tbuckley/cabot-search huggingface dataset:
ATNT-18A PHASE I STUDY OF MLN0128 AND BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA AND OTHER SOLID TUMORS
Authors: Lakshmi Nayak, John Hays, Alona Muzikansky, Sarah Gaffey, Khanh Do, John Hilton, Eudocia Lee, Mikael Rinne, Andrew Norden, Rameen Beroukhim, Vinay Puduvalli, Patrick Wen, L. Austin Doyle, Helen Chen, Geoffrey Shapiro, David Reardon
Journal: Neuro-Oncology (2015)

BACKGROUND: The P13K/Akt/mTOR signaling axis plays a central role in cell growth and survival in a variety of cancers. MLN0128 is an oral inhibitor of TORC1/2 complexes. Bevacizumab is a monoclonal antibody targeting VEGF with activity in some cancers. METHODS: We are conducting NCI 9552, a Cancer Therapeutic Evaluation Program (CTEP)-sponsored phase I trial of MLN0128 and bevacizumab. Eligibility criteria include histologically confirmed recurrent glioblastoma (GBM) and advanced solid tumors, >18 years old, KPS> 60, adequate bone marrow reserve and organ function. The study has 2 stages; dose escalation using a 3 + 3 design to estimate MTD/RP2D defined as the highest dose at which <2/6 patients experience dose-limiting toxicity (DLT); followed by dose expansion at MTD to include 10 patients with recurrent GBM and up to 30 with endometrial and ovarian cancer. During escalation, patients received increasing doses of oral MLN0128 beginning at 3 mg daily in combination with standard dose bevacizumab at 10mg/kg intravenously every 2 weeks in 28-day cycles. RESULTS: Thirteen patients consented for stage 1; one withdrew consent before starting study treatment. There were 7 men and 5 women. Median age and KPS were 56 years and 90. Eight patients had a diagnosis of GBM and 4, ovarian cancer. Three dose levels were evaluated, including MLN0128 at 3, 4 and 5 mg daily. At 5 mg dose level, 1/6 pts experienced a DLT of grade 3 fatigue. Two additional grade 3 events included reversible hypercholesterolemia and hypophosphatemia. Other toxicities were < grade 2. Of 8 GBM patients, 2 remain on treatment (1 complete response), 6 progressed; (median number of cycles, 3(range, 1-12). Of 4 ovarian cancer patients, 2 had partial responses,1 stable disease,1 progression. CONCLUSION: MLN0128 at 5mg oral daily in combination with bevacizumab at 10mg/kg intravenously every 2 weeks is the RP2D and well-tolerated. The dose expansion portion of the study is now enrolling.
Treatment of Advanced Non-Hodgkin's Lymphoma with Recombinant Leukocyte a Interferon
Authors: Kenneth A. Foon, Stephen A. Sherwin, Paul G. Abrams, Dan L. Longo, Mehmet F. Fer, Henry C. Stevenson, Jeffrey J. Ochs, Gino C. Bottino, Carolyn S. Schoenberger, Jacob Zeffren, Elaine S. Jaffe, Robert K. Oldham
Journal: New England Journal of Medicine (1984)

We report the results of a trial of recombinant leukocyte A interferon in previously treated patients with non-Hodgkin's lymphoma who were no longer responsive to chemotherapy. Patients received recombinant leukocyte A interferon (50X106 U per square meter of body-surface area) by intramuscular injection three times weekly for three months or longer. Forty-five patients were enrolled in the study, and 37 were evaluated for a response. Thirteen of 24 (54 per cent) evaluable patients with low-histologic-grade non-Hodgkin's lymphoma had objective responses (nine partial responses and four histologically confirmed complete responses). Two of six (33 per cent) with intermediate-grade lymphoma responded (one partially and one completely), and one of seven (14 per cent) with high-grade lymphoma had a partial response. The median duration of responses was eight months. Four of the five complete responders have continued to receive maintenance interferon and have been in complete remission for 3, 7, 9, and 12 months, respectively; one had a recurrence at a site of previous disease seven months after interferon had been stopped. Side effects were noted in most patients. All 16 responders had been heavily pretreated with combination chemotherapy, including doxorubicin in 8 of the 16. These results suggest that recombinant leukocyte A interferon may be an effective new therapy for some patients with low- and intermediate-grade non-Hodgkin's lymphoma. (N Engl J Med 1984; 311:1148–52.)
Abstract 2363: Loss of Sparc in p53-null astrocytes alters collagen deposition and promotes macrophage activation and tumor phagocytosis
Authors: Stacey L. Thomas, Chad R. Schultz, Ezekiell Mouzon, William A. Golembieski, Nancy Lemke, Laila M. Poisson, Jorge A. Gutierrez, Sandra Cottingham, Sandra A. Rempel
Journal: Cancer Research (2015)

Abstract Both the induction of SPARC expression and the loss of the p53 tumor suppressor gene are changes that occur early in glioma development. Therefore, the upregulation of SPARC may cooperate with the loss of p53 to enhance cell survival and inhibit apoptosis during glioma formation. This study determined whether the loss of Sparc in astrocytes that are null for p53 (p53-null/Sparc-null) would result in reduced cell survival and tumor formation and increased tumor immunogenicity in an in vivo xenograft brain tumor model. In vitro, the loss of Sparc in p53-null astrocytes resulted in an increase in cell proliferation (15-33%, p&amp;lt;0.01); however, there was an inhibition of growth in soft agar. Intracranial xenografts of p53-null/Sparc-wt and p53-null/Sparc-null astrocytes were assessed for tumor size, proliferation rate, and SPARC expression. At 7 days post-implantation, Sparc-null astrocytes produced significantly smaller tumors (Wilcoxon rank-sum test p = 0.0091, median = 0.709mm2 for Sparc-wt and 0.240mm2 for Sparc-null) with a significantly lower MIB-1 proliferation index (Wilcoxon rank-sum test p = 0.0345, median = 8.6% for Sparc-wt and 0.4% for Sparc-null). By CD68 and periodic acid Schiff +/- diastase staining of xenograft tumors, it was found that Sparc-null tumors had a massive infiltration of microglia/macrophages with a phagocytic appearance compared to the activated, but non-phagocytic, microglia/macrophages present within the Sparc-wt tumors. The loss of Sparc in astrocytes and the resulting increase in microglia/macrophage activation lead to an alteration in the tumor microenvironment with increased collagen deposition and altered collagen structure at both 7 and 50 days post-implantation as assessed by picrosirius red and polarized light microscopy. Sparc-null tumors had increased collagen deposition with a long fiber structure compared to the small bundles of collagen present in Sparc-wt tumors. Our results indicate that the loss of p53 by deletion/mutation in the early stages of glioma formation may cooperate with the induction of SPARC to potentiate cancer cell survival and escape from immune surveillance. Citation Format: Stacey L. Thomas, Chad R. Schultz, Ezekiell Mouzon, William A. Golembieski, Nancy Lemke, Laila M. Poisson, Jorge A. Gutierrez, Sandra Cottingham, Sandra A. Rempel. Loss of Sparc in p53-null astrocytes alters collagen deposition and promotes macrophage activation and tumor phagocytosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2363. doi:10.1158/1538-7445.AM2015-2363
Portal hypertension
Authors: J. Osterwalder
Journal: BMJ (2001)

Many orthopaedic surgeons do not think of patients just as malfunctioning elbowsEditor-As an orthopaedic surgeon specialising entirely in elbow and shoulder disorders I could not let the editor's choice on restoring the soul of medicine slip by without comment. 1Unlike the orthopaedic surgeon you refer to, I do read the BMJ each week (although I confess that my wife, a paediatrician, pays the subscription).I also note that in the editorial from the previous week on shoulder pain at work the one year prevalence of shoulder pain in the general population was estimated to be 20-50%, but only 40-50% of those affected consult a primary care physician, let alone an orthopaedic surgeon. 2 Most musculoskeletal complaints are influenced, if not caused, by circumstances of daily life.This is not just physical activity but psychosocial factors, including job pressures and stress at home.The commonest elbow complaint is tennis elbow.It is a considerable problem to those who have it; symptoms are undoubtedly influenced by a range of factors, and it is eminently suited to an integrated management approach.Those affected should consider changing the pattern of their lives, reduce stress, and seek advice and help from complementary and conventional practitioners, and they may even benefit from seeing an orthopaedic surgeon.Orthopaedic surgeons should read the BMJ, but equally the BMJ should be aware that many orthopaedic surgeons do not think of patients just as malfunctioning elbows.
Cyclic Premenstrual Congestive Heart Failure
Authors: Max G. Sherer, William E. R. Greer
Journal: New England Journal of Medicine (1951)

HEART FAILURE results when the heart is unable to respond with an increase in output sufficient to meet the demands of a person's daily activities. A cardiovascular system that is predisposed by disease may be thrown into failure in numerous ways. Abnormalities in fluid and electrolyte balance, resulting from excess salt intake,1 impaired renal function and hormonal activity exerting a salt-retaining effect on the kidney,2 3 4 5 play an important role in initiating and perpetuating congestive heart failure.Premenstrual salt and water retention is common.6 7 8 9 10 This results in cyclic gain and loss of weight with concomitant episodes of edema, bloating and distress, . . .
Preoperative Staging of Non–Small-Cell Lung Cancer with Positron-Emission Tomography
Authors: Remge M. Pieterman, John W.G. van Putten, Jacobus J. Meuzelaar, Eduard L. Mooyaart, Willem Vaalburg, Gerard H. Koëter, Vaclav Fidler, Jan Pruim, Harry J.M. Groen
Journal: New England Journal of Medicine (2000)

Determining the stage of non–small-cell lung cancer often requires multiple preoperative tests and invasive procedures. Whole-body positron-emission tomography (PET) may simplify and improve the evaluation of patients with this tumor.
QOL-15QUALITY OF LIFE IN MASSIVE OPTICOHYPOTHALAMIC GLIOMA. AN ANALYSIS OF AN EXPERIENCE IN 73 CASES TREATED OVER 18 YEARS
Authors: Datttatraya Muzumdar, Atul Goel, Rakesh Jalali
Journal: Neuro-Oncology (2015)

BACKGROUND: Visual pathway gliomas represent 1% to 5% of childhood brain tumors. About 43% occur in children <10 years old. Although benign, opticohypothalamic chiasmatic gliomas can have aggressive course in young children. PATIENTS AND METHODS: Seventy-three cases of opticohypothalamic chiasmatic were surgically treated in our department over the past 18 years (1990-2011). A retrospective analysis is presented. A semi-structured interview for disease domain specific quality of life (QOL) was performed in a focused group of 30 patients to elicit themes to provide a thematic analysis. RESULTS: The average age of presentation was 14.8 years and duration of complaints was 3 months. Headaches, vomiting and dimunition of vision were the most common complaints. The average size of the tumor was 7.4 cm. All patients underwent only biopsy of the tumor. The subfrontal approach was used in all patients. Ventriculoperitoneal shunt was required in 19 patients postoperatively. The average follow-up period was 7 years. Nonsymptomatic recurrence was noted in 8 patients. Overall, the median time to tumor progression was 55 months. The 5- and 10-year survival probabilities were 93 and 74%, respectively. The functional activity assessed by Barthel's Index is maintained in children with low grade optochiasmal gliomas treated with conformal RT. The decline in functional activity is seen in patients with tumor recurrence and in complications. However, there was improvement of functional activity after RT due to tumour control and rehabilitative support. The maximum improvement was seen in visually impaired patients. CONCLUSION: Barthel's Index is a simple, reproducible, quick and easy to perform. It is especially applicable for older children and adolescents and may be used as an outcome measure tool in clinics with resource limitations. The approach towards quality of life issues should be more aggressive including psychosocial intergration. There is a need for more objective and better quality of life studies.
Abnormal Spontaneous Rosette Formation and Rosette Inhibition in Lung Carcinoma
Authors: Robert L. Gross, Alex Latty, Elizabeth A. Williams, Paul M. Newberne
Journal: New England Journal of Medicine (1975)

Fifty-five children with CID and known ADA status were studies at a workshop held in Albany, New York. Erythrocyte ADA determinations were performed in 22 of the 55 patients, 13 of whom were ADA negative. The ADA defect appears to be transmitted as an autosomal recessive trait. Some patients with CID and ADA deficiency have characteristic radiologic abnormalities of the skeleton, which are not found in other illnesses. The thymus glands of all patients with CID and ADA deficiency who could be examined have evidence of thymic involution manifested by presence of Hassall's corpuscles and differentiated germinal epithelium; this is in contrast to "classic" thymus findings in CID with normal ADA. Adenosine deaminase probably plays an important, although as yet undefined, role in lymphocyte development and/or function. The deficiency of ADA in CID is the first enzyme defect observed in a deficiency disease of specific immunity.
P269 Perioperative outcomes in patients with Pulmonary Hypertension undergoing non-cardiac non-obstetric surgery in a Designated UK Pulmonary Hypertension Centre
Authors: RJ Hewitt, K Dimopoulos, D Alexander, TC Aw, S Finney, R Alonso-Gonzalez, C Harries, L Parfitt, J Wort, L Price
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Patients with pulmonary hypertension (PH) represent an extremely high-risk surgical group, with previous reported mortality 7–18%, and predicting perioperative risk is difficult. The aim of this study was to characterise a current cohort of patients with pulmonary hypertension undergoing surgery in a National UK Designated PH centre and to determine predictors of adverse events. <h3>Methods</h3> Consecutive patients with PH undergoing non-cardiac, non-obstetric surgery were identified by matching theatre and PH databases between 1<sup>st</sup> April 2008 and 1<sup>st</sup> April 2015. Demographics, recent echocardiogram, right heart catheterisation, B-natriuretic peptide (BNP), six-minute walk test (6MWT) and World Health Organisation functional class (WHO-FC) on last clinic visit was recorded. Anaesthetic and perioperative details; post-operative management, short-term morbidity and 28-day outcome were recorded. Data are mean±SD or median (range). <h3>Results</h3> 37 procedures requiring anaesthesia were identified in 32 patients with PAH (7 idiopathic PAH, 1 PVOD, 24 CHD-PAH, 4 CTD-PAH) and 1 CTEPH. Average age was 44.4 ± 13 years, 27(84%) were female. Baseline preoperative WHO-FC was II (3, 9%), III (28, 88%), IV (1, 3%). Baseline 6MWT distance was 317 ± 68 m; BNP 200 (12–2027) ng/L; RV systolic pressure (RVSP) 85 ± 16 mmHg, tricuspid annular planar systolic excursion (TAPSE) 18 ± 7 mm. Cases including oesophagogastroscopy (n = 4), dental extraction (n = 8) under general anaesthesia (GA) were classified as minor; 6 (16%) including mastectomy, laparotomy and fasciotomy as major surgical procedures. Almost all (95%) were performed under GA; most were elective procedures and were monitored on the high dependency or intensive care unit post-operatively. Cardiovascular perioperative complications occurred in 6 cases (16%) including death in 2 patients (5.4%) in the days following surgery, in both cases related to PH crises, resulting in right ventricular (RV) failure. Baseline parameters of RV function including RVSP, TAPSE and the presence of a pericardial effusion were associated with adverse events. <h3>Conclusion</h3> Perioperative mortality in patients with PH remains high, even in the current era. If surgery is deemed essential, PH centres with experts in cardiothoracic anaesthesia and ICU should be involved in preoperative planning with the PH multidisciplinary team guiding appropriate selection of patients, considering pulmonary haemodynamics and indices of RV function, as well as surgical factors.
Arrhythmias in Acute Myocardial Infarction
Authors: James F. Spann, Robert C. Moellering, Edgar Haber, Edwin O. Wheeler
Journal: New England Journal of Medicine (1964)

CARDIAC arrhythmias are frequent, serious complications of acute myocardial infarction1 2 3 and are associated with a 7 to 17 per cent increase in mortality.2 , 4 The extent to which arrhythmias are a direct cause of death in acute myocardial infarction has been estimated from clinical and pathological studies,5 6 7 but there has been little electrocardiographic documentation of the immediate preterminal rhythms. Documentation of possible transient disturbances of rhythm before the terminal arrhythmias has also been limited. Availability of a continuous electrocardiographic monitoring device has made it possible to detect and document the arrhythmias that follow myocardial infarction. The cardiac rhythm of 30 patients . . .
Non-Corticosteroid-Associated Osteonecrosis of the Femoral Heads in Two Patients with Inflammatory Bowel Disease
Authors: H J Freeman, W C Kwan
Journal: New England Journal of Medicine (1993)

Osteonecrosis, or nontraumatic (aseptic, avascular) bone necrosis, is a relatively common disorder estimated to account for more than 10 percent of all joint replacements1. Although a number of clinical entities have been associated with osteonecrosis (e.g., Gaucher's disease, systemic lupus erythematosus, rheumatoid arthritis, hemoglobinopathies, air embolism, pancreatitis, and chronic alcoholism), the incidence and pathogenesis of osteonecrosis in each condition are not well defined. Some patients with osteonecrosis have also been treated with corticosteroids. It is not clear, however, if osteonecrosis in patients treated with corticosteroids represents a drug complication, a complication of the disease process, or both1–5. . . .
<i>Notes from the Field</i>: Outbreak of Multidrug-Resistant<i>Salmonella</i>Infections Linked to Pork — Washington, 2015
Authors: Vance M. Kawakami, Lyndsay Bottichio, Kristina Angelo, Natalie Linton, Bonnie Kissler, Colin Basler, Jennifer Lloyd, Wendy Inouye, Elysia Gonzales, Krista Rietberg, Beth Melius, Hanna Oltean, Matthew Wise, Jennifer Sinatra, Paula Marsland, Zhen Li, Roxanne Meek, Meagan Kay, Jeff Duchin, Scott Lindquist
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

During June-July 2015, Public Health-Seattle & King County (PHSKC) and Washington State Department of Health (WADOH) investigated 22 clusters of Salmonella serotype I 4,[5], 12:i:- infections. Serotype I 4,[5], 12:i:- is the fifth most frequently reported Salmonella serotype in the United States, but is uncommon in Washington. On July 29, 2015, WADOH and PHSKC requested assistance from CDC to identify the infection source, determine risk factors, and make recommendations for prevention.
Abstract 2566: Combination of taxanes with mesothelin-targeted immunotoxin RG7787 induces synergistic killing of pancreatic cancer
Authors: Christine Campo Alewine, Emily Kolyvas, Klaus Boslett, Ira Pastan
Journal: Cancer Research (2015)

Abstract Pancreatic cancer has a poor prognosis with a 5 year median overall survival of just 6%. Most pancreatic adenocarcinomas express the cells surface antigen mesothelin (MSLN). RG7787 is a cytolytic fusion protein that uses an anti-mesothelin (MSLN) antibody Fab to target a modified, deimmunized Pseudomonas exotoxin A cytotoxic payload to cells that express MSLN. The immunotoxin is internalized by cells, releasing the toxin to the cytosol, where it enzymatically modifies elongation factor-2 causing a global halt in protein synthesis. We have previously observed that combination of paclitaxel with RG7787 significantly enhances anti-tumor effect in a KLM1 xenograft model of pancreatic cancer. Here, we report that co-treatment with nab-paclitaxel induces durable complete regressions in this model as well as explore the mechanisms underlying the favorable interaction of RG7787 with taxanes. We demonstrate that the enhanced killing with the combination can also be observed in vitro. Co-treatment lowers the dose of RG7787 required to achieve complete cell killing to the physiologic range. This favorable interaction requires the toxin portion of the molecule and cannot be replicated by treating with the anti-MSLN Fab alone. The timing of treatment with the two drugs is not critical, as similar cytotoxic effects are observed when taxane is given 24 hrs before, 24 hrs after or simultaneously with RG7787. Addition of taxane does not increase immunotoxin-mediated protein synthesis inhibition, nor can combination of taxane with the protein synthesis inhibitor cycloheximide reproduce the enhanced killing seen with the taxane/ RG7787 combination. Further studies exploring the critical factors in this interaction are ongoing. Citation Format: Christine Campo Alewine, Emily Kolyvas, Klaus Boslett, Ira Pastan. Combination of taxanes with mesothelin-targeted immunotoxin RG7787 induces synergistic killing of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2566. doi:10.1158/1538-7445.AM2015-2566
Reply
Authors: James E. Everhart, Elizabeth Wright
Journal: Hepatology (2013)

Amanzada et al. suggest that the ratio of gamma-glutamyl transferase (GGT) to alanine aminotransferase (ALT) activities may be a better predictor than GGT alone for virological response to pegylated interferon and ribavirin in chronic hepatitis C (HCV). Accordingly, we reanalyzed the data from the HALT-C trial, substituting GGT/ALT quintile for GGT quintile in all analyses. For the 1,319 patients, the quintile distributions for GGT/ALT were 0.07-0.61, 0.62-0.97, 0.98-1.50, 1.51-2.47, and 2.48-22.0. The responses to treatment at week 12 (EVR), week 20, and week 72 (SVR) in the HALT-C lead-in phase are shown in Fig. 1 using the same format as fig. 1 in the published article.1 The GGT/ALT ratio predicted treatment response modestly better than GGT alone, especially for SVR. Per quintile increase in GGT/ALT, the odds ratio (OR) for failure to achieve SVR was 1.85 (95% confidence interval [CI] 1.61-2.13) compared with an OR of 1.51 (95% CI 1.33-1.71) for GGT. Importantly, ALT/GGT performed no better than GGT alone in predicting clinical outcomes. For example, the hazard ratio (HR) per quintile increase in GGT/ALT was 1.11, slightly lower than the HR of 1.14 for GGT alone. As noted in their letter, the authors previously reported an OR for SVR of 26.7 for IL28b rs12979860 genotype CC homozygotes versus other genotypes (CT or TT) among patients with genotype 1 infection and GGT/ALT <0.70.2 This result was based on achievement of SVR in 45 of 52 (87%) patients with CC genotype and 42 of 78 (54%) patients with either CT or TT genotype. These SVR response rates result in an OR of 5.5, not 26.7. In HALT-C, using the same cutoff of 0.70 for the GGT/ALT ratio, we found an OR of SVR for CC versus other genotypes of 1.56 (95% CI of 0.91-2.67) among patients with low GGT/ALT. Only 26% of HALT-C patients (who were all nonresponders to prior treatment) had a GGT/ALT ratio of <0.70 compared to 49% of their patients. Thus, we found modest improvement in predicting virological response for GGT/ALT over GGT alone, little value of rs12979860 at low GGT/ALT, and no added value of GGT/ALT for clinical prognosis. Furthermore, we are unaware of a biological basis for the use of this ratio. James E. Everhart, M.D. Elizabeth Wright, Ph.D. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD