tbuckley/cabot-search huggingface dataset:
Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites
Authors: Harriet M. Kluger, Christopher R. Zito, Meaghan L. Barr, Marina K. Baine, Veronica L.S. Chiang, Mario Sznol, David L. Rimm, Lieping Chen, Lucia B. Jilaveanu
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Programmed death ligand-1 (PD-L1) tumor expression represents a mechanism of immune escape for melanoma cells. Drugs blocking PD-L1 or its receptor have shown unprecedented activity in melanoma, and our purpose was to characterize tumor PD-L1 expression and associated T-cell infiltration in metastatic melanomas. Experimental Design: We used a tissue microarray (TMA) consisting of two cores from 95 metastatic melanomas characterized for clinical stage, outcome, and anatomic site of disease. We assessed PD-L1 expression and tumor-infiltrating lymphocyte (TIL) content (total T cells and CD4/CD8 subsets) by quantitative immunofluorescence. Results: High PD-L1 expression was associated with improved survival (P = 0.02) and higher T-cell content (P = 0.0005). Higher T-cell content (total and CD8 cells) was independently associated with improved overall survival; PD-L1 expression was not independently prognostic. High TIL content in extracerebral metastases was associated with increased time to developing brain metastases (P = 0.03). Cerebral and dermal metastases had slightly lower PD-L1 expression than other sites, not statistically significant. Cerebral metastases had less T cells (P = 0.01). Conclusions: T-cell–infiltrated melanomas, particularly those with high CD8 T-cell content, are more likely to be associated with PD-L1 expression in tumor cells, an improved prognosis, and increased time to development of brain metastases. Studies of T-cell content and subsets should be incorporated into trials of PD-1/PD-L1 inhibitors to determine their predictive value. Furthermore, additional studies of anatomic sites with less PD-L1 expression and T-cell infiltrate are needed to determine if discordant responses to PD-1/PD-L1 inhibitors are seen at those sites. Clin Cancer Res; 21(13); 3052–60. ©2015 AACR.
Bronchogenic carcinoma: incidence of metastases to normal sized lymph nodes.
Authors: T Arita, T Kuramitsu, M Kawamura, T Matsumoto, N Matsunaga, K Sugi, K Esato
Journal: Thorax (1995)

BACKGROUND--The incidence of metastases to mediastinal lymph nodes was evaluated in patients with normal sized mediastinal nodes on the computed tomographic (CT) scan who underwent thoracotomy. The use of hilar lymph nodes in predicting mediastinal lymph node metastases was also assessed. METHODS--Ninety patients with non-small cell lung cancer who later underwent thoracotomy wer prospectively examined by CT scanning. Lymph nodes with a short axis diameter of 10 mm or more were considered abnormal. RESULTS--Mediastinal lymph node metastases were present at thoracotomy in 19 patients (21%). In 14 these lymph node metastases were misdiagnosed because the nodes were normal in size on the CT scan. In only one of the 19 patients with N2 nodes was an N1 lymph node enlarged, and four of the 19 patients with N2 nodes had metastases to these mediastinal nodes without N1 disease ("skipping metastases"). CONCLUSIONS--Metastases in normal sized nodes seen on the CT scan are a major problem in staging. Hilar lymph nodes did not help to predict reliably the presence or absence of metastases to the mediastinal lymph nodes.
Clinical outcome of transfemoral embolisation in patients with arteriovenous malformations of the liver in hereditary haemorrhagic telangiectasia (Weber-Rendu-Osler disease)
Authors: M Caselitz, S Wagner, A Chavan, M Gebel, J S Bleck, A Wu, H J Schlitt, M Galanski, M P Manns
Journal: Gut (1998)

Arteriovenous malformations of the liver in Osler's disease may present as high output cardiac failure. A few case reports suggested that treatment with arterial embolisation may have beneficial effects in such patients.To investigate the efficacy and safety of this treatment modality in a prospective pilot study.Four women and one man (aged 39-59 years) with the dominant hepatic manifestation of Osler's disease presented with symptoms of cardiac failure and elevated cardiac output. Arteriovenous malformations were treated in three to five sessions with arterial embolisation using coils. The outcome was analysed by measurement of cardiac output and scoring of clinical symptoms.Embolisation was technically feasible in all patients and adequate occlusion of vascular malformations was achieved in four patients. After completion of therapy symptoms improved in four patients, while one patient suffered from abdominal pain due to cholangitis. One patient died seven months after the embolisation treatment from variceal bleeding. Mean cardiac output significantly decreased from 14.2 (range 12-17.3) l/min to 8 (range 5.9-10.6) l/min (p = 0.043). After a median follow up of 23 months (range 7-50 months), three of five patients had a long lasting improvement of clinical symptoms and cardiac function.This first treatment series of patients with dominant hepatic involvement in Osler's disease indicates that arterial embolisation may prevent cardiac failure by significantly lowering cardiac output.
Effects of seasonal change in rugby league on the incidence of injury.
Authors: L H Phillips, P J Standen, M E Batt
Journal: British Journal of Sports Medicine (1998)

To assess the effects that the recent seasonal change in rugby league from winter to summer has had on the incidence of injury.All injuries that occurred during games and training were recorded throughout four consecutive seasons (three winter, one summer) for the first team squad of a British professional rugby league club. Data included nature of injury, days lost as the result of injury, player position, month, and season.An increasing incidence of injury over the four seasons was observed, with the summer seasons having an incidence almost double that of the first winter season recorded (696.8 per 1000 hours and 363.55 per 1000 hours respectively). The severity of injury was shown to decline over the four seasons. Most injuries were incurred in matches (74.9%) rather than during training (25.1%).The findings show an increasing incidence of injury in summer rugby but with decreased severity. It is not known if this is the result of playing back to back rugby seasons or is a consequence of a change in playing season and ground conditions.
Epithelial exposure to hypoxia modulates neutrophil transepithelial migration.
Authors: S P Colgan, A L Dzus, C A Parkos
Journal: The Journal of Experimental Medicine (1996)

Polymorphonuclear leukocytes (PMN) are central to the pathogenesis of a number of intestinal diseases. PMN-induced damage to the protective epithelium occurs in hemorrhagic shock, necrotizing enterocolitis and conditions resulting in intestinal reperfusion injury. In such diseases, tissue hypoxia has been implicated as a pathophysiologic mediator. Thus, we hypothesized that exposure of intestinal epithelia to hypoxia may modulate PMN-epithelial interactions. In this study, T84 cell monolayers, a human intestinal crypt cell line, and isolated human PMN were used to examine the influence of hypoxia/reoxygenation (H/R) on PMN transepithelial migration. Confluent T84 cell monolayers were exposed to hypoxia (range 2-21% O2 for 0-72 h) and reoxygenated with buffer containing PMN. Transmigration of PMN (basolateral to apical orientation) was driven by a transepithelial gradient of the chemotactic peptide tMLP. In response to hypoxia/reoxygenation (H/R), transmigration into, and across epithelial monolayer was increased in a dose- (EC50 approximately 7% O2) and time-dependent fashion (3.5 +/- 0.3-fold increase at 2% O2 for 48 h, P &amp;lt; 0.001). Such conditions of H/R were not toxic to epithelia and did not influence epithelial barrier function. The influence of H/R on PMN transmigration was protein synthesis-dependent (&amp;gt; 80% decreased in the presence of cycloheximide) and could be inhibited by addition of functionally inhibitory antibodies to the PMN beta 2 integrin CD11b/18 (&amp;gt; 80% attenuated) and to CD47 (&amp;gt; 90% decreased compared to control). Hypoxia induced epithelial production and basolateral release of the PMN activating chemokine interleukin-8 (IL-8, nearly sixfold increase over normoxic control) which remained avidly associated with the epithelial matrix. Treatment of epithelial cells with IL-8 antisense oligonucleotides resulted in decreased monolayer-associated PMN but did not influence PMN transmigration, suggesting that epithelial IL-8 production may serve as a recruitment signal for PMN to the basal surface of polarized epithelia. The present observations indicate that H/R provides a relevant stimulus for novel biochemical crosstalk between epithelia and PMN.
Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions
Authors: J. J. van Doormaal, E. van der Veer, P. C. van Voorst Vader, P. M. Kluin, A. B. Mulder, S. van der Heide, S. Arends, J. C. Kluin‐Nelemans, J. N. G. Oude Elberink, J. G. R. de Monchy
Journal: Allergy (2012)

Abstract Background Risk indicators of indolent systemic mastocytosis ( ISM ) in adults with clinical suspicion of ISM without accompanying skin lesions [urticaria pigmentosa ( UP )] are lacking. This study aimed at creating a decision tree using clinical characteristics, serum tryptase, and the urinary histamine metabolites methylimidazole acetic acid ( MIMA ) and methylhistamine ( MH ) to select patients for bone marrow investigations to diagnose ISM . Methods Retrospective data analysis of all adults, in whom bone marrow investigations were performed to diagnose ISM , was carried out. Results In total, 142 patients were included. SM was absent in all 44 patients with tryptase &lt;10 μg/l, in 45 of 98 (46%) patients with tryptase ≥10 μg/l and in 18 of 52 patients (35%) with tryptase &gt;20 μg/l. Above 43 μg/l, all patients had ISM ( n = 11). Male gender, insect venom anaphylaxis as presenting symptom, tryptase, MIMA , and MH were independent ISM predictors. If tryptase was ≥10 μg/l, the diagnostic accuracy of MIMA and MH was high (areas under the ROC curve 0.92). Conclusions In suspected patients without UP , the ISM risk is very low (if present at all) if tryptase is &lt;10 μg/l. If tryptase is ≥10 μg/l, this risk depends on MIMA and MH , being low if these are normal, but high if these are elevated. Male gender and insect venom anaphylaxis are additional risk indicators. We recommend refraining from bone marrow examinations in suspected patients without UP if tryptase is &lt;10 μg/l. Our results question the reliability of the minor diagnostic W orld H ealth O rganization criterion of tryptase &gt;20 μg/l.
Two Drug Interaction Studies Evaluating the Pharmacokinetics and Toxicity of Pemetrexed When Coadministered with Aspirin or Ibuprofen in Patients with Advanced Cancer
Authors: Christopher J. Sweeney, Chris H. Takimoto, Jane E. Latz, Sharyn D. Baker, Daryl J. Murry, James H. Krull, Karen Fife, Linda Battiato, Ann Cleverly, Ajai K. Chaudhary, Tuhin Chaudhuri, Alan Sandler, Alain C. Mita, Eric K. Rowinsky
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Pemetrexed is an antimetabolite that is structurally similar to methotrexate. Because nonsteroidal anti-inflammatory drugs (NSAID) impair methotrexate clearance and increase its toxicity, we evaluated the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or ibuprofen in advanced cancer patients. Experimental Design: In two independent, randomized, crossover drug interaction studies, cancer patients with a creatinine clearance (CrCl) ≥60 mL/min received an NSAID (aspirin or ibuprofen) with either the first or the second dose of pemetrexed (cycle 1 or 2). Pemetrexed (500 mg/m2) was infused i.v. on day 1 of a 21-day cycle, and all patients were supplemented with oral folic acid and i.m. vitamin B12. Aspirin (325 mg) or ibuprofen (400 mg; 2 × 200 mg) was given orally every 6 hours, starting 2 days before pemetrexed administration, with the ninth and final dose taken 1 hour before infusion. Pemetrexed pharmacokinetics with and without concomitant NSAID treatment were compared for cycles 1 and 2. Results: Data from 27 patients in each study were evaluable for the analysis of pemetrexed pharmacokinetics. Coadministration of aspirin did not alter pemetrexed pharmacokinetics; however, ibuprofen coadministration was associated with a 16% reduction in clearance, a 15% increase in maximum plasma concentration, and a 20% increase in area under the plasma concentration versus time curve but no significant change in Vss compared with pemetrexed alone. No febrile neutropenia occurred in any patient, and no increase in pemetrexed-related toxicity was associated with NSAID administration. Conclusions: Pemetrexed (500 mg/m2) with vitamin supplementation is well tolerated and requires no dosage adjustment when coadministered with aspirin (in patients with CrCl ≥60 mL/min) or ibuprofen (in patients with CrCl ≥80 mL/min).
Tumors of the Nervous System and Pituitary Gland Associated With Atomic Bomb Radiation Exposure
Authors: D. L. Preston
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: The risk of developing nervous system tumors following exposure to ionizing radiation is not well quantified. We characterized the incidence of nervous system tumors among atomic bomb survivors as a function of radiation dose. Methods: Tumors of the nervous system and pituitary gland diagnosed between 1958 and 1995 among 80 160 atomic bomb survivors were ascertained using the Hiroshima and Nagasaki tumor registries, medical records, and death certificates. Pathologists reviewed slides and medical records to provide histologic diagnoses. Poisson regression analyses were used to characterize radiation effects on tumor incidence, which are expressed as excess relative risk per sievert (ERRSv). All statistical tests were two-sided. Results: A statistically significant dose-related excess of nervous system tumors was observed in the cohort (ERRSv = 1.2, 95% confidence interval [CI] = 0.6 to 2.1). The highest ERRSv was seen for schwannoma (4.5, 95% CI = 1.9 to 9.2). The risk for all other nervous system tumors as a group is also statistically significantly elevated (ERRSv = 0.6, 95% CI = 0.1 to 1.3). Risk increases, although not statistically significant, were seen for meningiomas (ERRSv = 0.6, 95% CI = –0.01 to 1.8), gliomas (ERRSv = 0.6, 95% CI = −0.2 to 2.0), other nervous system tumors (ERRSv = 0.5, 95% CI = <−0.2 to 2.2), and pituitary tumors (ERRSv = 1.0, 95% CI = <−0.2 to 3.5). The dose–response relationships were linear. For nervous system tumors other than schwannoma, excess risks were higher for men than for women and for those exposed during childhood than for those exposed during adulthood. Conclusions: A statistically significant dose response was observed for all nervous system tumors combined and for schwannoma considered separately, indicating that exposure to even moderate doses (i.e., <1 Sv) of radiation is associated with an elevated incidence of nervous system tumors.
Atubular Glomeruli and Glomerulotubular Junction Abnormalities in Diabetic Nephropathy
Authors: Behzad Najafian, Youngki Kim, John T. Crosson, Michael Mauer
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Atubular glomeruli (AG) have been described in several renal disorders. However, little attention has been paid to AG in diabetic nephropathy (DN). Preliminary studies suggested that tip lesions were frequently present in type 1 diabetic (D) patients with proteinuria. The aim of this study was to determine the frequency of AG and their possible relationship with tip lesions in DN. Renal biopsies from eight proteinuric type 1 D patients with normal to moderately reduced GFR (76 ± 26 ml/min per 1.73 m2) and eight normal subjects were studied by light (LM) and electron microscopy (EM). Glomerular volume, volume of the glomerular corpuscle, which is tuft, and the fractional volumes of proximal, distal, and atrophic tubules per cortex were estimated using appropriate stereologic methods. Glomerulotubular junctions were examined on serial sections and classified into glomeruli attached to: normal tubules (NT); short atrophic tubules (SAT); long atrophic tubules (LAT); atrophic tubules with no observable glomerular opening (ATNO); and atubular glomeruli (AG). EM studies showed typical diabetic changes in biopsies, including increased GBM width (P < 0.00001) and mesangial fractional volume (P < 0.0001) and decreased filtration surface density (P < 0.01) compared with normal subjects. Seventeen percent of glomeruli in the D patients were atubular, and 51% were attached to atrophic tubules. Tip lesions were present in all SAT, 64% of LAT, 82% of ATNO, and only 9% of NT and were never observed in normal subjects. The relative volume of AG was smaller than glomeruli in other categories (P < 0.05). Fractional volume of proximal (P < 0.01) and distal (P <0.01) tubules per cortex were decreased, while fractional volume of cortical interstitium (P <0.00001) and atrophic tubules (P <0.01) were increased in D patients. Fractional volume of atrophic tubules, %AG, and percent of glomeruli with tip lesion explained 94% of the GFR variability in diabetic patients (P <0.05). Thus, AG and glomerulotubular junction abnormalities may be important in the development and progression of DN.
Long- and medium-term ozone effects on lung growth including a broad spectrum of exposure
Authors: G. Ihorst, T. Frischer, F. Horak, M. Schumacher, M. Kopp, J. Forster, J. Mattes, J. Kuehr
Journal: European Respiratory Journal (2004)

The effects of semi-annual and 3.5 yr mean ozone (O 3 ) concentrations on children's forced vital capacity (FVC) and forced expiratory volume in one second (FEV 1 ) were assessed over a study period of 3.5 yrs in 2,153 schoolchildren from 15 study sites in South Western Germany and Lower Austria. Spirometric parameters were assessed twice a year, and differences between consecutive measurements divided by days were considered as a measure of lung growth. Exposure was analysed in four classes, separately for winter and summer (semi-annual mean O 3 concentrations 22–30, 30–38, 38–46, 46–54 parts per billion (ppb) in summer and 4–12, 12–20, 20–28, 28–36 ppb in winter). Regression methods for repeated measurements were used, and these revealed a significantly lower FVC (FEV 1 ) increase estimated at −19.2 (−18.5) mL·100 days −1 for semi-annual mean O 3 exposure in summer between 46 and 54 ppb compared to exposure between 22 and 30 ppb. However, in winter, the estimated difference in FVC (FEV 1 ) was 16.4 (10.9) mL·100 days −1 between the semi-annual O 3 class 28–36 ppb and the 4–12 ppb class. By means of linear regression the study found that there was no association between growth rates and mean summer O 3 for FVC and FEV 1 over a 3.5 yr period. The authors conclude that medium-term effects on schoolchildren's lung growth are possibly present, but are in the long-term not detectable for forced vital capacity and forced expiratory volume in one second over a 3.5 yr period due to partial reversibility.
Clinical Presentation and Outcome of Patients with HIV Infection and Tuberculosis Caused by Multiple-Drug-resistant Bacilli
Authors: Margaret A. Fischl, George L. Daikos, Raj B. Uttamchandani, Rita B. Poblete, Jose N. Moreno, Ricardo R. Reyes, Ahmad M. Boota, Lisa M. Thompson, Timothy J. Cleary, Sandra A. Oldham, Mario J. Saldana, Shenghan Lai
Journal: Annals of Internal Medicine (1992)

Objective: To determine the clinical manifestations of patients with human immunodeficiency virus (HIV) infection and tuberculosis caused by multiple-drug-resistant bacilli compared with those with single-drug-resistant or susceptible bacilli. Design: Descriptive, case-control, and cohort studies. Setting: A large urban teaching hospital. Patients: Sixty-two patients with tuberculosis caused by multiple-drug-resistant bacilli (cases) and 55 patients with tuberculosis caused by single-drug-resistant or susceptible bacilli (controls). Measurements: Characteristics of clinical presentation, radiographs, pathologic abnormalities, antituberculosis treatment, and clinical course. Results: Twenty cases (32%) had concomitant pulmonary and extrapulmonary disease at presentation compared with 9 controls (16%; odds ratio, 2.4; 95% Cl, 1.0 to 5.9). More cases had alveolar infiltrates (76%; odds ratio, 3.6; Cl, 1.2 to 11.4), interstitial infiltrates with a reticular pattern (67%; odds ratio, 7.8; Cl, 1.0 to 83.5), and cavitations (18%; odds ratio, 6.6; Cl, 0.8 to 315.3) on initial chest radiographs compared with controls (49%, 19%, and 3%, respectively). Pathologic specimens from cases showed extensive necrosis, poor granuloma formation, marked inflammatory changes with a predominance of neutrophils, and abundant acid-fast bacilli. Twenty-five cases received two or more effective antituberculosis drugs for more than 2 months. Only 2 cases had three consecutive negative cultures for Mycobacterium tuberculosis; one patient died within 1 day of the last negative culture, and the other had positive cultures 496 days later. The remaining 23 cases had persistently or intermittently positive cultures despite therapy. The clinical course of these cases suggested overwhelming miliary tuberculosis with involvement of the lungs (77%), pleura (15%), stool (34%), meninges (13%), bone marrow (16%), blood (10%), lymph nodes (10%), and skin (8%). The median survival time was 2.1 months for cases compared with 14.6 months for controls (P = 0.001, log-rank test). Conclusions: Tuberculosis caused by multiple-drug-resistant bacilli in patients with HIV infection is associated with widely disseminated disease, poor treatment response with an inability to eradicate the organism, and substantial mortality.