tbuckley/cabot-search huggingface dataset:
IMPS-38CETUXIMAB THERAPY REQUIRES IMMUNE STIMULATION FOR EFFICACY IN PEDIATRIC GLIOBLASTOMA
Authors: Andrea Griesinger, Alexandra Sufit, Katharina Wyns, Jean Mulchahy Levy, Andrew Donson, Michael Handler, Nicholas Foreman
Journal: Neuro-Oncology (2015)

Pediatric glioblastoma (GBM) patients have <10% 5-year survival rate, and numerous experimental therapeutic approaches have failed to significantly improve survival. Effective therapies will therefore require a better understanding of the tumor and its environment. Myeloid cells and t-cells are increased in GBM compared to normal brain tissue, and have been shown to be immunosuppressive. This immunosuppressive tumor microenvironment will negatively impact immunotherapeutic approaches, such as EGFR-targeted antibody treatments, notably EGFR-targeted cetuximab and nimotuzumab. This class of antibodies has shown modest activity in pediatric GBM and we propose that adjuvant immune stimulatory treatment, to reverse inherent immunosuppression, will be required for improved efficacy. Here we investigate the effect of cetuximab in GBM cell line/immune effector cell co-cultures with and without immune stimulating adjuvants, IL-2 and GM-CSF. Different GBM cell lines were co-cultured with HLA-matched allogenic peripheral blood mononuclear cells and treated with cetuximab, GM-CSF, IL-2, or combinations of these. Cetuximab alone had no effect on cytotoxicity. However, addition of immune stimulants to cetuximab resulted in cytotoxicity in GBM cells as measured by accumulation of cleaved caspase 3/7. Combination of cetuximab with both GM-CSF and IL-2 resulted in the greatest cytotoxicity. Additionally, and ex-vivo pediatric GBM organotypic slice culture model was used to better evaluate immunotherapeutic strategies. Organotypic slice cultures contain patient, therefore autologous, infiltrating myeloid cells and t-cells, providing a clinically relevant model of GBM. The slices were treated for 10 days and followed by flow cytometric measurement of proliferation and cell death. Cetuximab alone reduced growth of tumor cells and also reduced cell death. Combination therapy of GM-CSF, IL-2, and cetuximab, however, increased immune cell proliferation, and reduced tumor cell proliferation and increased tumor cell cytotoxicity. We suggest that cetuximab, along with any other therapeutic antibody approach, requires combination immune stimulation in the treatment of GBM.
Changes in Diabetes-Related Complications in the United States, 1990–2010
Authors: Robert Motzer, Thomas Hutson, Lauren Mccann, Toni Choueiri
Journal: New England Journal of Medicine (2014)

correction a group of patients with intermediate-risk disease (hazard ratio for death with pazopanib, 0.90; 95% CI, 0.74 to 1.09), and the median overall survival was 9.9 months among 67 patients who received pazopanib (95% CI, 7.3 to 12.3) and 7.7 months among 52 patients who received sunitinib (95% CI, 5.4 to 11.9) in a group of patients with poorrisk disease (hazard ratio for death with pazopanib, 0.85; 95% CI, 0.56 to 1.28).Thirty-four patients who received pazopanib (6%) and 23 patients who received sunitinib (4%) continued on-study treatment.The median ontreatment period was 8.1 months for pazopanib and 7.6 months for sunitinib.The two most common reasons for treatment discontinuation were disease progression (in 311 of 554 patients who received pazopanib [56%] and in 329 of 548 patients who received sunitinib [60%]) and adverse events (in 132 of 554 patients who received pazopanib [24%] and 107 of 548 patients who received sunitinib [20%]).Safety results were consistent with those reported in our article. 1Post-study antiangiogenesis agents or inhibitors of the mammalian target of rapamycin were administered in 306 patients who received pazopanib (55%) and in 299 patients who received sunitinib (54%).In summary, similar overall survival outcomes support the findings of the primary analysis of progression-free survival, which showed the noninferiority of pazopanib versus sunitinib as firstline treatment for clear-cell renal-cell carcinoma.
Androgen deprivation therapy for biochemical recurrence in patients with seminal vesicle invasion after radical prostatectomy
Authors: F. P. Secin, F. J. Bianco, A. J. Vickers, P. Sogani, H. I. Scher, P. T. Scardino
Journal: Journal of Clinical Oncology (2005)

4655 Background: Tumor invasion into the seminal vesicles (SVI) after radical prostatectomy (RP) represents an unfavorable finding with high reported rates for PSA progression (40–95%). The best time to initiate androgen deprivation therapy (ADT) is unknown. Our aim was to describe the use of ADT and impact on survival for men with SVI whom their PSA rise after RP. Methods: Data was prospectively collected in 5,377 men with clinically localized prostate cancer who had RP in the PSA era. No patient received any treatment before surgery. The analysis was tailored to men with SVI and negative nodal disease (n=296). PSA progression (BCR) was defined by a rise in PSA after RP. The Kaplan-Meier method was employed to estimate freedom from ADT and survival after ADT. Cox-regression tested for risk factors of cancer survival (CSS) after ADT. Results: One hundred and thirty-nine men had BCR after a median time of 4.1 (95%CI, 2.5–5.7) years, 79 (57%) of these were treated with ADT after a median time of 3.4 years and 26% were free from ADT by 10 years. The median time of response to ADT after BCR was 8.6 years and the actuarial 10 year CSS was 58% (95%CI, 46–70%) as 18 men died from their prostate cancer. Eight men died of other causes while palliated with ADT, by 10 years 20% were likely to die with but not from their disease. We tested the effect of the Gleason score, time to BCR, PSADT, and presence of metastasis before ADT on survival in univariable analysis. None of those risk factors provided incremental value. However, men who nadired their PSA to undetectable levels after ADT had 73% less risk of dying from their cancers v. those with detectable post ADT PSA nadirs. Conclusions: Up to 35% of men with SVI are free from recurrence 10 years after surgery. Of those a significant proportion will be free from androgen ablation. Those whom receive ADT respond for a long time, especially if their PSA nadirs to undetectable levels. No significant financial relationships to disclose.
Case 20-2001
Authors: Dimitrios P. Kontoyiannis, James Versalovic
Journal: New England Journal of Medicine (2001)

Presentation of CaseA 64-year-old man was admitted to the hospital because of fever and bacteremia.The patient had had hypertension for 20 years, type 2 diabetes mellitus for 16 years, and coronary disease for 7 years, with a history of myocardial infarction and congestive heart failure. He also had proteinuria (+++) and mild, chronic renal insufficiency.He had otherwise been well until three weeks before admission, when he was traveling in the Middle East and began to have fever (peak temperature, 39.0°C), with fatigue and weight loss. Ten days before admission, treatment with ciprofloxacin (500 mg daily) was begun. . . .
Long noncoding RNA signatures define oncogenic subtypes in T-cell acute lymphoblastic leukemia
Authors: A Wallaert, K Durinck, W Van Loocke, I Van de Walle, F Matthijssens, P J Volders, F Avila Cobos, D Rombaut, P Rondou, P Mestdagh, J Vandesompele, B Poppe, T Taghon, J Soulier, P Van Vlierberghe, F Speleman
Journal: Leukemia (2016)
The Marketplace in Health Care Reform -- The Demographic Limitations of Managed Competition
Authors: Richard Kronick, David C. Goodman, John Wennberg, Edward Wagner
Journal: New England Journal of Medicine (1993)

The theory of managed competition holds that the quality and economy of health care delivery will improve if independent provider groups compete for consumers. In sparsely populated areas where relatively few providers are required, however, it is not feasible to divide the provider community into competing groups. We examined the demographic features of health markets in the United States to see what proportion of the population lives in areas that might successfully support managed competition.
Case 7-1996
Authors: G.L. Holmes, M.P. Frosch
Journal: New England Journal of Medicine (1996)

Presentation of CaseAn eight-year-old, right-handed boy was admitted to the hospital because of intractable seizures.The child sat at the age of 7 months, walked at 14 months, and talked meaningfully at 24 months. At the age of four years he began to have episodes of up to 30 seconds during which he held his hands over his ears, walked aimlessly, spoke nonsensically, and then fell asleep. Carbamazepine controlled the attacks initially. When he was seven years old valproate was substituted, without benefit.Sixteen months before admission, treatment with phenytoin was begun, with a decrease in the frequency of . . .
Retinitis Pigmentosa and Ataxia Caused by a Mutation in the Gene for the α-Tocopherol–Transfer Protein
Authors: Takanori Yokota, Toshiaki Shiojiri, Takanari Gotoda, Hiroyuki Arai
Journal: New England Journal of Medicine (1996)

To the Editor: The α-tocopherol–transfer protein (α-TTP) is presumed to function in the intracellular transport of α-tocopherol, the most biologically active form of vitamin E. We described a patie...
Lack of Effect of 2-Chlorodeoxyadenosine Therapy in Patients with Chronic Lymphocytic Leukemia Refractory to Fludarabine Therapy
Authors: Susan O'Brien, Hagop Kantarjian, Elihu Estey, Charles Koller, Bud Robertson, Miloslav Beran, Michael Andreeff, Sherry Pierce, Michael Keating
Journal: New England Journal of Medicine (1994)

Fludarabine and 2-chlorodeoxyadenosine are nucleoside analogues that have proved effective in patients with chronic lymphocytic leukemia (CLL). Although their mechanism of action is thought to be similar, a small number of patients who do not respond to fludarabine do respond to 2-chlorodeoxyadenosine. The extent to which 2-chlorodeoxyadenosine is effective in patients who do not respond to fludarabine is not known, however.
Predictors of Outcome in Bladder Cancer
Authors: John B Eifler, Daniel A Barocas, Matthew J Resnick
Journal: Journal of the National Comprehensive Cancer Network (2014)

Tumor stage and grade have largely been responsible for directing treatment algorithms in bladder cancer. However, the considerable heterogeneity of tumor biology in bladder cancer is incompletely characterized by stage and grade alone, and recent efforts to improve predictive models in bladder cancer may significantly improve accuracy and calibration. This article addresses how current nomograms and risk tables may be best used to individualize bladder cancer management.
The 24-Hour Dexamethasone Suppression Test in a Clinical Setting: Relationship to Diagnosis, Symptoms, and Response to Treatment
Authors: Walter Armin Brown, Robert Johnston, Demmie Mayfield
Journal: American Journal of Psychiatry (1979)

Of 54 male psychiatric patients undergoing dexamethasone suppression tests in a clinical setting, 40% of those with a major depressive disorder showed escape from suppression over the 24 hours after dexamethasone administration, while all of the patients with schizophrenia, neurosis, alcoholism, and drug abuse showed normal pituitary-adrenal suppression. Only 10% of the depressed patients showed resistance to suppression 8 hours after dexamethasone administration. There was no difference between depressed patients who did and did not show escape from suppression in type of previous episodes, family history, symptoms, or medication. However, those who showed escape tended to respond better to treatment and to be rated as having a more severe depression. The theoretical and clinical implications of these findings are not yet clear.
Is the United States Prepared for a Major Zika Virus Outbreak?
Authors: Lawrence O. Gostin, James G. Hodge
Journal: JAMA (2016)

From its initial discovery in Ugandan forests nearly 70 years ago, Zika virus has emerged as a worldwide public health crisis, with active transmission in more than 40 countries in the Americas and Caribbean.On February 1, 2016, the World Health Organization (WHO) declared a PublicHealthEmergencyofInternationalConcern(PHEIC), concerned about clusters of microcephaly and Guillain-Barré syndrome (GBS).A week later, the Centers for Disease Control and Prevention (CDC) triggered the highest "level 1" activation of its emergency operations center, and President Obama requested $1.86 billion in emergency funding. 1 On April 7, the WHO reported there is scientific consensus that Zika is a cause of microcephaly and GBS.Although none of the continental states has reported local mosquito-borne transmission, Health Secretary Sylvia Burwell warned that Zika has a "significant potential to affect national security or the health of Americans." 2 The virus severely threatens Puerto Rico, with one-quarter of its 3.5 million inhabitants projected to be infected. 3The Olympics in Brazil will have an amplifying affect because the competition will be during the Northern summer.Travelers visiting or returning to the United States could likely escalate the spread of Zika.Epidemiologists estimate that Zika could affect a majority of US states including large cities where Aedes species mosquitos are active.Epidemiologists estimate that Zika could affect a majority of US states including large cities where Aedes species mosquitos are active.
Impact of Harvested Lymph Nodes Count on Staging and Survival at Radical Resection for Non-Small Cell Lung Cancer: a Minimum of 14 Lymph Nodes Should Be Sampled
Authors: W. Liang, H. Pan, Q. Wang, L. Liu, G. Jiang, D. Liu, Z. Wang, Z. Zhu, J. He
Journal: Annals of Oncology (2014)
Decision Making by Analogy
Authors: D L Greenberg, R K Root
Journal: New England Journal of Medicine (1995)

A 27-year-old woman with a history of seizures since childhood was brought to the emergency department because of sharp left anterior pleuritic chest pain, a productive cough, increasingly severe shortness of breath, nausea, and one episode of vomiting. She had no fever, chills, sweats, diarrhea, dysuria, edema, orthopnea, or weight change. She had been ill only one day.The first thing I would worry about with the history of chest pain, productive cough, and shortness of breath is some sort of infection, possibly pneumonia. I would want to know about any recent seizure that might have predisposed her . . .
Absence of Therapeutic Benefit from Antacids or Cimetidine in Non-Ulcer Dyspepsia
Authors: Olof Nyrén, Hans-Olov Adami, Sandra Bates, Reinhold Bergström, Sven Gustavsson, Lars Lööf, Anders Nyberg
Journal: New England Journal of Medicine (1986)

We randomly assigned 159 patients with non-ulcer dyspepsia, defined as chronic or recurrent epigastric pain without concomitant symptoms of the irritable bowel syndrome and with no evidence of organic disease, to treatment for three weeks with an antacid suspension one and three hours after meals, 400 mg of cimetidine twice a day, or placebo, according to a double-blind, double-dummy model. The intensity and duration of epigastric pain were recorded by the patients four times daily during a one-week period without therapy and during the three weeks of treatment. The mean reduction in pain intensity after three weeks in the placebo group was 25 percent. Neither antacid nor cimetidine treatment resulted in more than a 4 percent better effect. The reduction of pain was statistically significant (P less than 0.01) in all three groups. The time course of the pain scores in the groups receiving active drugs followed closely those in the placebo group, and there were no significant differences between the groups at any stage of the treatment. We conclude that the neutralization or suppression of gastric acid is of no clinical value in patients with this syndrome.
Pulse Registration in the Study of Peripheral Arterial Disease
Authors: Edward A. Edwards, Leslie Ottinger
Journal: New England Journal of Medicine (1958)

THIS is a report of the volume pulses as registered from several levels of the limbs through the application of pneumatic cuffs connected to a transducing system. Such a method differs from plethysmography in that the individual pulse trace is here the object of scrutiny. There are reports in the literature of similar studies, but for the most part they are based on the recording of the pulse from a single site, such as the digit, or from the brachial or femoral arteries by means of needle puncture.Six normal subjects, as well as 50 patients, have been studied in . . .
Quality of life in patients with chronic thromboembolic pulmonary hypertension
Authors: Stephen C. Mathai, Hossein-Ardeschir Ghofrani, Eckhard Mayer, Joanna Pepke-Zaba, Sylvia Nikkho, Gérald Simonneau
Journal: European Respiratory Journal (2016)

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) experience debilitating symptoms that have a negative impact on their quality of life (QoL) in terms of physical capability, psychological wellbeing and social relationships. The use of QoL measurement tools is important in the assessment of treatment efficacy and in guiding treatment decisions. However, despite the importance of QoL, particularly to the patient, it remains under-reported in clinical studies of CTEPH therapy. CTEPH is unique in pulmonary hypertension in that it is potentially curable by surgery; however, a proportion of patients either have residual PH following surgery or are not operable. Although some patients with CTEPH have been treated off-label with pulmonary arterial hypertension-specific therapies, there have been few randomised controlled trials of these therapies in patients with CTEPH. Moreover, in these trials QoL outcomes are variably assessed, and there is little consistency in the tools used. Here we review the assessment of QoL in patients with CTEPH and the tools that have been used. We also discuss the effect of surgical intervention and medical therapies on QoL. We conclude that further studies of QoL in patients with CTEPH are needed to further validate the optimal QoL tools.
Abstract POSTER-BIOL-1352: Notch3 promotes anoikis resistance in ovarian cancer
Authors: Caitlin W. Brown, Alexander S. Brodsky, Richard N. Freiman
Journal: Clinical Cancer Research (2015)

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. Recently, a number of genome-wide studies in ovarian cancer patient samples have postulated that the course of disease can influenced by the Notch3 signaling pathway. In one study, 11% of human tumor samples showed mutation or amplification of the Notch3 receptor alone. Subsequent papers have correlated Notch3 overexpression in human samples with shorter progression-free survival as well as overall survival. In vitro studies have shown Notch3 to be involved in apoptosis resistance and chemoresistance, as well as cell cycle alterations. Together, these human studies have implicated Notch3 expression and amplification with decreased outcomes in ovarian cancer patients. To test the potential mechanism by which Notch3 over-expression promotes ovarian cancer, we examined several molecular and cellular functions of Notch3 in ovarian cancer cells. Decreasing the levels of Notch3 in ovarian cancer cells increases the susceptibility of these cells to apoptosis, which is consistent with previous studies. Using an effective siRNA-mediated knockdown of Notch3 combined with transfer to ultra-low attachment plates revealed a significant decrease in the ability of Notch3-knockdown IGROV-1 cells to remain viable in anchorage-independent conditions over 24 hours. Our data show that not only does Notch3 prevent apoptosis, but specifically promotes anoikis resistance. Further examining the mechanism underlying this novel finding revealed the positive roles of extracellular matrix proteins and FAK in promoting the anchorage-independent growth of IGROV-1 cells. Strikingly, mRNA and protein levels of col4α2 are reduced when Notch3 levels are decreased and exogenous collagen IV supplementation can largely reverse the anoikis sensitivity. Reduction of col4α2 expression by siRNA induces cell death on its own and high Notch3 expression levels correlate with higher col4α2 expression in human ovarian tumor samples. Together, these studies have revealed that Notch3 promotes anoikis resistance through col4α2 expression and may partly explain its positive correlation with poor survival in ovarian cancer patients. Citation Format: Caitlin W. Brown, Alexander S. Brodsky, Richard N. Freiman. Notch3 promotes anoikis resistance in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1352.
A novel occluder for endoscopic closure of gastrotomy: an ex vivo and in vivo animal study
Authors: Ji Kim, Bo-In Lee, Sung Lee, Joon Kim, Myong Baeg, Jae Park, In-Seok Lee, Byung-Wook Kim, Sang Kim, Hwang Choi, Myung-Gyu Choi
Journal: Endoscopy (2016)

<b>Background and aims:</b> We evaluated the feasibility of a novel occluder for endoscopic closure of natural orifice transluminal endoscopic surgery (NOTES) gastrotomy. <b>Methods:</b> The occluder is a self-expandable, membrane-covered, metal structure for endoscopic delivery through gastrointestinal (GI) wall defects. The procedure time and air-tightness of endoscopic closure for a 12-mm perforation were compared for a through-the-scope clip group and an occluder group in an ex vivo animal study. The feasibility and safety of the occluder for the closure of NOTES gastrotomy were also evaluated in an in vivo animal study. <b>Results:</b> In the ex vivo study, the median procedure time for closure was significantly shorter and the minimum air-leakage pressure was significantly greater in the occluder group than in the endoclip group. In the in vivo study, immediate air-tight sealing was achieved by application of the occluder and there were no serious adverse events. All animals showed spontaneous detachment of the occluder into the gastric lumen and complete healing within 4 – 8 weeks. <b>Conclusions:</b> The novel occluder can provide immediate and permanent sealing for NOTES gastrotomy.
A Comparison of Early-Onset Group B Streptococcal Neonatal Infection and the Respiratory-Distress Syndrome of the Newborn
Authors: Ronald C. Ablow, Shirley G. Driscoll, Eric L. Effmann, Ian Gross, Christopher J. Jolles, Ricardo Uauy, Joseph B. Warshaw
Journal: New England Journal of Medicine (1976)

In attempting to differentiate early-onset Group B streptococcal infection from hyaline-membrane disease we found features of severe Group B infection to be rupture of the membranes for more than 12 hours before delivery (four or eight versus one of nine), gram-positive cocci in the gastric aspirate (four or four versus none of one), apnea and shock in the first 24 hours of life (seven of eight versus none of nine), and the generation of lower peak inspiratory pressures on avolume-cycled respirator (mean of 36.5 +/- 2.8 versus 63.9 +/- 6.2 cm of water; P = 0.005). In eight fatal cases of Group B infection, four patients had radiographic features indistinguishable from hyaline-membrane disease whereas the other cases were consistent with neonatal pneumonia. Seven of the eight infected infants had no histologic evidence of coexisting hyaline-membrane disease. Microscopical features of Group B infection included cocci in unevenly distributed hyaline membranes and minimal atelectasis. Group B streptococcal infection differs clinically and pathologically from hyaline-membrane disease. Differentiating clinical features include early apnea and shock and lower inspiratory pressures on mechanical ventilation.