tbuckley/cabot-search huggingface dataset:
Gastric leiomyosarcomas: A SEER analysis.
Authors: John Scott Moody, Kevin Robert Kozak
Journal: Journal of Clinical Oncology (2012)

106 Background: Gastric sarcoma is an uncommon malignancy that represents approximately 1% of gastric malignancies. The presentation and outcomes of these patients remains poorly defined, and a dearth of information is available regarding the management of such patients. Methods: Patients with primary gastric leiomyosarcoma, diagnosed between 1988 and 2008, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Clinical characteristics and outcomes of these patients were defined and compared with the characteristics of gastric adenocarcinoma patients. Results: A total of 49,258 patients were identified for analysis, 574 with leiomyosarcoma. Gastric leiomyosarcomas were more likely to occur in younger patients, female patients, and were less likely to present with advanced disease. These tumors were more likely to occur in the gastric fundus or along the greater curvature of the stomach. The incidence of gastric leiomyosarcoma has dramatically decreased over the last decade, consistent with the likelihood that many of these tumors are now considered to represent GIST tumors with current pathologic techniques. Median overall survival for gastric leiomyosarcoma patients was 36 months whereas that for gastric adenocarcinomas was significantly shorter at 10 months (P &lt; 0.001 on Kaplan-Meier analysis). For non-metastatic patients, the median survival of leiomyosarcoma patients was 72 months versus 22 months for gastric adenocarcinoma patients. Cox proportional hazards modeling similarly demonstrated a decreased mortality risk associated with leiomyosarcoma (HR 0.52, 95% CI 0.47-0.57). A multivariable Cox analysis that examined tumor, patient and treatment characteristics demonstrated that leiomyosarcoma was independently associated with improved survival (HR 0.64, 95% CI 0.54-0.76). A Cox analysis for leiomyosarcoma patients alone showed that surgery was associated with improved survival (HR 0.14, 95% CI 0.06 – 0.34). Conclusions: Gastric leiomyosarcomas have been a distinct subset of gastric tumors with a superior prognosis than adenocarcinomas. Surgery has historically been a key component of successful management and is associated with improved survival.
Myeloma paraprotein epitope identification using a phage library of sterically constrained peptides
Authors: J. A. Zonder, M. A. Tainsky, M. J. Stone, K. Konduri, J. Oliver, S. Ratner
Journal: Journal of Clinical Oncology (2005)

6626 Background: Chronic antigenic stimulation has been hypothesized to be a causative factor in rare cases of multiple myeloma (MM). If true, one might identify relevant antigens by using phage display technology and biopanning to analyze epitopes of m-proteins in sera of MM patients (pts). This method obviates the need to prospectively identify candidate antigens. Methods: The Ig fractions of 17 pts with IgG paraproteins were purified on Protein G beads. The bead-bound m-proteins were then used to biopan a T7 library of random heptapeptides sterically constrained by intramolecular disulfide bridges (Gift of G. Froman). Phage selected via 3–5 rounds of biopanning were cloned by plaque isolation. Binding specificity was confirmed by blotting and chemiluminescent detection. The cloned phage inserts’ DNA was sequenced and the amino acid sequences of each insert deduced. Proteins containing homologies with these peptides were found by short-peptide BLAST search. To test whether the identified epitopes are common among MM pts, the phage clones were screened against IgG m-proteins from sera of 70 additional pts. Results: Phage clones were identified which reacted specifically with 3 of the 17 pt m-proteins in the panel. There were 7 selected clones in total, as multiple clones were found for two pts. None of the peptide sequences displayed strong homology with known human autoantigens. However, the peptide inserts of the isolated clones exhibited strong homologies with proteins of pathogens including Mycoplasma sp., Fusobacterium sp., influenza A, and Candida sp., some of which are antigens ubiquitously present in the environment. None of the Ig from 70 other sera cross-reacted with any of the selected phage. Conclusions: We have shown at least some MM paraproteins bind epitopes expressed by known human pathogens, supporting the possible role of chronic antigenic stimulation in myeloma pathogenesis. These findings are consistent with a previously published report (Scand. J. Immunol. 57:583;2003). In addition, the lack of any cross-reacting Igs from the large panel of sera makes it statistically unlikely that any of these pathogens, even if contributory to individual cases, are commonly causative. No significant financial relationships to disclose.
Exploring correlates of quality of life in older family caregivers to cancer patients.
Authors: Colleen Ann Cuthbert, Kathryn King-Shier, Joseph D. Ruether, Dianne Tapp, S. Nicole Culos-Reed
Journal: Journal of Clinical Oncology (2016)

186 Background: Family caregivers (FCs) have negative impacts to their physical and emotional health, and poorer quality of life (QoL) compared to non-caregivers. Most research on FCs has included heterogeneous samples, therefore little is known about specific groups such as older (age 60+) FCs. Older persons are at increased risk for health problems, may have co-morbidities, and be socially isolated. Understanding factors related to QoL may lead to interventions targeted to older FCs. The purpose of this study was to examine factors associated with QoL in older FCs to cancer patients. Methods: The data for this study are from a larger survey of FCs aged 60+, recruited from a hospital-based cancer facility. FCs were included if their care recipient had breast, prostate or colorectal cancer. QoL was measured using the MOSF-36. Analyses using descriptive statistics and Pearson’s correlations were conducted. Results: n = 168 participants consented, with n = 129 surveys returned. The majority of participants were female (60.5 %), 70 yrs old (sd 7.4), had at least a college diploma (65.2 %), were spouses of the patient 92.2%, and retired (60.5%). Mean caregiving hours per week was 24.2 (sd 26.3). Mean time as a caregiver was 31 months (45.9). The majority of patients were on treatment (75.2%) and were 71.3 yrs old (sd 7.5). The Physical Component Summary (PCS) of the MOSF-36 was significantly correlated with gender r = -.24, social support r = .25, sleep quality r = -.47, depression r = -.51, state anxiety r = -.40, and trait anxiety r = -.45 (all p’s &lt; .01). There were significant correlations between the Mental Component Summary (MCS) and social support r = .40, sleep quality r = -.40, depression r = -.77, gender r = -.25, state anxiety r = -.72, and trait anxiety r = -.71 (all p’s &lt; .01). The MCS was correlated with caregiving hours, r = -.197 (p &lt; .05), however, not with patient treatment status. The PCS was not correlated with caregiving hours or patient treatment status. Conclusions: Consistent with previous FC research across different diseases, QoL was associated with gender, caregiving hours per week, social support, sleep quality, depression, and anxiety. Interventions for older FCs of cancer patients could be targeted to specific factors of overall QoL.
Leukemia regression by targeting c-Kit activity with pazopanib.
Authors: A. Trujillo, C. S. McGee, E. Gars, R. Bosse, A. Meacham, E. Wise, S. Bais, C. R. Cogle
Journal: Journal of Clinical Oncology (2011)

6611 Background: Several small molecule tyrosine kinase inhibitors targeting angiogenesis have been approved for the treatment of solid tumors. In patients with leukemia, upregulated angiogenesis portends for a worse prognosis and leukemia cells are known to express receptors for angiogenic cytokines. Therefore, we hypothesized that inhibiting angiogenic receptors on leukemia cells leads to disease regression. Methods: Human acute myeloid leukemia (AML) cells (HL-60) were treated with the anti-angiogenic agent, pazopanib, alone and in combination with cytarabine. Cell proliferation was quantified using the XTT colorimetric assay and apoptosis was evaluated by PI and annexin staining. NOD/scid/IL2Rγ-/-(NSG) mice were xenotransplanted with AML cells and after engraftment, randomized to pazopanib alone, pazopanib in combination with cytarabine, cytarabine alone or no treatment. After eight days of treatment mice were euthanized and tissues harvested. Flow cytometry was used to quantify human leukemia engraftment in bone marrow. PCR studies were performed using human primers to VEGFR1/2, PDGFRαR and cKit to analyze receptor expression in HL-60. Results: The IC50 of pazopanib in HL-60 cells was 22.6µM (r = 0.98). Further studies showed that pazopanib in combination with cytarabine elicited a synergistic decrease in leukemia cell proliferation, of 26.7%, when compared to treatment with cytarabine alone. FACS analysis showed cells treated with pazopanib plus cytarabine underwent apoptosis. In xenotransplanted mice, those receiving pazopanib treatment showed significant leukemia regression compared to the untreated cohort (p < 0.05). PCR studies showed that HL-60 express high levels of cKit mRNA, but do not express VEGFR1, VEGFR2 or PDGFRαR suggesting a novel mechanism of action for pazopanib through the stem cell factor receptor. Conclusions: This is the first study to show regression of leukemia by using a multi-targeted approach of receptor inhibition for VEGFs, PDGFs and SCF. These data show that inhibition of c-Kit is capable of impairing leukemia cell proliferation, that leukemia cells depend on the microenvironment for pro-survival signaling and that the combination of pazopanib plus chemotherapy may be a promising therapeutic strategy for AML and advanced MDS.
SMAD4 gene mutation and prognosis of pancreatic adenocarcinoma.
Authors: Olfa Derbel, Arnaud de la Fouchardière, Julien Peron, Francoise Desseigne, Pierre Heudel, Pierre Guibert, Michel Rivoire, Pierre Meeus, Patrice Peyrat, Anne-Isabelle Lemaistre, Christelle De La Fouchardiere
Journal: Journal of Clinical Oncology (2013)

180 Background: Pancreatic adenocarcinoma remains resistant to many key cytotoxic chemotherapeutic agents and novel targeted therapies. The molecular heterogeneity of this cancer may account for therapy failures to date, although the growing arsenal of novel targeted agents could translate into patient survival. A better understanding of the cellular and molecular features of advanced disease will afford new opportunities for investigation, therapeutic intervention and clinical management of patients afflicted with pancreatic cancer. Methods: Data of 46 patients with pancreatic adenocarcinoma were analyzed. The clinicopathological parameters, the histologic features were determined and correlated to the stage at initial diagnosis and patterns of failure (locally advanced v metastatic disease). Using tissue microarray, we assessed the relationship of SMAD4 expression with the overall survival of patients. Results: Among the 46 treated patients, 32 underwent pancreaticoduodenectomy. 40% of patients died with metastatic disease and 15 % died with locally advance evolution. Loss of SMAD4 expression was found in 22% of patients and seems to be correlated with a high grade histologic features and progression to metastasis disease. Complementary data about correlation between the mutational status of SMAD4 and survival will be presented during congress. Conclusions: SMAD4 gene inactivation seems to be associated with poorer prognosis and disease progression. Prospective validation of SMAD4 as a predictive biomarker may personalize treatment strategies for patients with pancreatic cancer.
EGFR activation of IGF-IR in normal and malignant hepatocytes
Authors: H. Hallak, N. Damjanov
Journal: Journal of Clinical Oncology (2005)

9579 Background: IGF-I enhances the growth of a variety of cancer cell lines including prostate, bladder, colon, stomach, esophagus, liver, pancreas, and kidney, suggesting possible involvement of IGF-I in cancer development. IGF-I acts directly on cells via the IGF-IR, which is over-expressed in many tumors. Hepatocytes make and secrete IGF-I, however the role for IGF-I in hepatocyte growth has not been elucidated. Methods: We examined the dynamics of the IGF-I receptor (IGF-IR) in freshly isolated rat hepatocytes, and compared them to HepG2 cells, which were derived from human hepatocellular carcinoma. Results: In hepatocytes, IGF-I did not activate the IGF-IR, however, des(1–3)IGF-I, which weakly binds IGF-binding protein-3 (IGFBP-3), induces IGF-IR phosphorylation. In contrast to hepatocytes, in HepG2 cells, which lack the IGFBP-3 surface coating, IGF-I induces the tyrosine-phosphorylation of the IGF-IR in parallel with EGFR phosphorylation. Transactivation of the IGF-IR by EGF was inhibited by tyrphostin I-Ome-AG538, a tyrosine kinase inhibitor with high specificity for the IGF-IR, and by IGF-IR and EGFR siRNA transfection. EGFR siRNA did not completely inhibit MAPK activation in response to EGF, suggesting that ERB2 is compensating for ERB1. The transfection of hepatocytes with the IGFBP-3 siRNA restored the hepatocyte’s response to IGF, suggesting a role for IGFBP-3 in the inhibition of IGF activation. Immunohistochemistry of liver carcinoma shows that IGF-IR is overexpressed in cancer cells but not in the adjacent normal cells. Conclusions: The data demonstrate an EGF- and Src-mediated transactivation pathway for IGF-IR activation in hepatocytes and demonstrate a role for IGFBP-3 in the inhibition of IGF-I signaling. This study suggests a role for IGF-IR in liver cancer and suggests a role for both ERB1 and ERB2 in MAPK activation. This may help in the design of new therapeutic uses for IGF-I/IGF-IR inhibitors that could be combined to enhance the efficacy of the well-established EGFR inhibitors that are currently in use for cancer therapy and suggest that dual ERB inhibitors are likely to inhibit cell proliferation. Targeting of two tumor-associated molecules may enhance anti-tumor activity. No significant financial relationships to disclose.
Efficacy and safety of FOLFIRINOX in patients with pancreatic metastatic cancer.
Authors: Jean-Philippe Metges, Jean François Ramée, Roger Faroux, Jean Yves Douillard, Marc Porneuf, Isabelle Cumin, Pierre-Luc Etienne, Alain Gourlaouen, Guillaume Geslin, Nacredine Achour, Anne Helene Delalande, Patrick Soulie, Gerard Le Bihan, Catherine Le Roux, Laurent Miglianico, Philippe Deguiral, Loic Campion, Christian Riche, Francoise Grude
Journal: Journal of Clinical Oncology (2013)

248 Background: Efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) is one of the gold standard in metastatic pancreatic cancer as first-line therapy for patients with PS 0-1, good haematological and renal function and a subnormal bilirubin level. Pending approval, this treatment has been allowed in Brittany (B) and Pays de la Loire (PL) respecting these criteria. Methods: Observatory of Cancer B/PL is a network of 50 private/public cancer centers focused on good practice for cancer drugs use. Our aim is to evaluate the use of FOLFIRINOX between July 2010 and June 2013 in B/PL. Sex, age, successive chemotherapeutic regimens, toxicities, response rate, progression free survival (PFS) and overall survival (OS) have been studied. Results: Data of 79 patients, treated in 2010 (37%), in 2011 (54%) or early 2012 (9%) have been studied (44 men, median age 62 years [37-74]). 64 patients were metastatic when cancer was diagnosed. Principal site of metastases was liver (73%). 17 primary tumors were resected and 15 patients received an adjuvant chemotherapy (gemcitabine (n=14)).The median number of treatment cycles was 9 [1-24]. Objective response was observed in 29 patients (37%), disease stabilization in 18 patients (23%) and progression in 18 patients (23%). During treatment, 75% of patients had a dose adjustment and 30 % had one or more dose delays. 22 patients presented grade III/IV toxicity (almost neurotoxicity or haematologic). 42 patients had a second line of treatment (mainly gemcitabine) and 7 patients a third line. The median PFS and OS were respectively 174 days IC95% [125-216] and 309 days IC 95% [229-376]. Conclusions: Our preliminary results are relatively convenient with those of Conroy et al in 2011. A higher rate of response (37% vs 32%) has been found. Concerning PFS and OS, our results are clearly worst with 174 vs 195 days and 309 vs 338 days. Our results confirm the aggressiveness of this schedule with 75% of the patients requiring a dose adjustement. Analysis of all pancreatic metastatic patients treated by FOLFIRINOX in B/PL by the Observatory of Cancer allows to assess its good use in the real life.
Methylation-guided stratification of patients with high-risk prostate cancer for the prediction of clinical failure.
Authors: Kirill Litovkin, Steven Joniau, Evelyne Lerut, Annouschka Laenen, Olivier Gevaert, Martin Spahn, Burkhard Kneitz, Sofie Isebaert, Karin Haustermans, Monique Beullens, Aleyde Van Eynde, Mathieu Bollen
Journal: Journal of Clinical Oncology (2014)

155 Background: To explore differential DNA methylation of APC, CCDN2, GSTP1, PTGS2, and RARBas a tool to predict clinical failure (CF) in surgically treated patients with high-risk prostate cancer (PCa), as defined by a clinical stage T3a or higher, a biopsy Gleason score of 8 to 10 and/or pre-operative prostatic serum antigen levels more than 20 ng/ml. Methods: A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the marker genes. Formalin-fixed, paraffin-embedded radical prostatectomy samples from 218 patients with high-risk PCa, classified in a training and validation cohort, were analyzed. Kaplan-Meier analysis and Cox multivariate models were used. Results: First, high-risk PCa patients were ranked according to their GSTP1 methylation level, which varied from 0 to 80% in both cohorts. Next, we categorizedthe tumors into three groups based upon the GSTP1 methylation level: low methylation (LM, methylation less than 15%), moderate methylation ([MM], methylation 15 to 50%) and high methylation (HM, methylation more than 50%). When all five marker genes were combined, the median methylation values in the LM groups did not exceed 6% in both cohorts. In contrast, the median methylation values for the marker genes in the HM groups reached 45% in the training cohort and 50% in the validation cohort. Finally, the median methylation values in the MM groups amounted to 18% and 28% for the training and validation cohorts, respectively. Remarkably, patients belonging to the LM, HM, and the combined LM+HM groups had a 2- to 11-fold higher risk of CF as compared to those of the MM group, when correcting for established clinico-pathologic prognostic factors. In addition, the combined LM+HM group showed a significant association with cancer-related death in a multivariate analysis (Hazard ratio, 3.59) compared to the MM group, when both cohorts were combined for analysis. Conclusions: We found that differential methylation of GSTP1 allows the stratification of high-risk PCa patients into three molecular episubtypes, i.e. low, moderate and high DNA methylation level groups. Surprisingly, our data revealed that both low and high methylation levels of GSTP1 are independent predictors of CF.
Validation of a modified prognostic score including MGTM promoter methylation in primary glioblastoma.
Authors: C. Baraldi, F. Bertolini, E. Zunarelli, A. Valentini, R. Depenni, A. Falasca, P. Giacobazzi, M. Malagoli, S. Meletti, A. Fontana, P. F. Conte, G. Pinna
Journal: Journal of Clinical Oncology (2011)

e12510 Background: Recursive Partioning Analysis (RPA) is commonly used to define the stratification of patients with glioblastoma (GBM). Epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas and it is already encoded as an independent prognostic factor. We analyzed a modified prognostic scoring system including all clinical variables used by RPA classification (age, ECOG performance status and type of surgery) and O6-Methylguanine Methyltransferase (MGMT) promoter methylation. Methods: From August 2005 to May 2010, 134 consecutive patients with newly diagnosed primary GBM and treated at Modena University Hospital and Nuovo Ospedale Civile S. Agostino-Estense were included in this retrospective study. Patients were classified in three different classes (I, II and III) using the following prognostic variables: age (< 50 years versus ≥50), ECOG performance status (0 versus ≥1), type of surgery (gross tumor resection versus partial resection/biospy), MGMT promoter methylation status (methylated versus non-methylated). The prognostic score was calculated as follows: every favorable parameter was calculated as one point. We defined 3 prognostic classes: Class I: ≥ 3; Class II: 2; Class III: 0-1, respectively. All classes have been correlated with overall survival. Results: On 134 patients, MGMT status was available in 78 cases. Median survival times were 32.4, 8.6 and 8.8 months and corresponding 2-year survival rates 69%, 13.5% and <1 % for Class I, II and III, respectively. The same analysis has been performed in patients treated with post-operative concomitant chemoradiotherapy (CRT) (54 cases). Median survival time were 32.5, 13.4 and 8.9 months and corresponding 2- year survival rates 68.6%, 26.9% and <1%, for Class I, II and III, respectively. On both 78 and 54 patients the difference in survival between class I and III is statistically significant (p<0.0001). Conclusions: MGMT promoter methylation status may be considered to define a correct prognosis in patients with primary GBM, especially when treated with post-operative CRT.