tbuckley/cabot-search huggingface dataset:
Epigenetic regulation and functional roles of SHP1 in gastric carcinoma cell lines.
Authors: Moon Kyung Joo, Jong-Jae Park, Hyo Soon Yoo, Yong Jeoung, Jiwon Kim, Jin Sung Koh, Ho Kim, Jung Wan Choe, Beom Jae Lee, Jae Seon Kim, Young-Tae Bak
Journal: Journal of Clinical Oncology (2015)

61 Background: The SH2-containing protein tyrosine phosphatase 1 (SHP1) is an important negative regulator in cytokine-mediated signal transduction and cell cycling. Recent studies demonstrated that promoter methylation of SHP1 is frequently observed in gastric adenocarcinoma tissues. We tried in this in vitrostudy to reveal promoter hypermethylation and to investigate the effects of SHP1 in gastric carcinoma cell lines. Methods: We performed RT-PCR, Western blot, methylation specific PCR (MSP) and bisulfite pyrosequencing to demonstrate promoter hypermethylation of SHP1. To evaluate functional roles of SHP1, we transfected SHP1 plasmid and analyzed WST-1 assay, wound closure assay and Matrigel invasion assay. Results: We observed that both gene and protein expression of SHP1 were negative in 8 of 10 gastric cancer cell lines (SNU-1, SNU-5, SNU-16, SNU-638, SNU-719, MKN-28, MKN-45, AGS). MSP showed methylation-specific band only in all 10 gastric cancer lines. Bisulfite pyrosequencing revealed 96.5% and 97.3% of methylation frequency in AGS and SNU-719 cells. When treating SNU-719, MKN-28 and AGS cells with 5-Aza-2’-deoxycytidine (5-Aza-dc), SHP1 was re-expressed in all three cells. SHP1 expression is known to be correlated with Janus kinase (JAK) and signal transducers and activators of transcription (STAT) signaling pathway in epithelial cells. When introducing exogenous SHP1 in SNU-719 and MKN-28 cells by transient transfection, protein expression of constitutive phospho-JAK2 (Tyr 1007/1008) and phospho-STAT3 (Tyr 705) were substantially down-regulated both, which in turn decreased target gene expression of STAT3, including cyclin D1, MMP-9, VEGF and survivin. Induction of SHP1 significantly inhibited cell proliferation, migration and invasion in SNU-719 and MKN-28 cells. Conclusions: Epigenetic silencing of SHP1 is frequently caused by promoter hypermethylation in gastric carcinoma cell lines. Overexpression of SHP1 down-regulates JAK2/STAT3 pathway to modulate various target genes and inhibit cell proliferation, migration and invasion in gastric cancer cells.
Expression of the cellular and the humoral immune system in triple-negative carcinomas of the breast—Impact on prognosis?
Authors: M. Schmidt, C. von Toerne, H. Koelbl, M. Gehrmann
Journal: Journal of Clinical Oncology (2008)

22016 Background: Triple-negative carcinomas of the breast are characterized by negative expression of estrogen receptor (ER), progesterone receptor (PR) as well as HER-2. We aimed to assess proliferation as well as the expression of the cellular (T-cell) and the humoral (B-cell) immune system in triple-negative breast cancer and analyzed metastasis-free survival (MFS). Methods: We analyzed the gene expression patterns of 200 node-negative breast cancer patients which were not treated in the adjuvant setting with the Affymetrix HG- U133A array. After performing an unsupervised hierarchical cluster analysis using 2579 genes selected for variable expression within our dataset, we constructed metagenes for different cluster (proliferation, B cell, T cell). The interrelation of the median expression of these metagenes between triple-negative breast cancer and carcinomas expressing at least one of these three receptors was analysed with the Wilcoxon-Mann-Whitney test. MFS was compared according to the method of Kaplan Meier. Results: 25 carcinomas (13%) were triple-negative. MFS was similar between both groups (p = 0.223). The relative expression of the proliferation metagene was significantly higher in triple-negative carcinomas (p = 1.811e-5). Triple-negative breast cancer also showed higher expression of the T-cell metagene (p = 6.316e-5) and the B-cell metagene (3.551e-6) as compared to breast carcinomas expressing either ER or PR or HER-2. Conclusions: Our results indicate that substantial differences in proliferation and expression of genes of the cellular as well as the humoral immune system exist between triple-negative breast cancer and carcinomas expressing at least one of these three receptors. It is tempting to speculate that this up- regulation of the immune system might abrogate adverse effects of increased proliferation on survival in triple-negative breast cancer. No significant financial relationships to disclose.
Plasma concentrations of 5-FU and creatinine clearance as predictive markers for severe toxicities of capecitabine in patients with colorectal cancer.
Authors: Katsuya Makihara, Hideyuki Mishima, Sayaka Azuma, Kazuyo Miyagi, Katsuya Komori, Hiroko Hasegawa, Masayoshi Yasui, Masakazu Ikenaga, Toshimasa Tsujinaka
Journal: Journal of Clinical Oncology (2013)

428 Background: Pharmacokinetically guided dose adjustment of 5-fluorouracil (5-FU) are available but management of capecitabine has not been established. Patients with renal impairment often experience severe adverse events. The aim of this study is to assess the relationship between plasma concentration of 5FU, metabolites after administration of capecitabine, renal function and adverse events. Methods: Plasma concentration–time data for capecitabine, 5’-DFUR, 5’-DFCR and 5-FU were analyzed by blood samples within 60–180 min after administration of capecitabine on day 8 in colorectal cancer patients receiving capecitabine based regimen (capecitabine with or without oxaliplatin and bevacizumab). Concentrations of 5-FU were analized by a nanoparticle antibody-based immunoassay for 5-FU(My 5-FU R assay). Correlation between the peak concentration of capecitabine metabolites (Cmax) or creatinine clearance (Ccr) and toxicity (grade 3–4 diarrhea, grade 2-3 hand–foot syndrome and grade 3–4 anorexia) were assessed. When parameter of correlation exists, logistic regression analysis was done. ROC (receiver operating characteristic) analysis was conducted to explore the cut off value of the parameter associated with severe adverse events. Results: A total of 42 patients were analyzed. The Cmax of 5’-DFUR, 5-FU and Ccr were significantly correlated with the incidence of severe adverse events. Cmax of 5-FU (p = 0.015) and Ccr (p = 0.016) were also independent parameters. According to the ROC analysis, severe adverse events were observed in the patients whose Cmax of 5-FU was higher than 295 ng/mL and Ccr was lower than 64.8 mL/min. Conclusions: Plasma concentration of 5-FU and renal function are good predictive markers of adverse events after capecitabine administration. These results would lead to the appropreate indivisual dosage adjustment of capecitabine.
Who is receiving survivorship care plans? Findings from the 2012 Livestrong survey.
Authors: Ruth Rechis, Carla Bann, Stephanie Nutt, Linda Squiers, Naveen Rao
Journal: Journal of Clinical Oncology (2013)

9608 Background: There are more than 14 million cancer survivors in the US – a number that is on the rise. Care coordination resources will be essential to provide support to this growing population. Key stakeholders, including the Commission on Cancer (CoC) and the Institute of Medicine, have proposed survivorship care plans (SCPs) as a way to extend support. However, limited research has been conducted to date on SCPs. Methods: In 2012, the LIVESTRONG Foundation (LIVESTRONG) administered a survey to understand the role of a treatment summary (TS) and SCPs and how they fit into survivors’ care. Logistic regression models were conducted to identify factors associated with receiving SCPs or TS. Results: 5,303 survivors responded to these questions (Table). While 92% of these respondents received information about where to return to for cancer check-ups, only 51% reported receiving a TS and 17% reported receiving a SCP. Survivors who were more likely to receive SCPs if they had a navigator (p&lt;.001) and if they were male, Black, had finished treatment within the past year, or received care at a university-based medical center or community cancer center (p &lt; 0.05). Also, those receiving a SCP were significantly more likely to have had a detailed discussion with a provider regarding long-term side effects, emotional needs, and lifestyle recommendations. Specifically, 60% of those with a SCP discussed long-term effects compared to 39% who did not. Conclusions: Results here indicate that few survivors receive SCPs but survivors reported benefits from receiving them. Currently many workflow barriers impede delivering SCPs, and LIVESTRONG is working with key stakeholders including the CoC to automate the LIVESTRONG Care Plan powered by Penn Medicine’s OncoLink through a registry and EMR system to understand how to address this issue. [Table: see text]
Diagnostic accuracy of serum Ca 19–9 in predicting malignancy in patients undergoing pancreatic resection
Authors: T. S. Bekaii-Saab, S. M. Cowgill, W. E. Burak, W. S. Melvin, E. C. Ellison, P. Muscarella
Journal: Journal of Clinical Oncology (2004)

4210 Background: The differentiation between benign and malignant disorders of the pancreas may sometimes be difficult prior to surgical resection . The purpose of this study is to evaluate the diagnostic accuracy of serum CA19–9 concentration in predicting malignancy in patients undergoing pancreatic resection. Materials and Methods: Charts of all patients undergoing pancreatic resection at The Ohio State University Medical Center from 1992 to 2001 were reviewed. Demographic data, pathologic results, preoperative CA19–9 and total bilirubin concentrations were recorded. Fisher's exact test was used to assess relationships between the presence of cancer and the explanatory variables of CA19–9, jaundice, gender and age . Logistic regression models were also used to assess the significance of CA19–9 in predicting pancreatic malignancy, after controlling for the potential confounding variables of jaundice, age and gender. Results: Of 53 patients meeting criteria for entry into the study, 32 were noted to have malignancies within the surgical specimen on final pathological analysis. On univariate analysis, elevated CA19–9, jaundice and age >50 were all associated with presence of malignancy. Sensitivities, specificities, positive and negative predictive values are reported in the table below. All patients with benign pathologies were found to have CA19–9 levels of less than 150 U/ml. Regression analysis indicated that the association between CA19–9 and malignancy was lost when both age and jaundice were controlled for. Conclusions: While CA19–9 is a useful predictor for pancreatic malignancy, age and jaundice seem to be better predictors than CA19–9 alone. These data suggest that patients who will be undergoing pancreatic resection with either age >50 and jaundice, or CA 19–9 concentrations of more than 150 U/ml, should undergo resections with a curative intent for suspected malignancy. No significant financial relationships to disclose.
MicroRNA deregulation in peripheral nerve sheath tumor progression.
Authors: N. Presneau, Malihe Eskandarpour, Bernadine Idowu, Dina Halai, Eve Coulter, Stephen Henderson, Roberto Tirabosco, Adrienne M Flanagan
Journal: Journal of Clinical Oncology (2010)

10526 Background: Malignant peripheral nerve sheath tumors (MPNST) constitute a group of malignant tumors that arise from schwann cells of the peripheral nerve sheath. Neurofibromatosis type 1 (NF1), an autosomal dominant neurocutaneous disorder, affecting 1 in 3000 individuals worldwide, arises on a background of germ-line mutations of NF1. Neurofibromas (NF) are the benign counterpart of MPNST, but currently little is known of the mechanism involved in the transformation from benign to malignant disease. The aim of this study was to identify a molecular signature, which would distinguish NF from MPNST, and could then be exploited for the development of therapeutic agents against specific targets implicated in the disease. Methods: The cohort consisted of 10 NF and 10 MPNST, all obtained from individuals with NF1. Schwann cells isolated from 4 nerves from patients without nerve sheath disease acted as controls. An Agilent Human miRNA microarray was used in the study. Results: We identified a set of miRNAs for which the expression was deregulated in our index cases. Of the 7 most significantly deregulated miRNAs (miR-340, 139-5p, let7g, 210, 30e, 29c*, 29c), 6 were independently confirmed by TaqMan Expression Assays in the same panel of cases. Of these, miR-29c was the most significantly down-regulated in MPNST compared to NF (p=1.083e-05). COL1A1, COL21A1, COL5A2, and TDG were then predicted as potential miR-29c target genes using TargetScan and PITA, data mining of our previous gene expression data and reports from the literature. These genes were found to be significantly up-regulated in MPNST when compared to NF. The gene expression level of miR-29c and the target genes were confirmed in a further blinded study of 20 MPNST and 20 NF. Using a synthetic mimic for miR-29c and a GFP retroviral construct containing the pri-miR29c in an MPNST cell line exhibiting very low endogenous expression of miR-29c (SNF96.2), we demonstrated that the expression of these target genes is suppressed upon exogenous expression of miR-29c. Conclusions: using miRNA microarray we have generated a robust molecular signature that distinguishes MPNST from NF. Further functional studies of miR-29c are required to determine if these findings can be exploited for therapeutic use. No significant financial relationships to disclose.
Cediranib (AZD2171) for the treatment of recurrent small cell lung cancer (SCLC): A California Consortium phase II study (NCI # 7097)
Authors: S. S. Ramalingam, P. C. Mack, E. E. Vokes, J. Longmate, R. Govindan, M. Koczywas, S. P. Ivy, C. P. Belani, D. R. Gandara
Journal: Journal of Clinical Oncology (2008)

8078 Background: Cediranib is a highly potent inhibitor of VEGFR-1, -2 and -3 tyrosine kinases. We conducted a phase II study to evaluate its safety and efficacy in relapsed/recurrent SCLC. Methods: Patients with progression of SCLC following prior platinum-based chemotherapy (1 prior regimen only), ECOG performance status of 0, 1 or 2, and adequate organ functions were were treated with cediranib on a continuous, once-daily oral schedule (4-week cycles). Those with brain metastasis were excluded. Primary endpoint was response rate and the Simon-two stage design was utilized (estimated sample size = 37 pts). Results: Twenty five patients were enrolled. Baseline characteristics: median age 61 (36–86); male 13; and PS 0/1- 8/12 pts. Twelve patients were accrued to the first stage with the starting dose of 45 mg QD. Since 7 out of 12 patients failed to complete first cycle due to adverse events, the trial was amended to reduce the starting dose to 30 mg QD. Thirteen patients were treated at this dose level, as planned. Median of 2 cycles was administered (1–7). Salient grade 3 toxicities were fatigue (gr 3 - 4, gr 4- 2), diarrhea (1), skin rash (1), proteinuria (2), transaminitis (1), muscle weakness (1) and hypertension (1). One unconfirmed PR and 8 with SD were noted. Median PFS was approximately 8 weeks. Peripheral blood was evaluated serially for VEGF concentration and circulating endothelial cell (CEC) counts. A stark increase in CECs was noted at progression in several patients. Divergent results were observed with serial plasma VEGF levels, with several patients showing increasing levels while on therapy, however there was no clear correlation with anti-cancer effect. The response rate did not meet pre-defined target (20%) to continue full accrual to the study. Conclusions: The originally recommended dose of cediranib of 45 mg QD was not feasible in the patient population studied. The modest anti-cancer activity of cediranib (30 mg QD) supports its further evaluation as part of combination regimens, but not as monotherapy for recurrent SCLC. Supported by NCI N01-CM-62209, N01-CM-62201 & NO1 62205 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca
Prognostic model for survival in patients with advanced pancreatic cancer receiving palliative chemotherapy.
Authors: Yu Uneno, Tadayuki Kou, Masashi Kanai, Michio Yamamoto, Peng Xue, Yukiko Mori, Yasushi Kudo, Akira Kurita, Norimitsu Uza, Yuzo Kodama, Masanori Asada, Toshihiko Masui, Shujiro Yazumi, Shigemi Matsumoto, Kyoichi Takaori, Satoshi Morita, Manabu Muto, Tsutomu Chiba
Journal: Journal of Clinical Oncology (2015)

248 Background: The prognosis of patients with advanced pancreatic cancer (APC) is extremely poor. Several clinical and laboratory factors have been known to be associated with prognosis of APC patients. However, there are few clinically available prognostic models predicting survival in APC patients receiving palliative chemotherapy. Methods: To construct a prognostic model to predict survival in APC patients receiving palliative chemotherapy, we analyzed the clinical data from 306 consecutive patients with pathologically confirmed APC who received palliative chemotherapy. We selected six independent prognostic factors which remained independent prognostic factors after multivariate analysis. Thereafter, we rounded the regression coefficient (β) for each independent prognostic factor derived from the Cox regression equation (HR = e β ) and developed a prognostic index (PI). Results: Developed prognostic index (PI) was as follows: PI = 2 (if performance status score 2–3) + 1 (if metastatic disease) + 1 (if initially unresectable disease) + 1 (if carcinoembryonic antigen level ≥5.0 ng/ml) + 1 (if carbohydrate antigen 19-9 level ≥1000 U/ml) + 2 (if neutrophil–lymphocyte ratio ≥5). The patients were classified into three prognostic groups: favorable (PI 0–1, n = 73), intermediate (PI 2–3, n = 145), and poor prognosis (PI 4–8, n = 88). The median overall survival for each prognostic group was 16.5, 12.3 and 6.2 months, respectively, and the 1-year survival rates were 67.3%, 51.3%, and 19.1%, respectively (P &lt; 0.01). The c index of the model was 0.658. This model was well calibrated to predict 1-year survival, in which overestimation (2.4% and 0.2% in the favorable and poor prognosis groups, respectively) and underestimation (3.6% in the intermediate prognosis group) were observed. Conclusions: This prognostic model based on readily available clinical factors would help clinicians in estimating the overall survival in APC patients receiving palliative chemotherapy.
A phase II study of capecitabine-gemcitabine(CapGem) as a first line therapy in Bangladeshi patients with locally advanced or metastatic pancreatic adenocarcinoma
Authors: M. S. Reza, M. A. Hai, Q. Chowdhury
Journal: Journal of Clinical Oncology (2007)

15100 Background: Pancreatic cancer is one of the cancers with very poor prognosis because of its diagnosis at an advanced or metastatic stages. There is no consensus on the optimal management of locally advanced or metastatic pancreatic cancer. This phase II study was designed to evaluate the efficacy and safety of CapGem in patients (Pts.) with pancreatic adenocarcinoma. Methods: From January 2001 to December 2004, 30 pts with; histologically / cytologically proven, bidimensionally measurable locally advanced or metastatic pancreatic adenocarcinoma, age 18∼75 years with ECOG performance status 0∼3, no prior chemotherapy, life expectancy &gt;3 months, adequate bone marrow, renal, hepatic and haematological values were enrolled. It was an open - labeled, non-randomized, single - centered and prospective study. The pts received Capecitabine 750mg/m 2 twice dailly,days 1–14,orally and Gemcitabine 1000mg/m 2 days 1 &amp; 8, intravenous infusion at an interval of 21 days.The efficacy was measured by response rates, CA-19.9 &amp; pain status and safety was measured by adverse events and laboratory blood values. Results: This study consisted of 16 (53.33%) male and 14 (46.67%) female pts. Median age was 52 years. 18 (60%) pts were inoperable locally advanced and the remaining 12 (40%) were metastatic diseases where 8 hepatic and 4 pulmonary. In total, 152 cycles chemotherapy were administered with a median of 5.06 cycles per pt and 28/30 pts were evaluated for responses. The overall response was 9 ( 32.14%) with 2 complete and 7 partial responses. 14 pts (50%) had stable diseases and 5 (17.86%) had progressive diseases. There was 55% decrease in CA-19.9 and pain reduction was 60%. Overall survival was10 months. Grade 3 haematological toxicities were observed as follows: neutropenia 30% and anaemia 18%. Some non- haematological toxicities including nausea &amp; vomiting 30%, diarrhoea 20% and hand foot syndrome 10% were observed. Conclusions: This phase II study supports the use of CapGem combination in chemo naive locally advanced or metastatic pancreatic adenocarcinoma due to its promising anti-tumor activity with well-tolerated toxicities in Bangladeshi pts. No significant financial relationships to disclose.
Differential <i>in vivo</i> activity of docetaxel plus PS-341 combination therapy in non-small cell lung carcinoma (NSCLC) xenografts
Authors: P. H. Gumerlock, T. Kimura, W. S. Holland, C. D. D. Shih, P. N. Lara, D. R. Gandara
Journal: Journal of Clinical Oncology (2004)

7144 Background: Velcade (PS-341) is a selective proteasome inhibitor in early clinical trials in NSCLC patients. Docetaxel (Txt) is a microtubule-stabilizing taxane in wide clinical use for first- and second-line NSCLC therapy. We previously showed in NSCLC cell lines in vitro that the sequence of Txt prior to PS-341 showed the greatest levels of apoptosis by sub-G1 content and PARP cleavage, which was associated with accumulation of p27 and loss of Bcl2. Our hypothesis was that the combination of both agents will be more effective than either agent alone, and that the sequence of drugs will influence the response to treatment. Methods: We used the p53-null NSCLC Calu-1 xenograft model to evaluate responses to Txt or PS-341 and to combinations in the sequences of PS-341 before Txt, Txt before PS-341, and both simultaneously. Cells (5x106) were injected subcutaneously into each flank of male athymic nu/nu mice with 2 mice per group. The agents in the combination treatments were administered either together or 24hrs apart, with all regimens given weekly [IP doses: Txt: 10mg/kg; PS-341: 0.5mg/kg]. Tumor growth was measured up to six weeks after initial treatment. Results: PS-341 had a modest effect on tumor growth as a single agent (12% inhibition), while Txt had no effect. However, with each of the alternate sequences of drug administration (Txt→PS-341 and PS-341→Txt), tumor growth was inhibited approximately 40%. The simultaneous delivery of both drugs showed no inhibition of tumor growth compared to the control, demonstrating antagonism compared to PS-341 alone. Conclusions: Our studies demonstrate that different schedules of drug delivery affect the response to combinations of PS-341 with Txt. Furthermore, antagonism was suggested with simultaneous administration of both agents in vivo. Additional studies of alternate schedules are warranted, and these in vivo data set the stage for future clinical trials. Examination of apoptosis-associated proteins PARP, Caspase-3, p27, and Bcl2 is ongoing. (Aventis and Millennium provided docetaxel and PS-341, respectively.) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Oncology