tbuckley/cabot-search huggingface dataset:
Patient-derived models link re-entrant driver localization in atrial fibrillation to fibrosis spatial pattern
Authors: Sohail Zahid, Hubert Cochet, Patrick M. Boyle, Erica L. Schwarz, Kaitlyn N. Whyte, Edward J. Vigmond, Rémi Dubois, Mélèze Hocini, Michel Haïssaguerre, Pierre Jaïs, Natalia A. Trayanova
Journal: Cardiovascular Research (2016)

The mechanisms underlying persistent atrial fibrillation (AF) in patients with atrial fibrosis are poorly understood. The goal of this study was to use patient-derived atrial models to test the hypothesis that AF re-entrant drivers (RDs) persist only in regions with specific fibrosis patterns.Twenty patients with persistent AF (PsAF) underwent late gadolinium-enhanced MRI to detect the presence of atrial fibrosis. Segmented images were used to construct personalized 3D models of the fibrotic atria with biophysically realistic atrial electrophysiology. In each model, rapid pacing was applied to induce AF. AF dynamics were analysed and RDs were identified using phase mapping. Fibrosis patterns in RD regions were characterized by computing maps of fibrosis density (FD) and entropy (FE). AF was inducible in 13/20 models and perpetuated by few RDs (2.7 ± 1.5) that were spatially confined (trajectory of phase singularities: 7.6 ± 2.3 mm). Compared with the remaining atrial tissue, regions where RDs persisted had higher FE (IQR: 0.42-0.60 vs. 0.00-0.40, P < 0.05) and FD (IQR: 0.59-0.77 vs. 0.00-0.33, P < 0.05). Machine learning classified RD and non-RD regions based on FD and FE and identified a subset of fibrotic boundary zones present in 13.8 ± 4.9% of atrial tissue where 83.5 ± 2.4% of all RD phase singularities were located.Patient-derived models demonstrate that AF in fibrotic substrates is perpetuated by RDs persisting in fibrosis boundary zones characterized by specific regional fibrosis metrics (high FE and FD). These results provide new insights into the mechanisms that sustain PsAF and could pave the way for personalized, MRI-based management of PsAF.
Polymicrobial bloodstream infections (PBI): An under-realized complication in patients with cancer (2005–2006)
Authors: A. Safdar, G. H. Rodriguez, D. S. Raval, G. P. Bodey, K. V. Rolston
Journal: Journal of Clinical Oncology (2007)

19590 Background: Little attention has been directed to PBI in cancer patients. Methods: Fifty-four PBI episodes were evaluated retrospectively in 51 patients after obtaining IRB approval. PBI was defined as ≥ 2 organisms isolated from a single blood culture or sample(s) obtained within 72 hrs after the initial positive culture. All values are given as median ± s.d. Results: The age was 57 ± 16 years. Thirty-four patients had hematologic malignancy of whom, 73% had acute leukemia. Nearly half (47%) of the patients had refractory or relapsed cancer. Thirty-two (63%) were neutropenic (ANC 0 ± 144 cells/UL) and 31 patients (61%) had lymphocytopenia (ALC 0 ± 86 cells/UL). At the time of infection diagnosis, APACHE II score was 16 ± 5 and 5 (10%) patients were receiving systemic corticosteroids (&gt; 600 mg prednisone equivalent dose). Thirty-one PBI episodes (57%) occurred while patients were receiving systemic antimicrobial agents for prophylaxis or treatment. In 83% of PBI episodes, positive specimens were collected from central venous catheter (CVC). Catheter-related infection necessitating CVC removal occurred in nearly half of these cases (24/45). Twenty-two (41%) PBI episodes were associated with high bacterial load (&gt; 100 CFU/ml). The overall response to treatment was 86%. In 39 of 42 episodes (77%) treated with concordant antimicrobial therapy infection resolved. Whereas, in only 5 episodes (9%) treated with discordant antimicrobial therapy, infection resolution occurred (P = 0.07). There were no differences in PBI outcomes in patients with hematologic malignancies vs. solid-organ cancers, patients &gt; 50 years vs. &lt; 50 years of age or among neutropenic patients who had recovery of neutropenia during infection episode vs. patients in whom neutropenia persisted. Conclusions: The overall high response of concordant antimicrobial therapy for even high-risk cancer patients with PBI looks encouraging. No significant financial relationships to disclose. [Table: see text]
A Randomized Trial Comparing Surgical Adrenalectomy with Aminoglutethimide plus Hydrocortisone in Women with Advanced Breast Cancer
Authors: Richard J. Santen, Thomas J. Worgul, Eugeniusz Samojlik, Albert Interrante, Alice E. Boucher, Allan Lipton, Harold A. Harvey, Deborah S. White, Emma Smart, Charles Cox, Samuel A. Wells
Journal: New England Journal of Medicine (1981)

We randomized 96 postmenopausal women with metastatic breast carcinoma to receive surgical adrenalectomy or medical therapy with an adrenal inhibitor, aminoglutethimide (AG), plus replacement hydrocortisone. Before randomization, women were stratified according to disease-free interval, site of dominant disease, and estrogen-receptor status. Of 40 evaluable women treated with AG and hydrocortisone, 53 per cent had objective responses, as compared with 45 per cent of 29 women undergoing surgical adrenalectomy (P value not significant). Responses lasted a mean of 17.2 months in the medical group and >17.1 months in the surgical group (not significant). Estrogen levels fell similarly in response to either treatment, whereas AG and hydrocortisone preserved androgen production. A null hypothesis tested the single question asked by this study: "Is surgical adrenalectomy superior to treatment with AG and hydrocortisone?" Rejection at significance levels of P = 0.01 and P = 0.07 for differences of 20 per cent and 10 per cent, respectively, suggested that medical therapy with AG and hydrocortisone may be logically chosen in place of surgical adrenalectomy. (N Engl J Med. 1981; 305:545–51.)
Assessment of Rh Disease by Ratios of Bilirubin to Albumin and Hemopexin to Albumin in Amniotic Fluid
Authors: Ursula Muller-Eberhard, Richard Bashore
Journal: New England Journal of Medicine (1970)

We examined 105 amniotic-fluid samples from 36 Rh-sensitized pregnancies for concentration of bilirubin, protein, albumin and hemopexin (heme-binding beta glycoprotein). Bilirubin measurements obtained spectrophotometrically (Liley method) were compared with levels of total protein, albumin, hemopexin and chemically determined bilirubin. Ratios of the concentrations of chemically assessed bilirubin to albumin reflected most accurately the degree of fetal hemolysis and fetal outcome. A ratio above 0.10 was recorded in eight of 10 patients receiving intrauterine transfusions and in two requiring multiple exchange transfusions. A ratio below 0.05 indicated patients needing no or one transfusion. A rising ratio of hemopexin to albumin in 10 cases usually suggested no or mild involvement; leveling (six cases) and falling ratios (15 cases) were found when exchange or intrauterine transfusions were needed. Inconclusive or negative Liley values were observed in four cases, but ratios of bilirubin and hemopexin to albumin in combination correctly predicted the outcome in three of them.
Phase II trial of ipilimumab monotherapy in melanoma patients with brain metastases.
Authors: D. P. Lawrence, O. Hamid, D. F. McDermott, I. Puzanov, M. Sznol, J. Clark, T. Logan, F. S. Hodi, K. N. Heller, K. A. Margolin
Journal: Journal of Clinical Oncology (2010)

8523 Background: Ipilimumab (Ipi), a human monoclonal antibody that blocks CTLA-4, has activity in advanced melanoma. We present results from a phase II trial (CA184-042) to assess Ipi safety and activity in advanced melanoma patients (pts) with brain metastases (mets). Methods: This 2-stage trial required > 2 objective responses (ORs) among the first 21 pts in order to proceed to stage 2 of Arm A and to open Arm B. Ptshad measurable brain mets with at least one lesion > 0.5 cm and/or 2 lesions > 0.3 cm, and none > 3 cm in diameter. Prior whole brain radiotherapy and stereotactic radiotherapy to non-index lesions were allowed. Pts were steroid-free (Arm A) or required steroids for symptoms of brain mets at study entry (Arm B). Ipi at 10 mg/kg was given by IV, every 3 weeks for 4 doses; responding or stable pts could receive maintenance ipilimumab at 10 mg/kg, every 12 weeks. Tumor assessments by modified WHO criteria were performed every 6 weeks, beginning at week 6; ORs and SD were confirmed 4 weeks after the criteria were first met. Results: The study accrued 51 pts in Arm A and 21 pts in Arm B. In Arm A, 4/51 pts had a partial response (PR) and 5/51 pts had stable disease (SD) in global lesions (brain + non-CNS) at week 12, with additional unconfirmed responses. When evaluating brain lesions only in Arm A, there were 5 PRs and 6 SDs at week 12, with additional unconfirmed responses. The duration of responses ranged from 3 to 12+ months, and duration of SD ranged from 1 to 7 months. Median global PFS was 1.9 months (95% CI, 1.2–3.0). The analysis of pts enrolled in Arm B is ongoing. There were no unexpected toxicities in either arm. CNS AEs of any grade occurred in 38 of 51 pts (74.5%) (grade 3–4 in 14 pts [27.5%]) in Arm A, and in 12 of 21 pts (57.1%) (grade 3–4 in 6 pts [28.6%]) in Arm B. The most common CNS events (> 10% of pts) of any grade were headache, dizziness, and seizures; all but one were attributable to disease. There was no association between brain edema or cerebral hemorrhage and OR. Conclusions: Ipi has a similar level of activity in brain and non-CNS lesions. This is the first study to prospectively evaluate Ipi in advanced melanoma pts with brain mets, and the data support its potential use as a treatment for these pts. The analyses are ongoing and final data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Effects of Unbuffered and Buffered Acetylsalicylic Acid on Intragastric pH
Authors: Robert Rubin, E. W. Pelikan, C. J. Kensler
Journal: New England Journal of Medicine (1959)

IN spite of the widespread clinical use of acetylsalicylic acid in both buffered and unbuffered preparations, there is little information in the voluminous literature concerning the pharmacologic effects of the drug on gastric acidity in man.Schnedorf, Bradley and Ivy1 reviewed the literature and found no conclusive evidence that acetylsalicylic acid affected gastric acidity in man. In their own studies, however, they reported that doses of 1 to 2 gm. increased the total titratable acidity per milliliter of gastric aspirate by 27 to 58 per cent. A decrease in total acidity was observed when 3 gm. of sodium bicarbonate was . . .
Absence of Intact nef Sequences in a Long-Term Survivor with Nonprogressive HIV-1 Infection
Authors: Frank Kirchhoff, Thomas C. Greenough, Doreen B. Brettler, John L. Sullivan, Ronald C. Desrosiers
Journal: New England Journal of Medicine (1995)

Although disease develops within 10 years in most persons infected with human immunodeficiency virus type 1 (HIV-1), some remain symptom-free for prolonged periods.1,2 Most long-term asymptomatic survivors of HIV-1 infection still have evidence of disease progression in the form of declining CD4+ lymphocyte concentrations. However, some rare persons not only are asymptomatic but also maintain stable levels of CD4+ lymphocytes in the normal or near-normal range. Although the definition of nonprogression may vary, approximately 5 percent of seropositive persons have shown no HIV-related disease or declines in CD4+ cell counts despite 10 or more years of documented HIV-1 infection. . . .
Phase 1/2 trial of cabazitaxel with abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone acetate: Phase 2 results.
Authors: Joaquin Mateo, Karim Fizazi, Carmel Jo Pezaro, Yohann Loriot, Niven Mehra, Laurence Albiges, Diletta Bianchini, Andrea Varga, Charles J. Ryan, Daniel Peter Petrylak, Liji Shen, Jenny Zhang, Gerhardt Attard, Johann Sebastian De Bono, Christophe Massard
Journal: Journal of Clinical Oncology (2015)

268 Background:Abiraterone acetate (A) and cabazitaxel (C) improve survival for patients with mCRPC. We conducted an open-label trial of A+C to assess the antitumor activity and tolerability of the combination in patients (pts) previously treated with docetaxel (D) and A (NCT01511536). Here, we report results for the phase 2 part of the study, after the combination MTD was established (Massard C, et al. ASCO 2013). Methods: Pts received A (1,000 mg QD) and C (25 mg/m 2 every 3 weeks) with prednisone/ prednisolone (5 mg BID). Eligibility criteria included prior D and prior A for at least 3 months, disease progression by rising PSA, ECOG PS 0–1 and no prior C or mitoxantrone. The primary endpoint was PSA response rate (PSA-RR: ≥50% decrease confirmed ≥3 weeks later). A 1-sided exact test was planned to test a null hypothesis of PSA-RR 25%, with a type 1 error of 0.05. With a sample size of 26, this test would have a power of 83% under the alternative hypothesis of PSA-RR 50%. Secondary endpoints included progression-free survival (PFS), duration of response, radiological-RR, overall survival and safety. Results: Twenty-seven pts were treated in this phase 2 part of the study. The median time on A prior to A+C was 8.3 months (range 3.1–29.8). All pts previously received D and A; 4 pts (15%) had also received prior treatment with enzalutamide. The median number of C cycles administered was 7 (range 1–21). Main treatment-emergent adverse events (AE) Grade≥3 were neutropenia (15 pts; 55%; 1 pt [3.7%] had febrile neutropenia), fatigue (4 pts; 15%) and sepsis (3 pts; 11%). Seven pts (25.9%) required a dose reduction of C due to AE, but all patients received ≥80% of the planned dose intensity. Of 26 pts evaluable for the primary endpoint, 12 achieved a PSA response (PSA-RR 46.2%; 95% CI 26.6–66.4%), and therefore the null hypothesis was rejected (p&lt;0.01). Median PSA-PFS was 6.9 mo (95% CI 4.1–10.2 mo). Three out of 14 pts (21%) with measurable disease achieved a partial response per RECIST 1.1. Conclusions: The combination of abiraterone and cabazitaxel is well tolerated and demonstrated antitumor activity in the post-docetaxel, post-abiraterone setting. Clinical trial information: NCT01511536.
Abstract 5657: Growth Differentiation Factor-15 as a Biomarker in Pulmonary Arterial Hypertension and Hypoxia-induced Pulmonary Hypertension
Authors: Christopher J Rhodes, John Wharton, Luke Howard, J Simon R Gibbs, Almaz A Aldashev, Martin R Wilkins
Journal: Circulation (2009)

Circulating growth differentiation factor (GDF)-15 is a possible biomarker in idiopathic pulmonary arterial hypertension (IPAH). We sought to verify its prognostic value and evaluate GDF-15 in other forms of pulmonary hypertension (PH). GDF-15 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were assayed in 127 IPAH patients, 83 of whom received targeted therapy. GDF-15 was also measured in 16 connective tissue disease-associated PAH (CTD) patients, 64 healthy controls and 89 Kyrgyz highlanders (2500 –3600 m), 35 of whom had PH (HAPH; mean pulmonary artery pressure (mPAP) &gt;25 mmHg). GDF-15 levels were greater in IPAH (mean±SEM 987 ±81 pg/ml) and CTD (978 ±144 pg/ml) versus controls (306 ±16 pg/ml; P&lt;0.001). GDF-15 levels &gt;800 pg/ml were associated with decreased exercise capacity (p=0.002) and cardiac index (p=0.02), and increased NT-proBNP (p&lt;0.001), age (p&lt;0.001) and mean right atrial pressure (p=0.02), but did not correlate with mixed venous or arterial (SaO 2 ) oxygen saturation. 3 year mortality in IPAH was 21% (GDF-15 &lt;800 pg/ml) and 58% (GDF-15 &gt;800 pg/ml), with a hazard ratio of 5.12 (95% CI 1.89 –13.9; P&lt;0.001). GDF-15 remained an independent predictor of mortality after adjusting for clinical/haemodynamic measurements and combining NT-proBNP data improved risk stratification. SaO 2 was significantly lower in high altitude (90.4±0.4%) and HAPH subjects (87.3±0.7%) versus IPAH patients (93.3±0.6%; P&lt;0.001). GDF-15 was raised in HAPH, not high altitude residents (548±64 vs. 307±14 pg/ml; P&lt;0.001), and correlated with mPAP (p&lt;0.001). The data support the use of GDF-15 as a prognostic marker in IPAH and question whether hypoxia stimulates GDF-15 in PH.
Phase II study of bevacizumab and erlotinib in patients with recurrent glioblastoma multiforme
Authors: S. Sathornsumetee, J. J. Vredenburgh, J. N. Rich, A. Desjardins, J. A. Quinn, A. E. Mathe, S. Gururangan, A. H. Friedman, H. S. Friedman, D. A. Reardon
Journal: Journal of Clinical Oncology (2008)

13008 Background: Bevacizumab, a neutralizing monoclonal antibody to vascular endothelial growth factor (VEGF), has demonstrated promising radiographic response and promising survival benefit in combination with irinotecan in patients with recurrent glioblastoma multiforme (GBM). Erlotinib, an EGFR tyrosine kinase inhibitor, has shown anti-tumor activity in some glioma patients. Combination of bevacizumab and erlotinib has demonstrated safety and efficacy in several solid malignancies. In this study, we evaluate the combinatorial efficacy of bevacizumab and erlotinib in patients with recurrent GBM Methods: Twenty-five patients with recurrent GBM were enrolled. The primary outcome measure is 6 month progression-free survival. Radiographic response, pharmacokinetics and correlative biomarkers are secondary outcome measures. Patients are stratified based on concurrent use of enzyme-inducing anticonvulsants (EIAC). Bevacizumab is dosed at 10 mg/kg intravenously every two weeks. Erlotinib is orally administered daily with 200 mg/day for patients not on EIAC and 650 mg/day for patients on EIAC. Results: With a median follow-up of 32.3 weeks, the 6 month progression-free survival rate was 24%. Twelve patients (48%) achieved radiographic response. This treatment combination was well-tolerated. Common side effects include those previously seen with erlotinib therapy such as rash, diarrhea, mucositis and fatigue. One ischemic stroke and one asymptomatic intracerebral hemorrhage were observed. Conclusions: Combination of bevacizumab and erlotinib is safe and well tolerated in recurrent GBM patients. It is associated with promising radiographic response and encouraging survival benefit. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Schering-Plough Genentech Genentech, Schering-Plough Genentech™ BioOncology
Carcinoma of Colon and Rectum
Authors: Claude E. Welch, W. Philip Giddings
Journal: New England Journal of Medicine (1951)

TWO basically conflicting trends in the treatment of cancer of the colon and rectum are evident today. One school of surgeons, believing that present results are excellent, attempts to limit the number of radical operations and advocates the preservation of sphincters. The other school, apparently feeling that today's results are poor, advocates more extensive surgery than has been done in the past. Both groups have produced apparently logical support in the surgical literature, on both pathological and statistical grounds.The student who attempts to correlate the various statements that have been made in recent publications will therefore recognize many unsolved . . .
RTRB-07PRECLINICAL EVALUATION OF IRRADIATION THROUGH TUMOR TREATING FIELDS (TTFIELDS) CERAMIC TRANSDUCER ARRAYS
Authors: Mijal Munster, Shay Cahal, Roni Blatt, Moshe Giladi, Aviran Itzhaki, Eilon D. Kirson, Uri Weinberg, Yoram Palti
Journal: Neuro-Oncology (2015)

TTFields are an effective anticancer modality delivered via continuous, noninvasive application of low intensity, intermediate frequency, alternating electric fields. TTFields are delivered using insulated ceramic transducer arrays that are placed directly on the scalp in the region surrounding a tumor. Preclinical data suggest that the combination of TTFields with irradiation is most effective when TTFields are applied immediately after exposure to irradiation therapy. In practice, this could be accomplished by leaving the transducer arrays attached to the patients'  during radiation therapy. Initial investigations using an ion chamber connected to a unidos dosemeter demonstrated that the TTFields transducer arrays absorb only a small fraction of the irradiation energy but lead to a dramatic increase in the energy directly below the ceramic arrays. This could potentially abolish the skin sparing effect. The purpose of this study was to evaluate the impact of direct irradiation through the TTFields ceramic transducer arrays on rat skin. Insulated ceramic transducers with hydrogel identical to those used for TTFields application in glioblastoma patients were placed on a rat's head. No additional  adverse events were observed when single irradiation doses of 2-15 Gy were applied to the rat head through the transducers. In order to further test potential  damage in conditions similar to clinical practice, rats were irradiated with 2 Gy, five times a week for two weeks through ceramic arrays placed on the rat's dorsal skin. Skin screening revealed that irradiation through the ceramic arrays did not lead to adverse  reactions. These results should be further validated through clinical testings.
Case 4-1992
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, D.P. Schenkein, N.L. Harris
Journal: New England Journal of Medicine (1992)

Presentation of CaseA 52-year-old man was admitted to the hospital because of pancytopenia.There was a 25-year history of adult-onset diabetes mellitus, which was managed elsewhere with NPH insulin (42 U) and regular insulin (6 U) taken daily before breakfast. During the 9 to 12 months before entry the patient took cephalexin (500 mg twice daily) because of a recurrent ulceration of the right foot; the second through fourth toes were amputated during the 6 years before admission. The patient was well in other respects until two months before entry, when he experienced the onset of increasing fatigability and . . .
The Protective Efficacy of Polyvalent Pneumococcal Polysaccharide Vaccine
Authors: Eugene D. Shapiro, Anne T. Berg, Robert Austrian, Donna Schroeder, Valerie Parcells, Amy Margolis, Russell K. Adair, John D. Clemens
Journal: New England Journal of Medicine (1991)

Although the protective efficacy of pneumococcal polysaccharide vaccine has been demonstrated in randomized trials in young African gold miners, there has been controversy about its efficacy in older Americans at risk for serious pneumococcal infections. To assess the vaccine's protective efficacy against invasive pneumococcal infections, we conducted a hospital-based case–control study of the efficacy of pneumococcal vaccine in adults with a condition recognized to be an indication for receiving the vaccine.