HER2 unknown, p=0.01. Median OS from initial cancer diagnosis was 18.5 months (95%CI 13.6-33.7) for all pts, 28.9 (95%CI 21.32-NA) in HER2+, 10.8 (95%CI 6.37-NA) in HER2-, 18.6 (95%CI 10-NA) in HER2 unknown, p=0.015. The 1 year CNS PFS rate was 35% (95%CI 22.1 – 55.5%) for all pts, 53% (95%CI 29.9 – 94%) in HER2+, 18.2% (95%CI 5.3 – 63.7%) in HER2-, 33% (95%CI 15 – 74.2%) in HER2 unknown, p=0.053. Conclusions: HER2+ pts tended to develop CNS mets later than HER2-. HER2+ pts were more likely to receive CNS-directed interventions, with more HER2+ pts having surgery for CNS mets while more HER2- had supportive care. This analysis is the first to suggest that in pts with CNS mets, HER2+ pts had longer survival than HER2-, both from initial diagnosis and after developing CNS metastases.[Table: see text]
Alterations of plasma glutamine and surgical stress in gastric cancer surgery.
Authors: Hayashi Tsutomu , Aoyama Toru , Yamamoto Hiroshi , Yamada Takanobu , Sato Tsutomu , Rino Yasushi , Masuda Munetaka , Cho Haruhiko , Tsuburaya Akira , Ogata Takashi , Yoshikawa Takaki 
Published: January 2019

176 Background: The plasma glutamine levels are known to decrease after major surgery, which is related to a negative clinical outcome. However, the influence of surgical stress on the decrease in the plasma glutamine concentration is unclear. The aim of this study was to evaluate the change in glutamine in relation to the types of gastrectomy and approaches as well as the amount of surgical stress evaluated by serum interleukin-6(IL-6) as an objective indicator. Methods: This was a prospective observational study. The eligibility criteria were (1) gastric adenocarcinoma of the stomach confirmed by pathology and (2) patients scheduled to receive gastrectomy with D1 or D2 lymphadenectomy for gastric cancer. Blood samples were taken at 7 AM on the day of surgery and at 12 h after surgery to measure the plasma glutamine and interleukin-6 (IL-6) levels. Results: Between May 2011 and December 2011, 81 consecutive patients were enrolled in this study. The plasma glutamine level was significantly decreased in all patients, regardless of distal or total gastrectomy and laparoscopic or open surgery. No significant differences were observed in the IL-6 level between total and distal gastrectomy patients or between patients treated via a laparoscopic or open approach. Decreases in the plasma glutamine level were positively correlated with the logarithmically transformed-plasma IL-6 (logIL6) (r = 0.471, p < 0.001) overall. Conclusions: Decreases in the glutamine concentration depended on the amount of surgical stress. When conducting a clinical trial to evaluate glutamine administration, personalized adjustment may be key to avoiding glutamine depletion in response to surgical stress.
Randomized, open label, multicenter, phase II trial comparing transarterial chemoembolization (TACE) plus sorafenib with TACE alone in patients with hepatocellular carcinoma (HCC): TACTICS trial.
Authors: Kudo Masatoshi , Ueshima Kazuomi , Ikeda Masafumi , Torimura Takuji , Tanabe Nobukazu , Aikata Hiroshi , Izumi Namiki , Yamasaki Takahiro , Nojiri Shunsuke , Hino Keisuke , Tsumura Hidetaka , Kuzuya Teiji , Isoda Norio , Yasui Kohichiroh , Yoshimura Kenichi , Okusaka Takuji , Furuse Junji , Kokudo Norihiro , Okita Kiwamu , Arai Yasuaki ,   For the TACTICS Trial Group
Published: January 2019

206 Background: There is no proven evidence that combination therapy of TACE with sorafenib (TS group) prolong progression-free survival (PFS) and/or overall survival (OS) compared to TACE alone (T group) in patients with unresectable HCC. Methods: In this randomized, open label, multicenter, comparative trial (NCT01217034), patients with unresectable HCC, Child-Pugh score ≤7, ECOG performance status 0-1, no vascular invasion (VI), no extrahepatic spread (EHS), size≤10 cm and number≤10 and adequate organ function were randomized 1:1 (stratification by institution, Milan criteria in or out, and number of previous TACE 0 or 1-2) to T or TS. In TS group, sorafenib 400 mg once daily was pretreated for 2-3 weeks prior to TACE followed by 800mg once daily during on-demand conventional TACE sessions until the time to untreatable progression (TTUP), which was defined as the time to the date of a state when TACE continuation is not possible due to untreatable tumor progression, deterioration to Child-Pugh C or appearance of VI/EHS. Co-primary endpoints are PFS and OS. Multiplicity is adjusted using a gatekeeping hierarchical testing. PFS event in this trial was defined as death or time to TTUP. Key secondary endpoints were time to progression and safety. PFS is expected to 40% extension from 18 months (control arm) to 25 months, target HR was 0.71, with a power of 0.80. Results: The trial was conducted in 33 institutions and a total of 156 patients were randomized to T (n = 76) or TS (n = 80). Median PFS in the T group and TS group was 13.5 and 25.2 months (HR = 0.59, 95%CI 0.41-0.87; p = 0.006), respectively. The number of OS events has not reached. Median TTP was 13.5 and 24.1 months in the T and TS groups (HR = 0.56, 95%CI 0.38-0.83; p = 0.004). Median TTUP was 20.6 and 26.7 months in the T and TS groups (HR = 0.57, 95%CI 0.35-0.92; p = 0.02), respectively. There was no unexpected toxicity. Conclusions: Sorafenib in combination with TACE significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with the known safety profile with previous TACE combination trials. Clinical trial information: NCT01217034.
KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib.
Authors: Zhu Andrew X. , Finn Richard S. , Cattan Stéphane , Edeline Julien , Ogasawara Sadahisa , Palmer Daniel H. , Verslype Chris , Zagonel Vittorina , Rosmorduc Olivier , Vogel Arndt , Sarker Debashis , Verset Gontran , Chan Stephen Lam , Knox Jennifer J. , Daniele Bruno , Ebbinghaus Scot , Ma Junshui , Siegel Abby B. , Cheng Ann-Lii , Kudo Masatoshi 
Published: January 2019

209 Background: Immunotherapy approaches, including immune checkpoint blockade, have shown initial promising results in HCC. Anti PD-1 therapy with pembrolizumab has demonstrated antitumor activity and manageable safety in multiple cancers. KEYNOTE-224 (NCT02702414), an open label, phase 2 trial assessed the efficacy and safety of pembrolizumab in pts with advanced HCC previously treated with sorafenib. Methods: Eligible pts were age ≥18 y with confirmed HCC, radiographic progression after sorafenib and disease not amenable to curative treatment, Child Pugh A, ECOG PS 0-1 and predicted life expectancy > 3 mo. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, unacceptable toxicity, withdrawal of consent or investigator decision. Response was assessed every 9 wk (RECIST v1.1, central review). Primary endpoint was ORR (RECIST v1.1, central review). Secondary endpoints included DOR, DCR, PFS, OS, and safety and tolerability. Data cutoff date was Aug 24, 2017. Results: Of 104 treated pts, 23 continued therapy (median follow up 8.4 mo, range 0.4-13.6). Median age of pts was 68y (range 43-87), 21.2% were HBV+, 26% were HCV+, 94.2% were Child Pugh A, 79.8% had PD on sorafenib and 63.5% had extrahepatic disease. ORR was 16.3% (95% CI, 9.8 to 24.9) and similar across subgroups with different etiology. Median time to response was 2.1 mo (range 1.8-4.8) and 94% of responders were estimated to have a response duration ≥6 mo. Best responses were CR in 1 patient (1.0%), PR in 16 (15.4%), SD in 47 (45.2%) and PD in 34 (32.7%); DCR was 61.5%. Median PFS was 4.8 mo (95% CI, 3.4 to 6.6) and median OS (9.4 to NA) was not reached. The 6 mo PFS and OS rates were 43.1% and 77.9%, respectively. Treatment related (TR) AE occurred in 73.1% of pts; fatigue (21.2%) and increased aspartate aminotransferase (12.5%) were seen in ≥10% of pts and grades 3-5 TRAE in 25% including 1 death (ulcerative esophagitis). No cases of HBV/HCV flare occurred; immune mediated hepatitis occurred in 3 (2.9%) pts. Conclusion: Pembrolizumab treatment resulted in durable responses and favorable PFS and OS in pts with advanced HCC previously treated with sorafenib. Safety was generally comparable to that established for pembrolizumab monotherapy. Clinical trial information: NCT02702414.
Molecular and clinical characterization of BRAF mutations in pancreatic ductal adenocarcinomas (PDACs).
Authors: Guan Michelle , Bender R Joseph , Pishvaian Michael J. , Halverson David Charles , Tuli Richard , Klempner Samuel Jacob , Wainberg Zev A. , Singhi Aatur D. , Petricoin Emanuel , Hendifar Andrew Eugene 
Published: January 2019

214 Background: The activation of the RAS/RAF/MEK/ERK pathway is critical for the proliferation, survival, and tumorigenesis of PDACs. Oncogenic mutations in KRAS (90%) or BRAF (3%) are recurrent genomic alterations, but their co-occurrence is not well described. We reviewed BRAF alterations and clinical outcomes in consecutive PDAC patients (pts). Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. Perthera uses CAP/CLIA accredited multi-Omic profiling, including next generation DNA sequencing (NGS, Foundation Medicine) and proteomics/immunohistochemistry (Neogenomics Inc. and Caris Life Sciences, Inc.). We used a Fisher's exact test with multiple testing correction to compare frequencies of mutations and protein over-/under-expression between BRAF-mutated (n = 21) and BRAF wild type pts (n = 745). Results: Of 766 pancreatic cancer pts, 21 pts were identified with BRAF mutations. 18 pts were diagnosed with PDAC, 1 pancreatoblastoma, 1 pancreatic acinar cell carcinoma, and 1 mixed acinar neuroendocrine carcinoma. Amongst the 18 PDAC pts with BRAF mutations, nine variations were found: V600E (5/18), BRAF fusion (4/18), N486_P490del (3/18), T310I (1/18), K601N (1/18), G596R (1/18), exon 2-10 deletions & S467L (1/18), equivocal amplification of BRAF (1/18), and a BRAF inframe deletion (1/18). KRAS was mutated in 6% of BRAF mutated PDACs, compared to 94% in BRAF wild type PDACs (p < 0.001). Amongst KRAS wild type PDACs, 53% of CDKN2A mutated pts had BRAF mutations vs. only 15% of CDKN2A wild type cases (p < 0.05). Two BRAF mutated pts from the database were given BRAF inhibitors. A sustained response to the combination dabrafenib and trametinib was observed in a BRAF V600E mutated PDAC pt, while no response was seen in a pt with concurrent KRAS G12A & BRAF K601N mutations who received trametinib. Conclusions: BRAF mutations are significantly and inversely correlated with KRAS alterations. The most common BRAF alteration, V600E mutation, was found to be mutually exclusive with the KRAS mutation. Clinical trials targeting BRAF alterations in KRAS wild type pancreatic cancer appears warranted.
Neutrophil-to-lymphocyte ratio as a prognostic marker for metastatic pancreatic cancer.
Authors: Desai Jasmin Radhika , Colton Bradley Scott , Wang Hongkun , Marshall John , Kim Sunnie S. , Pishvaian Michael J. 
Published: January 2019

251 Background: Metastatic pancreatic cancer is a deadly disease, with a median survival that remains less than 12 months. However, more patients than ever before are surviving for more than 1 year, though it has been difficult to determine which patients have a better or worse prognosis. In the MPACT trial of gemcitabine + nab-paclitaxel vs gemcitabine alone, the neutrophil-to-lymphocyte ratio (NLR) prior to treatment was found to be a promising prognostic marker. However, the significance of NLR has not been confirmed. We examined our institutional experience with assessing the prognostic value of the NLR for patients with metastatic pancreatic cancer treated with standard chemotherapies. Methods: We performed an IRB approved retrospective chart review of patients with metastatic pancreatic adenocarcinoma. Patients were eligible if a routine blood count from which an NLR would be calculated was available prior to initiating any chemotherapy. 41 patients were identified who were treated with either FOLFOX (n = 9), FOLFIRINOX (n = 8) or gemcitabine + nab-paclitaxel (n = 24). Patients were stratified into two groups: NLR < 5 and NLR > 5. The median progression free survival and overall survival were determined, and statistical analyses performed to observe any correlation to NLR. Results: In this review, patients with an elevated NLR (NLR > 5) had an improved PFS and OS when compared with patients with a decreased NLR (NLR < 5). OS was 12.2 months in NLR > 5 and 11.0 months in NLR < 5. PFS was 4.7 months and 3.6 months, respectively. When comparing patients that were treated with 5-FU based regimens, the overall survival was similar with the NLR > 5 of 11.5 months and the NLR < 5 group of 11.0 months. However, those patients treated with gemcitabine and abraxane had more of a difference; patients with an NLR > 5 had an OS of 16.0 months and NLR < 5, the OS was 11.5 months. Conclusions: Our single institution experience suggests that NLR could be a marker for prognosis for metastatic pancreatic cancer. However, our data contradicts the results of the MPACT trial where an increased NLR was associated with a worsened overall survival. Therefore, additional confirmatory studies will need to be performed to find the true prognostic value of the NLR.
Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.
Authors: Hidalgo Manuel M. , Epelbaum Ron , Semenisty Valeriya , Geva Ravit , Golan Talia , Borazanci Erkut Hasan , Stemmer Salomon M. , Borad Mitesh J. , Park Joon Oh , Pedersen Katrina , Wolpin Brian M. , Ramirez Robert A. , Becerra Carlos , Shaw Stephen Michael , Oberkovitz Galia , Sorani Ella , Lustig Tzipora M , Vainstein Haras Abi , Peled Amnon , Von Hoff Daniel D. 
Published: January 2019

276 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.
An open label phase 1b/2 trial of TRC105 and sorafenib in patient with advanced/metastatic hepatocellular carcinoma (HCC) (NCT01806064).
Authors: Raghav Kanwal Pratap Singh , Mody Kabir , Greten Tim F. , Paluri Ravi Kumar , Lee Richard T. , Simpson Brian E , Adams Bonne J. , Theuer Charles P. , Kaseb Ahmed Omar 
Published: January 2019

301 Background: Endoglin plays a critical role in angiogenesis and is implicated in resistance to VEGF inhibition. TRC105, an endoglin antibody potentiates anti-tumor activity of sorafenib (S) in preclinical HCC models. The combination of TRC105 and S demonstrated encouraging evidence of activity, including a 33% partial response rate (5/15 pts) by RECIST, at RP2D doses of TRC105 in HCC ( Clin Can Res 2017). Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently, and most commonly included epistaxis, fatigue, headache and anemia. Methods: Following dose escalation, 21 pts will be enrolled at the RP2D. Four objective responses are required to reject the null hypothesis that the true response rate probability is < 5% with an alpha level of 0.1 and 80% power. Secondary endpoints: DR, PFS, frequency and severity of AEs, PK, immunogenicity, angiogenic biomarkers. Key inclusion criteria: disease not amendable to surgical or local therapies, ECOG ≤ 1; Child-Pugh A or B (7 points) classification. Results: Four pts have been enrolled in phase 1b at TRC105 10 mg/kg (n=4) weekly for four doses and 15 mg/kg every other week thereafter + S 800 mg daily without DLT. One of 3 evaluable pts achieved PR (41% reduction), ongoing at month 4. Serum levels of TRC105 exceeded the target concentration following 4 weekly doses of TRC105 at 10 mg/kg (mean = 59 µg/ml, range 43-80). Mean trough concentration decreased following every other week dosing (mean = 21 µg/ml, range 17-31). Common TRC105 related AEs included ≤ G2 epistaxis and G1 headache. Common S related AEs included G3 hand foot syndrome, ≤G3 periodontal disease, G2 hypertension, ≤G2 increased lipase, ≤G2 fatigue and G1 epistaxis. Conclusions: TRC105 dosed by a hybrid schedule of 10 mg/kg weekly for four doses followed by every other week dosing at 15 mg/kg was tolerable and did not potentiate the toxicity of S. The combination of TRC105 + S demonstrated additional signs of activity, including a PR in 1/3 evaluable pts. 21 pts will be enrolled at the RP2D to assess the primary endpoint of ORR by RECIST. Clinical trial information: NCT01806064.