tbuckley/cabot-search huggingface dataset:
Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors.
Authors: Pooja Ghatalia, Charity Morgan, Toni K. Choueiri, Guru Sonpavde
Journal: Journal of Clinical Oncology (2014)

e13502 Background: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are reported to cause congestive heart failure (CHF). However, the risk has not been systematically studied across all VEGFR TKIs, and the risk with TKIs that are relatively specific (axitinib) or less specific for VEGFRs is unclear. We performed a trial-level meta-analysis of randomized trials to determine the relative risk (RR) of CHF associated with use of FDA approved VEGFR TKIs. Methods: MEDLINE, conferences and clinicaltrials.gov databases were searched for trials published from Jan 1966 to March 2013. Eligible studies included randomized phase II and III trials comparing arms with and without a VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib, regorafenib). Data abstraction was conducted according to the PRISMA statement, and RR and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on heterogeneity. Trial quality was graded by the Jadad score. Results: A total of 10,647 patients from 16 phase III trials and 5 phase II trials were selected. All grade CHF occurred in 138 of 5752 patients receiving VEGFR TKIs and 37 of 4895 patients in the non-TKI group. High-grade CHF occurred in 17 of 1426 patients receiving VEGFR TKI and 8 of 1232 patients in the non-TKI group. The pooled estimate of RR for all grade and high-grade CHF for the TKI vs. no-TKI arms was 2.69 (p < 0.001; 95% CI: 1.86 to 3.87) and 1.65 (p = 0.227, 95% CI: 0.73 to 3.70), respectively. On subgroup analysis, the specificity of the VEGFR TKI or the tumor type being treated did not affect the risk of CHF. CHF was not reported in trials of 3 newer VEGFR TKIs (regorafenib, ponatinib, cabozantinib). All trials exhibited high quality (Jadad score 3–5). No evidence of publication bias was detected for all grade or high-grade CHF (p > 0.20 for both using the Egger test). Similarly, there was no evidence of heterogeneity in all or high-grade CHF. Conclusions: VEGFR TKIs were associated with an increased overall risk of CHF, but not high-grade CHF, independent of the TKI or tumor type. Better patient selection and monitoring may mitigate the risk of severe CHF.
Correlation of WT1 expression with tumor characteristics and clinical outcomes in mucinous breast carcinoma
Authors: H. Liang, F. Ye, B. C. Lembersky, R. Bhargava
Journal: Journal of Clinical Oncology (2009)

e22075 Background: Wilms' tumor 1(WT1) protein expression has been evaluated by immunohistochemistry (IHC) in various histologies of series of invasive breast carcinomas. It is overexpressed predominantly in the mucinous subtype, in both pure and mixed mucinous carcinoma. The objective of this study was to correlate WT1 expression with the clinical and biological features of mucinous breast carcinoma as well as with the clinical outcomes and management. Methods: A total of 83 cases of pure and mixed mucinous breast carcinoma diagnosed between January 1999 and May 2006 were selected from the Magee-Womens Hospital, University of Pittsburgh Medical Center pathology registry. WT1 expression was examined by IHC using tissue microarrays (TMA). Only nuclear staining for WT1 was counted. Patient age, tumor features, management, and clinical outcomes were recorded, and survival was documented at the last patient followup. Results: Median follow-up was 59m (13–158m). The vast majority of patients had strong expression of hormone receptors. Only 3 patients had HER2-positive tumors. Disease free survival (DFS) was 92%. Overall survival (OS) was 88%. Sixty four cases had sufficient tissue on TMA for WT1 expression. Among them, WT1 expression was identified in 21/33 (64%) of pure mucinous carcinomas and 9/31 (29%) of mixed type tumors. Patients in both WT1-positive and WT1-negative groups had similar rates of breast conserving surgery, adjuvant radiotherapy and endocrine therapies. However, patients in the WT1-positive group were older (median age 74 vs 55 years, p=0.02) and had smaller tumor (median tumor size 1.2 vs 1.75 cm, p=0.03) as compared to those in WT1-negative group. More patients with WT1-negative tumors received adjuvant chemotherapy (40.6% vs 13.8%, p=0.02). Although all the recurrences were observed in patients with WT1-negative tumors, there was no statistical association of DFS or OS with WT1 expression. Conclusions: Overall, both pure and mixed mucinous breast carcinomas have excellent prognosis. This retrospective study demonstrated that WT1 expression may be associated with favorable outcome/pathologic features for patients with mucinous breast carcinoma. Prospective clinical studies will help to further elucidate these findings. No significant financial relationships to disclose.
Biomarker testing methods in breast, gastric, and lung cancers: A benchmarking survey of NCI cancer centers.
Authors: Julian C. Schink, Julia R. Trosman, Christine B. Weldon, Kalliopi P. Siziopikou, William John Gradishar, Gregory J. Tsongalis, Jyoti D. Patel, Al Bowen Benson, Edith A. Perez
Journal: Journal of Clinical Oncology (2013)

e22093 Background: Biomarkers are an integral part of cancer care. A variety of testing methods exist, allowing institutional selection of which technologies to use and in what order to run them. This descriptive study provides a benchmark on methods used in practice for biomarker testing in breast (BC), gastric/esophageal (GC), and non-small cell lung cancers (NSCLC). Methods: We conducted an IRB-approved web survey of the 58 NCI designated cancer centers (pathologists and oncologists) providing adult care in BC, GC, and NSCLC. We developed a survey instrument with 14 BC, 5 GC, and 10 NSCLC items asking about methods used, order of testing, turn around time (TAT) and if tests are internally developed (ID). Results: For BC, 32% (18/57) of sites run concurrent rather than reflex HER2 FISH and IHC testing, citing quality assurance reasons. Average TAT for concurrent vs reflex testing is 6.5 and 9.5 days. Rates of ID tests are 14% (8/57) for PgR, 12% (7/57) for ER and 7% (4/57) for HER2. For GC, 39% (21/54) of sites run concurrent HER2 FISH and IHC tests, citing reasons of quality assurance and evolving guidelines. TAT for concurrent vs reflex testing is 6.3 and 9.5 days. 19% (10/54) of sites use ID HER2 tests. All reporting sites use EGFR and ALK testing in NSCLC and 96% use KRAS. 24% (13/55) of sites run them concurrently with an average TAT of 7.6 days, while the average TAT for sites with sequential testing is 22.8 days. CAP recommends a 10 day TAT for NSCLC tests, and 92% (12/13) of sites with concurrent testing meet this guideline vs only 11% (4/38) of sites with sequential testing (p&lt;.0001). Rates of ID tests are 57% (30/53) for KRAS, 47% (26/55) for EGFR and 35% (19/55) for ALK, for which a kit is listed on the FDA drug label. There is a difference in the use of ID tests between BC and NSCLC, p&lt;.0148. Conclusions: Concurrent testing for BC and GC HER2, and for NSCLC markers is a common practice at NCI cancer centers; and it improves TAT. Concurrent NSCLC testing allows meeting CAP TAT guideline, but sequential testing does not. New markers (GC HER2, EGFR, KRAS and ALK) are commonly adopted, with a higher rate of internally developed tests than for BC HER2. [Table: see text]
Use of microRNA to identify stage IV breast cancer patients to be targeted with phospholipase A2 disrupted cisplatin carrying liposomes: An ongoing phase I trial.
Authors: Ulrik Niels Lassen, Steen Knudsen, Pernille Braemer Hertel, Iben Kumler, Dorte Nielsen, Bent Ejlertsen, Morten Mau Soerensen, Nils Brunner, Ulla Hald Buhl, Mogens Winkel Madsen, Ida Kappel Buhl, Anker Hansen, Thomas Jensen, Eva Balslev, Jon Askaa, Peter Michael Vestlev, Anne-Vibeke Laenkholm, Peter Buhl Jensen
Journal: Journal of Clinical Oncology (2014)

TPS1139 Background: Cisplatin has shown activity in BRCA associated breast cancer patients but generally the use of cisplatin in breast cancer has been hampered by high toxicity and low response rates of approximately 10% (Baselga et al. JCO, 2013; 31:2586-2592.). We address both issues in an ongoing phase 1 study with a third generation liposomal cisplatin which is activated by secretory phospholipase A2 (sPLA2) present on the tumor cells, and in parallel by selecting patients with a companion diagnostic for an optimal cisplatin sensitivity microRNA profile and expression of sPLA2. Methods: A validated response prediction method is used in the cisplatin sensitivity prediction. The method uses cell line drug sensitivity data and cell line microarray data and clinical tumor big data analysis (Wang et al. J Natl Cancer Inst; 2013;105:1284–1291.). When the profile was probed on a published cohort of BC there were patients in all breast cancer subgroups that were predicted high likely sensitive. From the literature it is known that 80% of breast cancers are positive for sPLA2 (Yamashita et al. Br J Cancer; 1994;69: 1166-1170.). Methods: sPLA2 is determined by immunohistochemistry, microRNA obtained from formalin fixed paraffin embedded biopsies are assessed by use of Affymetrix chips. After an initial phase 1 dosing d1 q 3 wk reaching 120 mg the dose intensity was increased to d1 and d8 treatment q 3wk, and the 8th dose level has been reached on unselected patients with 120 mg cisplatin administered d1 and d8 and we now plan to extend the phase 1 study and include only biomarker positive patients. Currently 150 formalin fixed paraffin embedded (FFPE) patient biopsies have been screened and only the patients with an optimal profile are treatment candidates. In collaboration with the Danish Breast Cancer Cooperative Group (DBCG) the aim is to screen 600 BC patients with metastatic disease but currently not progressing. At progression only patients with in the highest 10% response likelihood will be candidates for expansion part of the phase 1 trial. Clinical trial information: NCT01861496.
Phase I-II trial of daily thalidomide in combination with docetaxel in patients with relapsed non-small cell lung cancer: A final analysis
Authors: C. W. Seidler, E. Scepansky, S. Khanani, J. Rooney, J. Gordon, W. Walsh
Journal: Journal of Clinical Oncology (2006)

17060 Background: Recent studies have shown that inhibition of vascular endothelium growth factor (VEGF) in combination with chemotherapy can improve the antitumor efficacy of chemotherapy in NSCLC. This study tested the effectivness and toxicity of thalidomide (an inhibitor of VEGF) combined with docetaxel as second-line therapy for progressive NSCLC. Methods: Patients(pts) with recurrent/progressive NSCLC, prior chemotherapy, measurable/evaluable disease, ECOG performance status (PS) 0–2 and adequate hematologic, renal and hepatic function were enrolled. Pts with uncontrolled CNS disease or hypercoagulable state were excluded. Doxetaxel 75 mg/M 2 was administered every 3 weeks (maximum of 8 cycles). Thalidomide was administered orally at a starting dose of 50 mg daily escalated by 50 mg every 3 weeks to a maximum dose of 200mg day and continued until disease progression, dose limiting toxicity, or completion of chemotherapy. Primary end-point was overall survival (OS), secondary end points were time to disease progression(TTP) by Kaplan Meyer method and response rate (RECIST criteria). Results: Of 28 enrolled patients, 26 were eligible for treatment and 25 were evaluable for disease progression and survival. For evaluable pts: mean PS = 1, median age 64.5 years, median number of prior chemotherapy regimens + 1.2. Response rate was 19.1% (1 complete response, 4 partial responses). Stable disease was observed in 9 patients (34.6%). TTP was 2.7 months (95% confidence interval [CI] 2.1–5.0+): median OS was 5.4 months (95% CI 3.1–9.3+). One episode each of febrile neutropenia requiring hospitalization and pulmonary embolism was observed. No grade 3–4 neuropathy was shown. Nonhematologic adverse events included constipation, alopecia, nausea and anorexia. Conclusions: These data suggest thalidomide in doses of 200mg/ day may be combined with docetaxel 75 mg/m 2 every 3 weeks in the second line treatment of NSCLC. The response rate, TTP and OS compare favorably with previously reported studies with docetaxel in this population. No significant financial relationships to disclose.
Role of Diastolic Stress Testing in the Evaluation for Heart Failure With Preserved Ejection Fraction
Authors: Masaru Obokata, Garvan C. Kane, Yogesh N. V. Reddy, Thomas P. Olson, Vojtech Melenovsky, Barry A. Borlaug
Journal: Circulation (2016)

Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging and relies largely on demonstration of elevated cardiac filling pressures (pulmonary capillary wedge pressure). Current guidelines recommend use of natriuretic peptides (N-terminal pro-B type natriuretic peptide) and rest/exercise echocardiography (E/e' ratio) to make this determination. Data to support this practice are conflicting.Simultaneous echocardiographic-catheterization studies were prospectively conducted at rest and during exercise in subjects with invasively proven HFpEF (n=50) and participants with dyspnea but no identifiable cardiac pathology (n=24).N-Terminal pro-B type natriuretic peptide levels were below the level considered to exclude disease (≤125 pg/mL) in 18% of subjects with HFpEF. E/e' ratio was correlated with directly measured pulmonary capillary wedge pressure at rest (r=0.63, P<0.0001) and during exercise (r=0.57, P<0.0001). Although specific, current guidelines were poorly sensitive, identifying only 34% to 60% of subjects with invasively proven HFpEF on the basis of resting echocardiographic data alone. Addition of exercise echocardiographic data (E/e' ratio>14) improved sensitivity (to 90%) and thus negative predictive value, but decreased specificity (71%).Currently proposed HFpEF diagnostic guidelines on the basis of resting data are poorly sensitive. Adding exercise E/e' data improves sensitivity and negative predictive value but compromises specificity, suggesting that exercise echocardiography may help rule out HFpEF. These results question the accuracy of current approaches to exclude HFpEF on the basis of resting data alone and reinforce the value of exercise testing using invasive and noninvasive hemodynamic assessments to definitively confirm or refute the diagnosis of HFpEF.URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01418248.
Prognostic significance of disseminated cancer cells in bone marrow in patients with squamous cell carcinoma of the esophagus using quantitative RT-PCR for CEA mRNA
Authors: K. Shinjo, Y. Kajiyama, Y. T. Ishii, I. Nagaoka, M. Tsurumaru
Journal: Journal of Clinical Oncology (2006)

20004 Background: The clinical significance of disseminated cancer cells in bone marrow has not been elucidated in esophageal cancer. The aim of this study was to evaluate the relation between quantity of disseminated cancer cells in bone marrow and clinical characteristics, including prognostic significance, in patients with squamous cell carcinoma of the esophagus using real time reverse transcriptase polymerase chain reaction (RT-PCR) for CEA (carcinoembryonic antigens) mRNA. Methods: Bone marrow samples were obtained from the 4 th or 5 th right rib on thoracotomy from consecutive 65 operative patients with esophageal squamous cell cancer, who received esophagectomy with lymph node dissection. After total RNA extraction, they were investigated by quantitative real time RT-PCR for CEA. We also performed qualitative analyses to confirm the results at least twice. We adopted quantitative results when qualitative analyses showed positive. Results: In bone marrow CEA mRNA was detected in 14 out of the 65 patients (21.5%). There were no significant differences in clinicopathological findings between positive and negative group for bone marrow CEA. However, after a short median follow-up of 12 months (3–19 months), 6 of 14 (42.9%) patients with positive CEA group had been dead compared to 4 out of 51 (7.8%) patients with negative CEA group. The survival time of both group showed a significant difference (p=0.0282). However, there was no relationship between the amount of cancer cells in bone marrow and patients’ survival. Conclusions: Disseminated cancer cells in bone marrow using quantitative RT-PCR for CEA mRNA may be a significant predictor for highly malignant squamous cell carcinoma of the esophagus. No significant financial relationships to disclose.
Trough plasma imatinib concentrations are associated with responses to standard-dose imatinib in chronic myeloid leukemia and could improve its clinical management
Authors: F. Mahon, G. Etienne, S. Picard, K. Titier, G. Marit, B. Begaud, J. Reiffers, N. Moore, M. Molimard
Journal: Journal of Clinical Oncology (2007)

7027 Background: Variable responses to imatinib in the treatment of myelogenous leukemia (CML) are incompletely understood. Previous studies focused on cellular mechanisms of resistance to imatinib. Another hypothesis for variable response lies in pharmacokinetic variability that may reduce drug exposure in patients receiving imatinib. Methods: Using high- performance liquid chromatography-tandem mass spectrometry, we assessed trough plasma imatinib concentrations at steady state (Cmin) in more than 150 CML patients. Major molecular response (MMR) was defined as a 3 logarithm reduction of BCR-ABL transcripts, quantified from peripheral blood using Q-RTPCR. In addition, suboptimal response criteria defined by the European Leukemianet were used to increase doses of imatinib. Results: i) we assessed Cmin in 85 CML patients and demonstated a correlation with imatinib doses (median values 813, 1,135, 1,709 ng/ml for respectively 300,400, 600 mg/day). ii) for 68 patients after at least one year's treatment mean Cmin were significantly higher in the group with MMR (34 patients) than in the group without (1,452.1±649.1 ng per milliliter vs. 869.3±427.5 ng per milliliter, P&lt;0.001) whereas there was no difference in the imatinib daily dose. For Cmin and their discrimination potential for MMR, the area under receiver-operating characteristic curve was 0.775, with best sensitivity (76.5 percent) and specificity (70.6 percent) at a plasma threshold of 1,002 ng per milliliter. iii) dose escalation of imatinid, 400mg up to 600mg was proposed in 8 patients in suboptimal response (3 according to cytogenetic criteria and 5 according to molecular criteria). The median Cmin increase from 573 ng/ml [181–1,376] to 1,139 ng/ml [733–2,262] and 5 patients had a cytogenetic (n=3) or a molecular (n=2) response. Conclusions: Monitoring of imatinib plasma levels could be very useful for the management of CML patients, or should at least be checked in the case of treatment failure or suboptimal response or in patients nonadherent with imatinib or with a drug-drug interaction suspicion. No significant financial relationships to disclose.
Exome sequencing of healthy phenotypic extremes links TROVE2 to emotional memory and PTSD
Authors: Angela Heck, Annette Milnik, Vanja Vukojevic, Jana Petrovska, Tobias Egli, Jochen Singer, Pablo Escobar, Thierry Sengstag, David Coynel, Virginie Freytag, Matthias Fastenrath, Philippe Demougin, Eva Loos, Francina Hartmann, Nathalie Schicktanz, Bernardo Delarue Bizzini, Christian Vogler, Iris-Tatjana Kolassa, Sarah Wilker, Thomas Elbert, Torsten Schwede, Christian Beisel, Niko Beerenwinkel, Dominique J.-F. de Quervain, Andreas Papassotiropoulos
Journal: Nature Human Behaviour (2017)
Construction and efficacy identification of the lentiviral vector harboring RNAi based on the <i>hyperplasia suppressor gene</i> (<i>HSG</i>).
Authors: Yuqing Lou, Rong Li, Jielin Liu, Yanwei Zhang, Ya Liu, Zuoguang Wang, Shaojun Wen, Baohui Han
Journal: Journal of Clinical Oncology (2014)

e22177 Background: Our previous study suggested that hyperplasia suppressor gene (HSG) induced apoptosis of mitochondrial pathway via MAPK signal transduction pathway. In order to study on the apoptosis mechanisms via mitochondrial pathway induced by the HSG gene on human lung adenocarcinoma cells, we constructed and identified the efficacy of a lentiviral vector harboring RNA Interference sequence targeting the HSG gene. Methods: Three siRNA sequences targeting the HSG mRNA were designed. The levtivirus vectors of GCSIL-GFP-HSG were constructed and confirmed by DNA sequencing. The 293T cells were co-transfected with pGCSIL-GFP-HSG, pHelperl.0 and pHelper2.0 in order to produce the virus stocks. The titer of the virus was also tested. The lentivirus was transfected to human A549 lung adenocarcinoma cells. The expression of the HSGgene was analyzed by Real-time PCR. Results: DNA sequencing suggested that the DNA sequences were consisted with it designed, which meant that the RNAi sequence targeting the human HSG gene was correct. Examination the co-transfected cells by fluorescence microscopy suggested that the cells grew well and had a strong fluorescence intensity. The titer of the virus was 3×108TU/ml. Real-time PCR shown that the expression of the HSG gene was knockdown after the lentivirus transfected to A549 cells. Conclusions: The lentiviral vector of the HSG gene of Homo sapiens has been successfully constructed. It could be further used in the research of oncology.
Withholding Proton Pump Inhibitors to Prevent Recurrent <i>Clostridium difficile</i>
Authors: Scott R. Bauer, Patrick O’Malley
Journal: JAMA Internal Medicine (2017)

Raseen Tariq, MBBS; Siddharth Singh, MBBS, MS; Arjun Gupta, MBBS; Darrell S. Pardi, MD, MS; Sahil Khanna, MBBS, MS
Role of PET scan in predicting response to neoadjuvant chemotherapy and long-term outcomes for stage II lung cancer.
Authors: Ankit Bharat, Brandon Guenthart, Valerie W. Rusch, Manjit S. Bains, Nabil P. Rizk
Journal: Journal of Clinical Oncology (2014)

7574 Background: While the role of neo-adjuvant chemotherapy (NAT) in stage IIIA non-small cell lung cancer (NSCLC) is well established, its efficacy in stage II is unclear. We evaluated the role of PET scan in predicting long-term outcomes in patients with stage II NSCLC undergoing surgical resection following NAT. Methods: Clinical stage II NSCLC (7th ed. AJCC) patients that underwent NAT between 1995 and 2010 were identified using a prospectively maintained database. All patients underwent clinical staging using CT scan and PET scan, with or without invasive lymph node staging. Chemotherapy regimen was unchanged during the study period. Results: Fifty-five patients with clinical stage II were identified who received NAT prior to surgery. The mean age was 63.1±10.2. Patients were predominantly white (69%) and female (53%). Most tumors were adenocarcinomas (70%), and most patients underwent a lobectomy (87%). Seventeen patients (30%) developed temporary interruption due to side effects from NAT. The 30-day perioperative mortality was 0%. Overall five-year and recurrence free survival were 65% and 70%, respectively. Mean preoperative PET SUV was 13.4±8.9 that decreased to 4.7±3.2 after NAT (p<0.01). Twenty-six (47%) patients had a greater than 50% reduction (PETc) while 15 (27%) did not (PETu) and 10 (18%) did not have restaging PET. There was no difference in invasive lymph node staging performed between PETu and PETc (30% vs 36%, p=0.8). The mean preoperative tumor size was no different (PETu 4.1 vs PETc 5.0). On final path the mean tumor size reduced 24% for PETc in contrast to 2% for PETu although this was not statistically significant. There was a 19% incidence of nodal metastasis in PETc group compared to 13% in PETu (p=0.07). PETc demonstrated a significantly improved survival compared to PETu (82.1% vs 40.8%, p=0.04). Conclusions: In patients with clinical stage II NSCLC, surgery after NAT was associated with low perioperative mortality and good long-term survival. Patients with a >50% reduction of SUV had a significant improvement in long-term survival.