bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventive effect of rikkunshito, traditional Japanese medicine, for chemotherapy-induced nausea and vomiting.
Authors: Kajiura Shinya , Hosokawa Ayumu , Nanjyo Sohachi , Yoshita Hiroki , Suzuki Nobuhiro , Yamawaki Hidemoto , Ueda Yuko , Ueda Akira , Mihara Hiroshi , Hasumoto Yuushi , Ando Takayuki , Fujinami Haruka , Nishikawa Jun , Ogawa Kohei , Sugiyama Toshiro 
Published: February 2017

131 Background: Supportive therapies are being developed for chemotherapy-induced nausea and vomiting (CINV). Rikkunshito is a Kanpo medicine, which is a part of traditionally practiced Japanese-based ancient Chinese medicine. It has been reported to be effective against cisplatin-induced anorexia in rats. In the present study, we evaluated the preventive effect of Rikkunshito for CINV in patients receiving high-dose cisplatin. Methods: We selected subjects who received chemotherapy including cisplatin (≥60mg/m2) for gastric or esophageal cancer between April 2010 and August 2012 at our institution. We targeted 20 cases treated without a reduction in the anti-cancer medication in the second course and added 7.5g/day of Rikkunshito, orally administered for seven days, to their second course treatment regimen. All cases were treated with 5-HT3 receptor antagonist and steroid, and palonosetron for the prevention of CINV in their first and second courses. We evaluated the complete response (CR, defined as no emesis and no rescue medication) rate and other toxicity, according to CTCAE v4.0, of the first and second courses. Results: The median age of the patients was 63 years (range, 49–77 years). The chemotherapy regimens were cisplatin + 5-FU in 15 cases with esophageal cancer, cisplatin + S-1 in five cases with gastric cancer. Anorexia in the first course was grade 0/1/2 = 5/11/4, but had been mitigated in the second course to grade 0/1/2 = 12/6/2 (P = 0.042). CR rate was 75.0% in the first course (95% CI, 56.0%–94.0%) and by the second course had improved to 95.0% (95% CI, 85.4%–100%). And about the other major toxicity, there was no significant difference between first and second courses. Conclusions: These results suggest that Rikkunshito has the potential to improve CINV in patients receiving high-dose cisplatin.
TH17 cells and early pancreatic tumorigenesis.
Authors: McAllister Florencia , Bailey Jennifer M , Alsina Janivette , Nirschl Christopher , Roeser Jeffrey , Blake Danielle , Lankapali Rachana , Sears Cynthia , Jaffee Elizabeth M. , Kolls Jay , Drake Charles G. , Pardoll Drew M. , Leach Steven D. 
Published: February 2017

144 Background: Chronic pancreatitis increases the risk of developing pancreatic ductal adenocarcinoma (PDAC), one of the deadliest human cancers. Activating Kras mutations have been detected in 30% of early pancreatic intraepithelial neoplasias (PanINs), increasing to 100% in PDAC. We hypothesized that inflammatory cells recruited to the pancreas in response to chronic injury can interact with epithelial cells harboring activated KrasG12D and affect the progression of PanIN lesions. Methods: We used the the transgenic Mist1:CreERT2; LSL-KrasG12D (KCiMist1) adult mice in which the LSL KrasG12Dallele is activated specifically in the acinar compartment. This model leads to the formation of PanINs with a classic "ductal" phenotype and the progression of lesions is accelerated by the induction of chronic pancreatitis with recurrent cerulein injections. Results: We have found that TH17 cells, a subtype of CD4+ T-helper cells known to play an active role in inflammation, are recruited to the pancreas during chronic pancreatitis and further increased upon KrasG12Dactivation. The differentiation of CD4+T cells into TH17 requires IL-6 and TGF-B, factors that are increased in the pancreatic tumor microenvironment. Stat3, a key transcription factor that determines the differentiation of TH17 lineage, is activated in the pancreatic dysplastic epithelium and in the stroma. We have discovered that PanINs from KCiMist1 mice overexpress the IL-17 Receptor (IL-17RA) by immunofluorescence and furthermore we confirmed this finding on human PanIN tissue arrays. Intrapancreatic injections of adenovirus encoding IL-17A, the main cytokine produced by TH17 cells, into KCiMist1 mice led to an increase in the progression of PanIN lesions by 6 weeks when compared with mice injected with control adenovirus. Finally, we transplanted IL-17-/- bone marrow into KCiMist1 mice and showed a significant decrease in metaplasia and PanINs formation when compared with mice transplanted with WT bone marrow. Conclusions: We found that TH17 cells, recruited to the pancreas in the presence of chronic pancreatitis, can accelerate the progression of early pancreatic tumorigenesis, setting the basis for future translational studies targeting TH17 cells.
Association of dilated main pancreatic duct with biological high proliferative activity in intraductal papillary mucious neoplasm.
Authors: Eto Tsugio , Hayashi Hiromitsu , Kuroki Hideyuki , Nakagawa Shigeki , Hashimoto Daisuke , Ikuta Yoshiaki , Chikamoto Akira , Beppu Toru , Baba Hideo 
Published: February 2017

187 Background: Intraductal papillary mucious neoplasms (IPMNs) are characterized by multifocal and malignant potential represented by an adenoma (IPMA)-carcinoma (IPMC) sequence. Biologically, accelerated cell proliferative activity play an important role in the malignant step to IPMN (IPMC). Here, we investigated the biological significance of clinically available malignant predictive markers (such as diameter of main pancreatic duct, cystic size, and a mural nodule) in cell proliferative activity. Methods: From 2002 to 2011, surgically resected pancreatic specimens of IPMN were obtained from 49 patients (IPMA in 27(55.1%) and IPMC in 22(44.9%) patients, respectively). Median age was 73 years old (range 46-86 year). Men and women were in 31 and 18 patients, respectively. Cell proliferative activity was evaluated by MIB-1 index using Ki67 immunostaininig. Results: The MIB-1 index (20.1%±13.2) in IPMC was significantly higher than that in IPMA (9.0%±6.8)(p=0.004). In the comparison between the groups with high MIB-1 index (>15%) and low index (<15%), the diameter of main pancreatic duct in the high MIB-1 index group was and significantly larger than that in the low MIB-1 index group (p<0.05), 9mm (1-27mm) and 4.5mm(2-15mm), respectively. On the other hand, the cystic size and a mural nodule did not show any significant differences between of them. Regarding with the type of IPMNs (main- or branch-duct type), 60.9% of main duct type belongs to the high MIB-1 index group, whereas 19.2% of branch-type was in high MIB-1 index group. Conclusions: An increased diameter of pancreatic main duct showed the positive correlation with the high cell proliferative activity in IPMNs. Mucin production-induced dilatation of main pancreatic may predict the biologically high tumor proliferative activity.
Targeting Hedgehog in pancreatic cancer: An innovative approach but not for all tumors.
Authors: Andrikou Kalliopi , Faloppi Luca , Loretelli Cristian , Mandolesi Alessandra , Bianconi Maristella , Scartozzi Mario , Berardi Rossana , Bearzi Italo , Cascinu Stefano 
Published: February 2017

205 Background: Exocrine pancreatic cancer is the fifth cause of cancer-related death in Europe and has a very poor prognosis for all disease stages. To date no medical treatment has significantly increased patients' survival. One of the reasons for pancreatic cancer's chemoresistance is the complex tumor architecture: cancer cells are surrounded by a dense desmoplastic stroma that blocks drugs delivery. Moreover, pancreatic cancer is characterized by a marked heterogeneity of cells, including cancer stem cells (CSCs) that act as tumor-initiating cells and hierarchically control the differentiated cancer cells. Recent studies in multiple pancreatic cancer model systems have implicated the Hedgehog signaling pathway in these tumor-stromal interactions. The Hedgehog signaling pathway, a crucial regulator of proliferation and differentiation during embryonic development, has been reported to be aberrant and SMO overexpression seems to be a mechanism of activation of this pathway in human pancreatic cancer fibroblasts. Several studies are ongoing to evaluate the potential role of Hedgehog inhibitors, we investigated the contribution of Hedgehog to pancreatic progression and aggressiveness, evaluating the associated of stemness and desmoplastic reaction. Methods: In 110 histological samples of pancreatic ductal adenocarcinoma were performed molecular biology assessment of SPARC, CD133, CD44, CD24, OCT3/4, SHH, IHH, DHH, SMO, PTCH1, PTCH2. Results: Our analysis showed a strictly correlation between overexpression of SMO and high levels of SPARC (p=0.0005) and stemness markers CD133 (p=0.04) and OCT3/4 (p=0.0023) Conclusions: Our data demonstrate a critical and conserved role of Hedgehog signaling in the regulation of stem cell lineages and in the determination of a pronounced desmoplastic reaction determining chemoresistance and disease progression. We can speculate that patients with an aggressive profile defined by SMO overexpression would be the best candidates for treatment with Hedgehog inhibitors. This evidence suggests that this pathway may hold promise for new therapeutic approaches.
FG-3019, a human monoclonal antibody to CTGF, with gemcitabine/erlotinib in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.
Authors: Picozzi Vincent J. , Pipas J. Marc , Koong Albert , Giaccia Amato , Bahary Nathan , Krishnamurthi Smitha S. , Lopez Charles D. , O'Dwyer Peter J. , Modelska Katharina , Poolman Vanessa , Chou James , Zhong Ming , Porter Seth , Neff Tom , Valone Frank 
Published: February 2017

213 Background: Connective tissue growth factor (CTGF) is overexpressed in PDAC and facilitates local desmoplasia, tumor survival and metastasis. FG-3019 is a CTGF-specific monoclonal antibody that decreases tumor growth and metastases and prolongs survival in orthotopic and KPC mouse models. This study evaluates safety and efficacy of FG-3019 with gemcitabine/erlotinib in patients with PDAC. Methods: In a nongoing open-label, dose-escalation study, FG-3019 was used in combination with gemcitabine and erlotinib in patients with previously untreated, measurable, locally advanced or metastatic PDAC. Cohorts 1−6 received FG-3019 Q2W at 3, 10, 15, 25, 35 or 45 mg/kg. Cohort 7 received 35 mg/kg on Day 1 and then 17.5 mg/kg QW. Cohort 8 received 45 mg/kg on Day 1 and then 22.5 mg/kg QW. Results: 75 patients were enrolled at 7 centers. Baseline data: Stage III= 15, Stage IV=60; ECOG=0 (n=32), ECOG=1 (N=43). No SAEs or DLTs related to FG-3019 occurred at any dose. In per protocol population (n=68) median PFS and OS were 4.3 and 9.4 months respectively. Baseline plasma CTGF levels correlated inversely with PFS and OS (p=0.0029) (ITT population). Median FG-3019 Cmax and Cmin increased linearly with dose. Because of considerable overlap between subjects across cohorts, outcomes are correlated with drug exposure. OS, but not PFS, correlated with exposure after the first FG-3019 dose (Day 1 Cmax, p=0.009; Day 15 Cmin, p=0.005; ITT population). 47% of evaluable subjects had >50% decrease in CA19.9.The magnitude of reduction correlated with Day 1 Cmax (p=0.04) and inversely with baseline plasma CTGF (p=0.01). As FG-3019 accumulated over time, minimum FG-3019 exposure (Cmin) of 150 ug/mL on Day 43 appeared to be a threshold. Median OS was 7.7 and >8.6 months for subjects < (n=15) or ≥ (n=43) 150 ug/mL respectively on Day 43 (p=0.0034). Day 43 Cmin < 150, none alive at 12 months: Day 43 Cmin >150, 8 alive at 12 months, 17 alive 6.7-12 months. Conclusions: FG-3019 combined with gemcitabine/erlotonib is well tolerated. Interim results in this open-label study suggest OS improves with increasing exposure to FG-3019. Clinical trial information: NCT01181245.
Identification of unique somatic mutations with functional relevance through genetic characterization of gallbladder cancer (GB ca).
Authors: Javle Milind M. , Rashid Asif , Kar Siddhartha P , Schalper Kurt , Wang Nicholas , Peto Myron , Vauthey Jean-Nicolas , Aloia Thomas A. , De Aretxabala Xavier , Mills Gordon B. , Spellman Paul , Roa Ivan 
Published: February 2017

214 Background: GB Ca is the leading cause of cancer mortality in Chilean women and its incidence is high in Southeast Asia. Molecular characterization of this disease is limited to small retrospective studies of prognostic biomarkers. Methods: 54 surgically resected GB Ca cases were selected. DNA was extracted from microdissected tumors; genetic mutations analyzed using two platforms a) Sequenom MassARRAY, a mass spectrometry-based approach for 90 targetable mutations including PIK3CA, KRAS, EGFR, FGFR, CTNNB1, MET, ALK and AKT and b) Exome sequencing using the Illumina HiSeq2000 sequencer for novel genetic variants in the coding regions. Sample preparation followed the standard Agilent SureSelect XT protocol with the 71Mb +UTR capture library. A stepwise filtering approach was used to identify variants by screening for nonsynonymous substitutions, comparison of exomes to matched control and dbSNP database to exclude common variants. Variants not predicted to affect protein function were excluded. KM survival curves and log rank test were used to correlate genotyping results with survival. Results: 46 cases were selected for Sequenom MassARRAY and whole exome sequencing performed on 8 cases and control non-tumor tissue. Sequenom identified mutations in KRAS (3 cases), IDH1 (4), ALK1 (1), MET (1), NRAS (3) and PIK3CA genes (2). Overall survival was poorer in KRAS [24 vs. 75 weeks, p=0.008] and IDH1 [27 vs. 80 weeks, p=0.0008] mutation carriers. Exome sequencing after filtering revealed genetic variants in 6 cases with an overall low mutation rate. There were no overlapping mutations and we identified 45 functional mutations in STK11, CDKN2A, IKZF3, GRM6, TP53 and CTNNB1 genes, known to be prognostic in other cancers. ABCB1 transporter, TP53 and STK11mutations were predicted to have high functional impact. Ingenuity pathway analysis identified p53, WNT/ ß-catenin, GBM and thyroid cancer signaling and cell cycle regulation to be the top hits. Conclusions: This first high-throughput genomic screening of GB Ca using different platforms identifies known and unique variants in cancer genes. Sequencing of additional cases and efforts to develop a GB Ca-specific somatic mutation panel are ongoing.
Extended neoadjuvant chemotherapy (CT) in borderline resectable pancreas cancer (BRPC): Is preoperative chemoradiation (CRT) essential?
Authors: Picozzi Vincent J. , Rocha Flavio G. , Rose J. Bart , Traverso L. William , Alseidi Adnan , Lin Bruce S. , Biehl Thomas A. , Ryan John A. , Moonka Ravi , Helton Scott 
Published: February 2017

236 Background: The optimum approach to maximize R0 resection rate in BRPC is unknown. We evaluated an approach in BRPC using extended duration neoadjuvant CT, typically without neoadjuvant CRT to assess R0 resection rate on an "intent to treat"basis. Methods: Patients (pts) were identified from a prospectively-maintained database from 2008-2012. Pts required (1) BRPC per radiographic staging using NCCN/AHPBA criteria, (2) no prior PC therapy (rx) PC, (3) negative staging laparoscopy prior to rx, and (4) all cancer rx at VMMC prior to decision on "downstaging" surgery (S). Pts were initially treated with gemcitabine/docetaxel CT until (a) disease progression, or (b) 24 weeks (wks), before assessment for local rx. Pts with systemic progression and/or inability to complete 24 wks of CT were excluded from local rx; pts with localized cancer at 24 wks judged unlikely to achieve R0 resection were offered 5FU-based CRT then reassessed; all other pts were offered S. Results: Of 70 identified pts, 12/70 (17%) are on initial CT; 58 are fully evaluable. 51/58 pts (88%) completed 24 wks of CT. Response rates to CT were (a) serologic 42/58 (72%) > 50% decline in baseline CA19.9 (median 85%), and (b) radiographic of 47 pts evaluable by RECIST, PR/SD/PD were 60%/32%/8% respectively. 14/58 pts (24%) did not receive local rx (7 intercurrent illness, 7 disease progression). 44/58 pts (76%) were offered local rx- 12/58 (21%) CRT and 32/58 (55%) S. 2 pts receiving CRT later underwent S. CRT. 29 pts (50% total evaluable pts, 85% pts undergoing S) achieved R0 resection;10/29 pts (35%) via en bloc venous resections. 5 pts were inoperable (3 local - subsequently given CRT, 2 systemic). At median f/u of 16 mo, 21/29 (72%) R0 resection pts remain disease free (range 7+-47+mo) along with 4/12 pts (33%) receiving CRT w/o R0 resection (range 12+ -30 mo). 25/58 (43%) fully evaluable pts remain progression free on an "intent to treat" basis. Median OS for all pts is 27 mo (95% CI 15-39 mo); 25/29 R0 resected pts remain alive ( median OS> 20 mo). Conclusions: (1) extended neaoadjuvant CT is a feasible approach in BRPC. (2) Gemcitabine/docetaxel has significant activity in localized PC. (3) Neoadjuvant CRT may not be essential to R0 resection in BRPC.
A novel simplified approach to incorporating lymph node ratio into gastric cancer staging.
Authors: Fisher Sarah B. , Squires Malcolm Hart , Patel Sameer H. , Kooby David A. , Cardona Kenneth , Russell Maria C. , Staley Charles A. , Maithel Shishir K. 
Published: February 2017

24 Background: Previous investigators have reported on the value of lymph node ratio (LNR, defined as the number of positive nodes divided by the total number of nodes assessed) in gastric adenocarcinoma (GAC) staging. Given the complexity of previously proposed staging systems, it has not gained widespread acceptance. The aim of our study was to offer a novel simplified approach to incorporating LNR into gastric cancer staging. Methods: 131 patients who underwent curative intent resection with lymphadenectomy for GAC between 1/00-6/11 were identified. Clinicopathologic factors were assessed. Primary outcome was overall survival (OS). Results: Median age was 64 yrs, 51% were male. Median tumor size was 3.5 cm, 67% were poorly differentiated, 20% had perineural invasion, 31% had lymphovascular invasion, and 6% had a positive margin. Locoregional nodal metastases were present in 59% (n=77, N0: 41%, N1: 18%, N2: 22%, N3a: 14%, N3b: 5%). Median number of lymph nodes (LN) assessed was 15.5. Mean FU was 27.3 mos, median OS was 29.3 mos. Median LNR was 0.4 (.04-1). Patients with LNR ≥0.4 had decreased OS as compared to patients with LNR <0.4 (15.1 vs 41.5 mos, p<0.0001); the survival of patients with LNR <0.4 was similar to that of node negative pts (48 mos, p=0.882). On Cox regression analysis, LNR ≥0.4 was more strongly associated with decreased OS (HR 3.09, 95%CI: 1.81-5.26; p<0.0001) compared to the AJCC 7th edition N stage (HR 1.36, 95%CI: 1.11-1.68; p=0.004). In the subset of patients who were inadequately staged and had <16 nodes examined, a LNR ≥0.4 was associated with reduced survival compared to a LNR <0.4 (17.3 vs 41.5 mos, p=.04). Conclusions: Compared to the current lymph node staging system, a lymph node ratio using 0.4 as the cutoff may more accurately predict survival outcomes. It seems to be particularly useful in patients who have inadequate nodal assessment. This simplified approach to lymph node ratio may be a more valuable staging tool than the current AJCC nodal staging system for gastric cancer and needs to be validated.
Effect of geographic variability for pancreatectomy rates on outcomes in patients with stage I and II pancreatic adenocarcinoma.
Authors: McDowell Bradley D. , Howe James R. , Chrischilles Elizabeth A. , Mezhir James J. 
Published: February 2017

240 Background: Low usage of pancreatectomy for stage I/II pancreatic cancer in the US has been reported, yet it is not clear to what extent this reflects underutilization of resection versus appropriate selection of operative candidates. To address this, we examined the geographic variation in pancreatectomy. Methods: We queried the US Surveillance, Epidemiology, and End Results (SEER) data for stage I/II pancreatic head cancer diagnosed from 2004-2009. Factors included in multivariate analyses (MVA) were age, gender, race, stage, and geographic region and primary endpoints were rate of pancreatectomy and median survival. Results: 10,520 patients with stage I (n=2,068) and stage II (n=8,452) pancreatic head cancer were analyzed. Pancreatectomy was performed in 528 patients (25.5%) with stage I disease and in 4,295 patients (50.8%) with stage II disease (overall resection rate=45.9%). Rates of resection significantly varied across the 18 SEER regions after controlling for age, gender, race, and stage in MVA (p<0.0001). For the analysis, SEER regions were divided into groups of high/medium/low rates of resection (56.3%, 46.6%, and 41.1%, respectively). Median survival in the high resection regions was 12 months, which was significantly longer than in low and medium resection regions (both=10 months, p<0.0001). MVA confirmed that regions with high resection rates have improved survival while controlling for age, gender, and race (Table). Conclusions: Pancreatectomy rates vary highly across geographic regions, and areas with higher rates of resection are associated with better outcome. These data may reflect poor adherence to treatment guidelines, which possibly reflects a lack of confidence in the effectiveness of pancreatectomy or expertise in performing the procedure. Studies that control for patient selection factors are underway to further elucidate these important findings. [Table: see text]
Phase II study of alternate-day oral therapy with S-1 for unresectable advanced pancreatic cancer: An updated report.
Authors: Satoi Sohei , Miyazawa Motoki , Tani Masaji , Kawai Manabu , Hirono Seiko , Okada Ken-Ichi , Yanagimoto Hiroaki , Kwon A-Hon , Kanbe Takamasa , Mukouyama Tomoyuki , Tsunoda Hiroaki , Chijiiwa Kazuo , Ohuchida Jiro , Kato Jun , Ueda Kazuki , Yamaguchi Taketo , Egawa Shinichi , Hayashi Kazuhiko , Shirasaka Tetsuhiko , Yamaue Hiroki 
Published: February 2017

252 Background: Based on the results of GEST, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended regimen of 4 weeks of administration interrupted by 2 weeks of drug withdrawal frequently causes adverse effect. Grade3/4 toxicities (%) in S-1 were neutropenia 8.8, anorexia 11.4, diarrhea 5.5. On the other hand, we experienced in clinical practice that the alternate-day administration of S-1 reduced adverse effects and was tolerable for unresectable advanced pancreatic cancer patients unwilling to continue the standard daily administration. We therefore conducted a multi-center cooperative prospective study to compare daily with alternate-day administration of S-1 for unresectable advanced pancreatic cancer. Methods: Patients with unresectable advanced pancreatic cancer (PS, 0 to 1; age, 20 to 80 years; no other therapy) were eligible for enrollment in this trial. S-1 was administered a dose of 40 to 60 mg twice daily, assigned according to body-surface area, on Monday, Wednesday, Friday, and Sunday (specified days). Each treatment cycle will be 42 days (6 weeks). The primary endpoint was overall survival (OS). Secondary endpoints were safety, response rate (RR), progression free survival (PFS), time to treatment failure (TTF). Results: A total of 50 patients were enrolled from Sep 2009 to Feb 2011. 48 patients were evaluable for response. Male/Female was 21/27, PS: 0/1 was 40/8. With a median follow-up time of 28.2 months, OS as primary endpoint was 8.4 months (95% CI, 5.4-10.8) with the 1 year survival rate 29.2%. PFS was 5.5 months, and TTF was 3.9 months. RR was 10.4% (95% CI: 3.5-19.1), and Disease Control rate was 79.2%. Grade 3/4 hematological and non-hematological toxicities were minor. All of those adverse reactions were tolerable and reversible. Conclusions: We will report the data from the final analysis at this meeting. The current data show mitigation of adverse effects with alternate-day administration of S-1, and it appears to be a more sustainable option for unresectable advanced pancreatic cancer. A randomized phase II trial comparing this regimen of S-1 with standard regimen of S-1 is ongoing. Clinical trial information: 000003453.