tbuckley/cabot-search huggingface dataset:
Impact of Cigarette Smoking on Cancer Risk in the European Prospective Investigation into Cancer and Nutrition Study
Authors: Antonio Agudo, Catalina Bonet, Noémie Travier, Carlos A. González, Paolo Vineis, H. Bas Bueno-de-Mesquita, Dimitrios Trichopoulos, Paolo Boffetta, Françoise Clavel-Chapelon, Marie-Christine Boutron-Ruault, Rudolf Kaaks, Annekatrin Lukanova, Madlen Schütze, Heiner Boeing, Anne Tjonneland, Jytte Halkjaer, Kim Overvad, Christina C. Dahm, J. Ramon Quirós, María-José Sánchez, Nerea Larrañaga, Carmen Navarro, Eva Ardanaz, Kay-Tee Khaw, Nicholas J. Wareham, Timothy J. Key, Naomi E. Allen, Antonia Trichopoulou, Pagona Lagiou, Domenico Palli, Sabina Sieri, Rosario Tumino, Salvatore Panico, Hendriek Boshuizen, Frederike L. Büchner, Petra H.M. Peeters, Signe Borgquist, Martin Almquist, Göran Hallmans, Ingegerd Johansson, Inger T. Gram, Eiliv Lund, Elisabete Weiderpass, Isabelle Romieu, Elio Riboli
Journal: Journal of Clinical Oncology (2012)

Our aim was to assess the impact of cigarette smoking on the risk of the tumors classified by the International Agency for Research on Cancer as causally associated with smoking, referred to as tobacco-related cancers (TRC).The study population included 441,211 participants (133,018 men and 308,193 women) from the European Prospective Investigation Into Cancer and Nutrition. We investigated 14,563 participants who developed a TRC during an average follow-up of 11 years. The impact of smoking cigarettes on cancer risk was assessed by the population attributable fraction (AF(p)), calculated using the adjusted hazard ratios and 95% CI for current and former smokers, plus either the prevalence of smoking among cancer cases or estimates from surveys in representative samples of the population in each country.The proportion of all TRC attributable to cigarette smoking was 34.9% (95% CI, 32.5 to 37.4) using the smoking prevalence among cases and 36.2% (95% CI, 33.7 to 38.6) using the smoking prevalence from the population. The AF(p) were above 80% for cancers of the lung and larynx, between 20% and 50% for most respiratory and digestive cancers and tumors from the lower urinary tract, and below 20% for the remaining TRC.Using data on cancer incidence for 2008 and our AF(p) estimates, about 270,000 new cancer diagnoses per year can be considered attributable to cigarette smoking in the eight European countries with available data for both men and women (Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Sweden, Denmark).
Anxiety and depression in relation to respiratory symptoms and asthma.
Authors: C Janson, E Björnsson, J Hetta, G Boman
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

The aim of this investigation was to study the relationship between psychologic status and respiratory health. The study comprised 715 persons aged 22 to 44 who participated in the European Commission Respiratory Health Survey. The study included a structural interview, spirometry, methacholine challenge, peak flow diary, skin prick test, and measurement of eosinophil activity in peripheral blood. The psychologic status was assessed by means of the hospital anxiety and depression (HAD) scale questionnaire. A significant correlation was found between anxiety and depression and the report of asthma-related symptoms, such as attacks of breathlessness after activity and waking with attacks of breathlessness (p < 0.01). However, there was no significant correlation between anxiety or depression and a self-reported diagnosis of asthma or objective asthma-related variables, such as peak flow variability or response to methacholine. When evaluating the combined influence of psychologic factors and objective variables, HAD score correlated independently with reported wheezing (p < 0.05), waking with attacks of breathlessness (p < 0.01), waking with chest tightness, attacks of breathlessness when at rest, and attacks of breathlessness after activity (p < 0.001). We conclude that there is an association between reported respiratory symptoms and psychologic status. However, there was no evidence that patients with diagnosed bronchial asthma had more anxiety and depression than those without asthma. This result indicates that it may be valuable to include psychologic status indicators in respiratory symptom questionnaires.
Treatment of Recurrent Endometrial Carcinoma: Progress Toward a More Personalized Approach
Authors: Giorgio Bogani, Valentina Chiappa, Domenica Lorusso, Francesco Raspagliesi
Journal: Journal of Clinical Oncology (2015)

TO THE EDITOR: The article by Slomovitz et al addresses an important and compelling clinical question regarding the treatment of recurrent endometrial cancer (EC). In their investigation, the authors provided further evidence for the safety profile and effectiveness of mammalian target of rapamycin (ie, everolimus) and aromatase inhibitors (ie, letrozole) for treating patients affected by progressive or recurrent EC. The authors reported important information regarding this combined therapy, thus seeding larger prospective investigations. They observed that the administration of everolimus plus letrozole correlates with encouraging response rates and survival outcomes, especially when compared with other therapeutic strategies. Of interest, one of the most important findings of the study is that serous histology is the strongest factor predicting nonresponse. However, two points regarding the treatment of recurrent EC deserve to be addressed: First, although the authors reported a complete analysis of the tumor specimens (reporting analyses on genes mutations), it should be interesting to evaluate the effect of this combined treatment in high-grade endometrioid EC. In fact, growing evidence questions the Bokhman’s dualistic model and supports that high-grade endometrioid EC much more closely resembles nonendometrioid type 2 cancer than endometrioid EC. By this point of view, we can speculate that in grade 1 and 2 endometrioid EC, everolimus plus letrozole may possibly provide more pronounced survival results in comparison with grade 3 and serous tumors. Moreover, the advantage of the combined treatment over both single strategies should be carefully evaluated in a risk-benefit ratio, given that indirect comparison of response rates in trials reporting activity of single-agent aromatase inhibitors or mammalian target of rapamycin inhibitors seems to show that they are roughly superimposable on the rates obtained with the combination at the price of reduced toxicity. Second, although the majority of patients affected by progressive or recurrent EC have systemic disease, we believe that, in selected cases, both exenterative and nonexenterative surgical procedures play an important role in locoregional control, thus improving progression-free and overall survival, especially in those patients suffering late recurrences. It would be extremely interesting to know the opinion of the authors on these issues. To us, in absence of clear evidence suggesting the more efficient treatment for recurrent EC, a personalized treatment is advocated. Novel therapies are needed for patients affected by high-grade and nonendometrioid EC.
P08.19 * PRIMARY INTRATHECAL MELANOMA ARISING FROM MENINGEAL MELANOCYTOSIS: A CASE REPORT
Authors: W. Moser, K. Thier, C. Hafner, F. Trautinger, K. Ungersbock, R. Sedivy, S. Oberndorfer
Journal: Neuro-Oncology (2014)

INTRODUCTION: Primary melanocytic tumours of the leptomeninges are rare diseases. The WHO classification of 2007 described four entities: diffuse melanocytosis, melanocytoma, malignant melanoma and meningeal melanomatosis. Meningeal melanocytosis is a benign proliferation of melanocytes with a risk of malignant transformation and is often associated with neurocutaneos melanosis. CASE REPORT: A 65-year-old male patient presented with low back pain and disturbed micturition. Neurological examination revealed left sided S1- sensory radiculopathy. His medical history was unremarkable. MRI of the lumbar spine showed a contrast-enhancing intrathecal tumour of the conus medullaris and MRI of the brain was suspicious of neoplastic meningitis. Spinal surgery exhibited a brown tumour mass with diffuse spreading of pigmented lesions along the arachnoidea. Histological, immunohistochemical, and molecular analyses showed an intrathecal melanoma with a wild-type BRAF genotype. Dermatological examination was unremarkable. Lumbar stereotactic radiotherapy was applied. Subsequently, 3 cycles of temozolomide (150mg/m2 on 5 days out of 28) and bi-weekly intrathecal liposomal cytarabine were administered. Despite the poor prognosis of neoplastic meningitis in melanoma, the patient survived without clinical for more than one year. 15 months after the initial diagnosis spinal MRI showed a local relapse and a second surgery was performed. This time molecular analysis of the tumor revealed the presence of the BRAF V600E mutation. Due to the initially slow tumor progression treatment with B-Raf inhibitors was withheld and immunotherapy with the anti-CTLA-4 antibody ipilimumab was initiated together with stereotactic radiotherapy of the conus medullaris. Three months later, the patient complained about diplopia and dizziness. Neurological examination revealed oculomotor nerve palsy. MRI of the brain showed a meningeal contrast-enhancement in the brainstem area. The B-Raf inhibitor vemurafenib was initiated in combination with intrathecally administered liposomal cytarabine and whole brain radiotherapy. Despite this the patient's condition deteriorated and he died two weeks later. Considering the long progression-free interval and the diffuse intrathecal melanocytic spread, the initial diagnosis of neoplastic meningitis was re-evaluated. Differential diagnoses include neoplastic meningitis from an unknown primary melanoma and malignant transformation of leptomeningeal melanocytosis. Retrospectively, we speculate that the patient had a leptomeningeal melanocytosis and consecutive malignant transformation. Treatment options are palliative and include intrathecal and systemic chemotherapy, radiotherapy, immunotherapy, as well as kinase inhibitors. Since evidence based guidelines are lacking therapy has to be selected on an individual basis.
Macrophage Depletion by Clodronate-Containing Liposomes Reduces Neointimal Formation After Balloon Injury in Rats and Rabbits
Authors: Haim D. Danenberg, Ilia Fishbein, Jianchuan Gao, Jukka Mönkkönen, Reuven Reich, Irith Gati, Evgeny Moerman, Gershon Golomb
Journal: Circulation (2002)

Background — Inflammation is critical to vascular repair after mechanical injury. Excessive inflammation enhances neointimal formation and restenosis. We examined whether transient systemic inactivation of macrophages at the time of vascular intervention could attenuate the degree of expected restenosis. Methods and Results — Liposomal clodronate (LC) inhibited the growth of cultured macrophages but had no effect on endothelial or smooth muscle cells and suppressed neointimal hyperplasia in hypercholesterolemic rabbits and rats after intravenous administration of LC, with no adverse effects. LC treatment reduced the number of blood monocytes and decreased macrophage infiltration in the injured arteries as well as smooth muscle cell proliferation, interleukin-1β transcription, and production and matrix metalloproteinase-2 activity. Conclusions — Macrophages play a pivotal role in vascular repair after mechanical arterial injury. Systemic inactivation and depletion of monocytes and macrophages by LC reduce neointimal hyperplasia and restenosis.
Mechanisms of subendocardial dysfunction in response to exercise in dogs with severe left ventricular hypertrophy.
Authors: L Hittinger, Y T Shen, T A Patrick, N Hasebe, K Komamura, T Ihara, W T Manders, S F Vatner
Journal: Circulation Research (1992)

The effects of exercise on regional myocardial blood flow and function were examined in the presence and absence of beta-adrenergic receptor blockade in 10 adult conscious dogs with severe left ventricular (LV) hypertrophy induced by aortic banding in puppies, which increased the LV weight/body weight ratio by 87%. Exercise at the most intense level studied increased LV systolic (+87 +/- 8 mm Hg) and end-diastolic (+28 +/- 5 mm Hg) pressures, systolic (+85 +/- 12 g/cm2) and diastolic (+49 +/- 11 g/cm2) wall stresses, and subepicardial wall thickening (+0.18 +/- 0.05 mm) but reduced subendocardial wall thickening (-0.45 +/- 0.12 mm) and full wall thickening (-0.42 +/- 0.13 mm). This was associated with a fall in the subendocardial/subepicardial (endo/epi) blood flow ratio to 0.87 +/- 0.06 from 1.24 +/- 0.08. Subendocardial dysfunction persisted during recovery, at a time when transmural blood flow distribution returned to baseline, suggesting myocardial stunning. At the least intense level of exercise studied, the endo/epi blood flow ratio did not fall (1.27 +/- 0.14), but increases in heart rate (+73 +/- 8 beats per minute) and LV systolic (+35 +/- 8 g/cm2) and diastolic (+27 +/- 3 g/cm2) wall stresses were observed, and subendocardial wall thickening fell significantly (-0.21 +/- 0.08 mm, p less than 0.05). With anticipation of exercise, subendocardial wall thickening was not changed. However, subendocardial dysfunction was even evident after 10 beats, i.e., the first 3 seconds of exercise, at a time when LV pressures and stresses had not increased. After beta-adrenergic receptor blockade with propranolol, the most intense level of exercise was associated with lesser increases in systolic and diastolic LV wall stresses, heart rate, and LV dP/dt, and the endo/epi blood flow ratio was no longer reduced below unity (1.17 +/- 0.09). In addition, there were no decreases in subendocardial or full wall thickening, and myocardial stunning was no longer observed. Thus, the subendocardial hypoperfusion and depression in subendocardial wall thickening observed during exercise in dogs with LV hypertrophy was prevented by pretreatment with beta-adrenergic receptor blockade. Furthermore, the subendocardial dysfunction occurred rapidly, before alterations in LV systolic or diastolic wall stress or an alteration in the endo/epi blood flow ratio.(ABSTRACT TRUNCATED AT 400 WORDS)
Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema
Authors: Takeo Ishii, Raja T. Abboud, Alison M. Wallace, John C. English, Harvey O. Coxson, Richard J. Finley, Karey Shumansky, Peter D. Paré, Andrew J. Sandford
Journal: European Respiratory Journal (2013)

Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes. Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed. The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted. We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation.
Clinical Spectrum of Glutethimide Intoxication
Authors: Joseph A. Chazan
Journal: JAMA (1969)

Documented glutethimide (Doriden) intoxication was the cause of 39 admissions (37 patients). On admission, 17 were responsive to deep pain and had uncomplicated clinical courses; 22 were comatose and had complicated clinical courses; and 2 died (overall mortality, 5%). The diagnosis was confirmed by elevated blood glutethimide levels in each case. However, the drug level in the blood on admission correlated poorly both with state of consciousness and with the duration of coma. The clinical course of 5 severely intoxicated patients treated with prolonged hemodialysis was contrasted with the course of the 12 severely intoxicated patients treated without hemodialysis. There was no evidence from this comparison that hemodialysis shortened the duration of coma, lessened complications, or improved survival.
Increased expression of the sodium/iodide symporter in papillary thyroid carcinomas.
Authors: T Saito, T Endo, A Kawaguchi, M Ikeda, R Katoh, A Kawaoi, A Muramatsu, T Onaya
Journal: Journal of Clinical Investigation (1998)

Iodide is concentrated to a much lesser extent by papillary thyroid carcinoma as compared with the normal gland. The Na+/I- symporter (NIS) is primarily responsible for the uptake of iodide into thyroid cells. Our objective was to compare NIS mRNA and protein expression in papillary carcinomas with those in specimens with normal thyroid. Northern blot analysis revealed a 2.8-fold increase in the level of NIS mRNA in specimens with papillary carcinoma versus specimens with normal thyroid. Immunoblot analysis using anti-human NIS antibody that was produced with a glutathione S-transferase fusion protein containing NIS protein (amino acids 466-522) showed the NIS protein at 77 kD. The NIS protein level was elevated in 7 of 17 cases of papillary carcinoma but was not elevated in the normal thyroid. Immunohistochemical staining revealed abundant NIS in 8 of 12 carcinomas, whereas NIS protein was barely detected in specimens with normal thyroid. Although considerable patient-to-patient variation was observed, our results indicate that NIS mRNA is elevated, and its protein tends to be more abundant, in a subset of papillary thyroid carcinomas than in normal thyroid tissue.
A new weaning and long term ventilation service – One year on
Authors: Verity Ford, Robert Angus, Biswajit Chakrabarti, Nick Duffy, John O'Reilly, Karen Ward, Jan Bennett, Victoria Molyneaux, Jackie Walsh, Julie Cheney, Robert Parker
Journal: European Respiratory Journal (2011)

Introduction:  In 2010 a purpose built 10 bed Ventilation Inpatient Centre (VIC) was opened. In its first year 230 patients received acute non invasive ventilation (NIV), and 164 electively established on domiciliary NIV. It now also manages weaning failure for tracheostomy ventilated ICU patients in a multidisciplinary, rehabilitation centred environment. The cost is less than half that of an ICU bed. A secondary role is assisting discharge of ventilator dependent patients to home or care facility. Well established in continental Europe and the USA, such units are rare in the United Kingdom. We reviewed our weaning cases to report our first years experience.   Results:    Conclusion:  Activity has risen steadily, all weaning beds are currently used with a waiting list for transfer. Most patients had an underlying diagnosis likely to prevent complete liberation from ventilatory support. Success in weaning from invasive ventilation has been largely through the use of nocturnal NIV. The service has been well received by patients, families and referring ICUs. ICU beds can be used for acute care, it is cost effective and provides a template for other service development.
C5a Mediates Peripheral Blood Neutrophil Dysfunction in Critically Ill Patients
Authors: Andrew Conway Morris, Kallirroi Kefala, Thomas S. Wilkinson, Kevin Dhaliwal, Lesley Farrell, Tim Walsh, Simon J. Mackenzie, Hamish Reid, Donald J. Davidson, Chris Haslett, Adriano G. Rossi, Jean-Michel Sallenave, A. John Simpson
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Critically ill patients are highly susceptible to hospital-acquired infection. Neutrophil function in critical illness remains poorly understood.Objectives: To characterize and define mechanisms of peripheral blood neutrophil (PBN) dysfunction in critically ill patients. To determine whether the inflamed lung contributes additional phagocytic impairment.Methods: Prospective collection of blood and bronchoalveolar lavage fluid from patients with suspected ventilator-associated pneumonia and from age- and sex-matched volunteers; laboratory analysis of neutrophil functions.Measurements and Main Results: Seventy-two patients and 21 volunteers were included. Phagocytic capacity of PBNs was 36% lower in patients than in volunteers (P < 0.0001). From several biologically plausible candidates only activated complement was significantly associated with impaired PBN phagocytosis (P < 0.0001). Phagocytosis was negatively correlated with serum C3a and positively correlated with expression of C5a receptor type 1 (CD88) on PBNs. C5a recapitulated impaired PBN phagocytosis and significantly down-regulated CD88 expression in vitro. C5a-mediated phagocytic impairment was prevented by blocking either CD88 or phosphoinositide 3-kinase, and completely reversed by granulocyte-macrophage colony-stimulating factor. C5a also impaired killing of Pseudomonas aeruginosa by, and migration of, PBNs, indicating that effects were not restricted to phagocytosis. Bronchoalveolar lavage fluid leukocytes from patients also demonstrated significantly impaired function, and lavage supernatant reduced phagocytosis in healthy neutrophils by 43% (P = 0.0001). However, lavage fluid did not affect CD88 expression and lavage-mediated impairment of phagocytosis was not blocked by anti-CD88 antibody.Conclusions: Critically ill patients have significant dysfunction of PBNs, which is mediated predominantly by activated complement. Further, profound complement-independent neutrophil dysfunction occurs in the inflamed lung.