tbuckley/cabot-search huggingface dataset:
Effect of toremifene on fracture risk in men younger than age 80 on androgen-deprivation therapy.
Authors: M. K. Brawer, M. R. Smith, S. B. Malkowicz, M. L. Hancock, R. A. Morton, M. S. Steiner
Journal: Journal of Clinical Oncology (2010)

4676 Background: The use of androgen deprivation therapy (ADT) in prostate cancer is associated with increased fracture risk. Previously we demonstrated in a phase III trial that toremifene, a selective estrogen receptor modulator (SERM), significantly decreased fracture incidence in men receiving ADT. Similar to other SERMs, there was an increase in venous thromboembolic events. This risk appeared to stratify to men ≥80 years of age. VTEs occurred in 1.5% and 2.5% of men <80, ≥80 respectively. To identify a patient population with the greatest benefit/risk profile we assessed the effect of toremifene in men <80 years. Methods: In this analysis of men <80 years of age receiving ADT for prostate cancer, 430 men received toremifene 80 mg and 417 received placebo (orally daily). All subjects were on ADT for ≥ 6 months, had a serum PSA ≤4 ng/mL, were ≥70 years of age or were at or below WHO thresholds for spine or hip (BMD). The primary endpoint was new vertebral fractures. Secondary endpoints included fragility fractures and bone mineral density (BMD). Results: Toremifene 80 mg demonstrated a 79.5% relative risk reduction in the incidence of new vertebral fractures (CI0.95: 29.8%-94.0%; p<0.005). The absolute reduction was 3.8% (4.8% placebo, 1.0% toremifene). Toremifene 80 mg significantly increased BMD at all sites measured (p<0.001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p<0.001 for all comparisons). Venous thromboembolic events occurred in 2.1% of the toremifene patients compared to 1.0% (p=0.26) of the placebo patients. Other adverse events were similar between groups. Conclusions: In men <80 years receiving ADT for prostate cancer, toremifene significantly decreased the incidence of new vertebral fractures. Toremifene also significantly improved BMD, bone turnover markers, and breast pain and tenderness. The risk of VTE was lower than in the overall study population. These results suggest an improved benefit/risk profile in men <80 years receiving ADT. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GTx Amgen, GTx, Novartis GTx Amgen, GTx, Novartis GTx
The ENCOURAGE mortality risk score and analysis of long-term outcomes after VA-ECMO for acute myocardial infarction with cardiogenic shock
Authors: Grégoire Muller, Erwan Flecher, Guillaume Lebreton, Charles-Edouard Luyt, Jean-Louis Trouillet, Nicolas Bréchot, Matthieu Schmidt, Ciro Mastroianni, Jean Chastre, Pascal Leprince, Amedeo Anselmi, Alain Combes
Journal: Intensive Care Medicine (2016)
Trastuzumab-mediated cardiotoxicity in the nontrial setting: Evaluation of patients receiving adjuvant trastuzumab at an academic centre
Authors: D. Withrow, S. Verma, R. Dent, S. Ahmed, J. Fralick, G. Dranitsaris, T. Petrella
Journal: Journal of Clinical Oncology (2009)

e11550 Background: Trastuzumab is effective in the treatment of HER-2 positive breast cancer. Although clinical trials have shown an increased risk of cardiotoxicity associated with trastuzumab, this risk has not been well studied in the non-trial setting. This study aims to examine (1) the incidence of cardiotoxicity associated with trastuzumab in the clinical setting (2) the relationship, if any, between risk factors and incidence of cardiotoxicity and (3) cardiac monitoring practices. Methods: A retrospective chart review was conducted of all patients receiving adjuvant trastuzumab therapy between August 2005 and May 2008, at a Canadian academic centre. The incidence of cardiotoxicity, defined as a significant reduction in left ventricular ejection fraction (drop of &gt;10% leading to an ejection fraction of &lt;50%) and/or New York Heart Association class III-IV CHF symptoms requiring trastuzumab delay or discontinuation was evaluated. Medical charts and patient surveys provided demographics, risk factors and cardiac toxicity for each patient. Results: 183 patients were included in the study. The average age of participating patients was 54.8 years and 51% of participants had node positive cancer. 72% were treated sequentially with Trastuzumab and 88% received anthracyclines. The incidence of cardiotoxicity was 6.0% (n=11). Upon univariate analysis, patient age was found to be the only variable significantly associated with the occurrence of cardiotoxicity (OR: 3.55, 95% CI 1.76–90.0). Left ventricular function was monitored by serial MUGA scan every 3.35 ±1.89 months as compared to the 3 month gold standard in clinical trials. Conclusions: In this study the incidence of cardiotoxicity was 6.0%. Patient age was the only significant variable associated with cardiotoxicity, as expected from previous studies. Clinically, this suggests that older patients may need more frequent monitoring for cardiac dysfunction via MUGA and/or ECHO scans. Future research needs to address the relationship between treatment regimens and the incidence of cardiotoxicity. Furthermore, we need to better define cardiotoxicity and the clinical significance of cardiac related symptoms. No significant financial relationships to disclose.
Birth Characteristics and Leukemia in Childhood&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: E. Fasal, E. W. Jackson, M. R. Klauber
Journal: JNCI Journal of the National Cancer Institute (1971)

The objective of this study, which used data derived from birth and death certificates, was to determine the independent effect of high birth weight on the risk of death from childhood leukemia. The effects of maternal age, birth order, and social class also were investigated. The population consisted of 802 non-mongoloid, single-born children who died in California at ages 1–9 years between 1959 and 1965 and of a matched control group known to have survived the first year of life. High birth weight was found significantly associated with an increased risk of leukemia mortality for children of both sexes combined. Analysis b.y sex showed the significance was confined to females. The estimated excess risks were 2.1-fold for females and 1.2-fold for males. Social class was the only other factor showing a significant association with leukemia mortality. The risk was greater for children of higher social class. Again, the association was significant only for females. The relative risks were 1.7 for females and 1.1 for males.
18F-FDG PET (PET) does not improve CT scan (CT) accuracy in the evaluation of colorectal cancer liver metastases after chemotherapy
Authors: L. Rimassa, A. Chiti, C. Carnaghi, R. Doci, M. Zuradelli, G. Abbadessa, F. R. Lutman, M. C. Tronconi, T. Pressiani, A. Santoro
Journal: Journal of Clinical Oncology (2006)

13530 Background: Neoadjuvant chemotherapy has been successfully used in the treatment of patients (pts) affected by liver metastases from colorectal cancer unsuitable for surgery. We evaluated separately the diagnostic accuracy of PET and CT in this setting in a small series of pts. Methods: We retrospectively reviewed the data from 19 consecutive pts (12 males, 7 females; median age 62 years; range 41–79) affected by liver metastases from colorectal cancer. All of the pts underwent systemic chemotherapy and were evaluated with PET and CT at the end of the treatment. Whole-body PET scan was performed in 3D mode on a Siemens Ecat Accel LSO full-ring scanner, 60 minutes after the injection of 310–450 MBq of 18 F-FDG. Contrast enhanced, 3 phases, liver CT was performed on a Philips Aura single slice system. Chemotherapy regimens were: FOLFOX (13 pts), FOLFIRI (2 pts), 5-FU-FA (2 pts), UFT-CPT-OXA (2 pts). Overall response rate was 68%. Median time interval between end of chemotherapy and CT was 6 wks (range 3–8), between end of chemotherapy and PET was 8 wks (range 5–13) and between end of chemotherapy and surgery was 10 wks (range 6–18). All pts underwent surgery to remove liver metastases and had histological confirmation of the lesions. Results: In 16 evaluable pts, 53 liver lesions were confirmed by histology. The table shows the results on a per-lesion basis. A complete agreement between PET or CT and histology was documented in 3 and 4 pts respectively. Conclusions: These results suggest that PET and CT had sub-optimal diagnostic accuracy in the post-chemotherapy evaluation of liver lesions from colorectal cancer. Moreover, the combined use of the two imaging techniques does not significantly increase the sensitivity of CT. Further data are needed to evaluate the metabolic changes induced by chemotherapy which may be the cause for inaccurate PET findings. [Table: see text] No significant financial relationships to disclose.
Clinics in neurology and neurosurgery of sport: asymptomatic cervical canal stenosis and transient quadriparesis
Authors: G Davis, K Ugokwe, E P Roger, E C Benzel, R C Cantu, M Rogers, J Dvorak, P McCrory
Journal: British Journal of Sports Medicine (2008)

The cervical spine is a relatively mobile structure commencing at the base of the skull and finishing at the relatively immobile thoracic spine. The cervical spinal cord and the paired vertebral arteries are critical occupants of the cervical spine, and injury to these structures results in catastrophic quadriplegia (spinal cord injury) or stroke (vertebral artery injury). Trauma to the neck is not uncommon in sport, but only rarely results in neurovascular injury or significant spinal instability. Every physician or trainer entrusted with the care of athletes’ fears that the next neck injury seen may be a catastrophic one and endeavours to seek every opportunity possible to prevent such disaster. The question is: which athletes are at risk? Is asymptomatic spinal canal stenosis a risk factor for spinal cord injury and does an episode of transient quadriparesis predispose an athlete to the development of catastrophic spinal cord injury?
The changes of molecular markers with neoadjuvant dose-dense doxorubicin hydrochloride, cyclophosphamide, and paclitaxel chemotherapy regimen.
Authors: D. Sener Dede, B. Gumuskaya, G. Guler, D. A. Onat, K. Altundag, Y. Y. Ozisik
Journal: Journal of Clinical Oncology (2010)

e21028
Comparison of cyclophosphamide, doxorubicin, and vincristine with an alternating regimen of methotrexate, etoposide, and cisplatin/cyclophosphamide, doxorubicin, and vincristine in the treatment of extensive-disease small-cell lung carcinoma: a Mid-Atlantic Oncology Program study.
Authors: G L Wampler, W J Heim, N M Ellison, J D Ahlgren, J G Fryer
Journal: Journal of Clinical Oncology (1991)

An alternating regimen for the treatment of extensive-disease small-cell lung cancer (SCLC) was compared with standard treatment with cyclophosphamide, doxorubicin, and vincristine (CAV) in 170 patients. Overall severity of toxicity was similar in both arms, with four toxic deaths in each arm (4.7%). Response results were also similar, with 54% complete and partial responses with the standard regimen and 53% complete and partial responses with the alternating regimen. Median survival time was 6.9 months with the standard regimen and 9.2 months with the alternating regimen (P = .078). The 2-year survival rate was 1.2% for the standard regimen and 4.7% for the alternating regimen. Survival benefit for treatment with the alternating regimen reached statistical significance only in those subsets of patients with poorer prognosis (male sex, performance status 3, liver metastases, bone marrow metastases, and oat cell histologic subtype).
Intraocular Neoplasms Induced by Methylazoxymethanol Acetate in Japanese Medaka (&lt;italic&gt;Oryzias latipes&lt;/italic&gt;)&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: W E Hawkins, J W Fournie, R M Overstreet, W W Walker
Journal: JNCI Journal of the National Cancer Institute (1986)

Intraocular neoplasms developed in the Japanese medaka, a small fish species, following a single brief exposure to methylazoxymethanol acetate [(MAM-Ac) CAS: 592-62-1]. Specimens 6-10 days old were exposed to doses of MAM-Ac up to 100 mg/liter for 2 hours and then transferred to carcinogen-free water for “grow-out.” Of 218 exposed fish examined, 98 (45%) had neoplastic lesions in various stages of development. Of those exposed to 30 mg/liter or more, 57% had the lesions. No lesions were found in eyes or other tissues of 95 control specimens. Early and advanced neoplastic lesions were recognized. Early lesions were characterized by complexes of neoplastic retinal epithelium and tubes that consisted of cells of the sensory retina. Areas of mitotically active, heterogeneous cells associated with such complexes gave rise to advanced neoplasms. We considered the advanced neoplasms to be medulloepitheliomas, which differentiated into three principal cellular patterns: 1) solid masses of unpigmented cells, which frequently showed photoreceptor differentiation as well as ductular formation; 2) heavily pigmented cuboidal to columnar cells resembling retinal epithelium that formed adenomatous patterns; and 3) teratoid medulloepitheliomas. Teratoid medulloepitheliomas, which we considered the most advanced and malignant lesions, consisted of heterogeneous, highly mitotic, invasive cells and contained heteroplastic elements including striated muscle, undifferentiated mesenchymal tissues, and hyaline cartilage. We suggest that MAM-Ac induces hyperplasia of retinal cells followed by establishment of aberrant growth zones containing miscoded cells that give rise to medulloepitheliomas.
Establishing a molecular taxonomy for epithelial ovarian cancer (EOC) from 363 formalin-fixed paraffin embedded (FFPE) specimens.
Authors: C. Gourley, C. O. Michie, K. E. Keating, S. Deharo, E. J. O'Brien, A. Winter, F. A. McDyer, J. M. Mulligan, L. A. Hill, T. S. Davison, T. Halsey, L. McCoy, C. Wilson, A. Williams, D. J. Harrison, D. P. Harkin, R. D. Kennedy
Journal: Journal of Clinical Oncology (2011)

5000 Background: Despite histological heterogeneity and evidence of some molecular subtypes (e.g. BRCA1/2-deficient) EOC continues to be treated as a single disease. Using unsupervised hierarchical clustering of DNA microarray expression data we aimed to identify molecular subgroups with a view to personalized therapy. Methods: Microarray expression analysis was performed on 363 FFPE EOC samples (by far the largest dataset to date) with linked prospectively collected clinical data. Unsupervised clustering was applied to the most variable genes. This was followed by computational classification in the serous samples only. Results: Unsupervised analysis of all samples identified 6 subgroups which were most significantly related to histology (p=3.65 x 10-27) and had different overall survival (OS; p<0.0001). Clear cell tumors were present in one group, mucinous in another, serous and endometrioid were spread across 4 groups each. When a similar approach was applied to pure serous samples (no mixed tumors; n=199) three subgroups were identified with different OS (p<0.0001). Intriguingly, the dominant discriminatory biology within the serous cohort was related to vasculature development (FDR p.vasc.dev.=7.31 x 10-7) and more specifically to angiogenic processes (FDR p.Angiogenesis= 8.59 x 10-5). Up-regulation of these angiogenesis-related genes predominated in only one of the 3 serous subgroups (58 out of 199 tumours). Class labels were assigned to these samples based upon expression of these angiogenesis-related genes and a gene expression signature was developed which could identify the novel angiogenesis molecular subgroup. Conclusions: 1) It is possible to consistently perform transcriptomic analysis from small FFPE ovarian tumor sections and cluster similar tumors. 2) We have identified 6 main clusters of EOC, strongly associated with histology and survival. 3) In the pure serous subgroup, 3 clusters were identified with significantly differing survival; one of these subgroups was defined by upregulation of multiple angiogenesis genes. In light of the recently reported activity of bevacizumab in EOC (GOG 218 and ICON7) this subgroup may explain the observed response.
An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma
Authors: Yotam Drier, Matthew J Cotton, Kaylyn E Williamson, Shawn M Gillespie, Russell J H Ryan, Michael J Kluk, Christopher D Carey, Scott J Rodig, Lynette M Sholl, Amir H Afrogheh, William C Faquin, Lurdes Queimado, Jun Qi, Michael J Wick, Adel K El-Naggar, James E Bradner, Christopher A Moskaluk, Jon C Aster, Birgit Knoechel, Bradley E Bernstein
Journal: Nature Genetics (2016)
Validation of genomic markers that predict distant recurrence risk via FISH assays in women with early stage breast carcinoma
Authors: T. M. Williams, G. T. Budd, M. Gunter, R. Hines, S. Masood, P. Pawloski, L. Schwartzberg, F. Wei, R. R. Tubbs
Journal: Journal of Clinical Oncology (2007)

10506 Background: Biomarkers offer the potential to better predict recurrence risk in early stage invasive breast cancer, especially if adaptable to common assays such as fluorescent in situ hybridization (FISH). We studied the ability of tumor copy numbers (CN) of 3 genes, BIRC5, CYP24, and PDCD6IP, to predict distant recurrence in women with breast cancer. Methods: We conducted a blinded, multi-site study of 350 women with lymph node negative, estrogen/progesterone receptor positive (ER/PR+), invasive ductal carcinomas with archived paraffin-embedded biopsy specimens available. Eligible women received local surgical and radiation treatment only (93) (LTO) or local treatment and tamoxifen therapy only (257), and had distant metastases or no evidence of distant recurrence with at least 5 years follow-up (FU). Tumors were subjected to FISH with DNA probes for the 3 genes to assess CN. A prognostic index (PI) was calculated for each patient based on the 3 genes’ CN. A predetermined threshold (3.0) was used to categorize PI's as low or high. Data were assessed by Fisher's exact analysis and by categorical and continuous Cox modeling. Results: The study included 350 women with Stage I (288) and II (62) disease. FU averaged 7.3 years. Distant recurrence occurred in 32 women (9.1%) overall and in 5.2% of women with Stage I disease. In a multivariate Cox analysis including continuous PI, age, tamoxifen treatment, grade, and tumor size, PI remained a significant predictor of recurrence for Stage I patients: OR=1.56, p=0.019, and Stage I/LTO patients: OR=6.02, p=0.00007. Using the PI as a categorical classifier, the high/low recurrence rates were significantly different: OR=2.24, p= 0.045. Similar results were seen in Stage I patients: OR=3.53, p=0.021 with recurrence rates of 3.5% and 11.5% in the low and high risk groups, respectively, and for the Stage I/LTO patients: OR=5.33, p=0.041. Conclusions: FISH analysis of 3 genes allows metastasis risk prediction in women with early stage ER/PR+ cancers. This may be particularly useful for Stage I cancers traditionally considered low risk. The markers are prognostic in that they predict metastasis in patients receiving only local therapy. No significant financial relationships to disclose.
Activity of the heat shock protein 90 (HSP90) inhibitor, SNX-2112, in pediatric cancer cell lines.
Authors: D. C. Chinn, W. S. Holland, J. M. Yoon, T. Zwerdling, P. C. Mack
Journal: Journal of Clinical Oncology (2010)

9565 Background: HSP90 plays a central role in regulating client proteins involved in malignant processes. Currently, geldanamycin derivatives have shown encouraging anti-tumor activity although they may be potentially limited by off-target toxicities. SNX-2112 is an orally administered selective and potent HSP90 inhibitor that has demonstrated preclinical anti-tumor activity in several models. As many childhood tumors are dependent upon HSP90 client proteins, we sought to test the pre-clinical efficacy of SNX-2112 in a panel of pediatric cancer cell lines both as a single-agent and in combination with cisplatin (CP). Methods: Eight pediatric cancer cell lines (derived from osteosarcoma, neuroblastoma, hepatoblastoma, and lymphoma) were studied. Short-term effects of SNX-2112 were assessed by MTT and longer-term effects by clonogenic assays. Efficacy of SNX- 2112 in combination with CP was assessed using median-effect analysis. Cells were exposed to treatment for 72 hours in both. For additional assays, 12nM and 70nM doses of SNX-2112 were used. Status of HSP72, HSC70, B-Raf, AKT1, HER2, PARP, and β-actin was assessed by immunoblotting. Cell cycling was measured using flow cytometry. Results: All cell lines demonstrated sensitivity to SNX-2112 with IC50 values ranging from 20-100nM. Longer-term growth assays indicated an observed IC50 between 10-20nM. Low dose treatments (12nM) resulted in a cytostatic response with a small increase in sub-G1 content, but limited effect on client protein levels. The 70nM dose exhibited a more prolonged inhibition and larger sub-G1 accumulation. Observed levels of AKT1 were markedly reduced over time along with an increase in PARP cleavage. Concomitantly, there was also an increase in B-Raf and HSP72 protein expression. In concurrently administered combination treatments, SNX-2112 acted synergistically with CP to inhibit cell growth. Conclusions: SNX-2112 showed marked single-agent activity in pediatric cancer cell lines with downstream effects on HSP90 client proteins. The combination of SNX-2112 and CP showed synergistic efficacy in two cell lines tested. Further studies of SNX-2112 as a single agent or in combination with CP are warranted in pediatric cancer. No significant financial relationships to disclose.
性别、健康和与健康状态相关的性生活寿命：基于两组美国中老年人群的横向调查研究
Authors: 张宁, 杨勇
Journal: BMJ (2010)

目的研究健康状态和性生活因素问的关系，评估不同性别中老年人群以及不同健康状态者的性生活寿命。 设计横向研究。 地点两个具有代表性的美国人群样本：MIDUS，美国国家中年发展研究调查人群，1995—1996；NSHAP，国立社会人群，健康和年龄计划，2005—2006。
Development of secretory leukocyte protease inhibitor (SLPI) variants resistant to degradation by neutrophil elastase
Authors: Arlene Glasgow, Nicolas Camper, Derek Quinn, Stuart Elborn, Sinéad Weldon, Cliff Taggart
Journal: European Respiratory Journal (2014)

Cystic fibrosis (CF) is characterised by repeated cycles of lung infection and inflammation, causing a gradual destruction of lung tissue and eventually the death of over 95% of patients due to respiratory failure. Neutrophil elastase (NE), a serine protease released by neutrophils as part of the innate immune response, plays a key role in this lung tissue degradation process. Secretory leukocyte protease inhibitor (SLPI) is a small cationic antiprotease displaying potent NE inhibition but also anti-inflammatory and antibacterial properties. SLPI has previously shown promising therapeutic activity in the treatment of CF lung disease, however its potential benefits are compromised by its rapid cleavage due to excessively high levels of NE in the  Pseudomonas aeruginosa  infected lung. In this study, two SLPI variants (SLPI-A16G and SLPI-S15G-A16G) were engineered by site-directed mutagenesis for resistance to cleavage by NE, in an attempt to improve the efficacy of this antiprotease. The variants showed enhanced resistance to degradation in the presence of excess NE as well as CF patient sputum when compared to wild-type SLPI. Both proteins retained strong NE inhibitory activity. The abilities of each variant to bind bacterial LPS and to interact with NF-κB DNA binding sites, two properties important for SLPI antibacterial and anti-inflammatory activity, were also preserved. These SLPI variants may therefore have increased therapeutic potential in the treatment of CF.