tbuckley/cabot-search huggingface dataset:
Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study.
Authors: G Frasci, P Comella, G Scoppa, C Guida, A Gravina, F Fiore, R Casaretti, A Daponte, A Parziale, G Comella
Journal: Journal of Clinical Oncology (1997)

Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT).Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort.Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability.CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.
Use of a very short protocol with no adjuvant in acute ovalbumin-sensitized allergic pulmonary response in mice for pre-clinical studies
Authors: Andrea Rodrigues, Camila Schmidt, Lucien Gualdi, Raquel Cao, Rodrigo Souza, Nailê Nuñez, Alisson Schleich, Renato Stein, Marcus Jomes, Paulo Pitrez
Journal: European Respiratory Journal (2011)

Many limitations have been raised over the murine models with ovalbumin (OVA) sensitization in asthma research. However, this model is still widely used as a pre-clinical study for some new specific targets for treatment. The use of adjuvant and long sensitization periods are some of the limitations raised. We have tested whether a shorter period of subcutaneous sensitization with OVA, with no adjuvant, induces a similar eosinophilic pulmonary response in mice, when compared with previous well-established control protocols. Adult BALB/c mice were used and divided into groups, according to the number of OVA sensitizations (once or twice, OVA: 20 μg) and number (twice and 3x) and dosage (40 μg and 100 μg) of intranasal OVA challenge. The shorter protocol (10 days- length) consisted of one subcutaneous OVA sensitization and three OVA challenges (100 μg). Total and differential cell counts from bronchoalveolar lavage (BAL), eosinophil peroxidase (EPO) from lung tissue and histopathology (HE) of the lungs were performed 24 hours after the last OVA challenge. Cell counts from BAL, EPO from lung tissue and histological lung abnormalities were not different between the groups studied. The shorter protocol induced a significant eosinophilic lung response to OVA. We conclude that the use of one subcutaneous OVA sensitization elicit a strong allergic pulmonary response, free of adjuvant, and in a 10-day protocol. Our findings suggest that very short protocols with no adjuvant can be used as one of the pre-clinical tests for new drug investigations, reducing cost and time of experiments, and avoiding the use of artificial adjuvants during sensitization.
Linking MRI and CT imaging with lung function measurements in cryptococcal mouse lung infection
Authors: Jeroen Vanoirbeek, Jennifer Poelmans, Erik Verbeken, Katrien Lagrou, Tom Dresselaers, Uwe Himmelreich, Greetje Vande Velde
Journal: European Respiratory Journal (2013)

Cryptococcus neoformans and C.gattii are pathogenic yeasts causing lung disease, which may spread to the brain causing life-threatening meningitis. Currently, histology remains essential to unravel cellular and molecular interactions, but imaging techniques are indispensable to define the relevant time frames for each animal individually to investigate crucial events in pathogenesis.  We aimed at dynamically monitoring cryptococcosis non-invasively in individual animals in a mouse model for cryptococcal pneumonia, establishing the kinetics of cryptococcal lung infection.  Balb/C mice were infected by inhalation of GFP-expressing C. gattii R265, scanned at baseline and weekly up to 5 weeks post infection (p.i.) with retrospectively gated MRI at 9.4T and CT. End stage lung function was tested (Flexivent) and lungs were collected for histological analysis.  While the mice showed no clinical signs of cryptococcosis, progression of the lung pathology and compensatory mechanisms could be visualized and quantified non-invasively using MRI and CT. The imaging results were in agreement with functional lung measurements and validated by histochemistry and fungal load quantification.  This is the first study showing that non-invasive monitoring of pneumonial cryptococcosis is feasible with lung MRI and CT resulting in high resolution and contrast images. This allows mouse individual longitudinal screening, visualizing infection onset and progression far before the appearance of any phenotypical signs of disease. Histological analysis and functional lung tests were found to be suitable to evaluate the disease, but are best considered as end-point measurements due to the invasiveness of the techniques.
Use and safety of a shortened histamine challenge test in an occupational study
Authors: A M Kremer, T M Pal, M Oldenziel, M Kerkhof, J G de Monchy, B Rijcken
Journal: European Respiratory Journal (1995)

A shortened histamine challenge test was used in a study of occupational airway disease. We evaluated the safety, defined as the absence of a decrease in forced expiratory volume in one second (FEV1) of greater than 40%. The occurrence of complaints, the repeatability of test results, and the average amount of time saved were measured. A standard protocol was used comprising 30 s tidal breathing with sequential doubling concentrations from 1 to 32 mg.ml-1 histamine. Subjects with no indication of hyperresponsive airways started at 4 mg.ml-1. If the decrease in FEV1 was &lt; 6%, a concentration step was skipped (fourfold increase in concentration). The test was terminated when the decrease in FEV1 was at least 18%. A total of 697 subjects performed a test. All subjects with a provocative concentration of histamine producing a 20% decrease in FEV1 (PC20) value of &lt; or = 4 mg.ml-1 (n = 16) started at the lowest concentration. Six subjects reached a &gt; or = 20% decrease in FEV1 (range 21-24%) after a fourfold increase in concentration. Five subjects had a decrease in FEV1 of greater than 40%, and this decrease occurred after a doubling concentration. Cough, flushing, and chest tightness were noted in 18% of the subjects. In 56% of the tested subjects, the shortest provocation scheme (phosphate solution followed by 4, 16 and 32 mg.ml-1 histamine) was applied, resulting in a time reduction of nearly 50% per test, and reducing the time needed to complete the study from 5 to 3 months. The shortened test was repeatable within one concentration difference.(ABSTRACT TRUNCATED AT 250 WORDS)
Radioimmunotherapy in relapsed/refractory mantle cell lymphoma patients: final results of a European MCL Network Phase II Trial
Authors: S Ferrero, A Pastore, C W Scholz, R Forstpointner, A Pezzutto, L Bergmann, L Trümper, J Finke, U Keller, P Ghione, R Passera, W Hiddemann, O Weigert, M Unterhalt, M Dreyling
Journal: Leukemia (2015)
New Vaccines for the World's Poorest People
Authors: Peter J. Hotez, Maria Elena Bottazzi, Ulrich Strych
Journal: Annual Review of Medicine (2015)

The 2000 Millennium Development Goals helped stimulate the development of life-saving childhood vaccines for pneumococcal and rotavirus infections while greatly expanding coverage of existing vaccines. However, there remains an urgent need to develop new vaccines for HIV/AIDS, malaria, and tuberculosis, as well as for respiratory syncytial virus and those chronic and debilitating (mostly parasitic) infections known as neglected tropical diseases (NTDs). The NTDs represent the most common diseases of people living in extreme poverty and are the subject of this review. The development of NTD vaccines, including those for hookworm infection, schistosomiasis, leishmaniasis, and Chagas disease, is being led by nonprofit product development partnerships (PDPs) working in consortia of academic and industrial partners, including vaccine manufacturers in developing countries. NTD vaccines face unique challenges with respect to their product development and manufacture, as well as their preclinical and clinical testing. We emphasize global efforts to accelerate the development of NTD vaccines and some of the hurdles to ensuring their availability to the world's poorest people.
Phase I trial of bortezomib, mitoxantrone and etoposide in relapsed/refractory acute leukemia
Authors: J. Filicko-O'Hara, B. Mookerjee, M. H. Carabasi, E. Besa, J. L. Wagner, N. Flomenberg
Journal: Journal of Clinical Oncology (2008)

7071 Background: Bortezomib is a proteasome inhibitor known to effect multiple signaling pathways. In hematologic malignancies, the inhibition of nuclear factor KB (NF-KB) activation and the induction of apoptosis in cells that overexpress bcl-2 have been implicated. The combination of mitoxantrone and etoposide has been successful in relapsed/refractory acute myeloid leukemia with complete remission (CR) rates of 35–45%, with median duration of CR of 4–5 months. Based on the ability to inhibit NF-KB, the addition of bortezomib should render malignant cells more susceptible to mitoxantrone and etoposide. Methods: Patients with relapsed or refractory acute leukemia were offered enrollment on a phase I study of escalating doses of bortezomib (0.7, 1.0, 1.3 mg/m2) on days 1 and 4, in combination with mitoxantrone 10 mg/m2 days 1–5 and etoposide 100 mg/m2 days 1–5. Dose escalation was allowed if not patient in the previous cohort had dose limiting toxicity defined as >grade 3 toxicity that was definitely related to study drug. Results: 11 patients (7 male, 4 female) were enrolled on this phase 1 study. All patients had refractory or relapsed acute leukemia (9 AML, 1 ALL, 1 biphenotypic leukemia). Median age was 63 years (range 48–71). All had disease that was either refractory to or had relapsed following standard therapy. 3 patients received bortezomib at a dose of 0.7 mg/m2, 5 patients received a dose of 1.0 mg/m2 and 3 patients received a dose of 1.3 mg/m2. No patient developed dose limiting toxicity at any level. 5/11 (45%) patients went into complete remission, documented by recovery (day 28) marrow; although 8/11 (73%) had had no evidence of disease on the nadir (day 14) marrow. 5/11 (45%) patients are alive at a median of 301 (range 82–474) days following initiation of therapy. Four have had further consolidative therapies including allogeneic stem cell transplantation. Conclusions: The combination of bortezomib, mitoxantrone and etoposide was well tolerated in this phase I study. The ability of the proteasome inhibitor bortezomib to enhance the effects of other cytotoxic agents may result in increased efficacy as well. A phase II study has been initiated to further study this combination. No significant financial relationships to disclose.
Outcomes of stereotactic body radiotherapy (SBRT) in 175 patients with stage I NSCLC aged 75 years and older
Authors: S. Senan, C. J. Haasbeek, M. E. Antonisse, B. J. Slotman, F. J. Lagerwaard
Journal: Journal of Clinical Oncology (2009)

9545 Background: Patients aged 75 years or older comprise more than 40% of all new cases of lung cancer. SEER data show lower compliance rates with guideline-recommended therapy in such patients. The elderly have increased post-surgical mortality and morbidity, and frequently require convalescence at extended-care facilities. SBRT is an image-guided technique used to deliver high biological doses of radiation in 3–8 fractions, in an outpatient setting. We report on clinical outcomes of SBRT in patients aged 75 years or older. Methods: Since 2003, 175 consecutive patients (67% male; 32% female) were treated with SBRT at a single center. The median age was 79 years, with 47% of patients aged 80 years or older. 56% of patients had T1 lesions and 44% T2 tumors. 79% of patients were considered medically inoperable and 21% declined to undergo surgery. Eligible tumors measured 6cm or less in maximal diameter, and all underwent an 18FDG-PET scan that revealed no metastases. The median age-adjusted Charlson co-morbidity score was 7 (range 2–12), and 25% had GOLD Class III or higher chronic obstructive pulmonary disease. Risk-adapted SBRT schemes were used with the same total dose of 60 Gy in 3 (31%), 5 (53%) or 8 fractions (16%) depending upon risk for toxicity. Quality of life was scored prospectively using validated EORTC instruments. Results: All patients completed planned SBRT and survival rates at 1 and 3 years were 85% and 46%. Survival rates correlated with performance score (p&lt;0.01) and pre-SBRT lung function (p&lt;0.01). Actuarial local-, regional- and distant failure rates at 3 years were 11%, 8% and 21%, respectively. 60% of patients reported no early side effects, and fatigue (31%), cough (6%), dyspnea (5%), local chest wall pain (3%) and chest wall erythema (2%) were observed in others. Severe late toxicity was uncommon, with RTOG Grade 3 or higher radiation pneumonitis observed in 2%, radiation-induced rib fractures in 2%, chronic chest wall pain in 3%, and non-malignant pleural effusion in 2% of cases. Conclusions: In a population consisting of frail elderly patients with stage I NSCLC, SBRT achieved high local control rates with minimal toxicity. This indicates that active diagnostic and therapeutic approaches are justified in elderly patients who may be unfit for surgery. [Table: see text]
Cluster of new influenza A(H1N1) cases in travellers returning from Scotland to Greece – community transmission within the European Union?
Authors: T Panagiotopoulos, S Bonovas, K Danis, D Iliopoulos, X Dedoukou, A Pavli, P Smeti, A Mentis, A Kossivakis, A Melidou, E Diza, D Chatzidimitriou, E Koratzanis, S Michailides, E Passalidou, P Kollaras, P Nikolaides, S Tsiodras
Journal: Eurosurveillance (2009)

On 26 and 27 May, the Hellenic Centre for Disease Control and Prevention in Greece reported two confirmed cases of new influenza A(H1N1) virus infection in travellers returning from Scotland. The two cases had no apparent traceable links to an infectious source. Herein we report details of the two cases and potential public health implications.
Obstructive sleep apnea in patients with typical atrial flutter: Clinical, prognostic and therapeutic implications
Authors: Núria Grau, Victor Bazan, Ermengol Valles, Miquel Félez, Carles Sanjuás, Miguel Cainzos, Begoña Benito, Joaquim Gea, Jordi Bruguera, Julio Martí
Journal: European Respiratory Journal (2012)

Background. The clinical yield of successful cavo-tricuspid isthmus (CTI) radiofrequency ablation for the treatment of atrial flutter (AF) is limited by a high incidence of atrial fibrillation (AFib) in the long term. The association of obstructive sleep apnea (OSA) could favor an incomplete arrhythmia control in this setting. We assessed the impact of continuous positive airway pressure (CPAP) therapy in reducing the occurrence of AFib after CTI ablation.

Methods. A cohort of consecutive patients undergoing successful CTI ablation for typical AF was screened for OSA and followed-up during 12 months. Upon diagnosis of severe OSA, CPAP therapy was initiated. Relationship of the following variables with the occurrence of AFib during follow-up was investigated: CPAP therapy initiation, hypertension, body mass index, underlying structural heart disease, left atrial diameter and previous AFib documentation prior to CTI ablation.

Results. We included 56 patients (age 66 ± 11 years, 12 female), 27 of whom (48%) were diagnosed from severe OSA. Twenty-one patients (38%) had AFib during follow-up. Freedom from AFib prior to ablation was associated with a lower incidence of AFib after this procedure (from 67% to 34% of cases; p = 0.019). Additionally, CPAP therapy initiation in those patients never being diagnosed from AFib resulted in a reduction of AFib episodes during follow-up (from 46% to 6% of cases; p = 0.025).

Conclusions. Severe OSA is a prevalent condition in patients with typical AF, and its treatment by means of CPAP therapy results in a lower incidence of new-onset AFib after CTI ablation.
Comparative Mutagenicity, Tumor-Initiating Activity, Carcinogenicity, and in Vitro Metabolism of Fluorinated 5-Methylchrysenes23
Authors: Stephen S. Hecht, Edmond LaVoie, Robert Mazzarese, Norio Hirota, Takaaki Ohmori, Dietrich Hoffmann
Journal: JNCI Journal of the National Cancer Institute (1979)

The comparative mutagenicity toward Salmonella typhlmurlum TA 100, tumor-initiating and complete carcinogenic activity on mouse skin, and in vitro metabolism of fluorinated derivatives of the carcinogen 5-methylchrysene (5-MeC) were studied. The compounds studied were 1-fluoro-5-methylchrysene (1-F-5-MeC), 3-fluoro-5-methylchrysene (3-F-5-MeC), 6-fluoro-5-methylchrysene (6-F-5-MeC), 7-fluoro-5-methylchrysene (7-F-5-MeC), 9-f1uoro-5-methylchrysene (9-F-5-MeC), 11-fluoro-5-methylchrysene (11-F-5-MeC), and 12-fluoro-5-methylchrysene (12-F-5-MeC). All seven fluoro compounds and 5-MeC were mutagenic toward S. typhlmurlum TA 100 when tested in the presence of liver homogenates from F344 rats treated with Aroclor 1254; the most mutagenic compound was 7-F-5-MeC. In the assays for tumor-initiating activity on skin of Swiss mice, 1-F-S-MeC and 3-F-5-MeC were significantly less active than was 5-MeC at both doses studied (30 and 100 μg), whereas 12-F-5-MeC was less tumorigenic than was 5-MeC at the 30-μg dose only. The other fluorinated compounds were as active as 5-MeC as tumor initiators. In agreement with these results, both 1-F-5-MeC and 3-F-5-MeC were inactive as complete carcinogens; 12-F-5-MeC was also significantly less carcinogenic than was 5-MeC. 6-F-5-MeC was more carcinogenic than was 5-MeC, whereas 7-F-5-MeC, 9-F-5-MeC, and H-F-5-MeC were as active as was 5-MeC. Examination of the in vitro metabolism of the fluorinated compounds by liver homogenates from Aroclor 1254-treated rats indicated that fluorine substitution inhibited the oxidative metabolism at the position of attachment and at neighboring positions. Thus in 1-F-5-MeC and 3-F-5-MeC, formation of the 1,2-dihydrodiol was inhibited and in 7-F-5-MeC, formation of the 7,8-dihydrodiol and chrysenols was reduced. In the metabolism of 12-F-5-MeC, the concentration of the 1,2-dihydrodiol was reduced compared to that of 5-MeC, whereas in 6-F-5-MeC, formation of the 7,8-dihydrodiol and chrysenols was inhibited.
Alterations in Adipose Tissue during Critical Illness
Authors: Lies Langouche, Sarah Vander Perre, Steven Thiessen, Jan Gunst, Greet Hermans, André D'Hoore, Blerina Kola, Márta Korbonits, Greet Van den Berghe
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Critical illness is characterized by lean tissue wasting, whereas adipose tissue is preserved. Overweight and obese critically ill patients may have a lower risk of death than lean patients, suggestive of a protective role for adipose tissue during illness.To investigate whether adipose tissue could protectively respond to critical illness by storing potentially toxic metabolites, such as excess circulating glucose and triglycerides.We studied adipose tissue morphology and metabolic activity markers in postmortem biopsies of 61 critically ill patients and 20 matched control subjects. Adipose morphology was also studied in in vivo biopsies of 27 patients and in a rabbit model of critical illness (n = 22).Adipose tissue from critically ill patients revealed a higher number and a smaller size of adipocytes and increased preadipocyte marker levels as compared with control subjects. Virtually all adipose biopsies from critically ill patients displayed positive macrophage staining. The animal model demonstrated similar changes. Glucose transporter levels and glucose content were increased. Glucokinase expression was up-regulated, whereas glycogen and glucose-6-phosphate levels were low. Acetyl CoA carboxylase protein and fatty acid synthase activity were increased. Hormone-sensitive lipase activity was not altered, whereas lipoprotein lipase activity was increased. A substantially increased AMP-activated protein kinase activity may play a crucial role.Postmortem adipose tissue biopsies from critically ill patients displayed a larger number of small adipocytes in response to critical illness, revealing an increased ability to take up circulating glucose and triglycerides. Similar morphologic changes were present in vivo. Such changes may render adipose tissue biologically active as a functional storage depot for potentially toxic metabolites, thereby contributing to survival.