bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of pathologic complete response by long-term neoadjuvant chemotherapy for gastric cancer: Early results of a randomized phase II study—A COMPASS trial.
Authors: Tanabe Kazuaki , Yoshikawa Takaki , Tsuburaya Akira , Nishikawa Kazuhiro , Ito Seiji , Matsui Takanori , Cho Haruhiko , Ito Yuichi , Suzuki Takahisa , Morita Satoshi , Miyashita Yumi , Sakamoto Junichi 
Published: February 2017

71 Background: Prognosis for stage III gastric cancer was not satisfactory even by D2 gastrectomy followed by S-1 adjuvant chemotherapy. Neoadjuvant chemotherapy will be another promising approach to improve the survival as demonstrated in some European trials, however, optimal duration and regimen have not been clarified yet. Methods: This trial compared efficacy of neoadjuvant chemotherapy using two and four courses of SC regimen; S-1 (80 mg/m2 for 21 days with 1 week rest) / cisplatin (60 mg/m2 at day 8), or PC regimen; paclitaxel / cisplatin (80 mg/m2 and 30 mg/m2, respectively at days 1, 8, and 15 with 1 week rest), by a two by two factorial design for stage II schirrhous / junctional tumors, stage III, or resectable stage IV. The primary endpoint was 3-year OS. Key secondary endpoints included pathological / clinical response, R0 resection, and adverse events. Sample size was set at 60 to 80 to achieve 10% improvement of 3-year OS by four courses or by PC with approximately 80% probability of the correct selection. Results: Between Oct 2009 and July 2011, 83 patients were assigned to arm A (2 courses of SC, n=21), arm B (4 courses of SC, n=20), arm C (2 courses of PC, n=21), and arm D (4 courses of PC, n=21). Clinical response (arm A/B/C/D) was 29%/40%/33%/24%. R0 resection (arm A/B/C/D) was 76%/75%/57%/76%. Pathological response (arm A/B/C/D), defined as tumor regression more than two third in the primary tumor, was 43%/40%/29%/38%. Pathological complete response (arm A/B/C/D) was 0%/10%/0%/10%. Major grade 3/4 toxicities (arm A/B/C/D) were anemia (14%/15%/0%/28.6%), neutropenia (10%/15%/14%/33%), nausea (0%/10%/5%/5%), and appetite loss (5%/10%/0%/5%). No surgical mortality was observed. Grade 3 morbidity classified by Clavien-Dindo was leakage in 5% (arm A), pancreatic fistula in 5% (arm C), and postoperative hemorrhage in 5% (arm B). Conclusions: This randomized phase II study suggested that pathological complete response could be induced by long-term neoadjuvant chemotherapy without increase of toxicities regardless of SC or PC regimen. Clinical trial information: UMIN000002595.
Impact of pretreatment systemic inflammatory response on survival in AGC patients receiving first-line chemotherapy.
Authors: Fujitani Kazumasa , Takiuchi Hiroya , Sugimoto Naotoshi , Imamura Hiroshi , Iijima Shohei , Imano Motohiro , Kimura Yutaka , Kurokawa Yukinori , Shimokawa Toshio , Tsujinaka Toshimasa , Furukawa Hiroshi 
Published: February 2017

88 Background: Systemic inflammatory response plays an important role in cancer progression. However, little is known about how it affects the advanced gastric cancer (AGC) patients receiving first-line chemotherapy. We assessed the impact of pre-treatment systemic inflammatory response on survival in AGC patients receiving S-1 based first-line chemotherapy. Methods: OGSG 0402 multi-institutional phase II trial randomly assigned 102 patients with previously untreated, locally advanced and/or metastatic measurable gastric adenocarcinoma to receive S-1 plus irinotecan (SI arm) (n=51) or S1 plus paclitaxel (SP arm) (n=51) to evaluate these two S-1 based regimens as first-line treatment for AGC [ASCO-GI 2009: abstract 9.]. Among these patients, 99 patients were identified in this study excluding 2 patients who had died before receiving the allocated treatment and one patient who was lost to follow-up. All patients had performance status (PS) of 0-1 except for one with PS of 2. Pre-treatment clinical findings, such as gender, age, body mass index (BMI), tumor status (unresectable vs. recurrent, intestinal vs. diffuse), number of metastatic sites, serum levels of albumin (Alb) and C-reactive protein (CRP), neutrophil lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR), were assessed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses. Results: Median OS and PFS were 390 days and 175 days for SI arm, and 363 days and 140 days for SP arm, respectively. Multivariate analysis identified the CRP level of 0.5 mg/dl or above (hazard ratio 1.96, 95% confidence interval 1.08 to 3.55, P=0.026) as a significant prognosticator for poor OS, and age of 60 years or greater (hazard ratio 1.92, 95% confidence interval 1.06–3.47, P=0.032) for shorter PFS. Conclusions: Pre-treatment CRP level was a most potent prognosticator for OS, reflecting the impact of systemic inflammatory response on survival, in AGC patients receiving first-line chemotherapy.
Phase II study of preoperative chemotherapy plus bevacizumab with early salvage therapy based on FDG-PET response in patients with locally advanced gastric and GEJ adenocarcinoma.
Authors: Won Elizabeth , Ilson David , Kelsen David Paul , Strong Vivian E. , Schöder Heiko , Janjigian Yelena Yuriy , Shah Manish A. , Coit Daniel G. , Brennan Murray F. , Capanu Marinela 
Published: February 2017

94 Background: Response on FDG-PET scan during preoperative chemotherapy has prognostic significance. PET non-responders do poorly whether they continue the same chemotherapy or proceed directly to surgery [JCO 24: 4692; 2006, Lancet Onc 8:797;2007) Early identification of treatment failure using PET scan may spare patients (pts) from inactive therapy and allow for cross-over to alternative therapies. We performed a phase II trial to examine the effectiveness of FDG-PET directed early switching to salvage chemotherapy measured by 2 year disease free survival (DFS) in the PET non-responding group. Methods: Pts with PET avid, EUS and laparoscopically staged T3 or Node positive resectable gastric or GEJ adenocarcinoma received induction with epirubicin 50mg/m2, cisplatin 60mg/m2, capecitabine 625mg/m2 bid days 2-21(ECX) and bevacizumab 15mg/kg day 1. PET scan was repeated at week 3. PET responders (≥35% decline in SUV) continued ECX for 2 more cycles. PET non-responders switched to 2 cycles of salvage therapy: docetaxel 30mg/m2 d1, d8 q21 days, irinotecan 50mg/m2 d1, d8 q21 days and bevacizumab 15mg/kg day 1. Pts had surgery 4 weeks after cycle 3. Results: 20 of planned 60 pts were enrolled before the study closed for poor accrual. 14 male (64%), 8 female (39%), median age 62, median KPS 90. 11(55%) had a PET response after the first cycle. 10/11 (91%) underwent R0 resection: 1/10 pathologic CR, 3/10 pathologic PR. 9/20 PET non-responders switched to the salvage regimen. 7/9 Non-responders had R0 resection, none achieved a pathological response. The DFS for PET responders was 27.8mos (95% CI 10.3-27.8) and DFS in salvage group has not been reached. There was no significant difference in DFS between the two groups (p= 0.4). Follow up for overall survival is ongoing. Biologic correlative studies are pending. Conclusions: Response on PET scan during induction chemotherapy can identify early treatment failures. The results for therapy cross-over indicate a potentially improved DFS with salvage chemotherapy. Results from this trial are hypothesis generating and merit evaluation in a larger clinical trial. Supported by a grant from Genentech. Clinical trial information: NCT00737438.
Gastrectomy after intravenous and intraperitoneal paclitaxel combined with oral S-1 for gastric cancer with peritoneal metastasis.
Authors: Kitayama Joji , Ishigami Hironori , Yamaguchi Hironori , Emoto Shigenobu , Watanabe Toshiaki 
Published: February 2017

96 Background: A new regimen of intravenous (IV) and intraperitoneal (IP) Paclitaxel (PTX) combined with oral S-1 is effective as the first line chemotherapy for gastric cancer with peritoneal metastasis. However, no information is available for the benefit of gastrectomy at salvage setting for the patients with clinical downstage. Methods: A total of 100 patients with peritoneal metastasis of gastric cancer received combination chemotherapy of PTX from both IV (50 mg/m2) and IP (20 mg/m2) routes using subcutaneous implanted peritoneal access ports at on days 1 and 8. S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Gastrectomy was performed in 60 patients who showed apparent shrinkage of peritoneal nodules as well as negative peritoneal cytology at 2nd look laparoscopy. In 30 of the 60 patients with gastrectomy, mRNA of carcinoembryonic antigen (CEA) in peritoneal lavages obtained from the port were quantitatively evaluated by CEA-mRNA Index (CmRI: CEA mRNA/ PBGD mRNA×104) at each chemotherapeutic cycle. Results: MST of the 100 patients was 23.5 months. MST and 1y-OS of the 60 patients with gastrectomy were 34.5 months and 83%, while those of the other 40 patients were 13.0 months and 39%, respectively. In all of the 30 gastrectomized patients, CmRI at the initial laparoscopy was considerably high (median=15368, 145-398179), which was fairly reduced after 3 courses of the combination chemotherapy before surgery (median=25, 0-10286, p=<0.001). Among them, 2y-OS of 22 patients whose CmRI was reduced to the value <200 after 3 course of chemotherapy was significantly better than that of the other 8 patients with CmRI >200 (76% vs 25% p=0.02), suggesting the volume of tumor cells in peritoneal cavity may be a critical determinant for postoperative outcome. Conclusions: Combination chemotherapy of S-1 plus IV and IP PTX followed by gastrectomy is a promising strategy for peritoneal metastasis of gastric cancer. Periodical measurement of CEA-mRNA levels in peritoneal cavity can be a useful biomarker to predict the clinical efficacy of conversion gastrectomy.
Survival in patients with esophageal cancer treated with surgery after chemoradiotherapy.
Authors: Shridhar Ravi , Freilich Jessica , Hoffe Sarah , Fulp William J. , Chuong Michael , Almhanna Khaldoun , Karl Richard C. , Meredith Kenneth 
Published: February 2017

98 Background: Chemoradiotherapy (CRT) followed by surgical resection is the standard of care for treating advanced esophageal cancer. However, the role of surgery has come into question in recent studies. The purpose of this study is to compare outcomes of patients treated with CRT with or without surgery. Methods: An IRB-approved database was queried to identify esophageal cancer patients treated with CRT with or without surgical resection between 2000 and 2011. Overall survival (OS) and disease-free survival (DFS) were calculated by the Kaplan-Meier method and log-rank analysis. Multivariate analysis for OS and DFS were calculated with a Cox proportional hazard ratio model. Results: We identified 232 patients treated with CRT (122 without surgery, 110 with surgery). Surgery was associated with a significant increase in OS and DFS. Median and 5 year OS for surgical versus nonsurgical patients was 42.2 months, and 42.3% versus 20.4 months and 29%, respectively (p = 0.0003). Median and 5 year DFS for surgical versus nonsurgical patients was 16.8 months and 29% versus 8.4 months and 22.8% (p < 0.001). MVA for OS revealed that lower stage (p = 0.0098), tumor length <5 cm (p = 0.0059), and surgery (p<0.0001) were prognostic for significantly decreased mortality, while age, gender, histology, tumor location, radiation dose, and radiation technique were not prognostic. MVA for DFS showed that tumor length <5 cm (p = 0.0112), radiation technique (p = 0.0023), and surgery (p = 0.0007) were prognostic for significantly decrease mortality, while lower stage (p = 0.069) and squamous histology (p = 0.055) were trending for decreased mortality. Age, gender, radiation dose, and tumor location were not prognostic for DFS. Conclusions: Surgery after CRT is strongly associated with increased OS and DFS in our esophageal cancer patient population. While we highly recommend surgical resection as part of trimodality treatment, it should only be performed in high volume centers. Longer followup in the already conducted randomized trials involving squamous cell carcinomas are needed to better qualify the initial negative results and randomized trials are need to address the role of surgery for adenocarcinomas.
Risk assessment for severe hypocalcemia requiring hospitalization with denosumab.
Authors: Autio Karen A. , Farooki Azeez , Glezerman Ilya , Chan Amelia , Barr Hallie C. , Seyboth Brian M. , Schneider Coursen Walker , Heller Glenn , Scher Howard I. , Morris Michael J. 
Published: February 2017

115 Background: Skeletal-related events (SRE) pose clinical risks to patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) that can be mitigated with denosumab. Hypocalcemia is a side effect, however risk factors are not well described. Methods: An IRB waiver was obtained to review medical records for all mCRPC pts receiving denosumab at MSKCC between March-August 2011 for baseline labs, calcium (ca) and vitamin D nadirs, details of hospitalizations, concurrent therapies, and comorbidities. Comparisons between groups were made using Fisher’s exact test and the Wilcox rank sum test. Results: Nine of sixty pts (15%) treated with 1-2 doses of denosumab developed severe symptomatic hypocalcemia (median nadir 6.5 mg/dL) requiring hospitalization for intravenous (IV) ca replacement. Ca/Vitamin D was recommended to all pts. Ca recovered in 17 days in those who did return to baseline levels (n=5). However, four of nine (44%) pts required repeated hospitalizations for IV ca, never recovered to baseline ca levels, and died of advanced disease within 3 months. Median vitamin D 25-OH was 22.5 ng/ml for hospitalized pts, and PTH was 198 pg/ml at ca nadir. Conclusions: Denosumab was associated with severe hypocalcemia sufficient to require hospitalizations for IV ca replacement in 15% of pts with mCRPC. PSA, Ca, Alk Phos, and current chemotherapy were associated with severe hypocalcemia requiring hospitalization for IV ca. Clinicians are cautioned regarding potential risk factors including advanced disease, vitamin D insufficiency, and possibly comorbidities affecting calcium absorption. [Table: see text]
Concurrent treatment with everolimus (RAD001) and hormonoradiotherapy in high-risk locally advanced prostate cancer: Results of a phase I trial.
Authors: Azria David , Rebillard Xavier , Coux Nathalie , Jarlier Marta , Thuret Rodolphe , Llacer-Moscardo Carmen , Charissoux Marie , Culine Stephane 
Published: February 2017

150 Background: Everolimus is able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving everolimus together with hormonotherapy and radiation therapy may kill more tumor cells. Methods: We conducted a phase I trial to evaluate the impact of everolimus (RAD001), an mTOR inhibitor, in patients treated concurrently with radiotherapy (RT) and ablative androgen treatment in high-risk locally advanced prostate cancer. Inclusion criteria were high-risk locally advanced non metastatic prostate cancer defined as clinical stage ≥ T3 or Gleason score ≥ 8 or PSA ≥ 20. The week before the beginning of RT, RAD001 was administered at different dose levels, twice daily, until the last day of irradiation. A nonsteroid antiandrogen was also given for 1 month at the beginning of RT. Prostate and seminal vesicle were irradiated up to 74Gy in 37 fractions of 2Gy with concomitant long-term LHRH analogue. The starting dose of RAD001 was 5mg/d with subsequent dose levels of 7.5 and 10 mg/d. The primary endpoint was the determination of the maximum tolerated dose (MTD). Dose escalation was implemented according to the continual reassessment method (CRM). Results: Fifteen patients were enrolled and 14 were assessable for toxicity and response. Significant toxicities were demonstrated at the 7.5 and 10 mg/d dose levels. Dose-limiting toxicity (DLT) occurred in two patients at dose level 7.5 mg/d and characterized by a grade 3 diarrhea and a grade 3 hydronephrosis due to dehydration and kidney lithiasis. DLT also occurred in two patients at dose level 10 mg/d (grade 3 diarrhea and grade 3 laryngopharyngeal infection). The MTD was reached at 7.5 mg/day (dose-level II). The recommended dose of RAD001 was 5 mg/d. After a median follow-up of 22 months, 12 patients are alive, 1 is dead (not related to cancer) and 2 patients had relapsed. Conclusions: Concomitant hormone-radiotherapy and everolimus is well-tolerated with mucositis, hypercholesterolemia, and urinary disorders. The recommended phase-II trial dose of everolimus in this combined setting is 5 mg/day. Clinical trial information: NCT00943956.
Arachidonic acid drives amoeboid transendothelial invasion through ligand independent activation of EphA2.
Authors: Brown Mick D. , Tawadros Thomas , Hart Claire , Clarke Noel W. 
Published: February 2017

221 Background: We have previously shown that the omega-6 poly unsaturated fatty acid arachidonic acid is a potent stimulator of prostate epithelial transendothelial migration across the bone marrow endothelium and can completely restore the invasive stimulatory capacity of adipocyte depleted human bone marrow stroma. Arachidonic acid induces of EphA2 ligand independent signaling via pAkt with subsequent downstream activation of FAK and Src. Here we present further characterization of the arachidonic acid induced EphA2 pathway. Methods: Transendothelial migration of PC-3 cells across the bone marrow endothelial cell line BMEC was followed by time lapse microscopy and by SEM with or without amoeboid or mesenchymal inhibitors. Western blot analysis of the PC-3 cells or their lipid raft (LR) components post AA stimulation was conducted and signaling pathways validated by siRNA knockdown. Results: Initial studies demonstrated a requirement of PC-3 cells to undergo a mesenchymal to amoeboid switch for transendothelial migration towards bone marrow stroma. The mesenchymal to amoeboid switch was also induced by direct treatment with arachidonic acid as characterized by induction of the Rho/Rock pathway and phosphorylation of myosin light chain. Knockdown of EphA2 by siRNA blocked the induction of the mesenchymal to amoeboid switch and prevented transendothelial invasion. Conclusions: Malignant prostate epithelial cells undergo a switch from mesenchymal to amoeboid movement in response to arachidonic acid in order to cross the bone marrow endothelial barrier.
PSA outcomes in patients with adenocarcinoma of the prostate with presenting PSA > 20 ng/ml.
Authors: Shasha Daniel , Debenham Brock John , Salant Robert , Harrison Louis Benjamin 
Published: February 2017

241 Background: Optimal treatment of prostate cancer with presenting PSA >20 ng/mL is debated within and between specialties, as reflected by variable PSA outcomes reported. We present our clinical outcomes in irradiated patients for this population. Methods: With IRB approval, we analyzed patient, disease, treatment, and PSA data of 149 patients with presenting PSA > 20 ng/mL radiated with curative intent 1997-2012 by a single physician (DS) at Beth Israel Medical Center (New York City). External beam radiation therapy (EBRT) was delivered first to prostate, seminal vesicles (SV) and draining pelvic lymph nodes to 45 Gy, then 5.4 Gy cone down, then a boost with either brachytherapy (BT) or 30.6 Gy conformal EBRT. BT was withheld in large volume of SV invasion by either DRE or by MRI. Hormonal therapy (HT) consisted of LHRH agonist +/- antiandrogen therapy. PSA was checked every 6 mos. Biochemical Failure (BF) was defined as post-treatment PSA nadir + 2 ng/mL. Results: 41% of patients were African American, 27% Hispanic, 21% Caucasian, and 6% Asian. The median patient age, Gleason score (GS), PSA, and T stage were 68 yrs (range 42-87), 30 ng/mL (range 20–280), 7 (range 5-10) and stage II (8% Tx, 29% T1, 32% T2, 22% T3a/b, 8% T3c). Combined EBRT and BT (CMT) were used in 70% (N=104); EBRT alone in 28% (N=42); BT alone in 2% (N=3). HT was given to 87% (N=129), (median duration 25 mos). Of CMT patients, 77% (N=81) had I-125 permanent seed implant, 22% (N=23) had Pd-103 implant, and 1% (N=1) had HDR temporary Ir-192 implant. With a minimum follow-up (FU) 2 years and median FU 4.9 years (range 2.0-14.1), overall BF was 18% (N=27), and median time to failure was 4 yrs (range 0.4–9.3). Of failures, median age was 64 (range 48-83), and 40% were African American; median pre-treatment PSA was 40 ng/mL (range 20–238), median stage was 3. BF occurred in 17/104 (16.3%) CMT patients (13/17 I-125 and 3/17 Pd-103), 9/42 (21.4%) EBRT patients, and 1/3 (33%) BT alone patients (1/1 I-125). All patients who failed received HT. Conclusions: Excellent overall biochemical outcomes in patients with presenting PSA > 20 ng/ml are reported, with only approximately 18% experiencing BF at a median FU of 4.9 years. Of all treatments analyzed, CMT yielded superior biochemical control.
Randomized phase III study of adjuvant versus progression-triggered treatment with gemcitabine (G) after radical cystectomy (RC) for locally advanced bladder cancer (LABC) in patients not suitable for cisplatin-based chemotherapy (CBC) (AUO-trial AB22/00).
Authors: Lehmann Jan , Kuehn Michael , Fischer Claus , Volkmer Bjoern , von Rundstedt Friedrich , Albers Peter , Becht Eduard , Bannowsky Andreas , Hofmann Rainer , Langbein Sigrun , Retz Margitta , Stoeckle Michael 
Published: February 2017

250 Background: Cisplatin-based chemotherapy (CBC) has been widely used in trials of adjuvant therapy for LABC after RC. A high proportion of patients are unfit for CBC after RC for LABC. We therefore performed a prospective randomized phase III trial on G-monotherapy administered as adjuvant therapy (G-adj) vs in case of progression (G-prog) in pts not suitable for CBC. Methods: Between 7/2000 and 12/2008 120 of 178 planned pts with LABC unfit for CBC were randomized between 6 adjuvant cycles of G (q3w) starting within 12 wks after RC and G in case of disease progression. The primary endpoint of the trial was progression-free survival (PFS). Secondary endpoints included cancer-specific (CSS) and overall survival (OS) as well as treatment related toxicity. Results: The trial of 178 planned pts was closed early due to slow accrual. Of 120 randomized pts from 29 centers 114 were eligible for analysis. Median age of 81 male and 33 female pts was 72 (45-82) years. Lymph-node positive disease was found in 52/114 (47%) of pts at the time of surgery. The intention-to-treat analysis demonstrated a 10% difference in PFS after 3 years 50% (G-adj) vs 40% (G-prog) with a median PFS of 23 mo (G-adj) vs 17 mo (G-prog). The difference in PFS was not statistically significant (nss) (p= 0.335; HR 1.375, 95%CI 0.719 - 2.627). CSS at 3ys: 56% (G-adj) vs 50% (G-prog) with a median CSS of 49 mo (G-adj) vs 38 mo (G-prog). The difference in CSS was nss (p= 0.622; HR 1.166, 95%CI 0.632 - 2.149). OS at 3ys: 49% (G-adj) vs 48% (G-prog) with a median OS of 32 mo (G-adj) vs 31 mo (G-prog). The difference in OS was nss (p= 0.426; HR 1.225, 95%CI 0.743 - 2.018). Treatment with G was usually well tolerated, with less than 15% grade 3/4 toxicities..There was one treatment related death in the G-adj arm. Conclusions: The study-hypothesis of a 15% difference in PFS after 3 years in favor of G-adj vs G-prog could not be confirmed. Nevertheless a marked difference in survival in favor of G-adj was shown by Kaplan-Meier plots regarding PFS, CSS and OS within the first 24 months after RC. Clinical trial information: NCT00146276.