bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic inflammatory response to predict clinical outcome in patients with resected pancreatic cancer treated with adjuvant gemcitabine monotherapy.
Authors: Morinaga Soichiro , Watanabe Takuo , Numata Masakatsu , Mikayama Yo , Tamagawa Hiroshi , Yamamoto Naoto , Shiozawa Manabu , Akaike Makoto 
Published: February 2017

223 Background: Systemic inflammatory response (SIR) has been shown to associate with poor outcome in either inoperable or operable pancreatic cancer. However, whether the presence of a SIR predicts poor clinical outcome of pancreatic cancer patients in adjuvant setting is unclear. The aim of present study was to determine the relationship between SIR, as evaluated by Modified Glasgow prognostic score (mGPS), and outcome of pancreatic cancer patients treated with adjuvant chemotherapy. Methods: A total of 42 resected pancreatic cancer patients were analyzed for mGPS before adjuvant gemcitabine chemotherapy. The mGPS was constructed as follows: patients with both an elevated C-reactive protein (> 0.3mg/dl) and hypoalbuminaemia (< 3.5mg/dl) were allocated a score of 2. Patients with one or none of these abnormalities were allocated a score of 1or 0, respectively. Results: There were 25 patients assigned to score 0, 12 patients to score 1, and 5 patients to score 2. The median OS in patients with score 0, score 1, and score 2 were 23.9 months, 10.3 months, and 9.9 months, respectively. The DFS in patients with score 0, score 1, and score 2 were 11.0 months, 5.9 months, and 3.6 months, respectively. The OS and DFS after surgery of the patients with SIR (score 1 and 2) were significantly poorer than that of the patients with score 0 (P=0.0278 for OS, P=0.0011 for DFS by log-rank test). Conclusions: The presence of SIR, as evaluated by Modified Glasgow prognostic score (mGPS), predicts poor clinical outcome in resected pancreatic cancer patients treated with adjuvant gemcitabine monotherapy.
Possible role of autophagy inhibition in hypoxia-induced chemoresistance of pancreatic cancer cells.
Authors: Ko Yoon Ho , Cho Young-Seok , Won Hye Sung , Jeon Eun Kyoung , Hong Young Seon 
Published: February 2017

224 Background: Autophagy is a catabolic process and provides metabolic support for the cell by degradation of intracellular macromolecules. Various types of stress, including hypoxia, activate autophagy. Recent studies have suggested that hypoxia has been shown to associate with resistance to chemotherapy and radiation therapy and hence poor prognosis in pancreatic cancer. This study investigated the role of autophagy in the treatment of pancreatic cancer with gemcitabine under hypoxic condition. Methods: To evaluate the role of autophagy inhibition in hypoxia-induced chemoresistance, BxPC-3 human pancreatic cancer cell line was used under normoxic and hypoxic conditions.We evaluated the extent of LC3-II, as an autophagosome marker, induced by gemcitabine, by western blotting to measure the hypoxia- or chemotherapy- induced autophagy. We then examined the effects of gemcitabine on induction of apoptosis under normoxic and hypoxic conditions. Next, to determine the effect of 3-MA, a known inhibitor of autophagy, on overcoming hypoxia-induced chemoresistance, the MTS assay and flow cytometry were performed. Results: Compared with normoxia, gemcitabine-induced cell death under hypoxia was significantly decreased, as a result of the reduced apoptosis. Western blotting analysis demonstrated that LC3-II was increased under hypoxia, compared with normoxia.However, we found that 3-MA can enhance the growth inhibition and apoptotic effect of gemcitabine, even under hypoxia. These findings mean that autophagy mediates the chemoresistance under hypoxia. Conclusions: Activated autophagy plays a role in hypoxia-induced chemoresistance of pancreatic cancer cells. These findings may have important implications for future therapeutic strategies using gemcitabine against pancreatic cancer.
A GEP-NEN analysis of incidence, ethic variation, and mortality using the SEER database.
Authors: Lawrence Ben , Kidd Mark , Gustafsson Bjorn , Chan Anthony , Schimmack Simon , Modlin Irvin M 
Published: February 2017

225 Background: A decade of epidemiological analysis of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has defined this malignancy as more common than previously recognized, but the cause of an apparent increase in incidence is controversial. The maturity of the contemporary SEER17 database allows this issue to be addressed. Methods: We analyzed the most recent SEER17 database (including 32,862 cases of GEP-NEN) to calculate incidence, primary site distribution and survival (cause-specific and all-cause) by age and ethnicity in 2000 to 2008, then examined 20-year limited-duration prevalence and the pattern of second cancer risk. Results: The incidence of GEP-NENs continues to rise (APC; 4.2% per year) and is now 3.6/100,000 but this reflects an improved diagnostic acuity rather than a true increase in disease occurrence. Of paramount import, the prevalence of GEP-NENs (23/100,000) accounts for only approximately 2% of the prevalence observed in autopsy studies (1,110/100,000), providing the necessary perspective to recognize the change in incidence as “trivial” relative to the undiagnosed disease burden. The current analysis also reminds us that GEP-NENs are not uniformly fatal. Cause-specific GEP-NEN survival is considerably more favorable than the commonly described ‘all-cause’ survival, so that many patients with rectal (62%), gastric (49%), small intestinal (44%), appendiceal (24%), and colonic (19%) NENs died from other causes. The high proportion of rectal primaries in Japan (56%) persists after population migration to the US (65%), suggesting a “relatively” stable inherited predisposition. The risk of second cancers after GEP-NENs is increased by 55% and occurs in organs with epithelium that contain neuroendocrine cells (both GI and distant), not limited to the luminal sites potentially exposed to a dietary carcinogen. Conclusions: The increase in GEP-NEN incidence is illusory, disease specific survival is higher than previously recognized while the stable ethnic differences and systemic second cancer risk support a non-environmental genetic etiology for tumorigenesis.
Activity of fractionated radioimmunotherapy (RAIT) with 90Y clivatuzumab tetraxetan (90Y-hPAM4) plus gemcitabine (Gem) in advanced pancreatic cancer (APC): Final results from a two-part study.
Authors: Ocean Allyson J. , Guarino Michael J. , Pennington Kenneth Lee , Springett Gregory M. , Gulec Seza A , Bekaii-Saab Tanios S. , Montero Alberto J. , Mitchell Edith P. , Kauh John S , Sung Max W. , Gold David V. , Horne Heather , Wegener William A. , Goldenberg David M. 
Published: February 2017

227 Background: A Phase I/II trial was undertaken to evaluate repeated cycles of 90Y-labeled anti-mucin humanized mAb (90Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC. Methods: Pts received Gem once-weekly x 4 with 90Y-hPAM4 on wks 2, 3 and 4, with cycles repeated until progression or unacceptable toxicity. In Part I, pts were treated in cohorts with escalating 90Y doses and Gem fixed at a low 200 mg/m2 dose for radiosensitization. In Part II, the Gem doses were increased up to standard levels, with 90Y doses fixed for first cycle, but decreased for subsequent cycles. Tumor responses were assessed by CT, FDG/PET and serum CA19-9; safety by NCI-CTCv3. Results: Of 100 untreated pts enrolled, 10 withdrew early, while 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 90Y-hPAM4 weekly x 3 at 90Y doses of 6.5 (N=4), 9 (N=12), 12 (N=17) or 15 (N=5) mCi/m2, with the same cycle repeated 1-3 times in 13 pts. Grade 3-4 platelets or ANC developed in 20/38 (53%) after cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 pts at 12 or 15 mCi/m2). There were 3 febrile neutropenias, 4 other infections treated with IV antibiotics, but no major bleeding or other AEs. By CT-RECIST criteria, 6 pts (16%) had PRs and 16 (42%) had stabilization as best response (58% disease control). After cycle 1, 52% (13/25) with PET-avid images became negative or had >25% SUV reduction, and 33% (9/27) with elevated CA19-9 levels decreased by >50%. The median overall survival was 7.7 mo., but 11.8 mo. for retreated pts [46% (6/13) survived ≥1 yr.], with improved efficacy at higher 90Y doses. In Part II, 52 pts received 12 mCi/m2 90Y-hPAM4 x 3 with Gem doses of 200 (N=17), 600 (N=8) or 1000 mg/m2 (N=27), with 13 pts now retreated at 90Y doses of 6.5 or 9 mCi/m2. Results so far indicate no advantage to giving higher doses of Gem with RAIT. Toxicity, response and survival data for this group will be presented at the conference. Conclusions: Fractionated RAIT with 90Y-hPAM4 combined with low-dose gemcitabine appears to be a manageable and active first-line therapy for APC. It may provide comparable efficacy yet less toxicity compared to other regimens.
Relationship between serum HER2 level and histologic HER2 status in patients with advanced/recurrent gastric cancer.
Authors: Sasaki Takahide , Fuse Nozomu , Kuwata Takeshi , Takahashi Mari , Asano Hiromichi , Kaneko Kazuhiro , Doi Toshihiko , Yoshino Takayuki , Kojima Takashi , Ochiai Atsushi , Ohtsu Atsushi 
Published: February 2017

24 Background: The HER2 extracellular domain can be quantitatively measured in terms of the serum HER2 level by using a CLIA. Increased serum HER2 levels have been reported to be found in 20-25% of metastatic breast cancer patients and correlated with HER2 protein overexpression, increased tumor volume, and worse prognosis. However, the prevalence of HER2 expression in the serum of gastric cancer (GC) patients is not known. Methods: This study retrospectively analyzed the tumor tissue and serum samples of 100 patients who had histologically confirmed advanced/recurrent stomach adenocarcinoma, had started chemotherapy at National Cancer Center Hospital East during 2007–2011, did not have any other active malignancies, and whose serum and tumor tissue samples had been collected and stored at the baseline. HER2 protein expression was determined by immunohistochemistry (IHC; I-VIEW Pathway 4B5 kit) with the GC scoring system (Hofmann, 2008), and gene amplification was determined by fluorescence in situ hybridization (FISH; PathVysion HER2 DNA probe kit), with HER2:CEP17 ≥ 2.0 seen in tumor tissue. Serum HER2 levels were measured using a CLIA (ADIVA Centaur XP). HER2 positivity was defined as IHC 2+ with FISH positive or IHC 3+. Results: The baseline characteristics were as follows: men, 66; median age, 66 years (range, 29–85); advanced/recurrent, 96/4; and intestinal/diffuse/mixed, 38/41/21. An IHC score of 0/1+/2+/3+ was noted in 41/32/6/21 patients, respectively. Gene amplification in FISH was noted in 28 cases. The number of HER2 positive patients was 21. The median serum HER2 level was 9.3 ng/mL (range, 5.0–332.4). With a cutoff level of 15 ng/mL (mean + 2SD of 241 healthy control women), the sensitivity of serum HER2 levels with respect to HER2 positivity was 52.4%; specificity, 93.7%; positive predictive value, 68.8%; negative predictive value, 84.1%; and accuracy, 85.0%. The area under the receiver operating characteristic curve was 0.894. Conclusions: Increased serum HER2 levels were noted in GC patients and were associated with HER2 overexpression in tumor tissue. Further investigations of serum HER2 in terms of the clinical significance are warranted.
HER2 expression in patients with advanced pancreatic cancer: Preliminary results from a multifactorial biologic analysis.
Authors: Faloppi Luca , Mandolesi Alessandra , Maccaroni Elena , Giampieri Riccardo , Bianconi Maristella , Bittoni Alessandro , Del Prete Michela , Antognoli Stefania , Scartozzi Mario , Bearzi Italo , Cascinu Stefano 
Published: February 2017

250 Background: Pancreatic cancer is the deadliest solid cancer and currently the fourth most frequent cause of cancer-related deaths. Many studies have demonstrated that pancreatic cancer is a group of heterougeneous disease with different therapeutical implications and prognosis. Aim of our analysis was to analyze the HER-family status in pancreatic cancer. Methods: We immunohistochemically assessed surgical specimens and macrobiopses for several biological targets. K-ras, HER-1, HER-2 and HER-3 were analyzed. Results: 62 specimens were analyzed in our centre. 30 samples were K-ras wild-type, 70% of these were EGFR positive. While 32 samples have a mutant form of K-ras, 87.5% were EGFR positive. HER-2 resulted negative in all specimens. In the K-ras wild-type group, 17% have high expression of HER-3, 20% a low one; in mutant K-ras group 16% are high expressing while 34% have a low HER-3. Conclusions: Over the past decades, there has hardly been any substantial therapeutic progress regarding clinical endpoints in pancreatic cancer, thus in the era of target therapies the molecular biological classification of these neoplasms have an ever more important role for developing tailored therapies. Our analysis show a low rate of k-ras mutations (52%) and seems to suggest that anti-EGFR strategies may represent an interesting treatment option in pancreatic cancer as long as a preliminary molecular selection is applied. Numerous international trials are evaluating the role of new drugs targeting HER-2 in association with chemotherapy in metastatic pancreatic cancer. On the contrary, our data suggest that HER-2 directed therapies are not likely to represent a relevant choice in this setting.
RTOG 0438: A phase I trial of highly conformal radiation therapy for patients with liver metastases.
Authors: Katz Alan W. , Winter Kathryn A. , Dawson Laura A. , Schell Michael C , Kim Joon-Hyung J. , Chen Yuhchyau , Roberge David , Crane Christopher H. , Willett Christopher 
Published: February 2017

257 Background: This multi-institutional phase I trial was conducted to determine the maximally tolerated dose (MTD) of hypofractionated, highly conformal radiation therapy (RT) in patients (pts) with liver metastases. Methods: Eligibility criteria included non-surgical pts with ≤ 5 liver metastases; total measurement for all lesions ≤ 8 cm. There were four dose levels (DLs) escalating from 35 Gy to 50 Gy in 5 Gy increments given in 10 fractions with defined normal tissue dose limits. Accrual began at 40 Gy. The clinical target volume (CTV) included all metastases identified on contrast CT/MRI with a 5 mm margin. The planning target margin ranged from 4 to 30 mm around the CTV. For quality assurance the Image-Guided Therapy Center (ITC) remote review tool was used to evaluate treatment planning images and dosimetry information. Dose limiting toxicities (DLTs) were defined as treatment-related grade (Gr) ≥ 4 hepatic, gastrointestinal (GI), thrombocytopenia, or radiation induced liver disease (RILD) within 90 days (dys) of the start of RT. Results: 26 pts were enrolled between 11/05 and 12/10, and 23 were evaluable; 8, 7, and 8 on the 40, 45, and 50 Gy DLs respectively. Two pts assigned to the 50 Gy DL received 35 Gy because of normal tissue constraints, therefore an additional 2 pts were accrued and treated at the 50 Gy DL. The study was temporarily closed for toxicity evaluation after 6 pts on each DL were followed for a minimum of 90 dys from start of treatment. There were no DLTs observed on any of the DLs. Four pts developed treatment-related Gr 3 toxicities; 2 each on the 45 and 50 Gy DLs. On the 45 Gy DL, 1 pt had two Gr 3 GI toxicities: enteritis (37 dys from RT start) and diarrhea (22 dys) while another pt had Gr 3 lymphopenia (23 dys). On the 50 Gy DL, 1 pt had Gr 3 hyperglycemia (74 dys) and another pt had three Gr 3 toxicities: lymphopenia (13 dys), colonic hemorrhage (325 dys), and GI obstruction (325 dys). Conclusions: When normal tissue constraints could be met, treatment of liver metastases with 50 Gy in 5 Gy/fx is feasible and safe in a multi-institutional setting. Further studies looking at higher doses and alternate fractionation regimens are warranted. Supported by RTOG U10 CA21661, CCOP U10 CA37422 and ATC U24 CA 81647 NCI grants.
Prognostic significance of LINE-1 methylation level in esophageal squamous cell carcinoma.
Authors: Baba Yoshifumi , Iwagami Shiro , Watanabe Masayuki , Shigaki Hironobu , Ida Satoshi , Nagai Yohei , Ishimoto Takatsugu , Iwatsuki Masaaki , Sakamoto Yasuo , Miyamoto Yuji , Baba Hideo 
Published: February 2017

26 Background: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of global DNA methylation level. LINE-1 methylation is a useful marker for predicting cancer prognosis and monitoring efficacy of adjuvant therapy. Esophageal squamous cell carcinoma, the major histological type of esophageal cancer in East Asian countries, is one of the most aggressive malignant tumors. Nonetheless, prognostic significance of LINE-1 hypomethylaiton in esophageal cancer remains uncertain. Methods: Using 217 curatively resected esophageal squamous cell carcinomas, we quantified LINE-1 methylation using bisulfite-PCR-pyrosequencing assay. Cox proportional hazards model was used to calculate mortality hazard ratio (HR), adjusted for clinical, epidemiologic, and pathological variables. Results: Esophageal cancers showed significantly lower LINE-1 methylation level compared to matched normal esophageal mucosa (p<0.0001; N=50). Tumoral LINE-1 methylation ranged from 24.8 to 91.8 of 0-100 scale (N=217; mean 64.5; median 65.0; standard deviation 12.8). LINE-1 hypomethylation was significantly associated with disease-free survival [log-rank p=0.0008; univariate HR= 2.31, 95% confidence interval (CI) 1.38-3.84, p=0.0017; multivariate HR=1.81, 95% CI 1.06-3.05, p=0.031] and overall survival (log-rank p=0.0013; univariate HR=2.21, 95% CI 1.33-3.60, p=0.0026; multivariate HR=1.87, 95% CI 1.12-3.08, p=0.018]. Conclusions: LINE-1 hypomethylation in esophageal cancer is associated with shorter survival, suggesting its role as a prognostic biomarker. Given that epigenetic changes, including DNA methylation alterations, are reversible and can thus be targets for therapy or chemoprevention, our findings may have considerable clinical implications.
Use of operability classifications to predict outcome of patients with anatomically resectable pancreatic adenocarcinoma treated with neoadjuvant therapy.
Authors: Tzeng Ching-Wei David , Fleming Jason B. , Lee Jeffrey Edwin , Xiao Lianchun , Pisters Peter W. T. , Vauthey Jean-Nicolas , Abdalla Eddie K. , Wolff Robert A. , Varadhachary Gauri R. , Fogelman David R. , Crane Christopher H. , Balachandran Aparna , Katz Matthew H.G. 
Published: February 2017

293 Background: We previously introduced a novel classification system for assessing “operability” in patients with localized pancreatic adenocarcinoma (PDAC) that integrates cancer biology, patient physiology, and tumor anatomy. We sought to analyze resection rates, reasons for no resection, and outcomes after neoadjuvant therapy (NT) of patients with both resectable anatomy and either “operable” or “borderline” biology/physiology. Methods: We evaluated consecutive patients (2002-2007) with radiographically resectable cancers treated with NT prior to potential resection. Borderline resectable anatomy (BR-A) was excluded. We compared clinical factors and outcomes of 217 patients classified by established criteria as “potentially resectable-operable” (PR-OP, no evidence of extrapancreatic disease, performance status [PS] ≤1); “borderline resectable-B” (BR-B, findings suspicious for extrapancreatic disease); or “borderline resectable-C” (BR-C, severe but reversible comorbidities or marginal PS ≥2). Results: 138 PR-OP, 41 BR-B, and 38 BR-C patients began NT. 62.7% of all patients underwent subsequent pancreatectomy. Resection rates after NT for PR-OP, BR-B, and BR-C were 74.6%, 46.3%, and 36.8%, respectively (p<0.001). Metastases were detected during NT in 23.0% of all patients and were the most common contraindication to resection in PR-OP (15.2%) and BR-B (46.3%) patients. PS rarely precluded surgery except in BR-C patients (31.6%). Factors independently predicting not utilizing surgery after NT were older age, poor PS, new pain medications, and complications on NT (p<0.05). Median OS of all patients was 20.9 (95% CI, 17.1-27.1) mo. Resected and unresected BR-B and BR-C patients had OS similar to that of PR-OP patients (resected medians 33.0, 39.8, 36.0 mo, respectively; unresected medians, 10.1, 12.6, 12.9 mo; p<0.001). Conclusions: Our operability classification system describes discrete clinical subgroups among PDAC patients with similar, resectable tumor anatomy but vastly heterogeneous physiology and cancer biology. It can be used with NT to predict outcomes, individualize treatment, and optimize survival rates.
Pattern of failure after hepatic arterial concurrent chemoradiotherapy for locally advanced hepatocellular carcinoma.
Authors: Seong Jinsil , Cha Haejung , Keum Woongsub , Yoon Hongin , Han Kwanghyub 
Published: February 2017

299 Background: We have previously reported outcome of concurrent chemoradiotherapy (CCRT) in advanced hepatocellular carcinoma (HCC) with median survival 13.1 months. We further analyzed patterns of failure as well as related clinical factors. Methods: Retrospective cohort analysis was done for 161 HCC patients given CCRT between May 2000 and August 2009. CCRT involved median radiation dose 45 Gy/25 fractions and intraarterial 5-Fu 500 mg thru chemoport. Patterns of failure were categorized; 1) infield, 2) intrahepatic-outfield, and 3) extrahepatic failure. Clinical factors were analyzed using Kaplan-Meyer method and multivariate analysis using Cox-proportional hazard model. Results: The median age was 55 years and most patients had Child-Pugh A (92%). Infield, intrahepatic-outfield, and extrahepatic failure were observed in 47 (30%), 67 (42%), and 66 patients (42%), respectively. For infield failure, median progression free survival (PFS) of patients treated with CCRT as initial treatment has not yet been reached compared with that in patients with treatment history before CCRT. (Median PFS NR vs. 17 months, p=0.001) For intrahepatic-outfield failure, pretreatment AFP > 500 ng/mL was associated with high incidence of this failure (Median PFS 22 months vs. 10 months, p=0.006). For extrahepatic failure, Age < 55 years and pretreatment AFP > 500 were significant factors for failure, which were also significant in multivariate analysis. Median PFS has not been reached in age <55 years and pretreatment AFP ≤ 500 ng/mL, compared with 10 months in age >55 years (p=0.011) and 14 months in pretreatment AFP > 500 ng/mL. (p=0.042). Conclusions: Infield, intrahepatic-outfield, and extrahepatic failure were observed in similar proportion. Pretreatment AFP ≥ 500 ng/mL was significant factor for intrahepatic-outfield and extrahepatic failure. Ages <55 years increased incidence of extrahepatic failure. Treatment history before CCRT was associated with infield failure.