bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pretreatment serum ferritin and overall survival in metastatic pancreatic cancer.
Authors: Zubritsky Lindsey , Alkhateeb Ahmed , Leitzel Kim , Ali Suhail M. , Campbell-Baird Cynthia , Connor James , Lipton Allan 
Published: February 2017

171 Background: Ferritin, an iron storage protein, is elevated in the serum of certain types of cancers, including breast and pancreatic. Ferritin has been shown to play a role in tumorigenesis and cancer cell growth and survival through angiogenesis, immune regulation, and iron delivery. Ferritin may serve as a potential biomarker in evaluating survival of pancreatic cancer patients. Methods: This study determined pretreatment ferritin levels in a phase III clinical trial of 162 patients with advanced pancreatic cancer. A quantitative sandwich ELISA (Human Ferritin ELISA (Assaypro, St. Charles, Missouri) was used to measure pretreatment serum ferritin levels in 162 patients with advanced pancreatic cancer. Serum ferritin level was correlated with overall patient survival using log-rank regression and Kaplan-Meier analysis on a continuous and categorical dichotomous basis (median cutpoint). Results: The median pretreatment serum ferritin in 162 patients was 832.6 ng/ml, a 25th and 75th percentile of 446 and 1735 ng/ml, respectively, and ranged from 51 ng/ml to 35914 ng/ml. When analyzed on a continuous basis, patients with higher serum ferritin had reduced overall survival (p= 0.001). When analyzed on a categorical basis (median 832.6 ng/ml), patients with higher ferritin had shorter overall survival (median 121 days vs. 180 days) (p=0.003). In multivariate analysis with pretreatment serum ferritin, TIMP-1, uPA, and VEGF, TIMP-1 remained the only significant predictive factor (p<0.0001), with ferritin trending toward significance (p= 0.076). Conclusions: Pretreatment serum ferritin in 162 patients with advanced pancreatic cancer was quantified using ELISA. Pretreatment serum ferritin predicted for significantly shorter overall survival in a phase III trial of metastatic pancreatic cancer. Pretreatment serum ferritin level has prognostic biomarker utility in pancreatic cancer, and should be evaluated as a predictive factor for response to novel treatment regimens.
An exploratory phase I trial of immunochemoradiotherapy in locally advanced and borderline resectable (LA/BR) pancreatic adenocarcinoma (PC).
Authors: Crocenzi Todd S. , Crittenden Marka , Wolf Ronald , Hammill Chet , Newell Pippa , Savoy Alan , Somogyi Lehel , Phillips Michael , Regan James , Owens Michael , Solhjem Matthew C. , Seung Steven , Kurup Anupama , Rogosin Shane Orion , Urba Walter John , Bifulco Carlo Bruno , Cai Xiaohong , Bageac Alexandru , Gough Michael 
Published: February 2017

174 Background: The primary aim of this exploratory trial was to determine the feasibility and safety of chemoradiotherapy (CRT) with combinatorial immunotherapy in LA or BR PC. Methods: 10 patients (pts) with untreated, LA (n=6) or BR (n=4) biopsy-proven PC received gemcitabine (GEM) in combination with telomerase peptide vaccine (GV1001) and sargramostim (GM-CSF) both by intradermal injection. Tadalafil was taken once daily throughout the course of therapy for myeloid derived suppressor cell inhibition. The 2nd month of treatment included external beam radiation therapy (50.4 Gy, 28 fractions) and concurrent twice-weekly GEM 50 mg/m2. Disease response was assessed at 12 weeks. Following recovery from either concurrent CRT or resection, 8 weeks of GV1001 + GM-CSF, tadalafil and GEM completed treatment. Peripheral blood was analyzed by quantitative multiparameter whole blood flow cytometry of immune cell subtypes. Samples were also cryo-preserved for future analysis of peripheral blood mononuclear cell (PBMC) populations and ELISPOT analysis of antigen-specific T cell numbers. Tumor resection specimens were sectioned for immunohistological analysis of macrophage and T cell infiltration. Results: 9 of 10 pts completed therapy to assess response. Grade (Gr) 3-4 hematologic adverse events (AE) were observed during CRT. Immune-related AE were infrequent and mild. 3 of 4 pts with BR disease and 1 with initial LA (unresectable) disease achieved R0 resection. No unanticipated surgical complications were observed. Changes in monocytes and granulocytes occurred throughout treatment and may correlate with clinical benefit. At least 50% reduction in serum CA19-9 was observed in 8 pts. Partial response (n=2) or stable disease (n=7) was achieved in 9 pts. Conclusions: Combinatorial immunotherapy concurrent with GEM-based CRT is feasible and appears safe in LA or BR PC. Initial biochemical responses as well as disease control were observed in the majority of pts. Preliminary immune correlative data suggest a relationship between hematopoietic populations and clinical response.
Circulating tumor cells as a possible marker for micrometastatic disease in patients with localized pancreatic cancer.
Authors: Aufforth Rachel D. , Baker Justin J. , Witek Malgorzata A. , Kamande Joyce W. , Kim Hong Jin , Kuan Pei-Fen , Soper Steven A. , Yeh Jen Jen 
Published: February 2017

175 Background: Circulating tumor cells (CTCs) are cells shed into circulation from tumors. They are increasingly recognized to be important biomarkers of disease burden in patients with solid tumors. Studies in pancreatic ductal adenocarcinoma (PDAC) have been limited due in part to low sensitivity of existing assays with extremely low numbers detected (0-15 per 7.5-15ml of blood). The development of newer microfluidic platforms has resulted in the ability to detect substantially greater numbers of CTCs. Methods: 15 patients with PDAC were enrolled in an IRB-approved study. Blood was collected in EDTA tubes and processed within 3 hours. CTCs were selected from 2-3ml of whole blood using monoclonal antibodies against epithelial cell adhesion molecule (EpCAM) and enumerated using a novel microfluidic platform. CTCs were confirmed by DAPI, CK8/18/19 and CD45 staining. Results: Patients with metastatic disease (n=12) had a mean of 29.7, median of 22 (3.5-107) CTCs per 1ml of blood. Patients with localized disease (n=3) had a mean of 3.8, median of 2.9 (2.3-6.2) CTCs per 1ml of blood. 0.5-1 CTCs per 1ml were detected in normal controls (n=2). The number of CTCs was significantly different between localized, metastatic and normal patients (p=0.01). 1 patient, initially thought to have localized disease by standard imaging but found to be metastatic at time of operation, had a mean of 45.9 CTCs per 1ml of blood compared to a mean of 3.8 CTCs per 1ml in patients who underwent a curative resection (p=0.009). Conclusions: Studies of CTCs in PDAC have been very limited. Our ability to detect large numbers of CTCs with good dynamic range suggests that further investigation into CTCs as a prognostic marker in PDAC is warranted. This is the first study that we are aware of to find CTCs in patients with localized disease. The presence of CTCs in patients with localized PDAC is surprising and may be associated with findings of unexpected metastatic disease at surgery. Further follow-up will be needed to determine if the presence of CTCs in these patients is a harbinger of shorter progression-free survival and overall survival after curative operations.
Analysis of toxicity and outcomes in patients undergoing hyperthermic isolated hepatic perfusion with melphalan for metastatic melanoma to the liver.
Authors: Golas Benjamin , Magge Deepa , Zureikat Amer H. , Zeh Herbert , Alexander H. Richard , Libutti Steven K. , Royal Richard E. , Hughes Marybeth S. , Holtzman Matthew Peter , Turaga Kiran , Pappas Sam G. , Gamblin T. Clark , Bartlett David L. , Pingpank James F. 
Published: February 2017

178 Background: Ocular melanoma (OM) has an annual incidence of 3500 to 4000 patients per year, with liver metastases (LM) accounting for the sole or dominant site of metastases in more than 80% of patients. For patients with LM, median survival is reported to be 2 to 7 months, with an estimated 1-year survival of 10%. We present results utilizing liver directed therapy with high-dose melphalan administered via hypertermic isolated hepatic perfusion (IHP) for patients with unresectable LM from OM. Methods: Between 10/1994 and 6/2012, 105 pts with unresectable LM underwent a 60 min hyperthermic (IHP) with melphalan (1-2 mg/kg IBW). IHP included hepatic isolation at laparotomy with inflow via a cannula in the gastroduodenal artery and outflow via a cannula in the isolated retrohepatic vena cava (IVC). Patients were followed for toxicity, radiographic response (WHO criteria), and hepatic progression-free (HPFS) and overall survival (OS). HPFS and OS probabilities were calculated by Kaplan-Meier. Results: There were 51 males and 54 females (mean age: 50 yr [range: 21-76]) with unresectable OM LM (median # metastases: 26 [range: 3-50]; median percent liver replaced by tumor: 22%). There were 3 operative/treatment mortalities (2.9%). There were 62 responses (CR: n=6, PR: 56) in 102 evaluable patients (61%). For all treated patients, median OS was 12 months (range: 1 to 115 months) with 2 and 3-yr survival of 31% and 21%, respectively. Conclusions: IHP with melphalan results in marked tumor regression and prolonged OS in patients with high hepatic tumor burden from metastatic OM. Although this is a non-randomized trial, response to IHP is associated survival superior to that reported with alternative therapies.
Clinical implications of luminal membrane expression of mesothelin in intraductal papillary mucinous neoplasms.
Authors: Einama Takahiro , Kamachi Hirofumi , Nishihara Hiroshi , Homma Shigenori , Kawamata Futoshi , Tahara Munenori , Taniguchi Masahiko , Furukawa Hiroyuki , Kamiyama Toshiya , Taketomi Akinobu , Matsuno Yoshihiro , Todo Satoru 
Published: February 2017

179 Background: We recently explored that the expression of mesothelin was related to an unfavourable patient outcome in pancreatic cancer. Furthermore, in gastric cancer, we investigated that the luminal membrane expression of mesothelin was a reliable prognostic factor. Intraductal papillary mucinous neoplasms (IPMNs) often exhibit a spectrum of dysplasia ranging from adenoma to carcinoma in the same lesions. Therefore, we investigated the immunohistochemical analysis of mesothelin expression in IPMNs, especially focusing on the localization of mesothelin. Methods: Tissue samples from37 IPMNs were immunohistochemically examined. The types of IPMNs were classified into 2 groups: low, intermediate and high-grade dysplasia (L-H grade dysplasia) and IPMN with an associated invasive carcinoma (Invasive carcinoma). The proportion and intensity of constituent tumor cells with mesothelin expression were analyzed and classified as positive expression or negative expression. Furthermore, among the ‘mesothelin-positive’ cases, the staining localisation of mesothelin was evaluated as ‘luminal membrane positive’ and/or ‘cytoplasmic positive’. Results: In 37 cases of IPMNs, mesothelin expression was observed in 21 cases (56.8%), 46.2% (12 of 26) of L-H grade dysplasia and 81.8% (9 of 11) of Invasive carcinoma; p=0.071. Luminal membrane positive was observed in 10 cases (27%), 18.2% (4 of 22) of L-H grade dysplasia and 21% (6 of 11) of Invasive carcinoma; p=0.00016. Cytoplasmic positive was observed in 17 cases (27.0%), 38.5% (10 of 26) of L-H grade dysplasia and 63.6% (7 of 11) of Invasive carcinoma; p=0.28. Among 37 IPMNs, 6 cases showed recurrence after surgery. Five cases exhibited mesothelin expression, and all 5 cases exhibited luminal membrane positive. Conclusions: we demonstrated the clinicopathological significance of the luminal membrane expression of mesothelin in IPMNs. The immunohistochemical examination of mesothelin expression should be clinically useful for prognostication and for decision making about further treatment procedures after surgical therapy in patients with IPMNs.
An experimental MODEL study to investigate the pathogenesis of oxaliplatin-induced liver injury.
Authors: Robinson Stuart M. , Mann Jelena , Manas Derek M. , Mann Derek A. , White Steve A. 
Published: February 2017

184 Background: Oxaliplatin based chemotherapy is widely utilized pre-operatively in patients with colorectal liver metastases. Its use is associated with injury to the liver in the form of sinusoidal obstruction syndrome (SOS) the presence of which can have a negative impact on surgical outcomes. The pathogenesis of this condition is poorly understood. Methods: C57Bl/6 mice (n=10 per group) were treated with 5-FU/oxaliplatin/folinic acid chemotherapy (FOLFOX) weekly for 5 weeks or their respective vehicle controls. Animals were culled one week following the final treatment and liver tissue harvested for histological and biochemical analysis. mRNA was extracted from snap frozen liver and subject to genome wide expression analysis the results of which were confirmed using qRT-PCR. To determine the effect of background steatosis on the development of liver injury the experiment was repeated using mice maintained on a high fat diet. To assess the ability of antioxidants to prevent SOS development diet was supplemented with 3% butylated hydroxyanisole (BHA). Results: H&E stained tissue sections confirmed the presence of SOS in all FOLFOX treated animals. Microarray identified changes in expression of over 604 genes in the liver of animals with FOLFOX induced SOS. In particular there was increased expression of genes implicated in oxidative stress (e.g. Metallothionein 1; 22 fold; p<0.001), cell cycle arrest (e.g. p21; 21 fold; p<0.001) and angiogenesis (VEGF-A; 2 fold; p<0.001). Administration of the antioxidant BHA alongside chemotherapy prevented the development of SOS confirming the role of oxidative stress in the pathogenesis of this condition. There was down regulation of a number of genes implicated in fatty acid synthesis (e.g. FASN; 8 fold; p<0.001). In support of this mice maintained on a high fat diet treated with FOLFOX do not develop steatosis unlike those treated with vehicle alone. Conclusions: FOLFOX chemotherapy is specifically associated with SOS and not hepatic steatosis. We have identified some of the molecular pathways involved in the pathogenesis of this condition. Manipulation of these pathways may be of therapeutic potential in preventing the development of chemotherapy-associated liver injury.
Loss of succinate dehydrogenase (SDHB) in midgut carcinoids as a prognostic factor: A new marker of personalized cancer medicine in neuroendocrine tumors?
Authors: De Braud Filippo G. , Pusceddu Sara , Milione Massimo , Buzzoni Roberto , Mazzaferro Vincenzo , Coppa Jorgelina Clara , Damato Angela , Seregni Ettore , Formisano Barbara , Pelosi Giuseppe 
Published: February 2017

186 Background: Gene mutations of the succinate dehydrogenase (SDH) complex have recently been involved in the pathogenesis of cancer cells. These mutations often are associated with SDH subunity B loss of activity and overexpression of HIF-1α. The immunoistochemical (IHC) loss of SDHB expression has recently been reported to be a surrogate marker of malignancy in pheocromocytomas and paragangliomas. The aim is the evaluation of SDHB levels expression in advanced midgut carcinoids and investigate its potential role as prognostic marker. Methods: 31 advanced midgut carcinoids were treated in our Istitution, including 24 males and 7 females, aged 55.5 yrs on average (range 19-75). All patients were G1 tumors with stage IV for synchronous liver metastases. 25/31 patients underwent surgical primary resection. IHC evaluation of the SDHB and MIB1 expression were carried out in 20 primary tumors (T) and 19 liver metastases (M). In 11 patients SDHB and MIB1 were tested in both T and M. SDHB was assessed according to the staining intensity scored 1 (low) or 2 (high) on the basis of the internal control represented by normal intestinal cells. Results: Loss of SDHB expression (IHC +1) was detected in 70% of T and in 90% of M. The value of MIB 1 labeling index: 1,3% represent a cut-off for distinguish low or high SDHB expression within these G1 midgut category (MIB 1≥ 1.3, SDHB +1: 90%; MIB 1 <1.3, SDHB +1: 10%). No difference in term of median OS was found between these 2 groups, 113 vs 103 mts respectively. In 11 pts the combined analysis (T+M) confirmed the loss of SDHB expression in 82% of metastases compared to 18% of primary tumors. These findings were inversely proportional to Mib-1 distribution that was 1,54% in metastastic sites and 0.7% in the primaries, respectively. Conclusions: This preliminary analysis suggests a possible correlation between SDHB expression loss, MIB1 increase and biological aggressiveness of advanced midgut carcinoids. A more extensive clinico-biological evaluation is warranted to clarify its relationship with survival and explore the role of SDHB as predictive marker to response of antiangiogenetic agents.
An alternative method to detect peritoneal recurrence of gastric cancer: Clinical application of CT colonography.
Authors: Iwasaki Kenichi , Cho Haruhiko , Watanabe Takafumi , Kuwabara Hiroshi , Hayashi Tsutomu , Shirai Junya , Fujikawa Hirohito , Yoshida Tetsuo , Yoshikawa Takaki , Tsuburaya Akira 
Published: February 2017

19 Background: Peritoneal metastasis (PM) is among the most frequent patterns of recurrence of gastric cancer: however, it cannot be detected by general axial CT or even by PET until it develops to massive ascites or an overt peritoneal mass. CT colonography (CTC) is used to screen for colon cancer, with the advantage that it can provide both colonic and extracolonic information at the same time. Methods: CTC was applied for patients that were suspected to have PM based on their clinical symptoms and general CT findings, without sufficient information to confirm the diagnosis, to detect signs of peritoneal metastasis earlier. PM diagnosis in CTC was defined as the finding of an abnormal deformity of the colonic wall without intraluminal tumor by both the attending doctors and radiologists. Results: Twelve patients suspected of having PM were enrolled in the study. Nine of those patients (75%) were positive for PM by CTC. Abnormal colonic deformities were also identified in other locations other than the lesions detected by general CT in 6 patients. All of the nine patients with positive PM were clinically confirmed to have PM, and had a poorer prognosis (median survival: 252 days). The three patients with negative PM are all alive without recurrence. Conclusions: CTC is thus considered to be a candidate for the early detection of PM. Further study with more patients is therefore warranted.
The natural history and role of surgical cytoreduction and systemic chemotherapy in high-grade mucinous adenocarcinomas of the appendix.
Authors: Overman Michael J. , George Binsah , Taggart Melissa W. , Eng Cathy , Royal Richard E. , Wolff Robert A. , Mansfield Paul F. , Fournier Keith F. 
Published: February 2017

199 Background: The natural history, clinical presentation, and impact of cytoreductive surgery (CRS) or systemic chemotherapy for high grade MAA has been poorly studied. Methods: A retrospective chart review of patients (pts) with moderate or poorly differentiated AA was completed from 1994-2010. Radiographic response was assessed semi-quantitatively form physician records and complete cytoreductive surgery (CRS) was defined as a completeness of cytoreduction score of 0 or 1. For CRS and chemotherapy subgroups efficacy endpoints were calculated from date of CRS or first chemotherapy dose, respectively. Results: 288 (136 moderate and 152 poor grade) pts were identified with a median age of 52 years (range: 25-82). Mucinous histology was present in 110 pts (38%) and differed by grade: 55% of moderate and 23% of poor. Stage IV presentation (n=163) occurred in 76% of poor grade but only 35% of moderate grade. Both median OS (4.5 vs. 2.7 yrs, P=0.04) and median OS for the stage IV subgroup (3 vs 1.9yrs, P=0.005) were improved for MAA vs. non-MAA. Moderate compared to poor grade had improved median OS (3.7 vs 1.9 yrs, P=0.002) for Stage IV disease, but this differed by mucinous histology (moderate mucinous 6.2yr vs. poor mucinous 1.6yr, P=0.001; moderate nonmucinous 1.4yr, poor nonmucinous 2yr). 39 MAA pts underwent a complete CRS (30 moderate and 9 poor) with a median time to recurrence of 1.5yrs and median OS of 9.2yrs. Improved OS was seen for pts with a complete CRS compared to pts with an incomplete CRS, P<0.001. 55 MAA pts received systemic chemotherapy (fluoropyrimidine/oxaliplatin in 30, irinotecan-based in 8, fluoropyrimidine-based in 16, and other in 1): median OS of 2.1yr, median TTP of 7.2 months, and radiographic response of 36%. No statistical differences were seen between chemotherapy groups. Conclusions: High-grade MAA represents a heterogenous disease with a statistically worse OS for poor as opposed to moderate histological differentiation. This data does not support the AJCC 7th edition use of a single mucinous high-grade category. The use of systemic chemotherapy appears to be a viable treatment option for these pts and a complete CRS is associated with improved OS.
Prospective phase II trial of GTX in metastatic pancreatic cancer: Laboratory and clinical studies.
Authors: Fine Robert , Lee Yoomi , Sherman William H. , Gulati Anthony Paul , Oberstein Paul Eliezer , Chu Kyung , Tsushima Dawn , Mowatt Kelley B , Schrope Beth , Lee James A , Allendorf John , Chabot John A , Schreibman Stephen M. 
Published: February 2017

209 Background: We found that in pancreatic cancer (PC) cells, when gemcitabine, docetaxel, capecitabine (GTX) are given in a sequence and time specific manner, it 1) increased Bax, Bak, Fas and decreased Bcl-2 and Bcl-XL expression; 2) increased hENT-1 expression >8 fold, which increased intracellular gemcitabine accumulation by 220%; 3) specifically inhibited MEK to ERK phosphorylation (p-MEK) by >70%. Methods: From this pre-clinical data, we developed the GTX regimen utilizing: capecitabine 750 mg/m2/BID capped at 2500mg/day for days 1-14; on days 4 and 11 gemcitabine at 750mg/m2 given over 75mins (FDR), followed by docetaxel at 30mg/m2. Week 3 is off all drugs. Forty four patients with previously untreated metastatic PC were enrolled and followed until death. ECOG PS was: 0(2%), 1(63%), 2(35%), and median age was 60 (33-72). Over 85% of patients had >3 liver metastases. Results: Median response rate (RR) was 38% with 14% CR in metastatic or primary sites and 40% stable disease using RECIST 1.0 indices. Median PFS was 6.9 months and median OS was 14.5 months. After failing GTX, 80% of patients received our second line synergistic regimen called ICM (irinotecan 80mg/m2 and cisplatin 25mg/m2 on days 1 and 8, and mitomycin C 5mg/m2 on day 1 only, out of a 28 day cycle). The 6, 12, 18, 24, 30 and 36 month survival on GTX was 77, 59, 35, 16, 14 and 7%, respectively. Grade3/4 toxicities were: leukopenia (32%), neutropenia (29%), febrile neutropenia (3%), anemia (12%), thrombocytopenia (12%), diarrhea (5%), HFS (3%), fatigue (8%), and mucositis (8%). GTX inhibited MEK to ERK phosphorylation (P-MEK). We performed IHC (0-4+) for P-MEK in 16 patients and found high P-MEK (3-4+) correlated with an 85% RR while low P-MEK (0-1+) correlated with a 90% rate of PD to GTX. Conclusions: GTX is an effective regimen for metastatic PC with durable RR, PFS, OS rates, and acceptable toxicities. IHC for P-MEK seems to be a good biomarker to identify subsets of patients who will respond to GTX. GTX is a rationally designed regimen derived from lab studies. GTX increases pro-apoptotic and decreases anti-apoptotic proteins, inhibiting MEK to ERK in the MAPK pathway. Clinical trial information: NCT00996333.