tbuckley/cabot-search huggingface dataset:
Abstract P3-11-10: Response to subsequent therapies after failure to achieve pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) in patients (pts) with triple negative breast cancer (TNBC)
Authors: Shalu Pahuja, Kandace McGuire, Nancy Davidson, Adam Brufsky, Priya Rastogi, Rachel Jankowitz, Barry Lembersky, Shannon Puhalla
Journal: Cancer Research (2015)

Abstract Background: More than half of pts with TNBC do not achieve a pCR after NAC, which carries a poor prognosis. It is unclear whether these patients respond to subsequent therapies on relapse. We sought to determine the time to progression (TTP) on subsequent therapies for recurrent disease in TNBC patients who did not achieve pCR to neo-adjuvant therapy. Methods: We retrospectively identified 117 TNBC pts who received NAC from 2009 through 2012 using an electronic database at the Magee Women’s Breast Cancer Program at the University of Pittsburgh. Patient records were then assessed for pts who did not achieve a pCR for time to local or distant recurrence (TTR) and time to progression (TTP) on susbequent therapies. Results: 86 of 117 TNBC pts did not achieve pCR to NAC defined as residual disease present in either the breast and/or axilla. Median follow up was 2 yrs (range 1-4yrs). Out of these 86 pts, 21 pts(25%) had recurrence in form of distant metastasis or local recurrence. Nearly all pts(95%) received anthracycline and taxane based NAC. Median TTR was 19 months (4-29 months). Therapies received in the metastatic setting most commonly included single agent capecitabine, paclitaxel, nab-paclitaxel, and eribulin. The most commonly received doublets included carboplatin with paclitaxel or gemcitabine. Median TTP on systemic chemotherapy was 15 weeks (3 -39 weeks), 6 weeks (1-24 weeks) and 6 weeks (2-9 weeks) in first, second and third line setting, respectively. Greater than 80% pts were able to receive two lines of systemic chemotherapy but &amp;lt;50% received third line treatment. Two pts died before initiating any systemic treatment. Conclusions: Response to subsequent chemotherapeutic regimens in metastatic setting in TNBC pts who do not achieve pCR to anthracycline and taxane based NAC is limited. This highlights the importance of identifying new agents and targeted therapies for this poor prognosis sub-type. Citation Format: Shalu Pahuja, Kandace McGuire, Nancy Davidson, Adam Brufsky, Priya Rastogi, Rachel Jankowitz, Barry Lembersky, Shannon Puhalla. Response to subsequent therapies after failure to achieve pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) in patients (pts) with triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-10.
Conflict of interest
Authors: C K Connolly
Journal: BMJ (1996)

time, which contrasts with a finding of an earlier study by them of similar duration, which indicated that the slope of the fall in glomerular filtration flattens if antihypertensive treatment is continued for a long time.'Because of possible hidden biases in observational studies it is premature to recommend special treatment for patients with diabetic nephropathy who are homozygous for the deletion polymorphism until prospective randomised studies have been carried out.
Abstract MP83: Post-traumatic Stress Disorder Symptoms and Increased Risk of Cardiovascular Disease: What Happens When Symptoms Remit?
Authors: Paola Gilsanz, Jennifer A Sumner, Ashley Winning, Andrea L Roberts, Jessica C Agnew-Blais, Eric B Rimm, Karestan C Koenen, Laura D Kubzansky
Journal: Circulation (2015)

Introduction: Women with trauma and post-traumatic stress disorder (PTSD) are at greater risk of cardiovascular diseases (CVD); whether symptom remission is associated with less risk remains unknown. Hypothesis: Women who experience trauma and developed persistent PTSD will have increased risk of CVD, but those whose symptoms remit will not have increased risk. Methods: We examined the association between time-updated trauma exposure, PTSD symptoms, and PTSD symptom remission in relation to incident CVD over a 20-year period in 36,958 healthy women in the Nurses’ Health Study II. We used proportional hazards models to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) for CVD events confirmed by additional information or medical record review (n=402; 202 myocardial infarctions and 200 strokes). Trauma exposure was assessed using the Brief Trauma Questionnaire. PTSD symptoms were assessed using Breslau’s PTSD screen; report of 4 or more (out of 7) symptoms was characterized as clinically-rele...
Diagnostic assessment of suspected cancer: Prospective cohort study of diagnostic delay intervals across three disease sites
Authors: J. Watters, E. Grunfeld, J. Jaffey, K. O’Rourke, D. Maziak, D. Patel, C. Morash, W. K. Evans
Journal: Journal of Clinical Oncology (2006)

6029 Background: Diagnostic assessment of patients with suspected cancer can involve multiple points of delay. Methods: We conducted a cohort study of prospective eligible patients referred to a regional hospital in Ottawa, Ontario, Canada over a 12 month period (2004 to 2005) for diagnostic assessment of suspected colorectal (C), lung (L) or prostate (P) cancer. The study addressed three different disease sites, each with a different pre-existing model of care delivery, so that variability could be described. Measurement of diagnostic delay intervals included days to diagnosis (from referral to diagnosis communicated to the patient) and, for patients with cancer, to surgery and to oncology consultation. Differences between disease sites for diagnostic delay intervals, quality of life, and patient satisfaction were analyzed. Results: The proportion of patients who were diagnosed with cancer was: 6.8% (9/132) for C; 80.2% (81/101) for L; and 35% (41/116) for P. The mean [SD] days to diagnosis was significantly less for L (45 [32]) than for either C (81 [68]) for P (82 [43]), (p=.0001). It was also significantly less for patents diagnosed with cancer (57.8)[41.4]) than for those without cancer (79.3)[58.9]) (difference -21.5; 95% CI -33 to -9; p=.0003); a finding which held when C was analyzed separately (33.8 [48.9] vs 84.8 [67.7]; p=.04). L patients had worse physical and mental functioning as measured by the SF36 Physical and Mental Component Scores. Patient satisfaction did not differ across disease site or for patients with and without cancer. Conclusions: Most studies of diagnostic delay intervals use administrative data. This study is unique in prospectively measuring intervals that cannot be captured from administrative data and thus provides important benchmark measures. L patients were most likely to have cancer. Although C patients were unlikely to have cancer, the diagnostic interval was substantially shorter in those with cancer than in those without, suggesting that clinicians have an effective process for triaging patients referred for diagnostic assessment. No significant financial relationships to disclose.
Nicotinamide and bacterial killing in patients with non-cystic fibrosis bronchiectasis
Authors: Hsien-Cheng Chang, Ahmed Omar, Simon Swift, Alain C. Vandal, George Liu, Pierre Kyme, Conroy Wong
Journal: European Respiratory Journal (2014)

Introduction:   In vitro  studies show that 1mmol/L nicotinamide (NAM) increases neutrophil-mediated killing of  Staphylococcus aureus and Pseudomonas aeruginosa .  Aims:  To assess the dose of orally administered NAM required to achieve a serum level of 1mmol/L. To assess the effect of NAM  in vivo  on up-regulation of neutrophil function and bacterial killing.  Methods:  Participants were given oral NAM for two weeks at twice daily doses of 1.5g, 2g, 2.5g, or 3g, with one healthy and one bronchiectasis participant for each dose. The primary end point was peak serum NAM level. The secondary endpoints were levels of C/EBPe, lactoferrin and cathelicidin expression in neutrophils, and the number of surviving bacterial colony-forming units (CFUs) after incubation of four respiratory pathogens with blood from participants.  Results:  The highest peak concentration of NAM achieved was 0.3mmol/L in the 3g twice daily dosing. NAM significantly enhanced blood killing of  Streptococcus pneumoniae,  with the adjusted estimate of relative change in CFUs per 0.1mmol/L increase in serum NAM levels being 0.44 (95% CI 0.34 to 0.56). NAM increased the CFUs of  P. aeruginosa  (1.34, 95%CI 1.17 to 1.54), and did not significantly enhance blood killing against  S. aureus  or  Haemophilus influenza.  NAM did not augment the expression of the neutrophil transcription factor C/EBPe or downstream antimicrobial peptides cathelicidin and lactoferrin.  Conclusion:  Doses of oral NAM up to 3g twice daily did not achieve the serum concentration of 1mmol/L. At lower concentrations, NAM significantly enhanced bacterial killing against  S. pneumoniae,  but did not enhance the expression of neutrophil markers.
Nuclear Export Inhibitors (NEIs) as Novel Cancer Therapeutics
Authors: Sarah Mutka, Shannon Ward, WenQing Yang, Sumati Murli, Robert Johnson, Pieter Timmermans
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

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CRM1 is an essential nuclear export protein responsible for shuttling a wide variety of important “cargo” proteins (e.g. p53, BCR-Abl, FOXO-3a) out of the nucleus and into the cytoplasm. Leptomycin B and its analogs are potent nuclear export inhibitors (NEIs) which derive their activity through the direct inhibition and covalent modification of CRM1. Analyses of the in vitro and in vivo activities of NEIs have revealed that CRM1 is a novel target for the treatment of cancer. NEIs cause the rapid nuclear accumulation of CRM1 cargo proteins in vitro . Nuclear export inhibition is rapidly observed (within 15 to 30 minutes) at drug concentrations as low as 10 nM, and the export blockade is long-lasting (greater than 24 hours). Activation of many CRM1 cargo proteins in the nucleus can lead to inhibition of proliferation, and treated cells arrest in the G1 phase of the cell cycle. Furthermore, exposure to NEIs also leads to an increase in multiple markers of apoptosis including plasma membrane alterations (Annexin V binding) and caspase activation. Comparisons of p53 wild-type and dominant negative pairs of tumor cell lines demonstrate that p53 wild-type cell lines are particularly sensitive to NEI-induced apoptosis. Induction of apoptosis is observed in tumor derived cell lines (e.g. SiHa, HCT-116 and LNCaP), but not normal cells (e.g. MRC5, WI-38, and IMR-90). NEIs show potent activity as single agents in multiple in vivo tumor models. Moreover, this mechanism may also have numerous applications in combination therapies, as NEIs are synergistic when combined with a broad spectrum of cancer therapeutics in in vitro experiments. Because of their novel mechanism of action, potent activity both in vitro and in in vivo tumor models, and promising application for combination therapies, NEIs have excellent potential as anti-cancer agents.
Intracellular Signaling Events in CD77-Mediated Apoptosis of Burkitt's Lymphoma Cells
Authors: Samir Taga, Karine Carlier, Zohair Mishal, Corinne Capoulade, Marianne Mangeney, Yann Lécluse, Dominique Coulaud, Cécile Tétaud, Linda Louise Pritchard, Thomas Tursz, Joëlle Wiels
Journal: Blood (1997)

Abstract In the hematopoietic system CD77, a glycolipid surface antigen, is restricted to group I Burkitt's lymphoma (BL) cell lines and a subset of germinal center B lymphocytes. Recently, we have reported that recombinant B subunits of Verotoxin, which specifically binds to CD77, induce programmed cell death of CD77+ BL cells. Here, we show that an anti-CD77 monoclonal antibody (38.13) immobilized on tissue culture dishes also induces apoptosis, and we have explored the signal transducing events leading to this cell death. We show that ligation of CD77 antigen causes an increase of the intracellular Ca2+ concentration owing to an influx of extracellular Ca2+ through calcium channels. Chelation of extracellular Ca2+ with EGTA partially prevents anti-CD77–induced apoptosis, indicating that this process is probably Ca2+ dependent. We show that the cross-linking of CD77 provokes an increase of intracellular cAMP levels followed by cAMP-dependent protein kinase activation. We report that BL cells produce ceramide when they are exposed to 38.13 but, unexpectedly, without a concomitant decrease in sphingomyelin or CD77 content. Finally, we provide evidence that C2-ceramide, calcium ionophore, and forskolin (which increases intracellular levels of cAMP) independently induce apoptosis of CD77+ BL cells and, moreover, that C2-ceramide and forskolin strongly synergize to cause cell death. The possible role of CD77-mediated apoptosis in the B cell selection that occurs in germinal centers is discussed.
Concurrent chemoradiotherapy (crt) with weekly docetaxel (d) for advanced head and neck cancer
Authors: G. López-Argumedo, G. López-Vivanco, R. Fernández, I. Díaz de Corcuera, A. Sancho, I. Rubio, A. Martínez-Bueno, J. Mañé, A. Muñoz, R. Barceló
Journal: Journal of Clinical Oncology (2006)

15516 Background: Concomitant CRT has become a standard treatment for advanced head and neck cancer. The aim of this study was to evaluate the efficacy and toxicity of concurrent CRT with D in patients (pts) with advanced squamous cell carcinoma of head and neck (SCCHN). Methods: Patients with untreated and unresectable stage III or IV (M0) squamous cell carcinoma of head and neck were included. Treatment consisted of D 20 mg/m 2 weekly with concomitant radiotherapy 70 Gy (2 Gy per day, 7 weeks). Results: From September 03 to October 05, sixty-four pts with advanced SCCHN, were recruited. Gender: 61 male, 3 female. Mean age: 56.5 years old (range 42–77). ECOG PS 0/1/2: 0/57/7. Primary sites of disease: oral cavity 8, oropharynx 26, hypopharynx 15 and larynx 15. Stage III 16 pts and stage IV 48 pts. Compliance: 393 administrations of D were given, median 6, mean 6 (range 1–8). Fifty-five pts (86%) completed the radiotherapy dose planned (mean dose of RT was 66 Gy). One refused more treatment with D after first administration. Nineteen pts required supportive percutaneous gastrostomy or nasogastric tubes previously or during therapy. Grade 2/3/4 toxicity per patient: anemia 4/2/0, mucositis 21/24/0, dermatitis 21/20/0. Neither thrombopenia nor neutropenia were observed. Four pts died of aspiration pneumonia during treatment, one of gastric perforation and two of unknown causes. Fifty-six pts were evaluable for response: CR 28 (44%), PR 23 (36%), SD 2 (3%), PD 3 (5%), with an overall response rate of 80%. Median overall survival was 74.86 weeks (95% CI: 40.40–109.32) and median progression free survival was 48 weeks (95% CI: 18.80–77.20). With a median follow up of 40 weeks 34 pts (53%) were alive and 21 of them (33%) remained free of disease. Conclusions: Concurrent weekly D with conventional radiotherapy showed a high response rate. Toxicity was manageable and allowed maintaining radiotherapy administration. Taking into account poor prognostic factors of our series, survival results seem promising. No significant financial relationships to disclose.
A Heritable Missense Polymorphism in <i>CDKN2A</i> Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution
Authors: Kyle M. Walsh, Adam J. de Smith, Helen M. Hansen, Ivan V. Smirnov, Semira Gonseth, Alyson A. Endicott, Jianqiao Xiao, Terri Rice, Cecilia H. Fu, Lucie S. McCoy, Daniel H. Lachance, Jeanette E. Eckel-Passow, John K. Wiencke, Robert B. Jenkins, Margaret R. Wrensch, Xiaomei Ma, Catherine Metayer, Joseph L. Wiemels
Journal: Cancer Research (2015)

Abstract Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case–control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 × 10−9) and Hispanic children (OR, 2.77; P = 3.78 × 10−4). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS “hits” and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors. Cancer Res; 75(22); 4884–94. ©2015 AACR.
Abstract P155: Weight Gain and Insulin Sensitivity in Adults With and Without Type 1 Diabetes
Authors: Lindsey M Duca, Irene E Schauer, Janet K Snell-Bergeon
Journal: Circulation (2015)

People with type 1 diabetes mellitus (T1D) have reduced insulin sensitivity (IS), which partially explains their increased risk of cardiovascular disease. However, there is limited data on how weight gain alters IS in T1D, and so this study aimed to analyze the effect of weight change on IS components in T1D and non-diabetic (non-DM) adults. This study included 1133 adults (T1D=528 and non-DM n=605) with a mean ± SD age of 38 ± 9 years from the Coronary Artery Calcification in Type 1 Diabetes cohort, examined at baseline and after 6.2±0.6 years. Weight change was categorized as follows: weight loss (WL), lost &gt; 2%), weight stable (WS), within 2% of baseline, and weight gain (WG), &gt; 2%. Estimated IS (eIS) was calculated by a model derived from a clamp study (Table) at each visit. Multiple age and sex adjusted least squares means were calculated by weight change group and diabetes status, and progression of coronary artery calcium (CAC) was examined by logistic regression. There was a significant improvement in eIS in the T1D WL group, along with a greater reduction in triglycerides and insulin dose and increase in adiponectin compared to the other weight change groups (Table). There was significant increase in eIS among the non-DM WL group, along with a reduction in triglycerides, fasting glucose, HbA1c and DBP and an increase in adiponectin. For each 2% increase in weight, the odds ratio (OR) for progression of CAC was 1.23 (95% CI 1.1-1.4, p=0.002), after adjusting for age, sex, diabetes status, and baseline BMI and CAC. The odds of CAC progression were decreased by 40% (OR 0.6, 95% CI 0.5-0.8, p=0.0007) for each SD increase in eIS, adjusting for the same variables. In conclusion, over 6 years of follow-up, weight loss increased eIS and related factors in both people with and without T1D, but was not associated with improved Hba1c in T1D. Additionally, weight gain was associated with a greater risk and eIS with a lower risk for CAC progression, demonstrating the importance of avoiding weight gain in prevention of subclinical cardiovascular disease.
Improving Adherence to Therapy and Clinical Outcomes While Containing Costs: Opportunities From the Greater Use of Generic Medications: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians
Authors: Niteesh K. Choudhry, Thomas D. Denberg, Amir Qaseem
Journal: Annals of Internal Medicine (2015)

The discrepancy between health care spending and achieved outcomes in the United States has fueled efforts to identify and address situations where unnecessarily expensive therapies are used when less costly, equally effective options are available. The underuse of generic medications is an important example.A literature review was conducted to answer 5 questions about generic medications: 1) How commonly are brand-name medications used when a generic version is available? 2) How does the use of generic medications influence adherence? 3) What is the evidence that brand-name and generic medications have similar clinical effects? 4) What are the barriers to increasing the use of generic medications? 5) What strategies can be used to promote cost savings through greater generic medication use? This article was reviewed and approved by the American College of Physicians Clinical Guidelines Committee.Clinicians should prescribe generic medications, if possible, rather than more expensive brand-name medications.
Susceptibility of head and neck cancer to an attenuated model of the oncolytic vesicular stomatitis virus expressing suicide genes
Authors: M. Porosnicu, J. Liu, D. Lyles
Journal: Journal of Clinical Oncology (2009)

e14604 Background: The predominant loco-regional progression of head and neck squamous cell carcinoma (HNSCC) makes it suitable for testing oncolytic viruses. Recent work from several laboratories including ours has focused on developing vesicular stomatitis virus (VSV) as a replication-competent anticancer viral vector. Attenuated strains, such as M protein mutant VSV (M51R) are more likely to be promoted in clinical research. The major shortcoming of viral therapy is related to the large proportion of tumor cells remaining uninfected. We are addressing this limitation in two ways: the expression of the cytosine deaminase-uracil phosphoribosyltransferase (C:U) suicide gene by the rVSV vector, expected to produce a strong bystander effect and the exploitation of the radiosensitizing potential of the 5-FU chemo-drug produced intratumorally, as well as of the VSV virus itself. Methods: We determined the extent of defectiveness in interferon pathways and susceptibility to oncolytic VSV in a collection of HNSCC cell lines and in patient HN primary tumor cells. We employed gene array to screen for differences in gene expression in sensitive and resistant models. We have generated the rVSV-C:U and M51R-C:U viruses and we tested our collection of HNSCC cell models to infection with these viruses in the presence and absence of 5-FC. In vivo experiments were performed on a localized and on a metastatic SQ-20B model of HNSCC in nude mice. Results: 1) the primary patient HNC cells are more resistant than the HNC cell lines to the M51R-VSV; 2) the activation of IFN pathways and /or alterations of AKT pathway is contributing to resistance to VSVs. 3) Addition of the suicide gene to the attenuated VSV provided significantly more oncolytic effect in vitro and in vivo. The efficacy and the radiosensitizing potential of M51R- C:U on a nude mice model of HNSCC (SQ-20B) will be presented. Conclusions: M51R-VSV has increased efficiency and radiosensitizing effect on HNSCC models. We can define an optimal approach to testing VSV vectors for treatment of HNSCC, with a clinical trial in HNSCC patients as our next goal. Finally, we have important new information, both from cell lines and patient tissues, for proof-of-principle that cancers can down-regulate antiviral responses. No significant financial relationships to disclose.
Cisplatin in the treatment of recurrent childhood primary brain tumors.
Authors: R W Walker, J C Allen
Journal: Journal of Clinical Oncology (1988)

Thirty-three patients were treated with intravenous (IV) cisplatin (CPDD) of whom 32 were considered evaluable. There were 14 medulloblastomas, five primitive neuroectodermal tumors (PNET), nine gliomas, three ependymomas, and one germ cell tumor. The overall response rate was 13 of 32 (41%). Eleven responses (five complete [CR], five partial [PR], one mixed [MR]) were noted in the patients with medulloblastoma. The response rate within this group was 79%. Toxicity was tolerable, although it precluded further therapy in five patients.