tbuckley/cabot-search huggingface dataset:
The influence of perioperative decreasing total psoas area on prognosis of esophagieal cancer patients.
Authors: Yuki Hirata, Hiroya Takeuchi, Yuji Kikuchi, Satoru Matsuda, Kazumasa Fukuda, Rieko Nakamura, Tsunehiro Takahashi, Norihito Wada, Hirofumi Kawakubo, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2016)

38 Background: Depression of skeletal muscle mass (sarcopenia) has been linked to postoperative mortality in several carcinomas and various types of surgeries. Total psoas muscle area (TPA) has received attention as one of the indicators of systemic total skeletal muscle volume. The objective of this study is to determine the correlation between the patients who decreased TPA during pre-post operation and prognosis of esophageal cancer treated by surgical resection. Methods: We enrolled 40 esophageal cancer patients who underwent esophagectomy between April 2008 and May 2009. TPA was estimated by measuring the cross-sectional area of the psoas major muscle at the level of the third lumbar vertebra using an image-analysing software, identified on a preoperative CT scan, and a postoperative CT scan, which was taken on post-operative day 6. We divided the patients who decreased TPA between pre-post operation, into “decreasing group”, and the patients who preserved or increased TPA, into “non-decreasing group”. We investigated their backgrounds and prognosis. Results: Eighteen patients (45.0%) were classified as decreasing group, and 22(55.0%) patients were classified as non-decreasing group. Tumor locations, TMN Stage, or rates of neo-adjuvant chemotherapy, did not significantly differ between the two groups. Five-year overall survival rates (54.2% vs 85.7%, P = 0.046) were significantly lower in decreasing group in comparison with non-decreasing group. Recurrence-free survival rates (42.9% vs 85.7%, P = 0.012) were also significantly lower in decreasing group. The incidences of anastomotic leakage, or postoperative pneumonitis, did not differ between the two groups. Conclusions: The patients who decreased TPA during perioperative period associated with poor prognosis of esophageal cancer. The surgical operation for esophageal cancer is highly invasive, therefore active nutrition support and early rehabilitation during perioperative period might be indispensable.
The role of multimodality therapy (MMT) in unresectable hilar cholangiocarcinoma (UHC).
Authors: N. A. Bhadkamkar, S. P. Kar, J. Weatherly, C. R. Garrett, J. Vauthey, A. O. Kaseb, P. Das, M. M. Javle
Journal: Journal of Clinical Oncology (2011)

e14626 Background: Unresectable hilar cholangiocarcinoma is commonly treated with gemcitabine-based chemotherapy. Consolidative radiotherapy (RT) is increasingly being used for patients with localized disease. Biliary obstruction and cholangitis are important causes of morbidity and mortality in UHC. The impact of MMT vs. chemotherapy alone on survival and biliary obstruction has not yet been characterized. Methods: Using the MD Anderson tumor registry, we identified 137 patients with UHC from 1998-2009 and retrospectively reviewed their records for demographic, epidemiologic, and treatment data. We performed analyses of overall survival (OS) using the Kaplan-Meier method with stratification by extent of disease (locally advanced vs. metastatic). We used the Pearson chi-square test to analyze the impact of RT on measures of disease-related morbidity. Results: The median OS of the entire group was 48 weeks. 64% of patients had locally advanced disease and 71% received at least one line of therapy. Patients receiving first-line gemcitabine plus cisplatin (n=42) had a superior OS when compared to those receiving other first-line therapies (n=55; 71 weeks vs. 50 weeks, p=0.02). There was no significant improvement in OS in those patients who received RT (n=48) vs. those who never received RT (n=49; 58 weeks vs. 54 weeks, p=0.96). However, OS with consolidative RT (n=13) was 113 weeks vs. 70 weeks with chemotherapy alone (n=29) [p=0.11]. RT did not significantly reduce the morbidity of UHC, including non-elective biliary stent exchanges (p=0.79), admissions for obstructive jaundice or cholangitis (p=0.57), and non-elective, cancer-related admissions (p=0.69). Conclusions: This series of UHC patients confirms the previously reported survival improvement with gemcitabine plus cisplatin in the first-line setting for bile duct tumors. The role of RT in reducing biliary complications from UHC remains unclear. Consolidative RT may increase survival in selected patients compared to chemotherapy alone, although this requires further investigation in prospective, randomized clinical trials.
Integration of a CD19 CAR into the TCR Alpha Chain Locus Streamlines Production of Allogeneic Gene-Edited CAR T Cells
Authors: Daniel T. MacLeod, Jeyaraj Antony, Aaron J. Martin, Rachel J. Moser, Armin Hekele, Keith J. Wetzel, Audrey E. Brown, Melissa A. Triggiano, Jo Ann Hux, Christina D. Pham, Victor V. Bartsevich, Caitlin A. Turner, Janel Lape, Samantha Kirkland, Clayton W. Beard, Jeff Smith, Matthew L. Hirsch, Michael G. Nicholson, Derek Jantz, Bruce McCreedy
Journal: Molecular Therapy (2017)
A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma.
Authors: V. Moreno Garcia, R. D. Baird, K. J. Shah, B. Basu, N. Tunariu, M. Blanco, P. A. Cassier, J. V. Pedersen, M. Puglisi, D. Sarker, D. Papadatos-Pastos, A. G. Omlin, A. Biondo, J. A. Ware, H. Koeppen, G. G. Levy, K. E. Mazina, J. S. De Bono
Journal: Journal of Clinical Oncology (2011)

3021 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent inhibitor of class I PI3K and demonstrates broad activity in preclinical xenograft models. Methods: A 2-stage phase I study of GDC-0941 was initiated (GDC4254g). Stage 1 utilized a 3+3 escalation design in patients (pts) with advanced solid tumors. Stage 2 is an expansion phase including pts with multiple myeloma, PIK3CA mutant (mt) tumors, and tumors evaluable by magnetic resonance imaging (MRI) methods. A single dose of GDC-0941 was administered followed by a 1-week washout and then QD dosing on a 21/28- or 28/28-day dose schedule. Objectives include: safety, pharmacokinetics, pharmacodynamic (PD) endpoints in tumor and platelet rich plasma (PRP); evaluating the use of imaging modalities (FDG-PET and functional MRI studies); and examining any relationship of PIK3CA mt status and PTEN expression and clinical activity. Results: Stage 1 has been completed with 42 pts enrolled in 11 cohorts (15-450 mg QD, 21/28-day schedule). Drug-related adverse events (AEs) reported in ≥ 10% of pts were nausea, diarrhea, fatigue, vomiting, dysgeusia, and decreased appetite. The MTD was exceeded at 450 mg with DLT of Grade (Gr) 3 maculopapular rash in 2 pts. Other drug-related AEs ≥ Gr 3 have been Gr 3 fatigue at 450 mg, Gr 3 neutropenia at 330 mg, and Gr 4 hyperglycemia at 130 mg. GDC-0941 displays dose-proportional PK. Decreased levels of pAKT in PRP correlated with GDC-0941 plasma concentrations. Signs of clinical activity include a partial response by RECIST in a pt with melanoma (V600E RAF mt) treated at 330 mg on-study for > 9 mo; a small bowel GIST (cKIT exon 9 mt) pt treated at 450 mg with 49% decrease by FDG-PET on-study for >7 mo; and an ovarian cancer (PTEN negative) pt treated at 100 mg with 30% decrease by FDG-PET, 56% decrease in pS6 staining in paired biopsies, and 80% decrease in CA-125 who was on study for ~5 months. Conclusions: GDC-0941 is generally well tolerated below 450 mg QD with signs of anti-tumor activity. Decreases in the PD markers pAKT and pS6 are consistent with downstream modulation of the PI3K pathway. The potential phase II dose is under evaluation.
Results of surgical treatment of colorectal cancer liver metastases in Latvia oncology center.
Authors: Armands Sivins, Lelde Lauka, Guntis Ancans, Sergejs Gerkis, Andrejs Pcolkins, Viesturs Krumins, Ineta Nemiro, Arta Strazdina, Ilona Kreice, Signe Plate, Svetlana Kasperova, Viesturs Boka, Marcis Leja
Journal: Journal of Clinical Oncology (2015)

485 Background: Colorectal cancer (CRC) is the third leading cause of cancer death. At the time of diagnosis 25% of patients present with stage IV disease and out of all CRC patients 50% develop liver metastases. About 15% of them have initially resectable disease. Surgical resection is the best treatment option as it is associated with longer survival. Latvia Oncology center (LOC) provide expertise in managment of all cancers, including metastatic CRC. Methods: Data about CRC patients with surgicaly treated liver metastases was colected and analysed from Latvia Oncology center in period 2011-2014. This data is also included in LiverMetSurvey international registry of patients operated for CRC liver metastases. 66 patients underwent hepatectomies, 10 patients had 2 or more surgeries due to a reccurent disease. Results: 77 surgeries were performed, 31 were hemihepatectomies and 46 were limited resections. Sinchronous surgery for liver metastases and primary tumor were performed in 19 cases: 11 for left colon cancer, 6 for rigt colon cancer and 2 for rectal cancer. Initially resectable liver disease was found in 70 cases. Unilateral metastases were diagnosed in 61 cases while there were 17 cases of bilateral disease. Postoperative complications developed in 18 patients, 5 of those after sinchronous surgeries for primary tumor. In 10 cases complications developed after major anatomical right sided hemihepatectomy and in 8 cases after atypical resections. Most frequent hepatic complications were infected collection in hepatic loge (n=9), non infected collection (n=3) and biliary leak (n=3); all of those were successfully treated with percutaneous dreinage. 1 patient died due to a postoperative liver insufficiency after right sided hemihepatectomy for recurrent disease. Conclusions: Overall 77 hepatectomies were performed, mostly limited non anatomical resections. In majority of patients 1 or 2 metastases were diagnosed. Initally resectable were 89% of cases. Mass of postoperative complications developed after major hepatectomies, were liver related and successfully treated with minimally invasive procedures. Complication rate (16%) in LOC is comperable to other Europian centers.
First-line gefinitib (G) for advanced non-small cell lung cancer (NSCLC) patients (pts) harboring sensitizing epidermal growth factor receptor mutations (EGFR-M+): Meta-analysis of randomized trials (RCT) exploring the magnitude of benefits over chemotherapy (CT).
Authors: D. Giannarelli, E. Bria, M. Milella, F. Cuppone, A. Ceribelli, V. Vaccaro, I. Sperduti, F. Cognetti
Journal: Journal of Clinical Oncology (2010)

e18076 Background: Retrospective and prospective data from RCT comparing G versus standard I-line CT strongly suggest superior efficacy of G in EGFR-M+ NSCLC pts. Here we evaluated the magnitude of such benefit using a literature-based meta-analysis approach. Methods: Hazard ratios (HR) with 95% confidence intervals (CI) were extracted from papers/presentations for progression-free and overall survival (PFS, OS); event-based relative risks (RR) with 95% CI were determined for response rates (ORR) and grade 3-4 toxicities. A random-effect model with a heterogeneity (Het) test was applied. Meta-regression with clinical predictors of outcome and sensitivity analyses according to trial design (retrospective versus prospective) were performed. Absolute differences (AD) and the number of patients needed to treat/harm (NNT/NNH) were calculated. Results: 4 RCT (651 Asian pts) were gathered (2 prospective trials in EGFR-M+ pts, 2 retrospective analyses of such subgroup). Efficacy results are shown in the Table. Neutropenia was significantly lower in pts receiving G (RR 0.012, 95% CI 0.02-0.059, p<0.0001, Het[p]=0.62), with an AD of 36.7%, corresponding to 2-3 NNH. A significant interaction was found for ORR in prospective trials (p=0.021). Meta-regression analysis indicated a significant correlation between female gender (p=0.019, 4 RCT), nonsmoking status (p=0.007, 3 RCT) and ORR. Conclusions: PFS and ORR are increased by approximately 25% in EGFR-M+ pts receiving I-line G, with significantly less toxicity. Whether II-line use of EGFR-TKI impacts on OS results remains to be determined. Outcome Pts (RCT) HR/RR (95% CI) p value Het (p) AD (%) NNT PFS 651 (4) 0.45 (0.37-0.54) <0.0001 0.42 26.0 3-4 OS 651 (4) 0.87 (0.65-1.15) 0.33 0.40 - - ORR 618 (4) 1.95 (1.49-2.62) <0.0001 0.051 22.6 4-5 No significant financial relationships to disclose.
Selective Uptake and Intracellular Distribution of Covalently Multimerized Human Stem Cell Factor (SCF)-Fusion Proteins into Human c-kit+ Acute Myeloid Leukemia (AML) Cells.
Authors: Julia Sadowski, Ulrike Erben, Jan F. Richter, Wilfrid Bleiss, Alexandra Bittroff-Leben, Eckhard Thiel, Michael Krauss, Michael Notter
Journal: Blood (2007)
Recursive partitioning analysis of selected molecular markers to predict mediastinal lymph node involvement in operable non-small cell lung cancer (NSCLC)
Authors: H. S. Bozcuk, A. Gumus, G. Ozbilim, A. Sarper, M. Ozdogan, M. Artac, M. Samur, B. Savas
Journal: Journal of Clinical Oncology (2005)

7320 Background: Mediastinal lymph node involvement is an important prognostic factor and may help guide the treatment in early NSCLC. Thus, we evaluated whether molecular markers like c-erb-B2, P glycoprotein (pgp) and p53 help with the estimation of the risk of mediastinal lymph node involvement in patients with operable NSCLC. Methods: Primary tumors of 70 NSCLC patients were retrospectively evaluated by immunohistochemistry for the expression of c-erb-B2, pgp and p53. Expression intensity of each marker was defined on a 0 to 1 scale. Data on clinical features was obtained from patient reports. Recursive partitioning analysis was carried out to select the features most closely associated with greater TNM lymph node stage (N0-N1-N2; expressed by a node score of 0 to 2). This analysis took into account both molecular marker profile and various clinical features. Results: Number of lymph nodes resected (< vs. ≥3), patient age (< vs. ≥77), and pgp expression (< vs. ≥0.4), in order, determined the extent of mediastinal lymph node involvement. However, this model had limited predictive power (R2=0.246). T stage according to the TNM system was not a significant factor. Overall, 4 categories were formed, with the mean node scores in parentheses, as the following: 1) resected lymph nodes <3 (0), 2) resected lymph nodes ≥3 & age ≥77 (0.11), 3) resected lymph nodes ≥3 & age <77 & pgp score <0.4 (0.69), and 4) resected lymph nodes ≥3 & age <77 & pgp score ≥0.4 (1.25). Conclusions: Pgp expression status of the primary tumor, in addition to patient age and number of mediastinal lymph nodes resected, may help to predict the risk of mediastinal lymph node spread prior to surgery. No significant financial relationships to disclose.
A multicenter, phase II study of CPX-1 liposome injection in patients (pts) with advanced colorectal cancer (CRC)
Authors: G. Batist, M. Sawyer, N. Gabrail, N. Christiansen, J. L. Marshall, D. R. Spigel, A. Louie
Journal: Journal of Clinical Oncology (2008)

4108 Background: CPX-1 is a novel, liposomal formulation of irinotecan (IRI) and floxuridine (FLOX). CPX-1 uses principles of fixed drug ratio dosing where synergistic drug ratios for chemotherapy doublets defined in vitro are then encapsulated within carriers that control in vivo pharmacokinetics and maintain the ratio systemically. Methods: Pts with advanced CRC, ECOG PS<2, adequate bone marrow, liver and renal function were eligible for this study (CLTR0105–201). Prior oxaliplatin was allowed. Approximately 30 IRI- naïve patients (Group 1) and 30 IRI-refractory (PD <6 months from last IRI treatment) patients (Group 2) were registered. CPX-1 infusions (90 min, 210 u/m2 (1 u = 1mg IRI and 0.36 mg FLOX)) were administered on Days 1 and 15 every 28 days until PD or toxicity. Dose reductions to 150 and 100 u/m2 were permitted for pts with drug-related grade 3/4 neutropenia and GI toxicities and for some pts with prior intolerance to IRI-based regimens. Response rate (ORR) according to RECIST and progression-free survival (PFS) were evaluated. Results: Study enrollment is closed, 26 patients, 13 male, median age 58 (46–77) yrs were enrolled in Group 1 and 33 (29 evaluable for efficacy), 20 male, median age 59 (36–81) yrs in Group 2. Group 1: ORR is currently 8% and disease control rate (DCR=ORR+SD) is 65%. Median PFS with 5 pts continuing to receive therapy is currently 3.2 months with 9 pts having a >4.0 month PFS. Group 2: Currently, no responses have been observed and DCR was 38%. The median PFS with 9 pts continuing to receive therapy is currently 1.8 months, with 6 patients having a >4.0 month PFS. Safety data are available for 51 pts; 34 (67%) had drug-related grade 3/4 toxicities. Grade 3/4 toxicities in > 2 pts: diarrhea (27%), neutropenia (24%), fatigue (14%), nausea (8%) and hypokalemia (6%). Five pts died on study with one death from pneumonia considered treatment related. Conclusions: CPX-1 is well tolerated and provides clinical benefit to pts with advanced CRC. CPX-1 appears to be more active than FOLFIRI used after FOLFOX (Tournigand) and will be studied further. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celator Pharmaceuticals, Inc. Celator Pharmaceuticals, Inc. Celator Pharmaceuticals, Inc.
Development and Validation of Biopsy-Free Genotyping for Molecular Subtyping of Diffuse Large B-Cell Lymphoma
Authors: Florian Scherer, David M. Kurtz, Aaron M Newman, Mohammad Shahrokh Esfahani, Alexander Craig, Henning Stehr, Alexander F. Lovejoy, Jake J. Chabon, Chih Long Liu, Li Zhou, Cynthia Glover, Brendan C. Visser, George Poultsides, Ranjana H Advani, Lauren S Maeda, Neel K. Gupta, Ronald Levy, Robert S. Ohgami, Eric Richard Davis, Gianluca Gaidano, Christian A. Kunder, Davide Rossi, Jason R. Westin, Maximilian Diehn, Ash A Alizadeh
Journal: Blood (2016)
Transforming growth factor (TGF) beta pathway and clinical outcome of pancreatic cancer.
Authors: Milind M. Javle, Dongfeng Tan, Yanan Li, Siddhartha P. Kar, Veera Baladandayuthapani, Xiaoqun Dong, Jacqueline Weatherly, Sunil Krishnan, Tzu-chuan Jane Huang, David R. Fogelman, James L. Abbruzzese, Robert A. Wolff, Donghui Li
Journal: Journal of Clinical Oncology (2012)

201 Background: TGF-beta acts both as a tumor suppressor or tumor promoter depending upon cellular context and stage of tumor progression. TGF-β exerts its effects through the TGF-beta-R1/ R2 receptors and the SMAD transcription regulators. We investigated the prognostic value of TGFβ signaling biomarkers in pancreatic cancer. Methods: We measured plasma TGF-beta-1 level using Meso Scale Discovery Multi-array Human TGF-beta-1 Assay in 643 pancreatic cancer patients. TGF-beta-R2 and SMAD4 protein expression were measured in 86 biopsies using immunohistochemisty (IHC). IHC intensity was scored 0-3. Percentage IHC-positive cancer cells were 0-3 (0: 0%+, 1: 1-10%+, 2: 10-25%+, 3: &gt;25%+). Final IHC score was measured as intensity x percentage. We also genotyped 3 SNPs of TGFB1 gene using the Taqman assay. Kaplan-Meier and log-rank tests were used to analyze overall survival (OS) by TGFβ1 level. Multivariate Cox proportional hazards models with relevant clinical covariates were used to assess the relationship between IHC score and OS. Results: In patients with locally advanced and metastatic disease (n = 355), there was a significant association of plasma TGF-beta-1 with overall survival (OS). OS of the top quartile of TGF-beta-1 levels (&gt;19.05 ng/mL) vs. those with low level was 27.7 weeks vs. 40 weeks, respectively [log-rank p = 0.0125, adjusted for baseline CA 19-9 and performance status (PS)]. No significant association between plasma TGF-beta-1 and OS was noted in surgical patients (n=288). In the multivariate Cox model, after adjusting for baseline stage, CA 19-9, PS, age and TGF-beta-R2 expression, complete loss of SMAD4 expression (IHC score 0) was significantly associated with lower OS (HR: 1.85, 95% CI: 1.06-3.23; p = 0.03). Progressive disease on gemcitabine-based therapy was more likely in SMAD4 IHC 0 group as compared with higher score (46.5% vs. 38.1% progressed; chi square p = 0.069). TGFB1 -1346T&gt;C CT/TT genotype correlated with shorter OS [HR (95% CI): 1.21 (1.02-1.45), p=0.03] after adjusting for clinical variables. Conclusions: This large retrospective study suggests an important stage-dependant role of the TGF-beta pathway in pancreatic cancer. Targeting this pathway in advanced pancreatic cancer may have therapeutic relevance.
Mesothelin expression in patients as a novel target in gastric cancer.
Authors: Ronan Joseph Kelly, Ira Pastan, Morgan L Cowan, Elizabeth Montgomery, Raffit Hassan, Christine Campo Alewine, Laiman Xiang, Peter B. Illei
Journal: Journal of Clinical Oncology (2014)

61 Background: Novel targets and therapeutics are of profound importance if we are to improve outcomes in gastric cancer. This study assessed the incidence of mesothelin expression in tumors of Western patients with gastric cancer. In addition, gastric cancer cell lines were then tested for their sensitivity to SS1(dsFv)PE38 (SS1P), a mesothelin-targeted immunotoxin. Methods: Tissue specimens from 127 patients with gastric or gastro-esophageal junction (GEJ) tumors were examined by immuno-histochemistry (IHC) for intensity of staining for mesothelin. Expression of HER2-neu, e-cadherin and c-Met were also assessed. Tumors were considered positive for mesothelin if moderate cytoplasmic/membranous or luminal staining was present in at least 10% of the cells. Gastric cancer cell lines were assessed for surface mesothelin expression by flow cytometry and the viability of cells treated with SS1P was measured. Results: Gastric and GEJ cancers were mesothelin positive in 64/127 tumors (50%) while only 9 tumors (7%) were Her2-neu IHC +3 positive and 8 tumors (6%) were c-Met positive (c-Met low 5% and c-Met high 1%). Mesothelin expression rates changed from stage I tumors to stage IV tumors (39% to 56% respectively). We found that both the AGS and MKN28 gastric cancer cell lines express mesothelin and are sensitive to the immunotoxin with EC50 values in the low picomolar range (0.4 and 0.3 ng/mL, respectively). Conclusions: Mesothelin is a cell surface glycoprotein that is expressed in 50% of resected gastric cancers. Gastric cancer cell lines were exquisitely sensitive to SS1P. The high expression of mesothelin and its sensitivity to the immunotoxin SS1P makes it an attractive tumor associated antigen for therapeutic targeting. Based on these observations clinical trials involving novel mesothelin targeted drugs in gastric cancer are currently in development.