tbuckley/cabot-search huggingface dataset:
A Comprehensive Identification of the Microrna Transcriptome and Its Application in B Cell Malignancies.
Authors: Cassandra L. Jacobs, Dereje D Jima, Jenny Zhang, Cherie Dunphy, Kristy L. Richards, William W.L. Choi, Gopesh Srivastava, Andrew M Evens, Leo I. Gordon, Magdalena Czader, David A Rizzieri, Anand S. Lagoo, Karen P. Mann, Christopher R. Flowers, Kikkeri Naresh, Micah Luftig, Daphne R Friedman, J. Brice Weinberg, Michael A. Thompson, Javed Gill, Brad S Kahl, Amy Chadburn, Sandeep Dave
Journal: Blood (2009)
Treatment outcome and incidence for late relapse of germ cell tumor (GCT) patients (pts): The memorial Sloan-Kettering Cancer Center (MSKCC) experience
Authors: E. A. Ronnen, G. V. Kondagunta, J. Bacik, S. Marion, D. F. Bajorin, J. Sheinfeld, G. J. Bosl, R. J. Motzer
Journal: Journal of Clinical Oncology (2005)

4522 Background: Late relapse GCT occurs > 2 years after initial chemotherapy and is associated with a poor prognosis (JCO 13:1170). The MSKCC experience with late relapse GCT was examined from two perspectives. First, we report the frequency of late relapse GCT after first-line chemotherapy at MSKCC. Second, our experience with salvage chemotherapy for pts with late relapse GCT was examined. Methods: The incidence of late relapse was calculated by retrospective analysis performed on 552 pts (Group A). All were treated with first-line chemotherapy programs at MSKCC from 1978–2001, had > 2 years of follow-up and had a complete response (CR). Separately, to evaluate treatment outcome for late relapse GCT, 29 pts with late relapse GCT were identified on salvage chemotherapy trials at MSKCC (Group B). Results: Of the 552 pts achieving a CR on first-line chemotherapy trials, 18 pts experienced a late relapse for an incidence of 3% (Group A). For Group B, 27 pts had nonseminoma, 2 had seminoma and all had testis primary site; median time to late relapse was 10.5 years (2.6–25.1). Outcome to salvage chemotherapy on MSKCC clinical trials was: 7 pts treated with TIP achieved a continuous CR; 4 to chemotherapy alone and 3 to chemotherapy plus resection of viable GCT. 1 pt progressed on TIP, and was rendered NED by salvage surgery. The median survival for the 29 pts was 23.9 months, with a median follow-up of 50.6 months for the 9 survivors (8 NED, 1 partial responder with negative markers). Conclusion: Late relapse GCT is infrequent, comprising 3% of patients treated with first-line chemotherapy at MSKCC. Primary management is surgery, since late relapse GCT is reported to be chemotherapy resistant. TIP resulted in durable CRs in 7 of 14 late relapse GCT patients who were not candidates for surgical salvage. A larger experience with TIP in late relapse GCT patients would better define treatment efficacy. Support: Craig D. Tifford Foundation. No significant financial relationships to disclose.
Activity of novel RET inhibitors against RET genotypes associated with medullary thyroid cancer.
Authors: A. W. Gramza, J. Patterson, J. Peters, M. Kaufman, S. Wise, D. Flynn
Journal: Journal of Clinical Oncology (2010)

5559 Background: Point mutations in RET tyrosine kinase, most commonly C634R and M918T, result in the development of medullary thyroid cancer (MTC). C634R and M918T occur in the cysteine-rich and kinase domain, respectively, and therefore activate RET by differing mechanisms. V804L, a mutation at the putative RET gatekeeper residue, has demonstrated resistance to several tyrosine kinase inhibitors (TKIs) in vitro. Notably, with other tyrosine kinases, mutations in the kinase domains or gatekeeper residues alter drug sensitivity. We evaluated the effect of these RET mutations on the response to TKIs in a cell based system. Methods: CHO cells expressing WT and mutant RET proteins were treated with a panel of TKIs consisting of compounds in preclinical development (DP-2490 and DP-3636) and drugs being studied for treatment of MTC in clinical trials (axitinib, motesanib, sorafenib, sunitinib, vandetanib). Drug sensitivity was determined by inhibition of RET kinase phosphorylation and IC50s were calculated using photodensitometry. Results: The IC50s of each TKI against the different RET mutants are presented in the Table. WT RET was most sensitive to all of the TKIs. DP-2490 and DP-3636 had IC50s < 1 nM against WT RET, and demonstrated superior potency against all of the RET mutants tested. All drugs tested were at least 5-fold more potent against C634R than M918T. V804L demonstrated complete resistance to axitinib, motesanib, and vandetanib at 5,000nM, but demonstrated increased sensitivity to the other compounds when compared to M918T. Conclusions: RET kinase is a therapeutic target for the treatment of MTC. Here, we demonstrate that RET kinase inhibition differs by RET genotype and kinase inhibitor. These findings are similar to those in other malignancies, and suggest that MTC tumor genotype may be predictive of response to individual TKIs that target RET. DP-2490 and DP-3636 represent the most potent RET inhibitors described to date and should be studied further for the treatment of MTC. Inhibitor IC50 (nM) RET wild-type RET C634R RET V804L RET M918T Axitinib 50 130 >5,000 2,350 Motesanib 150 250 >5,000 1,870 Sorafenib 30 60 390 430 Sunitinib 13 70 40 360 Vandetanib 60 110 >5,000 560 DP-2490 0.4 10 30 86 DP-3636 0.1 0.7 1.4 10 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Deciphera Deciphera
Phase II study of weekly topotecan in recurrent or metastatic cervical cancer: a GEICO study
Authors: M. Rubio, A. Santaballa, Y. Garcia, A. Gonzalez, I. Bover, E. Calvo, J. A. Contreras, J. del Campo, A. De Juan, A. Poveda
Journal: Journal of Clinical Oncology (2008)

5591 Background: Single-agent topotecan has demonstrated activity against persistent, metastatic and recurrent cancer of the uterine cervix. In combination with cisplatin has been shown to prolong survival in this setting although the benefit of combination therapy is scarce. Topotecan administered on a weekly basis has been reported to possess antineoplastic activities with lower toxicities than the standard 5-day regimen every 3 weeks in other tumors like ovarian or small cell lung cancers.Up to now there is no established second line treatment in cervical cancer. Methods: We studied in a multi-centre phase II trial the activity of weekly of Topotecan (3mg/m2/days 1, 8 and 15 on a 28-day cycle.) in recurrent or metastatic cervical cancer patients (pts) after failure to primary treatment with cisplatin chemotherapy. The primary objective was response rate evaluated by RECIST criteria. Secondary objectives were toxicity, PFS and OS (using Kaplan-Meier method). Results: Thirty three patients were included. Information is available currently for 30. Median age 55 years (range 33–76); Histology: squamous 66.7%, adenocarcinoma 26.7%, others 6.6%. Major sites of disease: local relapse (30%), nodes (20%) and lung (10%). Median number of cycles administered was 3.6 (1–11). Only five pts (16.7%) reported grade 3 toxicity (asthenia: 1, gastrointestinal: 1, neutropenia: 2, anemia: 2). Eight pts (26.7%) showed stable disease and 20 pts (66.6%) progression, 2 pts( 6.7%) were not evaluated for response. Median progression free survival was 4.17 months (95%CI: 3.19–5.15) and median survival was 14 months (95% CI: 10.16–18.11). Conclusions: These preliminary data show that weekly topotecan is an easy and well tolerated schedule but it has no activity at this dose in this population with recurrent cervical cancer previously treated with cisplatin based chemotherapy. No significant financial relationships to disclose.
P58 Evidence of dendritic cell dysfunction in cirrhosis and its restoration by Toll-like receptor 4 antagonism
Authors: N Shah, M Montes de Oca, D Dhar, N Davies, R P Mookerjee, M Jover-Cobos, A Habtesion, R Jalan
Journal: Gut (2010)

Introduction  Infection complicates the course of cirrhosis and is the main cause of admission of patients to hospital. Recent studies have shown evidence of immune paralysis during severe decompensation. Our studies have suggested that neutrophil dysfunction in alcoholic hepatitis patients may be associated with a defect of TLR4 signalling, which is a key pathogen response receptor.  Aim  The aims of this study were to characterise cellular immune function in a bile-duct ligated (BDL) model of cirrhosis and evaluate the role of TLR4 by using a selective antagonist, STM 28. (STM28 was kindly gifted by Professor Ken-ichi Tanamoto, Division of Microbiology, National Institute of Health Sciences, Tokyo 158-8501, Japan).  Method  18 C57BL/6 mice were studied: Sham operated, BDL (2 weeks after ligation) and BDL treated with TLR4 antagonist STM-28 (20 ug IP, 5 days). Peripheral blood was stained with fluorochrome-labellel antibodies specific for peripheral blood myeloid cells, dendritic cells (DC9s, plasmocytoid and myeloid, expression of CD86 in myeloid); monocytes (residents and inflammatory); total granulocytes and neutrophils; CD4/CD8 T-cells and the expression of CD25 in CD4 T cell population; B cells and NK cells. Flow cytometric analysis was performed on a FACS Canto II. Biochemistry was measured spectrophotometrically.  Results  A significant shift towards the myeloid subset of peripheral blood DCs was observed in BDL animals compared with sham (81% vs 54%, p=0.0002) accompanied by a significant decrease in the percentages of plasmocytoid DCs (2% vs 25%, p  Conclusion  In cirrhosis, myeloid subtype DCs are expanded and there is relative depletion of plasmacytoid DC9s and lymphophenia. Treatment with a TLR4 antagonist redresses a shift of dendritic cells from the myeloid back to plasmacytoid type. As the DC9s play a pivotal role in antigen presentation, TLR4 antagonism may play an important therapeutic role in decreasing susceptibility of cirrhotic patients to infection.
J-shaped association between P-wave duration and risk of atrial fibrillation: results from the Copenhagen ECG study
Authors: Jonas B. Nielsen, Adrian Pietersen, Claus Graff, Bent Lind, Johannes Struijk, Morten S. Olesen, Stig Haunsoe, Lars Koeber, Jesper H. Svendsen, Anders G. Holst
Journal: Circulation (2012)
Deficiencies in disaster funding
Authors: Annemarie ter Veen, Menno Bouma, Michel van Herp, Kace Keiluhu, Budi Subianto
Journal: BMJ (2005)

Family history of breast cancer Referral guidelines changed after acceptance of 10 minute consultationEditor-In their 10 minute consultation on family history of breast cancer Lucassen and Watson drew attention to the recently published guidelines from the National Institute for Clinical Excellence (NICE) on familial breast cancer. 1 2 It is unfortunate that the referral criteria were changed between the acceptance of this article in December 2003 and the final published guidelines in June 2004, which would result in the referral of the patient highlighted in the article for potential mammography screening, rather than for her reassurance.Women aged 40-49 years at moderate risk of breast cancer are entitled to annual mammograms. 2 The definition of moderate risk was based on a risk of at least 3% over the 10 year period from the age of 40 to 50.Available evidence, particularly from combined analyses of case-control studies of familial risks, 3 indicates that a woman reaches this category with a first degree relative (mother or sister) with breast cancer when younger than 40 years or two relatives on the same side of the family (one first degree and one second degree or two first degree) diagnosed at any age.The latter category differs from the draft NICE guidelines and previous referral criteria, which required that the two relatives be diagnosed at an average age of less than 60. 4 This age restriction was removed because it could not be justified on the basis of the available data.It should be noted, however, that referral on the basis of two elderly close relatives is likely to be restricted to the age groups of 30-49, with referral of only high risk groups (for example, two affected relatives diagnosed at an average age of less than 50 years) outside this age group.
Airway dimensions in COPD patients: Relationship with lung functions
Authors: Zheng-Xian Chen, Jia-Wen Yang
Journal: European Respiratory Journal (2011)

Background: There is growing attention about evaluating the airway abnormality in chronic obstructive pulmonary disease (COPD) using airway dimensions.

Objective: To investigate relationship between airway dimensions measured by multi-slice spiral CT (MSCT) and lung functions in COPD patients.

Methods: 25 COPD patients and 15 healthy subjects underwent MSCT scans and pulmonary function test.The airway wall thickness (T) and airway luminal area (Ai) of apical bronchus of the right upper lobe in the CT images were measured.The ratio of T and the total diameter (T/D) and percentage of airway wall area to outer area (WA%) of the bronchus were calculated from T and Ai.Ventilation function,lung volume,airway resistance and diffusion function were detected in pulmonary function test.

Results: There were significant differences between COPD patients and healthy subjects in T/√body surface area (BSA), T/D, Ai/BSA and WA%.

View this table:

Table 1. Airway dimensions in the two groups





T/√BSA, T/D, Ai/BSA and WA% correlated with airway obstruction (FEV1%) and vital capacity (VC), T/√BSA and WA% also with airway resistance (Raw) and residual volume (RV), T/D also with Raw and diffusion function (DLCO).

View this table:

Table 2. Correlation(r) between airway dimensions and lung functions in COPD patients





Conclusions: Airway dimensions measured by MSCT correlated strongly with lung functions and provided large amount of information about the airway abnormality in COPD.
Entertainment for adult cancer patients receiving outpatient chemotherapy: Best Entertainment during Session of Therapy Program (BEST program).
Authors: J. G. Kattan, L. j. Assaker, Y. N. Greige, R. J. Aintouri
Journal: Journal of Clinical Oncology (2010)

e19692 Background: Changing OPD environment from sadness to happiness is a big challenge for cancer care givers. For the first time, a social program including games, competition, and awards is dedicated to create attraction and fun for adult patients receiving one-day chemotherapy. Methods: OPD at Saint Joseph Hospital is an independent department including 12 beds and serving around 120 chemotherapy sessions per month. BEST program included social games such as best photo, best painting, best story, etc. Each game is played for 2 months period and ended by a winner selection and awards ceremony. The program was approved by Ste Joseph ethical committee and supported by sanofi-aventis. Psychological impact of the program is measured by HADS-questionnaire. Results: BEST program was initiated in August 2009. Disposable cameras were distributed to 50 patients as part of the first game: “best photo.” Photos were collected from 22 patients. 4 photos were selected as best photo at the end of September and awards distribution was held on October 13, 2009, during a special ceremony. The second game “best story” was launched during this ceremony. Patient satisfaction is universally encountered, and the department atmosphere is already gaining more happiness. 20 patients are randomly selected to fill twice the HAD-questionnaire, first at the initiation of BEST and second during the course of the program. Impact on quality of life according to HADS-questionnaire modification will be analyzed and presented. Conclusions: psychological support is almost lacking and underestimated in our cancer treated patients. BEST program represents a unique experience and temptation in adult patients to enhance their quality of life. Primary impression of patients already included in BEST program is very encouraging. No significant financial relationships to disclose.
Hyperhomocysteinemia in cancer patients with thrombosis is independent of methylene tetrahydrofolate reductase gene mutation
Authors: M. Tobu, D. A. Hoppensteadt, J. Cunanan, O. Iqbal, M. A. Demir, J. Fareed, S. Deitcher
Journal: Journal of Clinical Oncology (2004)

6152 Background: Methylene Tetrahydrofolate reductase (MTHFR) gene mutations and nutritional factors (folic acid/ B12) are primarily responsible for the observed increase in this surrogate marker. Since, cancer patients exhibit increased prevalence of thrombotic events, we hypothesized that upregulation of homocysteine may play a role in cancer associated thrombosis. However, initial screening of cancer patients in the ONCENOX study showed that the malignancy related thrombotic state was independent of molecular defects in Factor V Leiden, Prothrombin 20210 and MTHFR variants. (Hoppensteadt et al. Pathophysiology of Hemostasis and Thrombosis 2003; 33. S1. 03 A. 56). Methods: In the same group of 102 patients who were enrolled in a randomized open label, multidose, active comparator, parallel design study (ONCENOX) and in another group of cancer free patients with thrombosis enrolled in a treatment study with low molecular weight heparin (CORTES, n=50), blood levels of homocysteine were measured using a highly specific ELISA method (Diazyme Laboratories, San Diego, CA). Results: On a cumulative basis ONCENOX patients exhibited a relatively higher level of homocysteine (11.8± 4.7 μM/L) in comparison to normal (n=140, 4.6± 2.9 μM/L) and in contrast to cancer patients exhibiting homocysteine levels (7.8± 3.1 μM/L). No difference in the MTHFR gene mutation profile was noted in the three groups. These results clearly suggest that, cancer patients with thrombosis exhibited a relatively higher level of circulating homocysteine levels which are unrelated to a molecular defect in MTHFR. Conclusions: Cancer free patients with thrombosis do not exhibit this increase in circulating homocysteine levels. Thus, other relevant factors such as the use of chemotherapeutic agents like methotrexate and purine analogs may contribute to this apparently acquired upregulation of homocysteine. This observation warrants periodic monitoring of homocysteine in patients with thrombosis and cancer. Nutritional supplementation of folic acid and B12 may be helpful in the overall management of these patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Mitsubishi; Pfizer
Abstract 16188: Is Hypertrophic Cardiomyopathy Associated With Aortopathy: An Imaging and Epidemiologic Case Control Study
Authors: Khawaja Afzal Ammar, Mirza Mujadil Ahmad, Mirza Nubair Ahmad, Rayan Yousefzai, Janardhan Krishnaswamy, Bijoy K Khandheria, Renuka Jain, A. Jamil Tajik
Journal: Circulation (2015)

Introduction: A single prior case series has raised the concern that hypertrophic cardiomyopathy (HCM) and dilated aorta (DA) may be associated due to congenital or acquired reasons. This hypothesis has never been formally tested in prior research studies. Hypothesis: To evaluate the prevalence of DA in patients with HCM. Methods: We queried echocardiography database and electronic medical record system of our large tertiary care center for DA and HCM, respectively, over the last 4 years, in adults &amp;gt15 years of age DA was defined as a sinus of Valsalva dilation (SVD), HCM was defined based on the presence of ICD 9 codes presence and cause- effect analysis was carried out with stratified analysis, followed by multivariate logistic regression analysis. Results: We found 553 patients with hypertrophic cardiomyopathy. In the echocardiography database, (SVD) measurement was available on 37,914 patients with 1035 patients with DA. The prevalence of DA was more than twice in those with HCM as compared to those without HCM (odds ratio 2.35; 95% confidence interval 1.33, 3.84; p value 0.001). This association persisted in stratified analyses for 28 causes of aortopathy, without meaningful confounding. This association persisted in a multivariate logistic regression model which included age, sex, diabetes, hypertension, dyslipidemia, smoking and aortic valve disease (odds ratio 1.87; 95% confidence interval 1.01, 3.14; p value 0.02). This association was higher in strength to that between aortic valve disease and DA (OR 2.35 vs.2.03). Conclusions: Our data support the hypothesis that HCM is associated with DA. The strength of association approaches other established causes of DA.
Preliminary safety data from a randomized trial of perioperative epirubicin, cisplatin plus capecitabine (ECX) with or without bevacizumab (B) in patients (pts) with gastric or oesophagogastric junction (OGJ) adenocarcinoma.
Authors: A. F. Okines, R. Langley, F. H. Cafferty, S. P. Stenning, S. Falk, M. T. Seymour, D. Smith, G. W. Middleton, F. Y. Coxon, D. Cunningham
Journal: Journal of Clinical Oncology (2010)

4019 Background: Perioperative chemotherapy is a standard of care for localised oesophagogastric cancer. B is a monoclonal antibody targeting vascular endothelial growth factor (VEGF), a potent regulator of angiogenesis. Tumour VEGF expression and high preoperative serum VEGF are independent predictors of poor prognosis for resected gastric cancer. ST03 is an ongoing randomised phase II/III trial of perioperative ECX ± B in pts with operable gastric or OGJ adenocarcinoma. Methods: Pts receive 3 preoperative and 3 postoperative ECX ± B 7.5 mg/kg, then 6 × maintenance B in the experimental arm only. The Independent Data Monitoring Committee undertook a preplanned review of preliminary safety data relating to preoperative chemotherapy and surgery for the first 104 pts. We present these data here to reassure clinicians and patients involved in the trial. Results: 43 ECX and 42 ECX + B pts have completed preoperative chemotherapy, 38 (88%) and 37 (88%) respectively received all 3 cycles. Of the 10 pts who received < 3 cycles, 7 (3 ECX, 4 ECX+B) stopped due to toxicity. B was administered in all preoperative cycles in the ECX + B arm. 7 ECX and 4 ECX + B patients experienced a total of 12 notable adverse events during preoperative chemotherapy: venous thromboembolic events (5 ECX, 1 ECX+B), gastric perforations (1 ECX, 1 ECX+B), haemorrhagic events (1 ECX, 1 ECX + B), hypertension (1 ECX + B) and wound complication from previous laparoscopy (1 ECX + B). Surgical data on the first 104 pts are immature but will be complete at the time of presentation. 51 (27 ECX, 24 ECX + B) pts have undergone gastrectomy. 6 pts (3 ECX, 3 ECX + B) had postoperative wound healing complications. 2 ECX + B pts had other notable events (reversible posterior leucoencephalopathy syndrome possibly due to B + microangiopathic haemolytic anaemia due to disease progression in the bone marrow). Conclusions: Preliminary safety data indicate acceptable and similar rates of complications in the 2 arms. 154 pts have been randomised to Jan. 8, 2010; safety and feasibility of ECX + B will be formally assessed when 200 pts have completed preoperative treatment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche Roche