bluuebunny/crossref_metadata_2025_split huggingface dataset:
Geographic difference in safety and efficacy of systemic chemotherapy for advanced gastric or gastroesophageal carcinoma: A meta-regression approach.
Authors: Hsu C. , Shen Y. , Cheng C. , Cheng A. , Hu F. , Yeh K. 
Published: February 2017

109 Background: The standard of chemotherapy regimens for patients with advanced or metastatic gastric cancer vary and the clinical outcome were heterogeneous in Asian vs. non-Asian countries. Methods: Treatment group-based meta-analysis and meta-regression were performed to analyze results of randomized trials published since 2005 for advanced or metastatic gastric cancer patients who received systemic chemotherapy as first-line treatment. Data were extracted and synthesized according to the Cochrane guidelines. Results: Among the 24 trials (totally 6,502 patients) eligible for meta-analysis, Asian trials reported lower percentage of gastroesophageal junctional carcinoma, higher percentage of diffuse-type histology, and more frequent use of second-line chemotherapy. Meta- regression analyses indicate that, after controlling other patient or treatment factors, Asian trials are associated with 22.7% (95% CI: 19.5-26.0%, p<0.0001) lower incidence of grade 3-4 neutropenia and 3.5% (95% CI: 2.1-4.9%, p<0.0001) lower incidence of grade 3-4 diarrhea, which were the most commonly reported toxicity. The use of high-dose infusional 5-fluorouracil, compared with other fuoropyrimidine regimens, reported 16.6% lower incidence of neutropenia (95% CI: 13.3-19.9%, p<0.0001). Higher percentage of patients with gastroesophageal junction carcinoma and patients with 2 or more organs involved predicted poor progression-free survival. The use of second-line chemotherapy predicts better 1-year overall survival, which will increase by 9% (95% CI: 8-10%) for every 10 percent increase in patients who received second-line chemotherapy. Conclusions: Geographic region (Asian vs. non-Asian) plays an important role in the heterogeneity of gastric cancer clinical trials and is an independent predictor of safety in systemic therapy for gastric cancer. No significant financial relationships to disclose.
Radiotherapy, including sentinel lymph node, to superficial cancer of esophagus.
Authors: Kaburagi T. , Takeuchi H. , Oyama T. , Nakamura R. , Takahashi T. , Wada N. , Saikawa Y. , Kitagawa Y. ,   Keio University School of Medicine
Published: February 2017

126 Background: It is known that esophageal cancer frequently causes lymph node metastasis. Even if relatively early stage of esophageal cancer, reaching muscularis mucosae (T1a-MM: Japanese Classification of Esophageal Cancer) causes subclinical node metastasis to about 10%. So when radiation therapy (RT) is administered to these patients, field of irradiation should include the areas where subclinical node metastasis may exist. But the wider field of irradiation is, the more likely adeverse event is to occur. In this study, we examined utility of RT based on sentinel lymph node (SLN) theory. Methods: Before irradiation, Tc-99m tin colloid solution was endoscopically injected to the submucosal layer around the primary tumor and lymphoscintigraphy was examined to detect SLNs. And the irradiation field was planned as SLN regions were included. Patients with esophageal squamous cell carcinomas (ESCC) that reach cT1a-MM or cT1b and patients with ESCC who had underwent endoscopic resection and pathologically diagnosed pT1a-MM or pT1b were eligible if they had clinically no lymph node metastasis, no distant metastasis and no advanced cancer in other site. Between April 2001 and December 2009, 17 of these patients were received RT based on SLN theory. We retrospectively examined them. Results: Characteristics of the 17 pts were: median age; 67 (58-82), male/female; 15/2, T1a-MM/T1b-SM1/T1b-SM2; 4/2/11, definitive RT/adjuvant RT; 10/7, RT alone/concurrent chemoradiotherapy; 1/16. Average dose of irradiation was 57.0 ± 6.4Gy. Median follow-up is 81.4 months (7.9-127.2). Ten pts with definitive RT gained complete remission. Two minor local relapses of the primary tumors were observed. They underwent salvage endoscopic resection and survive without other relapse. There was no treatment related death. Grade 3 or 4 late toxicity was not observed. No significant financial relationships to disclose.
Phase II trial of irinotecan and cisplatin combination as first-line chemotherapy in patients with advanced esophageal squamous-cell carcinoma: An interim report.
Authors: Zhang X. , Shen L. , Li J. , Li Y. , Zhou J. , Lu Z. , Lu M. 
Published: February 2017

137 Background: Although the irinotecan and cisplatin combination has been used in esophageal cancer treatment, we tested the combination specifically in unresectable or metastatic esophageal squamous cell carcinoma with different doses to decrease the toxicity and keep the efficacy. Methods: Patients were eligible if they had histologic proof of unresectable or metastatic squamous cell carcinoma of the esophagus, between 18-75 years of age with a Karnofsky performance status ≥ 80. No prior chemotherapy was allowed. Patients were treated with irinotecan 130 mg/m2 and cisplatin 60 mg/m2 repeated 3 weeks. Response was evaluated every two cycles of treatment by using RECIST criteria. The sample size was calculated using Simon's 2-stage design. The primary end point of the study was objective response rate. The second end points are PFS and toxicity. Accrual was planned to a total of 46 patients with the targeted response rate of 50%. The first stage requires at least 7 or more out of 16 patients to have a confirmed partial or complete response before proceeding to the second stage. Results: Twenty one patients have been enrolled so far, of which 16 patients were assessable for response. The overall response rate was 43.8%(7/16), including one complete response (6.3%) and six partial response (37.5%). Among 13 patients who presented with dysphagia at baseline, 10 (62.5%) had the symptom either completely resolved or significantly improved. The most common toxicities were neutropenia, diarrhea and alopecia. Seven patients (33.3%) developed grade 3 neutropenia and one had (4.8%) with febrile neutropenia. One patient (4.8%) had grade 3 diarrhea. There were no treatment-related deaths. Conclusions: The combination of irinotecan plus cisplatin with lower doses showed equivalent efficacy and less toxicity in patients with unresectable or metastatic squamous-cell carcinoma of the esophagus. The study is ongoing. No significant financial relationships to disclose.
Effect of neoadjuvant dose-painted IMRT to 56 Gy for locally advanced esophageal cancer on outcomes.
Authors: Shridhar R. , Chuong M. D. , Hoffe S. E. , Biagioli M. , Almhanna K. , Weber J. , Kucera S. , Vignesh S. , Barthel J. S. , Meredith K. ,   Moffitt Esophageal Research Team
Published: February 2017

144 Background: Standard of care chemoradiation doses of 50.4 Gy for locally advanced (T3, T4, and/or node positive) esophageal cancer is associated with a pathologic complete response (pCR) rate of 40% at our institution. We evaluated whether pCR would be increased with 4D CT planning scans, intensity-modulated radiation therapy (IMRT) delivery with motion management, and dose painting to 56 Gy in 28 fractions. Methods: This retrospective review of 9 patients who have undergone esophagogastrectomy (7 adenocarcinoma, 2 squamous cell) evaluates our initial experience with neoadjuvant dose painted IMRT to 56 Gy. Pre-treatment workup included PET scan, chest and abdomen CT scans, endoscopic ultrasound (EUS), and EUS-guided fiducial marker placement. Fiducial markers were placed superior and inferior to the gross endoscopic tumor volume to facilitate analysis of tumor motion with 4D CT simulation. Internal target volumes (ITVs) of gross disease were generated to account for motion. Once the GITV was generated, a clinical target volume (CTV) encompassing a 3-4 cm superior margin and 3-4 cm distal margin was contoured. Two planning target volumes (PTVs) were created for dose painting: PTV 50.4 and PTV 56 Gy in 28 fractions. IMRT was utilized for all patients with either a weight belt or with compensators. Concurrent cisplatin and continuous infusion 5-FU were delivered with radiotherapy and patients were restaged 3-6 weeks after completion for response evaluation. Results: Treatment was well tolerated without any grade 3 acute morbidity. Surgical complications were not increased in this group overall. However, there was 1 patient with a chyle leak and radiation pneumonitis, but her case was complicated by having a remote history of radiotherapy. Six of the 9 treated patients were found to have a pCR (4 adenocarcinoma, 2 squamous cell). Two had a near CR with < 5 mm of residual disease. One additional patient with an initial bulky T4N1 tumor had 9 mm of viable tumor. Conclusions: With motion management, dose painted IMRT to 56 Gy is feasible and may be associated with improved rates of pathologic complete or near complete response. No significant financial relationships to disclose.
The Singapore liver cancer recurrence (SLICER) score for relapse prediction in patients with resected hepatocellular carcinoma.
Authors: Ng E. , Ang S. , Li H. , Lim K. , Choo S. , Ngeow J. Y. , Toh H. , Chow P. K. , Tan M. 
Published: February 2017

169 Background: Hepatocellular carcinoma (HCC) is a common worldwide cancer associated with extremely poor survival, with surgery the only option for cure in patients with localized disease. Current prognostic models for HCC are algorithms developed on datasets of mainly patients with metastatic or unresectable cancer, and may be less relevant to resectable HCC. Nomograms provide individualized outcome estimates. We constructed a postoperative nomogram, the Singapore liver cancer recurrence (SLICER) score, to predict outcomes of HCC patients who have undergone surgical resection. Methods: Records for Singaporean patients undergoing first-line curative surgery for localized HCC in one institution between 1992 and 2007 were retrospectively reviewed (n=405). Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation, was used. Calibration was tested with bootstrapping (n=200). We compared the performance of this model with other alternative models including CLIP, CUPI, BCLC, and Okuda scores using c-indices and likelihood analysis. Results: A nomogram (SLICER score) predicting FFR was designed, incorporating vascular invasion, tumor size, multifocality, ECOG status, pre-operative AFP, Childs-Pugh score and cirrhosis. Bootstrap estimates show good calibration at 1, 2, 3, and 5 years postsurgery Comparison of the SLICER score with alternative prognostic models shows superior performance (Table). Conclusions: The SLICER score enables individualized relapse predictions for patients following curative resection of localized HCC. It permits optimal patient selection for adjuvant therapy trials, biomarker development, and individual counseling. [Table: see text] No significant financial relationships to disclose.
Use of plasma angiogenesis-related factors to investigate the association of interleukin 8 and interleukin 6 levels with efficacy of sorafenib-based antiangiogenic therapy in patients with advanced hepatocellular carcinoma (HCC).
Authors: Shao Y. , Hsu C. , Huang C. , Cheng A. 
Published: February 2017

199 Background: Anti-angiogenic agents have become the most important class of therapy for patients (pts) with advanced HCC. However, biomarkers predictive of the efficacy of anti-angiogenic therapy remain lacking. Methods: Advanced HCC pts, enrolled in a phase II study (Hsu et al: J Hepatol 2010) and its extended cohort, were treated with sorafenib plus metronomic oral tegafur/uracil until disease progression. Plasma samples were collected before treatment and 4 weeks after the start of treatment. The levels of IL-6, IL-8, IL-13, CXCL10, PDGF and VEGF-A were analyzed by multiplexed bead suspension arrays (Bio-Rad, Hercules, CA, US). Levels of VEGF-C, VEGF-D, PlGF, fibroblast growth factor 2 (FGF2), SDF1-alpha and soluble VEGF receptor 2 were determined by ELISA. The baseline levels and post-treatment changes of these plasma factors were analyzed for their associations with treatment outcomes. Results: Among 68 pts treated with the protocol treatment, 64 were enrolled to this study. There were 4 partial responder (PR) and 33 patients with stable disease (SD) according to RECIST 1.0. The disease control rate (PR+SD) was 58%. The median PFS and OS were 3.7 and 7.4 months, respectively. Patients with progressive disease, compared to those with disease control, had significant increase of post- treatment IL-6 (p = 0.016) and IL-8 (p = 0.021), borderline significant increase of post-treatment FGF2 (p = 0.078) and significant decrease of post-treatment CXCL-10 (p = 0.046). High baseline IL-8 was significantly associated with poorer PFS and OS (p = 0.002 and 0.001, respectively). More increase of post-treatment IL-6 was associated with poorer PFS and OS (p = 0.087 and 0.018, respectively). By multivariate analysis, high baseline IL-8 and more post-treatment increase of IL-6 remained independent predictors for poorer PFS and OS. Conclusions: High baseline IL-8 and more post-treatment increase of IL-6 in plasma were associated with poor treatment outcomes in advanced HCC pts treated with sorafenib-based anti-angiogenic therapy. This study was supported by the grant of NSC 98-3112-B-002-038. No significant financial relationships to disclose.
Intraductal papillary neoplasm of the bile duct (IPNB): A biliary equivalent to IPMN of the pancreas?
Authors: Rocha F. G. , Lee H. , Katabi N. , DeMatteo R. P. , Fong Y. , D'Angelica M. I. , Allen P. J. , Klimstra D. S. , Jarnagin W. R. 
Published: February 2017

201 Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a type of cholangiocarcinoma characterized by intraductal growth, mucin production and a better outcome compared to the more common nodular-sclerosing type. IPNB may be analogous to IPMN of the pancreas and may be a precursor of invasive cholangiocarcinoma, but its pathogenesis and natural history are ill-defined. This study examines the incidence, clinicopathologic features and outcome of IPNB in a single center. Methods: A consecutive cohort of patients with bile duct cancer (hilar, intrahepatic or distal) was reviewed and those with papillary features identified. Histopathologic morphology and immunohistochemical staining for cytokeratin and mucin proteins were utilized to classify IPNB into subtypes. Survival data were analyzed and correlated with clinicopathological parameters. Results: Between 1993 and 2008, 40 IPNBs were identified in hilar (24/144), intrahepatic (4/86) and distal (12/113) bile duct cancer specimens (11.7%). Histopathologic examination revealed 27 pancreatobiliary, 4 gastric, 3 intestinal, and 6 oncocytic subtypes; cytokeratin and mucin staining was similar to that of IPMNs of the pancreas. Invasive carcinoma was seen in 29/40 (72%) IPNBs. Overall median survival was 59 months and was not different between IPNB locations or subtypes. Factors associated with a worse median survival included depth of invasion (39 months for > 5mm, 128 months for < 5mm, and 144 months for none, p <0.05), R1 vs R0 resection (36 months vs 82 months, p <0.05), MUC1 expression (53 months for positive vs 144 months for negative, p <0.006), and CEA expression (42 months for positive vs 128 for negative, p<0.02). Expression of MUC2, MUC5A, MUC6, CDX2, mesothelin, p53, Ki67, HepPar1, and B72.3 were not predictive of outcome. Conclusions: IPNBs are an uncommon variant of bile duct cancer, representing approximately 10% of all cases, occur throughout the biliary tract and share histologic and clinical features with IPMNs of the pancreas. These lesions may represent an alternative carcinogenesis pathway. Given their significant malignant potential, they should be treated aggressively with margin-negative resection. No significant financial relationships to disclose.
Contribution of environment and genetics to oxidative stress in pancreatic cancer (PC) patients (pts).
Authors: Hocevar B. A. , Chiorean E. G. , Kamendulis L. , Perkins S. M. , Johnston E. L. , DeWitt J. , Li L. , Klaunig J. E. 
Published: February 2017

211 Background: Several risk factors have been identified as contributors to PC development, including tobacco and alcohol use, and exposure to environmental chemicals. A common denominator of these risk factors is the ability to induce oxidative stress/damage. An individual's genetic makeup may also contribute to oxidative stress, as oxidative stress/damage genes exhibit single nucleotide polymorphisms (SNPs), which can alter protein expression or activity. The goal of this study was to (1) determine if increased oxidative stress/damage is observed in PC pts and (2) to assess the contribution of environmental and genetic factors to oxidative stress/damage parameters. Methods: An oxidative stress/damage profile was generated from blood samples of newly diagnosed PC pts (n=20), from non-cohabiting genetic relatives (n=20) and/or from non-genetic relatives living in the same household (n=20). This profile consisted of measurement of total antioxidant capacity (Trolox equivalent antioxidant capacity, TEAC), direct and oxidative DNA damage (COMET), and malondialdehyde (MDA) levels. Expression of SNPs in selected oxidative stress/response genes was also evaluated. Environmental and dietary/lifestyle information was collected using a detailed questionnaire. Results: PC pts, when compared to healthy nonrelated but cohabitating relatives, displayed a significant increase in direct DNA damage (p=0.002), while oxidative DNA damage, TEAC and MDA levels were similar. When comparing PC pts to healthy genetic relatives, increased levels of TEAC, direct and oxidative DNA damage approached or were statistically significant (p = 0.061, 0.002, and 0.062 respectively). Analysis of 26 selected SNPs in oxidative stress/ damage genes in the PC pts vs healthy controls revealed that expression of CYP2A6 (L160H), rs1801272, and TNF (-308G>A), rs1800629, approached statistical significance (p=0.05 and 0.20 respectively). Conclusions: Increased oxidative DNA damage observed in PC pts vs healthy related, but non-cohabitating relatives, suggests that environmental exposures contribute to oxidative stress. In combination with a specific genetic background, environmental influences may increase the risk of PC. No significant financial relationships to disclose.
Signal transducer and activator of transcription 5b (STAT5b) as a novel target for anti-neoplastic therapy in human pancreatic cancer.
Authors: Moser C. , Ruemle P. , Schenk H. , Geissler E. K. , Schlitt H. J. , Stoeltzing O. , Lang S. A. 
Published: February 2017

217 Background: Activation of signal transducer and activator of transcription 5b (STAT5b) has been associated with tumor growth and metastases in various tumor entities. A number of cytokines, growth factors, and oncogenes that can induce STAT5b activity are also implicated in pancreatic cancer growth and metastases. Hence, we sought to determine STAT5b expression in human pancreatic cancer specimen and effects of selective STAT5b inhibition on pancreatic cancer cells. Methods: Expression of STAT5b in human pancreatic adenocarcinomas was determined by immunohistochemistry. For in vitro experiments, human pancreatic cancer cell lines (BxPC-3, HPAF-II, L3.6pl) were used. Cancer cells were transfected with STAT5b shRNA plasmid to create stable STAT5b knock-down. Effects of STAT5b inhibition on growth and motility of tumor cells was investigated by MTT and modified Boyden chamber assays. In vivo effects of STAT5b blockade were determined in subcutaneous mouse model. Results: Nuclear expression of STAT5b was detected in 42/80 human pancreatic adenocarcinomas. In human cancer cell lines, stable knock-down of STAT5b had no effect on growth of tumor cells in vitro. However, tumor cell motility was significantly reduced upon STAT5b blockade (p<0.05). Moreover, expression of various signaling intermediates and transcription factors including c-myc was impaired upon STAT5b knock-down. In a subcutaneous tumor model, inhibition of STAT5b led to significantly reduced tumor growth (p<0.05) which was also reflected by final tumor weights (p<0.05). Furthermore, as revealed by immunohistochemistry, blockade of STAT5b significantly reduced tumor vascularization in vivo (p<0.05). Conclusions: STAT5b is expressed in human pancreatic adenocarcinomas. Blockade of STAT5b impairs cancer cell motility in vitro, suggesting antimetastatic potential. Moreover, inhibition of STAT5b significantly reduces tumor growth and tumor vascularization in vivo. Hence, STAT5b might be an interesting target for antineoplastic therapy in human pancreatic cancer. No significant financial relationships to disclose.
Role of histone deacetylase expression on regulating cancer stem cells in intrahepatic cholangiocarcinoma.
Authors: Saito Y. , Shimada M. , Morine Y. , Iwahashi S. , Utsunomiya T. , Imura S. , Ikemoto T. , Mori H. , Hanaoka J. 
Published: February 2017

219 Background: Histone deacetylase (HDAC) modulates gene expressions by chromatin remodeling during malignant transformation, and showed malignant behavior in intrahepatic cholangiocarcinoma (IHCC) (ASCO GI 2008). HDAC inhibitors have recently been found to repress the function of hypoxia inducible factors (HIF) through inducing hyperacetylation of histones. We also reported that the correlation between the expression of CD133, which was one of the cancer stem cell marker, and HIF-1α in IHCC (J Gastroenterol. 2010), and hypothesized that the cancer stem cell could be regulated by histone acetylation through the HIF-1α pathway. The aim of this study was to elucidate the potential mechanism of HDAC for the regulation of malignant behavior including the cancer stem cell in IHCC. Methods: Thirty-five patients with IHCC who underwent hepatic resection were evaluated. The expressions of HDAC1 (sc-6298 Santa Cruz Biotechnology, USA), HIF-1α (NB100-105 Novus Biologicals, USA) and CD133 (Ab27699 Abcam Inc, UK) were determined immunohistochemically, and the patients were divided into two groups: HDAC1 positive group (n=21); and negative group (n=14). Clinicopathological variables including HIF-1α and CD133 expressions were analyzed according to these expressions. Results: The HDAC1 expression correlated significantly with higher stage, lymph node metastasis, and vascular invasion. The prognosis in the HDAC1 positive group was poorer than in the HDAC1 negative group (5-year survival: 77.9% vs. 7.9%, p=0.001). In the multivariate analysis, HDAC1 positive expression was identified as the only independent prognostic factor for disease free survival (Hazard Ratio: 7.194, p=0.0018). There was a significant correlation between HDAC1 expression and HIF-1α expression (p=0.007), and also between HIF-1α expression and CD133 expression (p=0.10). Furthermore, co-expressions of these markers in same cancer cells were proven by immunofluorescent staining in the serial section. Conclusions: The findings suggested that histone acetylation regulated cancer stem cell through the HIF-1α pathway; therefore, HDAC1 might be a possible promising molecular target in IHCC. No significant financial relationships to disclose.