tbuckley/cabot-search huggingface dataset:
Randomized Trial of Neoadjuvant Chemotherapy Comparing Paclitaxel, Ifosfamide, and Cisplatin With Ifosfamide and Cisplatin Followed by Radical Surgery in Patients With Locally Advanced Squamous Cell Cervical Carcinoma: The SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study
Authors: Alessandro Buda, Roldano Fossati, Nicoletta Colombo, Francesca Fei, Irene Floriani, Desiderio Gueli Alletti, Dionyssios Katsaros, Fabio Landoni, Andrea Lissoni, Carmine Malzoni, Enrico Sartori, Paolo Scollo, Valter Torri, Paolo Zola, Costantino Mangioni
Journal: Journal of Clinical Oncology (2005)

Neoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival.Patients (n = 219) were randomly assigned to ifosfamide 5 g/m(2) during 24 hours plus cisplatin 75 mg/m(2), or paclitaxel 175 mg/m(2) plus ifosfamide 5 g/m(2) during 24 hours and cisplatin 75 mg/m(2) every 3 weeks for three courses.Grades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%; odds ratio, 3.22; 95% CI, 1.69 to 5.88; P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75; 95% CI, 0.48 to 1.17; P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66; 95% CI, 0.39 to 1.10; P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88; 95% CI, 2.50 to 13.84; P < .0001).The TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for survival.
Pathophysiology of protracted acute renal failure in man.
Authors: S M Moran, B D Myers
Journal: Journal of Clinical Investigation (1985)

Postischemic acute renal failure (ARF) induced by cardiac surgery is commonly prolonged and may be irreversible. To examine whether persistence of postischemic, tubular cell injury accounts for delayed recovery from ARF, we studied 10 patients developing protracted (36 +/- 4 d) ARF after cardiac surgery. The differential clearance and excretion dynamics of probe solutes of graded size were determined. Inulin clearance was depressed (5.0 +/- 1.7 ml/min), while the fractional urinary clearance of dextrans (radii 17-30 A) were elevated above unity. Employing a model of conservation of mass, we calculated that 44% of filtered inulin was lost via transtubular backleak. The clearance and fractional backleak of technetium-labeled DTPA ([99mTc]DTPA, radius = 4 A) were identical to those of inulin (radius 15 A). The time at which inulin or DTPA excretion reached a maximum after an intravenous bolus injection was markedly delayed when compared with control subjects with ARF of brief duration, 102 vs. 11 min. Applying a three-compartment model of inulin/DTPA kinetics (which takes backleak into account) revealed the residence time of intravenously administered inulin/DTPA in the compartment occupied by tubular fluid and urine to be markedly prolonged, 20 vs. 6 min in controls, suggesting reduced velocity of tubular fluid flow. We conclude that protracted human ARF is characterized by transtubular backleak of glomerular ultrafiltrate, such that inulin clearance underestimates true glomerular filtration rate by approximately 50%, and by sluggish tubular fluid flow, which strongly suggests the existence of severe and generalized intraluminal tubular obstruction. Because all patients also exhibited extreme hyperreninemia (16 +/- 2 ng/ml per h) that was inversely related to inulin clearance (r value = -0.83) and urine flow (r value = -0.70), we propose that persistent, angiotensin II-mediated renal vasoconstriction may have delayed healing of the injured tubular epithelium.
Association of p16 Homozygous Deletions with Clinicopathologic Characteristics and EGFR/KRAS/p53 Mutations in Lung Adenocarcinoma
Authors: Reika Iwakawa, Takashi Kohno, Yoichi Anami, Masayuki Noguchi, Kenji Suzuki, Yoshihiro Matsuno, Kazuhiko Mishima, Ryo Nishikawa, Fumio Tashiro, Jun Yokota
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The p16 gene is frequently inactivated in lung adenocarcinoma. In particular, homozygous deletions (HD) have been frequently detected in cell lines; however, their frequency and specificity is not well-established in primary tumors. The purpose of this study was to elucidate the prevalence and the timing for the occurrence of p16 HDs in lung adenocarcinoma progression in vivo. Experimental Design: Multiple ligation-dependent probe amplification was used for the detection of p16 HDs in 28 primary small-sized lung adenocarcinomas and 22 metastatic lung adenocarcinomas to the brain. Cancer cells were isolated from primary adenocarcinoma specimens by laser capture microdissection. HDs were confirmed by quantitative real-time genomic PCR analysis. Results: HDs were detected in 8 of 28 (29%) primary tumors, including 2 of 8 (25%) noninvasive bronchioloalveolar carcinomas, and 5 of 22 (26%) brain metastases, respectively. No significant associations were observed between p16 HDs and gender, age, smoking history, stage, and prognosis. HDs were detected with similar frequencies (17–29%) among adenocarcinomas with epidermal growth factor receptor (EGFR) mutations, with KRAS mutations, and without EGFR/KRAS mutations, and with similar frequencies (22–28%) between adenocarcinomas with and without p53 mutations. Conclusions: p16 HDs occur early in the development of lung adenocarcinomas and with similar frequencies among EGFR type, KRAS type, and non-EGFR/KRAS type lung adenocarcinomas. Tobacco carcinogens would not be a major factor inducing p16 HDs in lung adenocarcinoma progression.
Response to Comment on: Besser et al. Lessons From the Mixed-Meal Tolerance Test: Use of 90-Minute and Fasting C-Peptide in Pediatric Diabetes. Diabetes Care 2013;36:195–201
Authors: Beverley M. Shields, William Henley, Rachel E.J. Besser, Andrew T. Hattersley, Johnny Ludvigsson
Journal: Diabetes Care (2013)

We thank Dr. Chaudhary and colleagues (1) for their interest in our article (2). The authors raise some statistical questions about the analysis of the effects of age at diagnosis and fasting C-peptide on the time to insulin deficiency. We are happy that our analysis and results are correct but would like to clarify the assumptions made and to highlight a minor issue with the presentation of these results in Fig. 3 of our article.

The authors point out that Kaplan-Meier graphs should begin from unity at time zero (diagnosis). We can confirm that this was the case in our analysis, but we agree that …
Prognostic significance of multidetector CT in normotensive patients with pulmonary embolism: results of the protect study
Authors: David Jiménez, José Luis Lobo, Manuel Monreal, Lisa Moores, Mikel Oribe, Manuel Barrón, Remedios Otero, Dolores Nauffal, Ramón Rabuñal, Reina Valle, Carmen Navarro, Consolación Rodríguez-Matute, Celso Álvarez, Francisco Conget, Fernando Uresandi, Drahomir A Aujesky, Roger D Yusen
Journal: Thorax (2013)

In patients with acute pulmonary embolism (PE), rapid and accurate risk assessment is paramount in selecting the appropriate treatment strategy. The prognostic value of right ventricular dysfunction (RVD) assessed by multidetector CT (MDCT) in normotensive patients with PE has lacked adequate validation.The study defined MDCT-assessed RVD as a ratio of the RV to the left ventricle short axis diameter greater than 0.9. Outcomes assessed through 30 days after the diagnosis of PE included all-cause mortality and 'complicated course', which consisted of death from any cause, haemodynamic collapse or recurrent PE.MDCT detected RVD in 533 (63%) of the 848 enrolled patients. Those with RVD on MDCT more frequently had echocardiographic RVD (31%) than those without RVD on MDCT (9.2%) (p<0.001). Patients with RVD on MDCT had significantly higher brain natriuretic peptide (269±447 vs 180±457 pg/ml, p<0.001) and troponin (0.10±0.43 vs 0.03±0.24 ng/ml, p=0.001) levels in comparison with those without RVD on MDCT. During follow-up, death occurred in 25 patients with and in 13 patients without RVD on MDCT (4.7% vs 4.3%; p=0.93). Those with and those without RVD on MDCT had a similar frequency of complicated course (3.9% vs 2.3%; p=0.30).The PROgnosTic valuE of CT study showed a relationship between RVD assessed by MDCT and other markers of cardiac dysfunction around the time of PE diagnosis, but did not demonstrate an association between MDCT-RVD and prognosis.
Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer in the Elderly: A Population-Based Study in Ontario, Canada
Authors: Sinead Cuffe, Christopher M. Booth, Yingwei Peng, Gail E. Darling, Gavin Li, Weidong Kong, William J. Mackillop, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2012)

Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly. Retrospective analyses of the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial and the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis suggest that the elderly benefit from adjuvant chemotherapy. However, the elderly were under-represented in these studies, raising concerns regarding the reproducibility of the study results in clinical practice.By using the Ontario Cancer Registry, we identified 6,304 patients with NSCLC who were treated with surgical resection from 2001 to 2006. Registry data were linked to electronic treatment records. Uptake of chemotherapy was compared across age groups: younger than 70, 70 to 74, 75 to 79, and ≥ 80 years. As a proxy of survival benefit from chemotherapy, we compared survival of patients diagnosed from 2004 to 2006 with survival of those diagnosed from 2001 to 2003. Hospitalization rates within 6 to 24 weeks of surgery served as a proxy of severe chemotherapy-related toxicity.In all, 2,763 (43.8%) of 6,304 surgical patients were elderly (age ≥ 70 years). Uptake of adjuvant chemotherapy in the elderly increased from 3.3% (2001 to 2003) to 16.2% (2004 to 2006). Among evaluable elderly patients, 70% received cisplatin and 28% received carboplatin-based regimens. Requirements for dose adjustments or drug substitutions were similar across age groups. Hospitalization rates within 6 to 24 weeks of surgery were similar across age groups (28.0% for patients age < 70 years; 27.8% for patients age ≥ 70 years; P = .54). Four-year survival of elderly patients increased significantly (47.1% for patients diagnosed from 2001 to 2003; 49.9% for patients diagnosed from 2004 to 2006; P = .01). Survival improved in all subgroups except patients age ≥ 80 years.Uptake of adjuvant chemotherapy for NSCLC increased in patients age 70 years or older following reporting of pivotal adjuvant chemotherapy trials, but it remained below that for patients younger than age 70 years. Adoption of adjuvant chemotherapy appears to be associated with significant survival benefit in the elderly (age ≥ 70 years), with tolerability apparently similar to that of patients who are younger than age 70 years.
Breast Cancer Risk After Salpingo-Oophorectomy in Healthy BRCA1/2 Mutation Carriers: Revisiting the Evidence for Risk Reduction
Authors: B. A. M. Heemskerk-Gerritsen, C. Seynaeve, C. J. van Asperen, M. G. E. M. Ausems, J. M. Collée, H. C. van Doorn, E. B. Gomez Garcia, C. M. Kets, F. E. van Leeuwen, H. E. J. Meijers-Heijboer, M. J. E. Mourits, T. A. M. van Os, H. F. A. Vasen, S. Verhoef, M. A. Rookus, M. J. Hooning
Journal: JNCI Journal of the National Cancer Institute (2015)

Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO.We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO.Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval [CI] = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77).In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.
New Approaches to the Treatment of Osteoporosis
Authors: Barbara C. Silva, John P. Bilezikian
Journal: Annual Review of Medicine (2010)

Although safe and effective agents are currently available to treat osteoporosis, fragility fractures remain a significant problem worldwide. Recent improvements in the understanding of the cellular, biochemical, and molecular pathways of bone biology have led to the development of newer agents to treat osteoporosis, which may lead to further improvements in outcomes. In this review, we summarize the most recent advances in the field, including new modes of administration of existing drug classes, various approaches to combination therapy, and drugs with novel mechanisms of action to treat osteoporosis.
Critical Roles of Pten in B Cell Homeostasis and Immunoglobulin Class Switch Recombination
Authors: Akira Suzuki, Tsuneyasu Kaisho, Minako Ohishi, Manae Tsukio-Yamaguchi, Takeshi Tsubata, Pandelakis A. Koni, Takehiko Sasaki, Tak Wah Mak, Toru Nakano
Journal: The Journal of Experimental Medicine (2003)

Pten is a tumor suppressor gene mutated in human cancers. We used the Cre-loxP system to generate a B cell–specific mutation of Pten in mice (bPtenflox/floxmice). bPtenflox/flox mice showed elevated numbers of B1a cells and increased serum autoantibodies. Among B2 cells in bPtenflox/flox spleens, numbers of marginal zone B (MZB) cells were significantly increased while those of follicular B (FOB) cells were correspondingly decreased. Pten-deficient B cells hyperproliferated, were resistant to apoptotic stimuli, and showed enhanced migration. The survival kinase PKB/Akt was highly activated in Pten-deficient splenic B cells. In addition, immunoglobulin class switch recombination was defective and induction of activation-induced cytidine deaminase (AID) was impaired. Thus, Pten plays a role in developmental fate determination of B cells and is an indispensable regulator of B cell homeostasis.
Prevention of Type II Diabetes by Physical Training: Epidemiological considerations and study methods
Authors: Hilary King, Andrea M Kriska
Journal: Diabetes Care (1992)

Disease prevention may be considered at three levels: primary (avoiding disease occurrence), secondary (early detection and reversal), and tertiary (prevention or delay of complications). Physical exercise could potentially contribute to all of these. Metabolic studies suggest the major effect of exercise is at the level of insulin sensitivity/resistance. Therefore, it may have the greatest benefit in primary prevention and in the early stages of the disease. Studies of migrants and of active and inactive professions support this notion. There is also provisional support for the benefit of exercise on metabolic control and prevention or delay of chronic complications in non-insulin-dependent (type II) diabetic patients. In designing a trial of exercise, aspects such as single/multifactorial intervention, the age range of subjects, and choice of outcome measures must be considered. The most widely used methodological tool in assessing physical activity levels in population studies is the activity questionnaire, which is nonreactive, practical, applicable, and accurate relative to other methods. A positive approach to exercise training for both the patient with type II diabetes and the general community appears to be warranted. However, trials examining the efficacy of activity intervention, with independent evaluation of both short- and long-term outcomes, are still needed.
Defective hMSH2/hMLH1 protein expression is seen infrequently in ulcerative colitis associated colorectal cancers
Authors: L Cawkwell
Journal: Gut (2000)

Ulcerative colitis is associated with an increased risk of colorectal cancer above that of the normal population. The relative risk correlates with the extent and duration of the disease but the genetic basis of ulcerative colitis associated cancer risk is not known.To assess the prevalence of microsatellite instability and mismatch repair gene abnormalities in ulcerative colitis associated colorectal cancer.Forty six patients with colorectal cancer, with a previous histological diagnosis of ulcerative colitis.The frequency of microsatellite instability and/or immunohistochemical expression of hMSH2 and hMLH1 was assessed. Thirty three cases were investigated using both approaches.Although 6/41 (14.6%) cases showed microsatellite instability at one or more markers, only one case (2. 4%) exhibited high level instability (at least two markers affected). Of 38 cases which were assessed using antibodies against hMSH2 and hMLH1, only one case (2.6%) showed loss of expression. This case, which showed loss of hMSH2 expression, was the same case which exhibited high level microsatellite instability. The 33 cases which were investigated using both approaches showed that loss of expression of either hMSH2 or hMLH1 was not seen in any case which exhibited microsatellite instability in no more than one marker.This study suggests that both high level microsatellite instability and loss of expression of hMSH2/hMLH1 are infrequent events in ulcerative colitis associated colorectal cancers. Low level microsatellite instability was not associated with loss of expression of either hMSH2 or hMLH1.
CERTAIN INTRACRANIAL TUMOURS: THEIR VARIABILITY AND MULTIPLICITY
Authors: W. E. C. Dickson
Journal: BMJ (1933)

VALLECULAR -DYSPHAGIALMEIAJURA valleculace, and by section of the lateral pharyngo-epiglottic folds.Removal of the free portion of the epiglottis was suggested.This latter appears to be the rational treatment if the symptoms are sufficiently severe.The epiglottis in man is a vestigial structure, and it is well known that its removal, either by surgery or by disease, is devoid of any harmful after-efiects, provided always that it is the free portion only that is removed.In the secondary forms of vallecular dysphagia treat- ment naturally would be directed towards the primary lesion.SUMMARY 1. Dysphagia, caused by filling and retention of food in the valleculae, is described.2. This type of dysphagia may be a distinct entity of clinical importance-of -unknown pathology-and present as primnary vallecular dysphagia.3. Alternatively, it may occur as a secondary phenomenon due to some manifest disturbance of the neuro- muscular mechanism of swallowing, or to local disease in the pharynx or oesophagus.These cases are termed " secondary vallecular dysphagia," and.they are not clinically important, as their symptoms are overshadowed by the existence of a more grave lesion.4. Treatment of primary vallecular dysphagia has in most cases resolved itself into explanation and reassur- ance, with disappearance of symptoms.In more severe cases, however, it might be necessary to amputate the free portion of the epiglottis.5. Treatment of the secondary forms would be dictated by the nature of the causative lesion.Our thanks are due to Dr. Walker and the staff of the x-ray department of the Royal Southern Hospital for their help in the examination of the cases on whiclh this paper is based.
Hypoxia Targeted Gene Therapy to Increase the Efficacy of Tirapazamine as an Adjuvant to Radiotherapy
Authors: Rachel L. Cowen, Kaye J. Williams, Edwin C. Chinje, Mohammed Jaffar, Freda C. D. Sheppard, Brian A. Telfer, Natasha S. Wind, Ian J. Stratford
Journal: Cancer Research (2004)

Abstract Solid tumors are characterized by regions of hypoxia that are inherently resistant to both radiotherapy and some chemotherapy. To target this resistant population, bioreductive drugs that are preferentially toxic to tumor cells in a hypoxic environment are being evaluated in clinical trials; the lead compound, tirapazamine (TPZ), is being used in combination with cisplatin and/or with radiotherapy. Crucially, tumor response to TPZ is also dependent on the cellular complement of reductases. In particular, NADPH:cytochrome P450 reductase (P450R) plays a major role in the metabolic activation of TPZ. In a gene-directed enzyme prodrug therapy (GDEPT) approach using adenoviral delivery, we have overexpressed human P450R specifically within hypoxic cells in tumors, with the aim of harnessing hypoxia as a trigger for both enzyme expression and drug metabolism. The adenovirus used incorporates the hypoxia-responsive element (HRE) from the lactate dehydrogenase gene in a minimal SV40 promoter context upstream of the cDNA for P450R. In a human tumor model in which TPZ alone does not potentiate radiotherapeutic outcome (HT1080 fibrosarcoma), we witnessed complete tumor regression when tumors were virally transduced before treatment.
Haemodynamic effects of nasal continuous positive airway pressure in severe congestive heart failure
Authors: R Liston, PC Deegan, C McCreery, R Costello, B Maurer, WT McNicholas
Journal: European Respiratory Journal (1995)

Nasal continuous positive airway pressure (NCPAP) during sleep may be a useful adjunct to medical therapy in patients with stable severe congestive heart failure (CHF), particularly when there is a coexisting respiratory sleep disorder. However, the direct haemodynamic effects of NCPAP in patients with severe stable CHF have not yet been adequately assessed. Right heart catheter studies were performed in seven awake males (aged 51-75 yrs) with stable CHF, before, during and after the application of 5 cmH2O NCPAP over 3 h. All patients had left ventricular ejection fractions &lt; or = 30% and baseline pulmonary capillary wedge pressures &gt; 12 mmHg, and six patients were in atrial fibrillation. Cardiac index fell from baseline in all patients whilst on NCPAP, with the greatest fall at 2 h (from 3.3 +/- 0.3 (mean +/- SEM) at baseline to 2.8 +/- 0.2 l.min-1.m-2) and rose back to baseline after NCPAP withdrawal. Systemic vascular resistance (SVR) increased during NCPAP application (1,268 +/- 108 to 1,560 +/- 82 dyn.s-1.cm5), with baseline SVR showing a significant negative correlation vs percentage fall in cardiac index (CI) at 2 h on multiple linear regression analysis (r2 = 0.8). These data indicate that domiciliary nocturnal NCPAP should not be prescribed as part of the therapy in severe CHF without first determining the individual patient's cardiac response to such therapy.