tbuckley/cabot-search huggingface dataset:
Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Childrens Cancer Group.
Authors: J L Finlay, J M Boyett, A J Yates, J H Wisoff, J M Milstein, J R Geyer, S J Bertolone, P McGuire, J M Cherlow, M Tefft
Journal: Journal of Clinical Oncology (1995)

PURPOSE In a previous randomized trial, the addition of adjuvant chemotherapy to postoperative radiotherapy proved beneficial in the treatment of childhood high-grade astrocytomas. The present study tests the hypothesis that an eight-drug adjuvant chemotherapy regimen would improve survival in such children compared with the three-drug regimen of the prior study. PATIENTS AND METHODS Between April 1985 and May 1990, patients between the ages of 18 months and 21 years with newly diagnosed high-grade astrocytomas were eligible for this study, as determined by the treating institution's histopathologic diagnosis. Treatment consisted of postoperative local-field radiotherapy and adjuvant chemotherapy, either lomustine (CCNU), vincristine, and prednisone (control regimen) or eight-drugs-in-1-day chemotherapy (experimental regimen). Two cycles of postoperative preirradiation chemotherapy were administered in the experimental regimen. Patients were evaluated radiographically every 3 months after irradiation. RESULTS Eighty-five eligible patients were randomized to the control regimen and 87 to the experimental regimen. The progression-free survival (PFS) and overall survival (OS) at 5 years were 33% (SE = 5%) and 36% (SE = 6%), respectively. There was no statistical difference in outcome between the two chemotherapy regimens. In patients with confirmed diagnoses of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM), anaplastic astrocytoma, greater than 90% resection, and nonmidline tumor location were characteristics predictive of an improved PFS. There was a difference in toxicity between the two chemotherapeutic regimens, with greater myelosuppression and hearing loss in the experimental regimen. Tumor recurrence occurred primarily within the primary tumor site. CONCLUSIONS There is no benefit to the treatment of high-grade astrocytomas in children with eight-drugs-in-1-day chemotherapy compared with CCNU, vincristine, and prednisone. Extent of tumor resection and histopathologic diagnosis are significant prognostic variables. The overall outcome for children with high-grade astrocytomas remains poor.
Recombinant Mal d 1 facilitates sublingual challenge tests of birch pollen‐allergic patients with apple allergy
Authors: T. Kinaciyan, B. Nagl, S. Faustmann, S. Kopp, M. Wolkersdorfer, B. Bohle
Journal: Allergy (2015)

It is still unclear whether allergen-specific immunotherapy (AIT) with birch pollen improves birch pollen-related food allergy. One reason for this may be the lack of standardized tests to assess clinical reactions to birch pollen-related foods, for example apple. We tested the applicability of recombinant (r) Mal d 1, the Bet v 1-homolog in apple, for oral challenge tests. Increasing concentrations of rMal d 1 in 0.9% NaCl were sublingually administered to 72 birch pollen-allergic patients with apple allergy. The dose of 1.6 μg induced oral allergy syndromes in 26.4%, 3.2 μg in 15.3%, 6.3 μg in 27.8%, 12.5 μg in 8.3%, 25 μg in 11.1%, and 50 μg in 4.2% of the patients. No severe reactions occurred. None of the patients reacted to 0.9% NaCl alone. Sublingual administration of 50 μg of rMal d 1 induced no reactions in three nonallergic individuals. Our approach allows straight forward, dose-defined sublingual challenge tests in a high number of birch pollen-allergic patients that inter alia can be applied to evaluate the therapeutic efficacy of birch pollen AIT on birch pollen-related food allergy.
Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants
Authors: Jean-Christophe Rozé, Gilles Cambonie, Laetitia Marchand-Martin, Véronique Gournay, Xavier Durrmeyer, Mélanie Durox, Laurent Storme, Raphaël Porcher, Pierre-Yves Ancel
Journal: JAMA (2015)

<h3>Importance</h3> There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants. Less pharmacological closure and more supportive management have been observed without evidence to support these changes. <h3>Objective</h3> To evaluate the association between early screening echocardiography for PDA and in-hospital mortality. <h3>Design, Setting, and Participants</h3> Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011. Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable. <h3>Exposures</h3> Early screening echocardiography before day 3 of life. <h3>Main Outcomes and Measures</h3> The primary outcome was death between day 3 and discharge. The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis). <h3>Results</h3> Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired. Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, −12.0 [95% CI, −17.3 to −6.7). Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]). No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed. In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04]. <h3>Conclusions and Relevance</h3> In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions. However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity.
Pathogenic potential of an autoprocessed form of neutrophil elastase
Authors: Therese Dau, Rim Sarker, Ali Önder Yildirim, Oliver Eickelberg, Dieter Jenne
Journal: European Respiratory Journal (2014)

The activity of neutrophil elastase (NE) is tightly contained by serpins with a1-antitrypsin (a1PI) as the main extracellular inhibitor. Disruption of the protease inhibitor balance as seen in patients with a1PI deficiency or experimentally by intratracheal instillation of neutrophil elastase is associated with the development of lung emphysema.  Characterization of the murine homolog of NE revealed a self-cleavage site near its S1 pocket between the Ala188-Gly189 bond resulting in a two-chain form of NE (tc-NE). In this study we studied the impact of tc-NE on the protease inhibitor balance.  We successfully removed this self-cleavage site by two mutations which changed Gln187 to Lys and Ala188 to Gly. Differences between the stable single-chain (sc-NE) and the two-chain form of NE (tc-NE) were then determined by enzyme kinetics and inhibitor studies. Western blot analysis was used to identify the naturally occurring form of NE. Finally, sc- and tc-NE were applied to mice.  We found that the reactive center loop of a1PI was cleaved by the tc-NE more slowly as compared with sc-NE. In line with this observation, inhibition and covalent complex formation of tc-NE and a1PI was significantly impaired. Small molecule inhibitors also displayed a decline in their affinity for tc-NE. The sc-NE as well as the tc-NE was found in murine and human PMNs. Both forms of NE were able to induce pathological changes in mice.  In conclusion tc-NE maintained its pathogenic properties, but was less susceptible to inhibition by a1PI. Local release of tc-NE from dying neutrophils and during frustrated phagocytosis most likely increases tissue damage and should be considered for the development of more efficient anti-elastase therapies.
Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. West Japan Study Group for Lung Cancer Surgery.
Authors: H Wada, S Hitomi, T Teramatsu
Journal: Journal of Clinical Oncology (1996)

PURPOSE We performed a study to determine whether postoperative mild chemotherapy to maintain the patient's quality of life (QOL) and immunoactivity could also prolong survival. SUBJECT AND METHODS From December 1985 to July 1988, 323 patients with completely resected primary non-small-cell lung cancer (stage I to III) were enrolled. The subjects were randomized into three treatment groups, as follows: cisplatin (CDDP) 50 mg/m2 body surface, vindesine (VDS) 2 to 3 mg/kg body weight for three courses, and 1-year oral administration of tegafur (FT) plus uracil (UFT) 400 mg/kg body weight (CVUft group, 115 patients); 1-year oral administration of UFT 400 mg/kg body weight (Uft group, 108 patients); or surgical treatment only (control group, 100 patients). RESULTS The overall 5-year survival rates were 60.6% for the CVUft group and 64.1% for the Uft group versus 49.0% for the control group. The results of statistical testing were P = .053 (log-rank test) and P = .044 (generalized Wilcoxon test) among the three groups, P = .083 (log-rank) and P = .074 (Wilcoxon) between the CVUft and the control groups, and P = .022 (log-rank) and P = .019 (Wilcoxon) between the Uft and the control groups, which indicates higher survival rates in the CVUft and the Uft groups compared with the control group. A multivariate statistical analysis on prognostic factors using Cox's proportional hazards model was performed with the following results: P = .037, hazards ratio = 0.64 with a 95% confidence interval (CI) of 0.42 to 0.97 (control v CVUft group); and P = .009, hazards ratio = 0.55 with a 95% CI of 0.36 to 0.86 (control v Uft group). CONCLUSION Significantly favorable results were obtained in the CVUft and Uft groups compared with surgery alone. These data showed significant prognostic advantages in the postoperative adjuvant chemotherapy groups.
Abstract 2856: Fibroblast growth factor receptor 1 gene amplification as an independent prognostic factor for recurrence in patients with resected squamous cell esophageal cancer
Authors: Hyo Song Kim, Seung Eun Lee, Yoon Sung Bae, Joo Hang Kim, Hye Ryun Kim, Dae Joon Kim, Hyunki Kim, Yoon-La Choi, Byoung Chul Cho
Journal: Cancer Research (2014)

Abstract Purpose To evaluate investigate the prognostic role of fibroblast growth factor receptor 1 (FGFR1) amplification in patients with surgically resected esophageal squamous cell carcinoma (ESCC). Patients and methods Gene copy number of FGFR1 was investigated in microarrayed tumors from 549 patients with ESCC who underwent curative esophagectomy. Gene copy number was evaluated by fluorescent in situ hybridization, and an FGFR1 amplified tumor (FGFR1 amp+) was prespecified if one of the following criteria is fulfilled: (I) FGFR1/centromer 8 (CEN8) ration is ≥ 2.0, (II) average gene copy nucleus is ≥ 6.0, and (III) percentage of tumor cells containing ≥ 15 gene copies or large cluster is ≥ 10%. Results FGFR1 amplification was detected in 8% (44 of 549) of ESCC. The average copy number per nucleus was 2.7 (range, 0-15.5) and the mean FGFR1/CEN8 ratio was 2.2 (range, 0-6). The 5-year disease free survival of the FGFR1 amp+ group was significantly shorter compared with that of the FGFR1amp- group (38.8% vs 63.7% P=0.012). In Cox proportional hazard model, patients with FGFR1 amp+ had a significantly greater risk of recurrence compare to amp- group after adjusting for sex, smoking status, pathologic stage, histology, and adjuvant chemotherapy (HR 1.74; 95% CI, 1.10-2.76, P=0.018). Of note, there was a trend toward worse overall survival for FGFR1 amp+ group compare to amp- group (5-year OS 32.0% vs 50.8%, P=0.11). FGFR1 amp+ group was significantly more likely to be smokers than FGFR1amp- group (97.7 % vs 2.3%, P=0.001). With increment of total cigarette smoking dosage, the incidence of FGFR1 amp+ significantly increased (P trend=0.005). Conclusions FGFR1 amplification is an independent prognostic factor for recurrence in surgically resected ESCC. FGFR1 amplification may have potential clinical application to the development of novel therapeutic strategies for ESCC Citation Format: Hyo Song Kim, Seung Eun Lee, Yoon Sung Bae, Joo Hang Kim, Hye Ryun Kim, Dae Joon Kim, Hyunki Kim, Yoon-La Choi, Byoung Chul Cho. Fibroblast growth factor receptor 1 gene amplification as an independent prognostic factor for recurrence in patients with resected squamous cell esophageal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2856. doi:10.1158/1538-7445.AM2014-2856
No evidence exists to support use of penicillin
Authors: T. Stokes, R. Shukla, P. Monk
Journal: BMJ (1996)

Birger Knapskog call for a change in the current British guidelines on the prevention of meningococcal disease without adequately substantiating their arguments.'Their view contradicts the lat- est guidelines from the Public Health Laboratory Service's Meningococcal Infections Working Group2 and will cause confusion when clarity is paramount.The failures in administration of prophylaxis cannot be overcome without clear guidelines and may result in preventable life threatening illness.The prevention of secondary cases of menin- gococcal disease in Britain is by chemoprophylaxis with rifampicin, ciprofloxacin, or ceftriaxone for all household and kissing contacts of patients with the disease.2Chemoprophylaxis is effective3; resistance to rifampicin is rare in Brit- ain; and parents are advised to seek medical attention if a contact develops fever or a rash, even if months have elapsed since the illness.4Kristiansen and Knapskog argue that the addition of penicillin could prevent systemic dis- ease but do not provide convincing evidence to support their claim.The Department of Health and the Communicable Disease Surveillance Centre in Britain do not recommend the use of penicillin, and to advocate a change in policy in We receive more letters than we can publish: we can currently accept only about one third.
Spectrum of adverse drug reactions during MDR TB treatment
Authors: Kavita Mody, Mandar Kubal
Journal: European Respiratory Journal (2013)

Introduction: A wide range of adverse drug events have been reported with MDR TB treatment which may contribute to treatment default.  Aim: To identify potential adverse drug reactions(ADRs) in MDR TB patients on treatment.  Methods: 50 patients (30males & 20 females) on MDR TB treatment were regularly followed up in outpatient clinic to understand any potential ADRs arising from the treatment.  Results: 80% of the patients developed GI disturbances (nausea / vomiting / dyspepsia / loss of appetite). Depression was the commonest neurological ADRs (15%) in addition to peripheral neuropathy (5%) and giddiness (2%). 10% patients developed skin discoloration, in addition to rash (5%) and pruritus (4%). Anemia and thrombocytopenia were noted in 6% and 3% patients respectively. 70% patients complained of distressing arthralgias while 30% had uric acid elevations. Jaundice developed in 5% of the patients. Most prominent endocrine problem was hypothyroidism (20%). No cardiac, renal or visual side effect was reported during the study.  Conclusions: A wide variety of ADRs are seen during MDR TB treatment. Many are significant enough to contribute to treatment default. The treating physician has to look out for these signs during every consultation. Patients must be educated regarding these events and counseled to not default, but seek consultation for the same.
Membrane diffusion of the lungs in patients with chronic renal failure
Authors: J Moinard, H Guenard
Journal: European Respiratory Journal (1993)

Patients with chronic renal failure (CRF) and haemodialysis treatment usually have a reduced CO transfer factor. The aim of this study was to evaluate the effects of alveolar wall fibrosis and of anaemia on gas diffusion in the lungs. The NO and CO transfer factors of the lung (TLNO and TLCO) were measured, simultaneously, in 15 patients haemodialysed three times a week for 1-10 yrs. Assuming that NO is highly reactive with blood, Tlno is thus directly proportional to the membrane diffusion factor (DmCO). The lung capillary blood volume (Vc) was derived from the set of the two transfer equations. Transfer factors were measured between haemodialysis sessions. All patients but one were anaemic, with haemoglobin concentrations ranging 61-151 g.l-1. All had decreased Vc, and a decreased DmCO was observed in 14 patients. However, after correction for the anaemia, Vc values were normal with the exception of three patients. The percentage decrease in DmCO with respect to normal was correlated with the time elapsed since the first haemodialysis. These results support the idea of a progressive development of haemodialysis-induced chronic lung disease, that may be related to a mechanism of complement activation by a bio-incompatible membrane (Cuprophane). Accordingly, patients with compromised cardiopulmonary functions should be dialysed with a bio-compatible membrane.
Effectiveness of rivastigmine in Alzheimer's disease
Authors: P. Bentham, R. Gray, E. Sellwood, J. Raftery, M. Rosler, C. E Selai, M. R Trimble, M. N Rossor, R. J Harvey, J G Storosum, B J van Zwieten-Boot, A J A Elferink
Journal: BMJ (1999)

Editor—Two recent reports on rivastigmine in Alzheimer’s disease1,2 provide further proof that cholinesterase inhibitors produce modest improvements in cognitive testing and in clinical impression of change. The new claim is of improved functionality with rivastigmine, which, if true, would be an important advance in the management of Alzheimer’s disease.

Unfortunately, however, these studies do not establish that functional ability is improved. Both studies rated functionality using the progressive deterioration scale, which was developed to assess quality of life not activities of daily living.3 It contains considerable duplication (for example, four questions on handling finances), and only two items relate peripherally to the basic activities of dressing and eating. It cannot be concluded, therefore, that improved scores equate to improved functionality.

Moreover, Rosler et al misrepresent the small improvement in progressive deterioration score seen with rivastigmine (2.8 on a 100 point scale) by citing in the discussion that one third of patients taking higher dose rivastigmine attained at least a 10% improvement in score without noting that 20% of placebo patients also improved to this extent. The benefit was actually only 13% (33% v 20%), which is reduced to 10% (29% v 19%) on more appropriate intention to treat analysis.

The intention to treat analyses are also potentially biased because of non-random drop outs: 77 (32%) of 243 higher dose rivastigmine patients did not have a 26 week assessment compared with 31 (13%) of the 239 placebo patients. Alzheimer’s disease is progressive and so replacing missing data by carrying forward values obtained earlier in the trial underestimates natural deterioration. No improvements in progressive deterioration score were seen in the lower dose rivastigmine group, which had the same drop out rate as the placebo group.

Thus it remains unclear whether cholinesterase inhibitors produce sufficient benefit in Alzheimer’s disease to justify their widespread use. Clearly, any delays in progress to severe dependency or institutionalisation would be worth while both clinically and economically. Improved functionality, fewer neuropsychiatric symptoms, and reduced burden and stress on carers would also be important. But none of these has been reliably established for rivastigmine or donepezil. Longer term placebo controlled trials addressing these outcomes are urgently required.4 One such study, the national AD2000 donepezil trial, has recently opened and already includes 150 patients. To resolve current uncertainties about the best use of cholinergic agents, widespread support—from clinicians and purchasers—for studies such as AD2000 should be encouraged.
Sleep study characteristics in patients with mucopolysaccharidosis
Authors: Ayse Tana Aslan, Cigdem Kasapkara, Leyla Tumer, Alev Hasanoglu, Fatih Ezgu
Journal: European Respiratory Journal (2013)

Background:  Mucopolysaccharidoses (MPS) are inherited lysosomal storage disorders caused by the deficiency of hydrolases involved in the degradative pathway of glycosaminoglycans. In MPS, upper airway obstruction has multiple causative factors, may severely affect morbidity and mortality.   Methods:  We evaluated upper airway obstructive disease and related clinical findings through home sleep study in 19 patients (11 with MPS VI, 4 with MPS I, 4 with MPS II) with MPS followed at Gazi University Pediatric Pulmonology Unit. Patients underwent home based sleep measurements and sleep-respiratory problems were asked in a detailed clinical history. Measurements of apnea, apnea-hypopnea index, hypopnea index, oxygen desaturation index,  minimal oxygen saturation were obtained through home sleep study   Results:  For 19 children, the disorder was normal in 1, mild (AHI 1.5-5/h) in 5, moderate (AHI 5-10) in 2, and severe (AHI>10) in 11. The prevalence of OSA was 94.7% (18/19) in patients with MPS. Snoring, witnessed apnea, pectus carinatum, and macroglossia were the main clinical findings. Echocardiograms showed evidence of pulmonary hypertension in 13 patients.   Conclusion:  Home sleep study is very quick, easily available screening test to determine the abnormalities of breathing during sleep and urge the clinicians to take necessary action for patients with severe manifestations.