tbuckley/cabot-search huggingface dataset:
Photoradiation in the Treatment of Recurrent Breast Carcinoma&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: T J Dougherty, G Lawrence, J H Kaufman, D Boyle, K R Weishaupt, A Goldfarb
Journal: JNCI Journal of the National Cancer Institute (1979)

Photoradiation, with the use of hematoporphyrin derivative (Hpd) activated by visible light in the red region of the spectrum, was an effective treatment for controlling local and regional chest wall recurrences of breast carcinoma. With sufficient time between iv injection of the drug and local activation with red light, cutaneous and subcutaneous masses were treated effectively without undue damage to overlying and adjacent skin. This high therapeutic ratio resulted from the ability to Hpd to accumulate and/or to be retained to a higher degree in malignant tissue than in many normal tissues. This technique can be used as a primary treatment or upon tumor recurrence following conventional modalities such as surgery, chemotherapy, and radiation therapy.
In vitro and in vivo pharmacological profile of RP6503, a novel dual PI3K δ/γ inhibitor, in pulmonary disease systems
Authors: Swaroop Vakkalanka, Kasiviswanath Routhu, G. Babu, Sridhar Veeraraghavan, Srikant Viswanadha
Journal: European Respiratory Journal (2013)

Introduction:  Dual PI3Kδ/γ inhibition has been strongly implicated as an effective new treatment in allergic and non-allergic inflammatory pulmonary disorders and autoimmune diseases. The objective of the experiments was to explore the therapeutic potential of RP6503, a novel, small molecule PI3Kδ/γ inhibitor, in airway diseases.   Methods:  Potency and selectivity of RP6503 for PI3Kδ and γ isoforms and subsequent downstream activity was determined in several enzyme and cell-based assays. Efficacy of inhaled or intra-nasally administered RP6503 was examined in animal models relevant to asthma and COPD.   Results:  RP6503 had high potency against PI3Kδ (IC 50 =29.3 nM) and γ (IC 50 =28.1 nM) enzymes with selectivity over α (>10,000-fold) and β (>60-fold) isoforms as well as 441 diverse kinases (>50-fold). Cellular potency was confirmed in target-specific assays, namely anti-FceR1-(IC 50 =48.0 nM) or fMLP (IC 50 =52.4 nM)-induced CD63 expression in human basophils. RP6503 potently inhibited several immune cell responses  in vitro  including neutrophil functions, mast cell degranulation, and cytokine release from macrophages. Nebulization with RP6503 inhibited LPS-induced lung TNFα and neutrophil infiltration in rats (ED 50 =0.1 mg/kg). Intranasal administration of the compound also significantly reduced ovalbumin-induced lung eosinophil infiltration in guinea pigs (ED 50 =0.02 mg/kg), and attenuated cigarette smoke-induced neutrophil infiltration in mice (ED 50 =0.003 mg/kg).   Conclusions:  Results demonstrate that RP6503 is a potent and selective dual PI3Kδ/γ inhibitor with therapeutic potential in asthma and COPD. RP6503 is currently in preclinical development.
Non-Hodgkin's lymphoma of the gastrointestinal tract: an analysis of clinical and pathologic features affecting outcome.
Authors: A F List, J P Greer, J C Cousar, R S Stein, D H Johnson, V H Reynolds, F A Greco, J M Flexner, K R Hande
Journal: Journal of Clinical Oncology (1988)

Clinical and histopathologic data from 87 patients with primary non-Hodgkin's lymphoma of the gastrointestinal (GI) tract diagnosed between 1974 and 1984 were reviewed. B-cell lymphomas of intermediate- or high-grade histology constituted 78% of lesions. Stage of disease varied with histologic grade, with a preponderance of advanced disease (stages IIIE and IV) in patients with low-grade lymphoma (15 of 21) (71%), compared with higher grade lesions (38%, P = .01). Among patients with nonlocalized (stages IIE through IV) lymphoma of intermediate- or high-grade histology, surgical resection of the primary focus afforded a higher rate of complete remission (CR) (70% v 50%) and sustained CR (61% v 21%, P = .04) after cytotoxic therapy compared with the nonresected cohort. The median survival in the resected group was 51 months + compared with 13 months in the nonresected patients (P = .012). Differences in outcome were attributable to a high risk of treatment-related complications (perforation and/or hemorrhage) (43% v 0%, P = .001) and local relapse (29% v 4%, P = .05) in nonresected individuals. Life-threatening local complications were not observed in patients with low-grade lymphoma managed solely with medical therapy. Histologic findings from surgically staged patients identified presence of extravisceral disease and intermediate- or high-grade tumor histology as features predictive of transmural invasion, enabling potential identification of patients who might be optimally managed by resection of the primary GI focus before initiation of cytotoxic therapy.
A novel pleural-bladder pump for management of pleural effusion
Authors: Philippe Astoul, Y.C. Gary Lee, Nick A. Maskell, Charles-H. Marquette, Noel Johnson, Steve Whittaker, Edouard Fonck
Journal: European Respiratory Journal (2013)

Recurrent pleural effusions are common. Pleurodesis has a suboptimal success rate and is unsuitable for patients with trapped lung. The alfapump® system is a battery-powered, fully implantable pump system, designed to move peritoneal fluid to the urinary bladder for excretion. Its safety and effectiveness have been shown in patients with liver disease. Whether the alfapump can be applied to drain pleural effusions warrants investigation.

This is a pilot feasibility study to explore the use of the alfapump system in pigs with normal pleura. The animal ethics committee in Hopital Nord, Marseille, approved the study.

Female pigs (30kg, n=2) were anesthetised and ventilated mechanically. A pleural drainage catheter was inserted under pleuroscopic assistance. A second catheter was inserted in to the urinary bladder. Both catheters were tunneled subcutaneously and attached to the pump, which was implanted 6 cm below the costal border. A range of ventilation parameters were tested to create variety of physiological conditions. Fluid was introduced into the pleural space to create multiple effusions to assess the efficacy of the alfapump to remove fluid to the bladder.

The alfapump successfully transported fluid from the pleural cavity to the bladder at an average rate of 3.3 ± 0.3 ml/sec. The pressure variations caused by the respiratory cycles and the variations in the amount of fluid (from 0 to 392ml) in the pleural cavity had no impact on the pumping. We confirmed that pumping automatically stopped when the pleural cavity was empty.

This study demonstrated that the alfapump could be used successfully in anesthetised pigs. Its safety and efficacy in the management of pleural effusion requires clinical evaluation.
The pathologic physiology of chronic Bright's disease. An exposition of the "intact nephron hypothesis".
Authors: N S Bricker, P A Morrin, S W Kime
Journal: Journal of the American Society of Nephrology (1997)

Clinical and experimental data relating to the functional capacity of the surviving nephrons of the chronically diseased kidney for the most part support the thesis that these nephrons retain their essential functional integrity regardless of the nature of the underlying form of chronic Bright's disease. There are instances in which specific alterations of function correlate with pathologic involvement of a particular site of the nephron but these appear to represent the exceptions, and in general the more advanced the disease becomes, the less evident are the differentiating features. Studies on dogs with unilateral renal disease indicate that the functional capacity of the nephrons of the diseased kidney parallels that of the nephrons of the contralateral normal kidney. These data tend to exclude widespread intrinsic damage to the functioning nephrons by the underlying pathologic processes. From these observations, as well as from certain supporting clinical and experimental observations, it is suggested that the majority of surviving nephrons in the patient with bilateral renal disease similarly are functionally intact. Concepts of the pathologic physiology of the kidney, based on the "intact nephron hypothesis", are presented. Within the framework of this hypothesis it is concluded that (1) the diseased kidney consists of a diminished number of nephrons, most of which retain essentially normal functional abilities; (2) certain of the apparent abnormalities in function in bilateral renal disease may relate to adaptive changes imposed by the decreased nephron population and the attendant derangements in body fluids rather than to structural distortion of nephrons; (3) the over-all flexibility of the diseased kidney decreases as the number of constituent nephrons decreases; but (4) there is an orderly and predictable pattern of excretion for all substances.
Inspiratory muscle training in sub-acute stroke patients
Authors: Monique Sartor, Marina Depolo, Maria Fernanda Donaire, Marta Alvarado, Esther Duarte, Anna Guillen, Mauricio Orozco-Levi, Maria Camellia Barrerra, Eva Mª Pascual Pascual, Diego A. Rodríguez, Ferran Escalada, Ester Marco
Journal: European Respiratory Journal (2013)

INTRODUCTION: Stroke induces several degrees of respiratory muscle dysfunction (RMdys). Nevertheless, potential benefits resulting from respiratory muscle training (RMT) on these patients remains unknown. The aims of this study were to assess prevalence of RMdys and to evaluate the benefits of a 3-week RMT in stroke patients.

METHODS: The study, including 88 stroke patients (age 67±11 years; 59% male), contemplates two work packages: i) to determine the prevalence and severity of RMdys and; ii) a randomized clinical trial (RMT versus usual care) to assess the impact of a 3-week RMT using the Orygen-Dual Valve®. Main outcome was respiratory muscle strength estimated by the maximal inspiratory and expiratory pressures (PImax and PEmax, respectively). RMdys was considered when PImax or PEmax was under 70% of predicted values.

RESULTS: At 12 days after stroke, 71 patients presented impairment in respiratory muscle strength (mean normalized PImax and PEmax were 44±22 and 43±21%, respectively; p=ns). Patients in the RMT group showed a greater improvement in PImax (45% vs. 26% for RMT and control group respectively; p=0.03). The improvement in PEmax was similar between both groups (p=ns).

CONCLUSION: Our results suggest that there is high prevalence of RMdys in sub-acute stroke patients. A 3-week RMT using the Orygen-Dual Valve® shows to be an effective and safe tool to improve respiratory muscles weakness. Further studies are required to establish an association between respiratory weakness and disease prognosis.

Supported by FIS (PI10/01560).
Evidence-Based Medicine on the Internet
Authors: Robert Kiley
Journal: Journal of the Royal Society of Medicine (1998)

Whatever the long-term outcomes of practising evidencebased medicine prove to he for the delivery of effective health care, there is little doubt of the impact it has had on the printing and publishing industries. For example, in the past 12 months the Medline database alone has indexed more than 300 articles on this topic. Over the same period, a search of Whitaker's Books in Print for titles that contain the words 'evidence based' identifies more than a dozen new books, whilst Ulrich's Periodicals Directory records the launch of five new journals on this theme. Fear of information overload is compounded by the results of an Internet search which highlights the existence of 5000+ evidence-based medicine Web sites. The purpose of this brief article is to highlight a few resources on the Internet that can help the busy health professional understand and practise evidence-based medicine.
Hypoxia induces IL-18 and neutrophil influx in lung parenchyma possibly mediated by MIP-2
Authors: Fadila Telarevic Cero, Karl Otto Larsen, Øystein Sandanger, Else Marit Løberg, Geir Arve Christensen, Ole Henning Skjønsberg
Journal: European Respiratory Journal (2012)

Background:  Increased levels of interleukin (IL)-18 have been found during experimental alveolar hypoxia and IL-18 have previously been shown to induce neutrophil migration, production of macrophage inflammatory protein 2 (MIP-2) and enhanced neutrophil functions (Verri, W.A. et al. Eur J Immunol 2007; 37:3373-80, Kinoshita, M. et al. Infect Immun. 2011; 79:2670-80).   Aims:  To study circulating levels of IL-18 during one week of hypoxia exposure in mice, and to investigate whether induction of IL-18 corresponds with inflammatory changes in lung parenchyma.   Methods:  IL-18 levels in blood was determined in C57Bl/6j mice (n=4 at each time point) exposed to hypoxic conditions at 6 hours (h) and 1-7 days. Lungs were harvested at each time point for histological analyses. Concentration of MIP-2 in blood was determined at 6h, 12h, 1-3 days.   Results:  The levels of circulating IL-18 were significantly increased at all time points peaking at day 1 (Figure 1A) compared to normoxic controls. Histology revealed perivascular infiltration of neutrophil granulocytes increasing from day 1 to day 3. At day 7 neutrophils were still present, but to a lesser extent than at day 3. The concentration of MIP-2 was significantly increased at day 1 (Figure 1B).   Conclusions:  The increase in IL-18 induced by alveolar hypoxia may promote the subsequent influx of neutrophils in lung parenchyma, possibly mediated through the neutrophil chemoattractant MIP-2.
Does a clinical score helps in the management of hospital-acquired pneumonia in nonventilated patients?
Authors: Bertrand Herer, Zbiniev Gazevic
Journal: European Respiratory Journal (2011)

Hospital-acquired pneumonia (HAP) is increasingly frequent in nonventilated (NV) patients. Because of the difficulty of obtaining invasive diagnostic procedures outside an intensive care unit (ICU), a clinical score could be useful for the management of NV patients. We tested the diagnostic accuracy of a score (SCOPNOFOR) suitable for NV patients with clinical suspicion of HAP, obtained by combining the following clinical parameters (minimal value = 0, maximal value = 9): non cancerous comorbid condition (0=absent, 1=present); solid cancer (0=absent, 1=present); tracheal secretions (0=absent, 1=nonpurulent, 2=purulent); previous antibiotics (0=yes, 1=no); radiographic infiltrate (0=no or diffuse, 2=localized); NV ICU (2) or ward (0) patient. The score was calculated before a protected specimen brush was obtained by bronchoscopy in all cases and its value was computed with bacteriological result to assess sensitivity (Se) and specificity (Sp). HAP was confirmed in 45 (54%) of 84 suspected episodes disclosing in major part nonfermenting (35.6%) and enteric (42.2%) gram-negative bacilli, staphylococcus (26.7%) and streptococcus (26.7%) spp. Polymicrobial HAP was present in 37.8% of episodes. The mean ± SD SCOPNOFOR value was 5.3±1.6 and 4.3±1.5, respectively, for the 45 HAP episodes and the 39 non confirmed HAP episodes (p=0.003). Se and Sp were respectively at a SCOPNOFOR value more than 5, 53% and 79%, and more than 6, 27% and 95%. We conclude that SCOPNOFOR misclassify approximately 50% to 75% of patients with definite HAP according to the chosen cut-off. These data support the need for establishing an etiologic diagnosis in suspected HAP in NV patients.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a biomarker for the effect of PTK787/ZK 222584 (PTK/ZK) as second-line mono-therapy in patients with stage IIIB or stage IV non-small cell lung cancer (NSCLC)
Authors: B. Morgan, M. A. Horsfield, J. Stattaus, A. Khalil, T. C. Gauler, V. Gounant, B. Fischer, D. Laurent, H. Krissel, W. E. Eberhardt
Journal: Journal of Clinical Oncology (2007)

7676 Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R) in NSCLC-tumors is linked to poor prognosis and shorter overall survival. PTK/ZK (PTK/ZK) is a novel, oral, anti-angiogenic compound blocking all currently known VEGF receptors (VEGF-R1–3). DCE-MRI measures early changes in tumour-associated vasculature in response to treatment and has been successfully used as a biomarker for biological activity of PTK/ZK in liver metastases from colorectal cancer. Methods: This is a prospective, multi- centre, phase-II study of PTK/ZK in pretreated patients with advanced stage NSCLC. 54 patients (pts) received 1,250 mg PTK/ZK once daily (qd), followed by 58 patients receiving 1,250 mg (500 am + 750 mg pm) PTK/ZK twice daily (bid). Response evaluation was based on RECIST. Disease stabilization of at least 12 weeks based on CT/MRI-imaging was defined as clinically relevant drug activity. DCE-MRI was performed 2- 4 hours after PTK/ZK administration, on day 2 and at day 28. Contrast enhancement for the whole tumour was assessed by calculating the transfer constant (K trans ) using a two-compartment model. Results: DCE-MRI was performed successfully in 35 pts in the qd cohort on day 2 and 29 pts in the qd cohort at day 28. There was a statistically significant mean reduction in K trans at day 2 of 35.2 % (p&lt;0.0001, N=35, paired ‘t’ test) and at Day 28 of 38.1% (p&lt;0.0001, N=29). 32 pts with day 2 DCE- MRI were evaluable for response assessment with 10 (31%) achieving SD at 12 weeks and 22 (69%) with progressive disease (PD). Both the SD group and the PD group had significant mean reductions in K trans at day 2 (39.4% and 37.1%, respectively). However, the difference between SD and PD was not statistically significant. Data for the bid cohort will be presented at the meeting. Conclusions: PTK/ZK causes statistically significant reduction in tumour vascular parameters of lung tumours. K trans has previously been shown to correlate with clinical outcome. However, for the qd cohort, no correlation could be demonstrated. This may be due to the limitation of the sample size as well as the heterogeneity of the targeted lesions selected for this study. [Table: see text]
Value of Epidermal Growth Factor Receptor, HER2, p53, and Steroid Receptors in Predicting the Efficacy of Tamoxifen in High-Risk Postmenopausal Breast Cancer Patients
Authors: Ann S. Knoop, Søren M. Bentzen, Mette M. Nielsen, Birgitte B. Rasmussen, Carsten Rose
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Few studies have examined the possible importance of biologic prognostic factors in breast cancer connected with differentiation and growth in predicting response to a specific adjuvant treatment. HER2, epidermal growth factor receptor (EGFR), and p53 have all been suggested as possible markers of tamoxifen resistance. The aim of this study was to investigate interactions between adjuvant treatment with tamoxifen and the content of EGFR, HER2, and p53 in steroid receptor–positive patients. PATIENTS AND METHODS: A total of 1,716 high-risk postmenopausal breast cancer patients were randomly assigned to treatment with tamoxifen (868 women) or to observation (848 women) in a prospective trial (Danish Breast Cancer Cooperative Group’s 77c protocol). The content of the steroid receptors and expression of p53, EGFR, and HER2 were determined by immunohistochemical analysis of paraffin-embedded tissue. The length of follow-up was 10 years. The end point for this analysis was disease-free survival. RESULTS: Multivariate analysis demonstrated no increased risk of recurrence after treatment with tamoxifen for HER2-, EGFR-, and p53-positive, high-risk, steroid receptor–positive patients. Patients with steroid receptor–positive tumors and positive immunohistochemical staining for HER2, EGFR or p53 benefited from treatment with tamoxifen for 1 year, although the latter variable contained independent prognostic information by itself. CONCLUSION: With the statistical power of the present randomized study, we did not find support for the hypothesis that HER2/EGFR or p53 status predicts benefit from tamoxifen treatment in estrogen receptor–positive patients with early-stage breast cancer. Thus, neither HER2, EGFR, nor p53 overexpression/accumulation should be used as a contraindication for giving tamoxifen.
Capecitabine, an Oral Fluoropyrimidine Carbamate With Substantial Activity in Advanced Colorectal Cancer: Results of a Randomized Phase II Study
Authors: Eric Van Cutsem, Michael Findlay, Bruno Osterwalder, Walter Kocha, David Dalley, Richard Pazdur, Jim Cassidy, Luc Dirix, Chris Twelves, David Allman, Jean-Francois Seitz, Jürgen Schölmerich, Hans Ulrich Burger, Jaap Verweij
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III. PATIENTS AND METHODS: Three capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m 2 /d bid continuously; arm B, 2,510 mg/m 2 /d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m 2 /d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off). RESULTS: One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response [PR] + complete response [CR]) were reported for eight patients with two CRs (21%; 95% confidence interval [CI], 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity. CONCLUSION: Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.