tbuckley/cabot-search huggingface dataset:
When the Air Hits Your Brain. Tales of Neurosurgery., by Frank Vertosick Jr
Authors: M P Powell
Journal: BMJ (1997)

Clodronate, a halogenated bisphosphonate, can inhibit the growth of human thyroid carcinoma (TC) cells. Previously, we found that a clodronate-induced Ca<sup>2+</sup> transient was correlated with clodronate-induced growth inhibition in TC cells. However, the details of the signaling process underlying the antiproliferative effect of clodronate on TC cells are not clear. In this study, we investigated the antiproliferative mechanism of clodronate on papillary TC (PTC) cells and xenotransplanted animals using a combination of pharmacological drugs. Reverse transcription-polymerase chain reaction analysis confirmed the endogenous expression of P2Y receptor isoforms in PTC cells. The P2 antagonist suramin not only inhibited the antiproliferative effect of clodronate and ATP on TC cells but also blocked all the Ca<sup>2+</sup> transients induced by clodronate and ATP. The release of Ca<sup>2+</sup> from the endoplasmic reticulum and membrane depolarization of mitochondria was observed during the clodronate-induced Ca<sup>2+</sup> transients. The results of terminal deoxynucleotidyltransferase dUTP nick-end labeling assays and flow cytometry with annexin V and caspase-3 staining suggest that both ATP and clodronate induce apoptosis. Significant inhibition of tumor invasion and colony formation was also observed in clodronate-treated PTC cells. We further demonstrated that only the cAMP inhibitor 9-(tetrahydro-2-furanyl)-9<i>H</i>-purin-6-amine (SQ22536), and not inhibitors of phospholipase C [1-[6-[[17β-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1<i>H</i>-pyrrole-2,5-dione (U73122)] or store-operated Ca<sup>2+</sup> entry (2-aminoethyl diphenylborinate), can significantly reverse the effect of clodronate. Finally, in vivo animal and green fluorescent protein imaging studies further proved that the tumor inhibitory effect of clodronate on xenotransplanted CG3 cells can be reversed by treatment with suramin. In conclusion, we demonstrated that clodronate-induced PTC cell apoptosis and tumor inhibition are partially mediated by the P2Y receptor-cAMP cascade.
Converse airway effects of nicotine in vitro and in vivo
Authors: Yuan Xu, Lars-Olaf Cardell
Journal: European Respiratory Journal (2012)

Cigarette smoke, which contains high concentrations of nicotine and endotoxin (LPS), plays a pivotal role in the development of asthmatic airway inflammation and hyperreactivity (AHR). But the mechanisms behind this are poorly known. The present study examines the effects of nicotine and LPS on murine airways both  in vitro  and  in vivo .  In the  in-vitro  model, murine tracheal segments were cultured in presence of nicotine (10 μM) and/or LPS (10 μg/ml) for 4 days. Smooth muscle contractibility was assessed with myograph and inflammatory mediator expressions measured with real-time PCR. In the  in-vivo  model, mice were exposed to nicotine (24 mg/kg/day) via osmotic pumps for 28 days followed by intranasal (i.n.) LPS (1 mg/ml) instillation during the last 3 days. Airway resistance was measured using FlexiVent® after i.v. methacholine challenge and inflammatory cells in the bronchoalveolar lavage fluid were counted.   In vitro , nicotine increased contractions to bradykinin (BK) and des-Arg9-BK. Carbachol contractions only increased after combined nicotine and LPS exposure. Moreover, nicotine specifically up-regulated Toll-like receptor 2 and 4 as well as inflammatory mediators COX-2 and MCP-1.  In vivo , nicotine had no effects alone, but i.n. LPS caused both AHR and acute pulmonary neutrophillic inflammation. 28-days of  in-vivo  nicotine exposure suppressed the LPS-induced AHR both in central and peripheral airways and prevented pulmonary neutrophil infiltration.  It is interesting to note that the local smooth muscle effect of nicotine differs markedly from the  in-vivo  effect which involves a much more complex system of inflammatory cells and mediators. This is important to acknowledge when evaluating the toxic effect of nicotine.
Phase II study of capecitabine and irinotecan combination chemotherapy in patients with advanced gastric cancer
Authors: J. Baek, J. Kim, Y. Chae, Y. Cho, S. Sohn, Y. Choi, H. Shin, J. Chung, G. Cho, W. Yu
Journal: Journal of Clinical Oncology (2006)

14037 Background: Several studies have shown the efficacy of capecitabine and irinotecan combination chemotherapy for advanced colorectal cancer, while no results have yet been reported for advanced gastric cancer. Accordingly, the current study evaluated the efficacy and safety of a combination regimen of capecitabine plus irinotecan in patients with advanced gastric cancer. Methods: Patients with previously untreated metastatic or recurrent, measurable gastric cancer received oral capecitabine 1000 mg/m 2 twice daily from day 1 to 14 and intravenous irinotecan 100 mg/m 2 on days 1 and 8, based on a 3-week cycle. Results: Forty-one patients were enrolled in the current study, among whom 38 were assessable for efficacy and 40 assessable for toxicity. Three complete responses and 16 partial responses were confirmed, giving an overall response rate of 46.3%. At a median follow-up of 269 days, the median time to progression and overall survival were 5.1 months and 8.6 months, respectively. Grade 3/4 neutropenia occurred in 4 patients and grade 3 febrile neutropenia was observed in 2 patients. Grade 3 diarrhea and grade 2 hand-foot syndrome occurred in 6 patients and 8 patients, respectively. Conclusions: The combination of capecitabine and irinotecan was found to be well tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important first-line treatment option for advanced gastric cancer. No significant financial relationships to disclose.
India has low doctor to patient ratio, study finds
Authors: Sanjeet Bagcchi
Journal: BMJ (2015)

India has one government doctor for every 11 528 people and one nurse for every 483 people, figures from a report on the country’s health sector have shown.

The National Health Profile 2015 report found that 938 861 doctors were registered in India in 2014.1 It also found that government hospitals had one bed for every 1833 people, although this ratio was far worse in some states—Bihar, for example, …
Effects of regorafenib (REG) therapy on health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) in the phase III CONCUR trial.
Authors: Jane Chang, Christopher Ngai, Dawn Odom, Christina Radder, Christian Kappeler, Rui-hua Xu, Shukui Qin, Tae Won Kim, Jin Li
Journal: Journal of Clinical Oncology (2015)

3560 Background: In the phase III CORRECT and CONCUR trials, REG significantly improved overall survival (OS) vs placebo (PBO) in patients with mCRC whose disease progressed on standard treatments. In CORRECT, overall HRQoL was similar between REG and PBO. This analysis reports the HRQoL effects of REG in CONCUR. Methods: CONCUR (NCT01584830) was an international, multicenter trial which enrolled patients in Asia (N = 204). Patients were randomized 2:1 to receive REG 160 mg (n = 136) or PBO (n = 68) once daily for weeks 1–3 of each 4-week cycle. Planned HRQoL analyses were conducted using the European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) and the EuroQol-five dimension (EQ-5D) questionnaires. EORTC QLQ-C30 global health status (GHS) and the EQ-5D index and visual analogue scale (VAS) scores were expressed as least squares mean (LSM) time-adjusted area under the curve (AUC) to allow comparison of change in HRQoL across the treatment period. An exploratory post-hoc analysis assessed time to deterioration (TTD) of HRQoL, defined as the earliest ≥ 10-point score decline in GHS or physical functioning (PF) domain score, progression or death. Results: Overall changes from baseline in HRQoL scores appeared similar in the REG and PBO groups. LSM time-adjusted AUC of the EORTC QLQ-C30 GHS domain, EQ-5D index and VAS scores did not differ significantly between groups (table). TTD of HRQoL was significantly longer with REG vs PBO in post-hoc analyses (table). Conclusions: REG provided additional clinical benefit while maintaining HRQoL vs PBO in Asian patients. Clinical trial information: NCT01584830. LSM time-adjusted AUC (95% CI) REG (n = 131) PBO (n = 63) EORTC QLQ-C30 GHS 60.76 (58.81 to 62.71) 61.16 (58.48 to 63.83) Difference from PBO −0.40 (−3.53 to 2.72) EQ-5D index 0.70 (0.67 to 0.73) 0.74 (0.70 to 0.78) Difference from PBO −0.03 (−0.08 to 0.01) EQ-5D VAS 69.28 (67.48 to 71.08) 70.46 (68.01 to 72.91) Difference from PBO −1.18 (−4.01 to 1.66) Median TTD (95% CI) REG (n = 136) PBO (n = 68) EORTC QLQ-C30 GHS 8.0 (7.6 to 8.0) 7.0 (5.9 to 7.4) HR 0.54 (0.40 to 0.74; p < 0.01) EORTC QLQ-C30 PF 7.9 (7.3 to 8.0) 7.0 (5.0 to 7.6) HR 0.59 (0.44 to 0.80; p < 0.01)
US food safety regulations are out of date, report says
Authors: Charles Marwick
Journal: BMJ (2003)

Food safety regulations in the United States are out of date, inflexible, and erratically enforced. Federal and state criteria on food safety that were developed over decades in response to different problems and concerns need to be linked to specific public health goals, and new criteria should be established on the basis of the latest scientific data and methods, says a report from the US Institute of Medicine.

“Our scientific knowledge is emerging faster than the regulatory system. There is need for flexibility in drafting and enforcing the regulations,” said Dr Samuel Earl …
Correlation of HER2 gene amplification, HER2 and EGFR expression (protein and mRNA) with lapatinib efficacy in women with metastatic breast cancer
Authors: M. F. Press, R. S. Finn, A. Di Leo, D. A. Cameron, C. E. Geyer, A. Martin, B. Newstat, R. Gagnon, M. Arbushites, M. Koehler
Journal: Journal of Clinical Oncology (2008)

1007 Background: Lapatinib (L), an oral small molecule tyrosine kinase inhibitor of EGFR and HER2, is approved in combination with capecitabine for the treatment of women with HER2+ metastatic breast cancer (MBC). The optimal method to select patients (pts) for L therapy has not been determined. To address this issue, selected biomarkers were analyzed in pts from two randomized phase III MBC trials. Methods: In available BC tissue from EGF30001 pts (paclitaxel ± L in HER2-negative/unknown MBC, N=579) and EGF100151 pts (capecitabine ± L in HER2+ MBC, N=399), HER2 gene amplification was evaluated by fluorescence in situ hybridization (FISH), HER2 messenger RNA (mRNA) by reverse transcriptase-polymerase chain reaction (RT-PCR), protein expression by HercepTest immunohistochemistry (IHC), EGFR mRNA level by RT-PCR, and EGFR protein by IHC. HER2 and EGFR status was compared with clinical outcome across treatment arms to assess potential marker associations. Results: HER2 was amplified in 47% (345/733) and had IHC3+ immunostaining in 30.6% (224/730), with a significant correlation between HER2 gene and protein status (p<0.01). EGFR immunostaining (IHC 1+, 2+ or 3+) was identified in 27.9% (214/767). Any EGFR IHC correlated with EGFR mRNA levels determined by RT- PCR (R=0.59, p<0.01). HER2 gene amplification/overexpression, but not EGFR expression, was associated with significantly improved time-to-progression, objective response rate, and clinical benefit in separate and pooled analyses of both trials. No similar improvement in outcome was seen in pts with FISH-negative and IHC 1+ or 2+ tumors. mRNA expression for HER2 as performed here does not add value beyond FISH or IHC evaluation, although the mRNA sample set was small (N=138). There was no correlation between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER2 status. Conclusions: Benefit from L in women with HER2+ MBC appears to be limited to patients with positive FISH or IHC3+ intensity. Evaluation of HER2 by mRNA analysis did not improve patient selection in these studies. EGFR determination did not contribute to improved pt selection. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Roche GlaxoSmithKline Genentech, Inc., GlaxoSmithKline, Roche Genentech, Inc., GlaxoSmithKline
A Sucrose-Enriched Diet Promotes Tumorigenesis in Mammary Gland in Part through the 12-Lipoxygenase Pathway
Authors: Yan Jiang, Yong Pan, Patrea R. Rhea, Lin Tan, Mihai Gagea, Lorenzo Cohen, Susan M. Fischer, Peiying Yang
Journal: Cancer Research (2016)

Abstract Epidemiologic studies have shown that dietary sugar intake has a significant impact on the development of breast cancer. One proposed mechanism for how sugar impacts cancer development involves inflammation. In the current study, we investigated the impact of dietary sugar on mammary gland tumor development in multiple mouse models, along with mechanisms that may be involved. We found that sucrose intake in mice comparable with levels of Western diets led to increased tumor growth and metastasis, when compared with a nonsugar starch diet. This effect was ascribed in part to increased expression of 12-lipoxygenase (12-LOX) and its arachidonate metabolite 12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE). We determined that fructose derived from the sucrose was responsible for facilitating lung metastasis and 12-HETE production in breast tumors. Overall, our data suggested that dietary sugar induces 12-LOX signaling to increase risks of breast cancer development and metastasis. Cancer Res; 76(1); 24–29. ©2016 AACR.
Capecitabine: Efficacy in advanced breast cancer
Authors: S. Aggarwal
Journal: Journal of Clinical Oncology (2004)

827 Background: Capecitabine is a 5 flouropyrimidine derivative that is an orally administered, tumor activated and tumor selective agent. The drug has shown an excellent response in anthracycline and taxane refractory metastatic breast cancer patients (pts). Methods: Pts of advanced breast cancer were treated with capecitabine alone or in combination with other agents.The response rate, toxicity, and time to tumor progression (TTP) was evaluated. Results: : 23 pts (between jan'2000 to march'03) with metastatic breast cancer were treated with capecitabine. The mean age was 55 years. All except one patients had received prior chemotherapy either as adjuvant and or for metastatic disease. Mean number of prior chemotherapy regimens received were two. 5-flurouracil was part of prior chemotherapy in ten patients. Mean number of metastatic sites were two. Only six patients had single site of metastasis. Site of metsastasis was lungs in 12, liver in 10, bones in 12, skin in 5. Sixteen patients received capecitabine alone, five with docetaxel and two with herceptin.The dose of capecitabine was 1000mg/sq.mt twice a day for fifteen days given every 28 days, Docetaxel –80mg/sq. mt on day 1 or herceptin ( in standard dose ) was added . The response rate was as follows : CR 1pt., PR 8pts., SR 5pts., PD 9pts. ( RR –43% ). The response rate was related to number of prior chemotherapy received and whether capectabine was given alone or in combination. The major toxicity of the protocol was either diarrhea ( 25% ) and palmar plantar erythrodysesthesia ( 45%). TTP will be evaluated. Conclusions: Capecitabine is an effective agent in advanced breast cancer in patients pretreated with anthracyclines and taxanes. Combination of capecitabine and docetaxel is superior to capecitabine alone. No significant financial relationships to disclose.
Transcriptional silencing of Fanconi anaemia genes and clinical outcome in head and neck cancer
Authors: M. Gasco, A. Sullivan, P. Smith, P. Farrell, G. Numico, I. Colantonio, M. Merlano, T. Crook
Journal: Journal of Clinical Oncology (2004)

9546 Background: Fanconi anaemia (FA) is an autosomal recessive disorder characterised by abnormal response to DNA damage. Both leukemia and solid tumours, including head and neck squamous cell carcinomas (HNSCC), occur at a high rate in FA patients. We have analysed the structure and expression of specific components of the FA pathway in a series of HNSCC and have sought correlation between lesions in the FA pathway and response to chemo-radiotherapy. Methods: FANC gene structure was analysed by DNA sequencing, and transcriptional silencing using methylation-specific PCR, bisulphite sequencing and immunocytochemistry. The patient cohort comprised 70 individuals with inoperable HNSCC treated with chemo-radiotherapy. Results: No FANC gene mutation was present in any of the 70 cancers. However, aberrant CpG methylation in the transcriptional regulatory elements of FANCC, FANCD2, FANCF, FANCG, FANCL was detected in a high proportion of carcinomas but not normal tissue. Methylation of at least one of these FANC genes was present in 67% of cases. Methylation of two or more FANC genes was detected in 20%. Gene expression was reduced in cases with methylation. Aberrant methylation of specific FANC genes was present in pre-malignant dysplasias, implying that loss of expression is an early event in tumourigenesis. Clinical outcome was strongly influenced by trascriptional silencing of the FANC genes. Complete response (CR) to chemo-radiotherapy was higher in cases with methylation of one or more FANC genes (p= 0.02). Overall survival (OS) and progression-free survival (PFS) were higher in cases with FANC gene methylation (OS p= 0.01), (PFS p=0.03). Conclusions: Transcriptional silencing of FANC genes occurs commonly in HNSCC and may have clinical utility in predicting the clinical outcome of patients treated with chemo-radiotherapy. No significant financial relationships to disclose.
Immunosuppression Taper to Induce Graft-Verus-Tumor Activity As the Sole Therapy for Early Relapse after Reduced Intensity Allogeneic Hematopoietic Cell Transplantation
Authors: Natasha Kekre, Haesook T. Kim, Gita Thanarajasingam, Philippe Armand, Joseph H Antin, Corey S Cutler, Sarah Nikiforow, Vincent T. Ho, Edwin P. Alyea, John Koreth, Robert J. Soiffer
Journal: Blood (2014)
Disappearing Post-Pneumonectomy Pleural Fluid without Bronchopleural Fistula
Authors: Danielle A. Smith, Colin Gillespie, Malcolm M. DeCamp, Ankit Bharat
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Figure 1. Preoperative chest computed tomography revealing the central left upper lobe tumor. The tumor invaded the left pulmonary artery and the left lower lobe bronchus as shown in the crosssectional (A) and coronal (B) images. A 65-year-old woman underwent left pneumonectomy for T2aN1 squamous cell carcinoma (Figures 1A and 1B). She was discharged on postoperative Day 4, breathing room air. The left pleural space demonstrated the expected fluid increase (Figures 2A and 2B). However, after 3 weeks, chest radiography revealed decreased pleural fluid. Chest tomography 1 week later showed complete absence of fluid (Figures 2C and 2D). She remained without cough, fevers, or symptoms suggestive of bronchopleural fistula (1–4). The complete blood cell count and biochemical panel were normal. Thoracotomy and chest tube incisions were well healed. Bronchoscopy (Figure 3A), bronchogram, ventilation scan (Figure 3B), esophagram, and chest and/or abdominal imaging were also normal and revealed no ascites or seroma. She received systemic chemotherapy, but during the 16th week she died of cardiac arrest. Autopsy showed a massive pulmonary embolism. The left bronchial stump was intact, and the pleural space was empty, with negative microbial cultures. There were no diaphragmatic fenestrations. Hence, we determined this was benign evacuation of the pneumonectomy space. We propose that bronchoscopy and ventilation scan should be performed to confirm benign evacuation of the pneumonectomy space. If negative, the patient should undergo surveillance with repeat bronchoscopy because some of these patients might have microscopic bronchopleural fistula (5). However, pleural instrumentation, with thoracentesis or thoracoscopy, should not be performed, to avoid seeding infection. n
Predictive biomarkers of everolimus efficacy in HER2+ advanced breast cancer: Combined exploratory analysis from BOLERO-1 and BOLERO-3.
Authors: Dennis J. Slamon, Sara A. Hurvitz, David Chen, Fabrice Andre, Ling-Ming Tseng, Guy Heinrich Maria Jerusalem, Sharon Wilks, Ruth O'Regan, Claudine Isaacs, Masakazu Toi, Howard A. Burris, Wei He, Markus Riester, Douglas Robinson, Tanya Taran, Luca Gianni
Journal: Journal of Clinical Oncology (2015)

512 Background: Two phase 3 trials BOLERO-1 and BOLERO-3 evaluated the addition of everolimus (EVE) to trastuzumab (TRAS) + chemotherapy in HER2+ advanced breast cancer (ABC). In BOL-3, heavily pretreated patients (pts) derived a statistically significant benefit from EVE, while BOL-1 (first-line EVE) did not meet the primary endpoints. This analysis aimed to identify biomarkers predictive of EVE efficacy using data from both trials. Methods: Exons of 282 cancer related genes were analyzed by next generation sequencing (NGS). PTEN levels were determined by IHC. Hyperactive PI3K pathway was defined as pts with low PTEN or known PIK3CA or AKT1 E17K mutation (narrow def) or mutation in any member of the PI3K/Akt/mTOR pathway (broad def). Correlations between biomarkers and PFS were evaluated by uni- and multi-variate Cox models. Results: Five hundred and sixty-one archival tumor samples (BOL-1 302; BOL-3 259) were successfully analyzed. PI3K pathway gene alterations were seen in ~45% of samples. A trend of greater benefit from EVE was observed in pts with PI3K pathway activation (individual trials). In a combined analysis from both trials, pts with PIK3CA mutations (HR = 0.69) or low PTEN (HR = 0.5) derived more benefit from EVE. A robust positive correlation between PI3K hyperactivity and PFS benefit was observed using both narrow def (HR = 0.67 vs normal PI3K activity HR = 1.2) and broad def (HR = 0.61 vs normal PI3K activity HR = 1.38). In a multivariate analysis, interaction between PI3K status and treatment effect was statistically significant (p = 0.016). Conclusions: This exploratory analysis suggests that pts with hyperactive PI3K signaling pathway derive greater benefit from adding EVE to TRAS + chemotherapy in HER2+ ABC. Clinical trial information: NCT00876395, NCT01007942. Tx BOL-1 BOL-3 n/N* Median PFS (mo) HR n/N* Median PFS (mo) HR PIK3CA Wild type PBO 31/48 17.1 1.13 66/82 6.6 1.04 EVE 51/89 18.5 58/77 6.8 Mutant PBO 17/19 7.6 0.70 37/42 5.7 0.67 EVE 30/39 12.0 28/29 6.9 PTEN Normal PBO 53/90 13.8 1.02 93/110 6.7 1.03 EVE 87/163 16.1 84/107 6.8 Low PBO 12/18 16.8 0.56 12/15 5.5 0.49 EVE 17/31 23.5 13/15 9.5 PI3K pathway Normal PBO 26/41 17.1 1.18 57/70 6.97 1.15 EVE 40/72 18.2 49/67 6.83 Hyperactive PBO 27/35 10.9 0.72 46/54 5.59 0.63 EVE 44/66 13.9 39/42 6.93 *n = no. of events; N = no. of pts.