bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of p53 protein overexpression in localized gastrointestinal stromal tumors of the small intestine.
Authors: Park Young Soo , Kon Young Wha , Ryu Min-Hee , Ryoo Baek-Yeol , Park Hye Jin , Yook Jeong Hwan , Kim Byung Sik , Kang Yoon-Koo 
Published: February 2017

212 Background: Mutation of c-kit is a relatively early event in the tumorigenesis of gastrointestinal stromal tumors (GISTs). p53 alteration has been suggested as an additional genetic change that affects patient outcome in some studies. However there has been few studies in GISTs of the small intestine. The aim of this study was to determine the prognostic significance of p53 alterations in localized GISTs of the small intestine. Methods: We retrospectively reviewed 113 patients with completely resected localized GISTs in the small intestine who were not treated with adjuvant imatinib between 1994 and 2008. Immunohistochemical staining of CD117, CD34, S-100, SMA and p53 were performed in all patients and mutational analyses of c-kit exons 9, 11, 13 and 17 were conducted in 81 (56.6%) patients. Results: The median follow-up after diagnosis was 84 months (range, 40-146 months). Overexpression of p53 were observed in 38 patients (33.6%). p53 overexpression was strongly correlated with high mitotic index (p = 0.01) and higher risk groups based on the National Institutes of Health’s (NIH) risk category (p = 0.019). On univariate analysis, patients with p53 overexpression showed worse recurrence-free survival (RFS, p = 0.003). c-kit mutation status was not a prognostic factor (p = 0.411). Multivariate analysis indicated that p53 overexpression remained as independent poor prognostic factors for RFS (hazard ratio = 2.66, p = 0.026) as well as tumor size and mitosis. The p53 overexpression was marginally associated with poor RFS in the low or intermediate risk groups according to NIH's risk category (p = 0.081). Conclusions: Our results suggest that the p53 overexpression is an independent prognostic factor for RFS in localized GISTs of the small intestine. Additionally, p53 overexpression could be a helpful marker for selecting patients for further treatment in low or intermediate risk group patients.
Adjuvant chemotherapy in patients with resectable cholangiocarcinoma.
Authors: Wirasorn Kosin , Ngamprasertchai Thundon , Khantikaew Narong , Pakkhem Ake , Ungarereevittaya Piti , Jindaprasert Jarin , Sookprasert Aumkhae 
Published: February 2017

219 Background: Cholangiocarcinoma patients usually have poor treatment outcome and high mortality rate. The role of adjuvant chemotherapy is controversy. Our study aimed to evaluate benefits of adjuvant chemotherapy in resectable cholangiocarcinoma patients. Methods: A retrospective study included 263 patients who underwent curative resection in Srinakarind university hospital. These patients had pathological report with clear margin (R0) or microscopic margin (R1). Results: There were 138 patients received adjuvant chemotherapy. This group had significantly lower mean age than patients without chemotherapy (57.7 ± 8.5 vs. 60.4 ± 9.0 years, p = 0.01). Level of serum albumin above 3g/dL was more common in adjuvant chemotherapy group than another one (87.7% vs. 79.2%, p = 0.04). Patients who received adjuvant chemotherapy had significantly longer overall median survival time (21.6 vs. 13.4 months, p = 0.01). Patients with combination of gemictabine and capecitabine regimen had the longest survival time (median overall survival time of gemcitabine and capecitabine 31.5, 5-FU and mitomycin 17.3, 5-FU alone 22.2, capecitabine alone 21.6, and gemcitabine alone 7.9 months, p = 0.02). Benefits of adjuvant chemotherapy were likely to be found in patients who had high risk features, i.e. high level of CEA, high level of CA19-9, advanced stage, T4 stage, nodal involvement and R1 margin. Conclusions: Adjuvant chemotherapy may significantly prolong survival time in resectable cholangiocarcinoma patients, particularly the high risk group.
Stereotactic radiotherapy (SRT) for primary and metastatic liver tumors with functional treatment planning.
Authors: Kirichenko Alexander V. , Thai Ngoc , Lappinen Erik , Gayou Olivier , Day Ellen , Kotinsley Katherine , Gott Susan 
Published: February 2017

222 Background: We report on outcomes and toxicity of liver SRT/SBRT based on 3D-CT/SPECT treatment planning with conformal avoidance of well perfused functional normal liver volumes (FNLV). Methods: 51 patients with unresectable metastatic (36) or primary (15) hepatic tumors (65 targets) completed SRT planning with 99mTc sulfur colloid 3D-SPECT/CT to define FNLVs. Various degrees of FNLV retraction as a result of hepatic cirrhosis or systemic or intrahepatic chemotherapy were observed. For conformal avoidance of the residual FNLV, total dose and fractionation were adapted to FNLV constraints. 4D-CT and SPECT-based dosimetry were compared and treatment outcomes and toxicity were analyzed with medium followup 14.5 months (3-36months). Results: The in-field local control rate was 95%, hepatic failure free survival - 88%, hepatic progression free survival - 78% and overall survival - 70%. 25% patients developed Grade ≤ 2 elevation of liver enzymes with no incidence of “classic” radiation-induced liver disease. No patients with hepatic cirrhosis had Child-Pugh score progression. The most common toxicity was Grade ≤ 2 fatigue. For the group, FNLVs were significantly reduced compared to CT-derived NLV (p<0.01) with marked FNLV contraction in patients with Child-Pugh ≥ B cirrhosis, those who completed hepatic resections or received TACE within 2 months prior to SRT. Treatment planning with incorporated SPECT/CT helps to reduce volumes of functionally active liver parenchyma receiving doses above prescription threshold in patients with HCC compared to conventional 4D-CT treatment planning (p<0.01). There was no such correlation for non-HCC patients. Conclusions: 3D-SPECT/CT treatment planning allows identification and conformal avoidance of FNLV from high radiation doses facilitating safety of liver SRT in patients with preexisting liver disease. Outcomes are favorable, however participation in prospective Phase III trial would estimate true value of this method.
Quality of life in a multicenter phase II trial of neoadjuvant full-dose gemcitabine, oxaliplatin, and radiation in patients with resectable or borderline resectable pancreatic adenocarcinoma.
Authors: Serrano Aybar Pablo Emilio , Herman Joseph M. , Zalupski Mark , Kim Edward Jae-hoon , Ben-Josef Edgar , Bekaii-Saab Tanios S. , Wolfgang Christopher Lee , Laheru Daniel A. , Moore Malcolm J. , Dawson Laura A. , Ringash Jolie , Wei Alice Chia-chi 
Published: February 2017

226 Background: Pancreatic cancer remains incurable for the great majority of patients afflicted with the disease. The purpose of this study was to evaluate health related quality of life (HRQoL) following neoadjuvant full dose gemcitabine, oxaliplatin and radiation therapy (30 Gy) for pancreatic adenocarcinoma in a multi-institutional Phase-II trial. Methods: Fifty-seven patients were evaluable for the HRQoL component of this trial that consisted of two cycles of neoadjuvant chemoradiation with gemcitabine and oxaliplatin followed by pancreatectomy and two additional cycles of adjuvant chemotherapy. The effects of therapy on HRQoL were evaluated using: EORTC-C30, EORTC-PAN26 and FACT-HEP. Results: There were 20 patients (35%) with untreated resectable and 37 (65%) with borderline resectable pancreatic cancer. Thirty-nine patients (69%) completed two cycles of preoperative chemotherapy and surgery, 26 (40%) underwent a pancreaticoduodenectomy and 9 (14%) a distal pancreatectomy. Twenty-six patients completed postoperative adjuvant therapy. The median age was 64 (range 42-82); patients younger than 65 had a higher global HRQoL score at 6 months (p=0.046) following the initiation of treatment. There was no difference in the HRQoL according to type of operation performed. EORTC-C30 Global HRQoL remained statistically and clinically unchanged compared to baseline levels at all time-points. FACT-Hep Trial Outcome Index and Total score showed a statistically significant but not clinically meaningful decline following cycle 2 of neoadjuvant treatment (p=0.002 and p=0.004), returning back to baseline levels after 6 months. This may in part be explained by a decrease in the functional (p=0.004) and physical (p=0.001) wellbeing, an increase in diarrhea (p=0.044), digestive symptoms (p=0.037) and an increased fatigue (p<0.001). Conclusions: We report that this neoadjuvant chemoradiation protocol did not have a clinical impact on global HRQoL. Overall this regimen was well tolerated with no negative effect on quality of life following the conclusion of treatment. Clinical trial information: NCT00456599.
Preoperative chemoradiotherapy for pancreatic cancer encountered vertebral compression fractures.
Authors: Otani Keisuke , Teshima Teruki , Nishiyama Kinji , Ito Yuri , Kawaguchi Yoshifumi , Konishi Koji , Takahashi Hidenori , Ohigashi Hiroaki , Araki Nobuhito , Ishikawa Osamu , Oshima Kazuya 
Published: February 2017

227 Background: Preoperative chemoradiotherapy (CRT) with gemcitabine (GEM) for pancreatic cancer at our institute achieved excellent cure rates, while treated patients encountered vertebral compression fractures (VCFs) frequently. Methods: From January 2006 to December 2011, 220 patients (male/female: 134/86, median age: 66 (range: 33-84)) with resectable pancreatic cancer have been treated with preoperative CRT with GEM. This method consisted of concurrent radiotherapy (50-60 Gy in 25 fractions over 5 weeks) and chemotherapy (GEM 1,000 mg/m2intravenous, weekly for 12-15 weeks, 3 times during 4 weeks). Three-dimensional conformal radiotherapy was used and its fields covered both primary pancreatic tumor and retropancreatic tissues with 50 Gy level. Boost irradiation to the roots of celiac and superior mesenteric arteries with 2.4 Gy/fr using field-within-field technique has been started since 2009. The risk factors for VCF and its causes were retrospectively analyzed for 1,308 Th10-L3 vertebral bodies. Results: Follow-up time from the initiation of CRT ranged from 3.4-73.9 months (median: 17.9). Median overall survival time of these patients was 40.6 months. Radical surgery was completed in 164 patients (75%). Twenty-five patients (11%) diagnosed as VCF (CTCAE v4.0 grade1/2: 12/13) and 22 of them were at 3.6-23 months from CRT. Cumulative incidence rates at 2 years were 18.9% in total, 8.5% in male and 38.4% in female (p = 0.0002). Corresponding rates were 5.1% in age < 60 and 24.9% in age ≥ 60 (p = 0.0107). On their courses 37 de novo VCFs (Th10/11/12/L1/2/3: 2/3/11/13/7/1) were observed at first and 9 patients repeated VCFs near the initial VCFs. Dose-volume factors of each vertebral bodies also significantly correlated with VCF; vertebrae whose mean dose were < 38 Gy/ ≥ 38 Gy developed VCFs in 2.7%/10.0% at 2 years (p < 0.0001), vertebrae whose V30 were < 80%/≥80% developed VCFs in 2.4%/10.6% (p < 0.0001). Conclusions: Besides women and higher age, dose-volume factors of radiotherapy were risk of developing VCF in patients with pancreatic cancer after preoperative CRT with GEM. These findings should be considered to avoid VCFs as late adverse event after CRT for pancreatic cancer, especially in IMRT era.
Treatment-related hypertension (HTN) as a predictive biomarker for clinical outcomes in patients (pts) with advanced pancreas cancer (APCA) treated with bevacizumab (B): A pooled analysis of four prospective clinical trials.
Authors: Martin Ludmila Katherine , Wei Lai , Van Loon Katherine , Iyer Renuka V. , Pant Shubham , Fogelman David R. , Ko Andrew H. , Bekaii-Saab Tanios S. 
Published: February 2017

239 Background: Phase III studies of B in unselected APCA pts have been negative. Recent data suggest subsets of pts may benefit from B, but no validated predictive biomarkers exist for B efficacy in APCA. The pathogenesis of B-related HTN (B-HTN) is not well understood, but studies suggest association between B-HTN and improved clinical outcome in various advanced solid tumors. We conducted a pooled analysis of raw data from 4 prospective clinical trials to evaluate that predictive role of B-HTN in APCA. Methods: Relevant raw data were collected from 4 multi-institution single-arm phase II trials of GEM-based doublet chemotherapy + B as 1st line treatment of APCA. Pts were grouped according to B-HTN of any grade (Group 1) and no B-HTN (Group 2). Clinical outcomes including OS, TTP, ORR, and DCR (disease control rate = ORR + SD >16 weeks) were compared between Group 1 and 2. For pts in Group 1, outcomes were also compared according to CTCAE HTN grade (1-2 vs 3-4). Results: 166 pts (85 M, 81 F) with median age 55 (31-85) were included. Group 1= 37 pts (Grade 1-2 HTN, N=18; Grade 3-4 HTN, N=19), Group 2 = 129 pts. Demographics were similar except % stage 4 (92% group 1, 100% group 2, p=0.01). Results are summarized in the Table. Group 1 had significantly prolonged mOS and mTTPand improved ORR and DCR vs Group 2. There was no difference in outcome according to HTN grade. Conclusions: B-HTN of any grade may be an important pharmacodynamic biomarker for B in APCA. This subset of pts could benefit from B and identification of characteristics that predict development of B-HTN may aid in future pt selection for B therapy in APCA. Future prospective studies may consider pharmacodynamic titration of B to grade > 1 HTN to potentially maximize B efficacy. [Table: see text]
The feasibility of R0 resection of locally advanced pancreatic cancer (LAPC) encasing major visceral arteries (T4 lesions) using arterial resection and reconstruction: Short- and long-term outcomes.
Authors: Genyk Yuri , Barzi Afsaneh , El-Khoueiry Anthony B. , Matsuoka Lea , Sutton Vanessa , Buxbaum James , Iqbal Syma , van Dam Jacques , Selby Rick , Lenz Heinz-Josef 
Published: February 2017

243 Background: LAPC is found in about 40% of patients with pancreatic cancer at initial presentation. Tumors involving major visceral arteries are commonly deemed unresectable. In this study we analyzed the feasibility of R0 resection of LAPC encasing major visceral arteries using arterial resection and reconstruction. Methods: The following data were collected prospectively following pancreatic resection with vascular reconstruction in patients with LAPC: age, gender, operative details, post-operative complications, chemotherapy and/or radiation therapy and overall and disease free survival. Patient survival was calculated utilizing Kaplan-Meier survival probability estimates. Results: From Dec., 2002 to Sep., 2012, 12 patients with LAPC (8 males and 4 females, median age 58.5 yrs (range: 51–78 yrs)) underwent pancreatic resection with concomitant resection and reconstruction of major visceral arteries in our institution. The arterial involvement included celiac artery (n=8), and superior mesenteric artery (n=4). Resections included pancreatico-duodenectomy (n=8), distal pancreatectomy (n=3), and total pancreatectomy (n=1). Management of the arterial involvement included: resection of celiac axis without reconstruction (n=2), resection and reconstruction of one artery (n=6), two arteries (n=3) and three arteries (n=1). R0 resection was accomplished in 9, R1 in 2, and R2 in 1 patient. One patient (8%) died peri-operatively from pulmonary thromboembolism. Chemo- or chemo-radiation therapy was not protocolized. To date, 5 patients are alive and disease free at 7, 9, 11, 23 and 117 months, and 1 patient is alive with recurrence at 107 months. Six-month patient survival was 75% and median overall survival (MOS) was 19 months. Conclusions: The MOS in this patient population with systemic therapy is around 9 months. Although the sample size in our study is limited, observed MOS of 19 months is encouraging and provides the opportunity to reconsider the contraindications to surgical management of such patients with T4 LAPC. Timing of perioperative chemotherapy will be evaluated in a prospective trial.
A phase I study of DENSPM (N1, N11-diethylnorspermine) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Goyal Lipika , Supko Jeffrey G. , Berlin Jordan , Blaszkowsky Lawrence Scott , Carpenter Amanda , Heuman Douglas M. , Stuart Keith E. , Cotler Scott , Senzer Neil N. , Berg Carl L. , Clark Jeffrey W. , Hezel Aram F. , Ryan David P. , Zhu Andrew X. 
Published: February 2017

260 Background: DENSPM, a synthetic analog of the naturally occurring polyamine spermine, offers a novel approach for treating HCC by inducing polyamine depletion and inhibiting cell growth. The objectives of this multicenter phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), and preliminary antitumor activity of DENSPM in HCC. Methods: Forty-four patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤ 3, and Karnofsky score ≥ 60% were enrolled in a dose escalation study of DENSPM given intravenously on days 1, 3, 5, 8, 10, and 12 of each 28-day cycle. The starting dose of 30 mg/m2 was escalated at a fixed increment of 15 mg/m2 until the MTD was identified. A sensitive LC-MS/MS assay with a 6.4 nM limit of quantitation was developed and validated to characterize the plasma PKs of DENSPM. Results: Thirty-eight patients (male 79%; median age 61years; Child A 84%; Asian 5%; ≥1 prior systemic therapy 45%) received at least one dose of DENSPM. The most common adverse events (AEs) were fatigue (53%), nausea (34%), diarrhea (32%), vomiting (32%), anemia (29%), and increased AST (29%). The most common grade 3/4 AEs were fatigue/asthenia (13%) and increased AST (13%), hyperbilirubinemia (11%), renal failure (8%) and hyperglycemia (8%). The MTD was 75 mg/m2and was not directly associated with major treatment-related safety concerns. DENSPM plasma levels decreased very rapidly during the initial 60 min post-infusion. The total body clearance, 66.7±35.8 L/h/m2 (mean±SD) for the initial dose was comparable to that in solid tumor patients with normal to near normal hepatic function. However, drug concentrations ≥10 nM persisted for several days after dosing and remained detectable in samples obtained before day 12 dosing in 11/16 (68.8%) patients. No responses were seen but 9/27 (33.3%) evaluable patients achieved stable disease. Conclusions: DENSPM toxicity was dose dependent, the 75 mg/m2 MTD was relatively well-tolerated, and the PK behavior was favorable. Nevertheless, the study was terminated early because of insufficient evidence of clinical benefit in HCC patients. Further evaluation of DENSPM as a monotherapy for HCC does not appear to be justified. Clinical trial information: NCT00081900.
Phase I study of safety, pharmacokinetics, and efficacy of TSU-68 plus S-1 combination in patients with advanced hepatocellular carcinoma.
Authors: Ikeda Masafumi , Shiina Shuichiro , Nakachi Kohei , Mitsunaga Shuichi , Shimizu Satoshi , Kojima Yasushi , Ueno Hideki , Morizane Chigusa , Kondo Shunsuke , Sakamoto Yasunari , Tateishi Ryosuke , Asaoka Yoshinari , Koike Kazuhiko , Arioka Hitoshi , Okusaka Takuji 
Published: February 2017

262 Background: Sorafenib is the standard chemotherapy for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. TSU-68 is an oral anti-angiogenesis agent that blocks VEGFR-2 and PDGFR. TSU-68 and S-1 have shown favorable efficacy and safety profile for advanced HCC (Kanai et al. 2011; Furuse et al. 2010). This study investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of the TSU-68 plus S-1 combination in patients (pts) with advanced HCC. We also determined the maximum tolerated dose of TSU-68 plus S-1 on the basis of the frequency of associated dose-limiting toxicity (DLT) in this population. Methods: Pts who had not received any prior systemic therapy received 400 mg/day TSU-68 orally and one of the following doses of S-1: 50 mg/m2 (level 0), 80 mg/m2 (level 1), or 100 mg/m2 (level 2). Treatment duration was 4 weeks followed by 2-week rest (A group) or 2 weeks followed by 1-week rest (B group). The starting treatment dose and duration level was 1B, followed by progression to levels 2A and 2B. Treatment safety and tolerability at each level were assessed by enrolling 6 pts according to CTCAE v3.0. Results: Eighteen pts (6 each at levels 1B, 2A, and 2B) were enrolled (age, 58-85 years; male/female, 15/3; HCV/HBV/nBnC, 12/3/4; Child-Pugh class A/B, 18/0). Two pts each at levels 1B (grade 3 gastrointestinal bleeding, grade 2 ascites) and 2A (grade 3 fatigue, grade 3 hand-foot skin reaction) showed DLTs, but no pts at level 2B showed DLTs. The common adverse events were hemoglobin decrease, hypoalbuminemia, and anorexia; these were mild in severity (grade 1-2). PK data from 12 pts at levels 1B and 2A indicated that the area under the curve (AUC) of TSU-68 and 5-FU was unlikely to be affected by TSU-68 plus S-1. Response rate, disease control rate, median time to progression, and median overall survival time were 27.8%, 61.1%, 160 days, and 391 days, respectively. Conclusions: Our findings revealed thatthe TSU-68 plus S-1 combination was well tolerated and had favorable efficacy in patients with advanced HCC, and we recommend treatment with 400 mg/day TSU-68 and 100 mg/m2 S-1 for 4 weeks followed by 2-week rest in these patients. Clinical trial information: Japic CTI-121970.
Analysis of patterns of failure and prognostic factors in resected extrahepatic bile duct cancer: Implications for postoperative adjuvant radiotherapy.
Authors: Kim Jae-Sung , Koo Tae Ryool 
Published: February 2017

266 Background: This study is aimed to analyze the patterns of failure and evaluate the prognostic factors in the patients with extrahepatic bile duct cancer (EBDC) for the potential role of postoperative adjuvant radiotherapy (PORT). Methods: We retrospectively reviewed the medical records of 106 patients with EBDC who received curative intent surgical resection. The definitions of tumor location were as follows: proximal EBDC (n = 29) from the confluent portion of the bilateral hepatic bile ducts to the junction of cystic duct, and distal EBDC (n = 77) from the junction of cystic duct to intrapancreatic portion. Nine patients underwent adjuvant chemoradiotherapy or chemotherapy. Results: The median follow-up time was 24 months for the surviving patients. Forty patients experienced locoregional failure (LRF) initially; 13 (45%) with proximal EBDC and 27 (35%) with distal EBDC. The hepatoduodenal ligament (HL) and tumor bed were the most common LRF sites. Distant metastasis (DM) occurred in 10 patients (34%) with proximal EBDC and 15 patients (19%) with distal EBDC. The liver was the most common organ of DM. In the multivariate analysis, perineural invasion (PNI) and postoperative high carbohydrate antigen (CA) 19-9 were associated with poor LRPFS. Conclusions: Both proximal and distal EBDC showed remarkable proportion of LRF. Because the HL and tumor bed are where routinely covered by PORT, it can be speculated that the addition of PORT can improve LRPFS in these patients. Especially PORT needs to be considered in patients with PNI and postoperative high CA 19-9 to improve locoregional control.