tbuckley/cabot-search huggingface dataset:
The utilization of new oncology drugs: A global perspective
Authors: B. Jönsson, F. Lichtenberg, J. Lundkvist, C. Svedman, N. Wilking
Journal: Journal of Clinical Oncology (2007)

6612 Background: A number of new innovative cancer drugs have recently been approved or are in the process of being approved. We have analysed the access and uptake of 65 oncology drugs in 25 countries (19 European countries, Australia, Canada, Japan, New Zealand, South Africa and the USA) over a 10 year period based on sales data provided by IMS Health. Methods: We calculated an index of number of patients treated based on sales per inhabitant or per person who died from a specific cancer type. The age composition (vintage) of the drug arsenal used was calculated based on sales for cancer drugs introduced before 1995; between 1995–1999, 2000–2002 and after 2002 respectively. The vintage of the drug arsenal used was also analysed in relation to different economic and health care system characteristics. We performed three types of analysis of the effect of cancer drug vintage on cancer survival and mortality using difference-in-difference research designs. Results: Different patterns of uptake were seen in the countries studied, both with respect to speed of uptake and level of use. Fast uptake of most new drugs was seen in Austria, France, Switzerland, Spain and the USA, and slow uptake as well as low usage was seen in Poland, Hungary, New Zealand, South Africa and the UK. For some of the most recently approved drugs the variation in uptake is especially marked. The vintage of the cancer drug “arsenal” used also differs significantly between countries. Nearly half (44%) of the observed improvement in the two-year cancer survival rate between 1992 and 2000 at 50 USA cancer centres could be attributed to the use of newer cancer drugs. Around one sixth (14% − 19%) of the inter-country differences in 5-year cancer survival rates across 5 major European countries is due to differences in the uptake of newer drugs (post-1985) in each country. Nearly one third (30%) of the decline in cancer mortality rates seen during the period 1995 –2003, could be accounted for by the use of newer drugs. The observed decrease in mortality of 16% would have been only 11% if newer drugs had not been used. Conclusions: Patient access to innovative cancer drugs varies significantly between countries affecting mortality rates, and further research is needed into the determinants and consequences of these variations. No significant financial relationships to disclose.
Ideal Total Joint Arthroplasty Antibiotic Prophylaxis Unknown
Authors: Jason S. Lipof, Benjamin F. Ricciardi, Thomas G. Myers
Journal: JAMA Surgery (2019)

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Timing of Choledochal Cyst Perforation
Authors: Mei Diao, Long Li, Wei Cheng
Journal: Hepatology (2019)

1Department of Pediatric SurgeryCapital Institute of PediatricsBeijingP. R. China 2Department of Paediatrics and Department of Surgery, Southern Medical School, Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonVictoriaAustralia 3New Century HealthcareHong Kong * Address Correspondence and Reprint Requests to: Long Li, M.D., Ph.D. (requests for reprints) Department of Pediatric Surgery, Capital Institute of Pediatrics 2 Ya Bao Road, Chao Yang District, Beijing 100020, P.R. China E‐mail: [email protected] Tel.: +86‐10‐85695669 or Prof. Wei Cheng, M.B.B.S., F.R.C.S. (Edin), Ph.D. Department of Paediatrics and Department of Surgery, Southern Medical School, Faculty of Medicine, Nursing and Health Sciences, Monash University 246 Clayton Road, Clayton, Victoria 3168, Australia E‐mail: [email protected] Tel.: +61 3 9594 5674
Heart Failure Risk Stratification and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Type 2 Diabetes Mellitus
Authors: David D. Berg, Stephen D. Wiviott, Benjamin M. Scirica, Yared Gurmu, Ofri Mosenzon, Sabina A. Murphy, Deepak L. Bhatt, Lawrence A. Leiter, Darren K. McGuire, John P.H. Wilding, Per Johanson, Peter A. Johansson, Anna Maria Langkilde, Itamar Raz, Eugene Braunwald, Marc S. Sabatine
Journal: Circulation (2019)

Background: Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing heart failure. Sodium-glucose cotransporter-2 inhibitors reduce the risk of hospitalization for heart failure (HHF) in patients with T2DM. We aimed to develop and validate a practical clinical risk score for HHF in patients with T2DM and assess whether this score can identify high-risk patients with T2DM who have the greatest reduction in risk for HHF with a sodium-glucose cotransporter-2 inhibitor. Methods: We developed a clinical risk score for HHF in 8212 patients with T2DM in the placebo arm of SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using multivariable Cox regression, and independent clinical risk indicators achieving statistical significance of P &lt;0.001 were included in the risk score. We externally validated the score in 8578 patients with T2DM in the placebo arm of DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58). The relative and absolute risk reductions in HHF with the sodium-glucose cotransporter-2 inhibitor dapagliflozin were assessed by baseline HHF risk. Results: Five clinical variables were independent risk predictors of HHF: prior heart failure, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. A simple integer-based score (0–7 points) using these predictors identified a &gt;20-fold gradient of HHF risk ( P for trend &lt;0.001) in both the derivation and validation cohorts, with C indices of 0.81 and 0.78, respectively. Although relative risk reductions with dapagliflozin were similar for patients across the risk scores (25%–34%), absolute risk reductions were greater in those at higher baseline risk (1-sided P for trend=0.04), with high-risk (2 points) and very-high-risk (≥3 points) patients having 1.5% and 2.7% absolute reductions in Kaplan-Meier estimates of HHF risk at 4 years, respectively. Conclusions: Risk stratification using a novel clinical risk score for HHF in patients with T2DM identifies patients at higher risk for HHF who derive greater absolute benefit from sodium-glucose cotransporter-2 inhibition. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01107886 and NCT01730534.
Copy number variations of apoptosis-regulating genes and MKI67 gene in primary and recurrent soft tissues sarcomas.
Authors: Tatiana V. Ausheva, Oleg I. Kit, Inna A. Novikova, Evgeniya M. Nepomnyashchaya, Natalya N. Timoshkina, Larisa N. Vashchenko, Irina Dashkova, Emma Kechedzhieva, Elena Andreiko, Artem A. Barashev, Anna V. Antonets, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2019)

e22517 Background: Soft tissue sarcomas (STS) are relatively rare malignant tumors of mesenchymal origin, constituting about 1% of all solid human tumors. About 11% of STS cannot be classified. The relapses of STS are difficult to predict. So, the studying of molecular origin of STS remains to be an actual issue. We analyzed copy number variations (CNVs) of apoptosis-regulating genes and MKI67 gene in primary and recurrent STS. Methods: 32 patients with primary STS and 26 patients with relapses were investigated. Relative CNVs of bax, bcl2, casp3, casp8, casp9, p53, mdm2 and M kI67 were detected with the use of RT–qPCR in fresh frozen tumor and normal tissues obtained while surgical access. Relative Copy Quantitation (RCQ) was accounted with GAPDH and ACTB as reference genes. Results: The frequencies of CNVs of the studied genes in groups of primary and recurrent STS are presented in the table below. A significant change only in the group of primary STS sarcomas was observed for CNV of MDM2, whereas the amplification of the CASP3 and MKI67 genes was characteristic of recurrent sarcomas. CNVs of BAX and CASP8 were significantly more frequent in primary STS. Increased amplification of MDM2 gene, was observed only for liposarcomas among all the others STS. The literature describes amplification of chromosome 12q13-15 where MDM2 gene is localized as a diagnostic feature of liposarcoma which is consistent with our observations [Todorov SS, Kit OI Modern understanding of the morphogenetic features of liposarcomas // Archives of Pathology. 2012. T. 74. №6. p.59-61]. Conclusions: The study showed the potential role of CNV of the BAX, CASP3, CASP8 and MKI67 genes to develop an approach to predicting the course of STS and the effectiveness of the MDM2 gene amplification as an additional marker for liposarcoma molecular classification.[Table: see text]
HER2 evaluation process for neoadjuvant targeted therapies in breast cancer.
Authors: Yoshio Mizuno, Naoko Takeda, Junichi Yamada, Hiroaki Abe, Yuko Inoue, Hiroshi Seto, Kazuhiko Sato
Journal: Journal of Clinical Oncology (2013)

3034 Background: Treatment with a combination of HER2-targeted therapies has emerged as an addition of trastuzumab to neoadjuvant chemotherapy regimens in breast cancer patients and it goes on increasing. For clinical HER2 determination, immunohistochemical (IHC) analysis is an attractive method and all IHC 2+ cases are categorized as equivocal and should be reflexed to fluorescence in situ hybridization (FISH) testing. However, research in recent years with respect to false-negative cases for HER2 testing have been reported, and it comes to the question of what considering the indication for trastuzumab in the neoadjuvant chemotherapy. To clarify these controversial points in applying the results of HER2 testing in the clinical setting, we performed a retrospective analysis of core needle biopsy (CNB) and surgical specimen results. Methods: 422 patients underwent primary operations for early breast cancer at Tokyo-West Tokushukai Hospital (Tokyo, Japan) from October 2008 to December 2012. Among these patients, 262 patients who received CNB prior to operation were enrolled. Those patients who received preoperative chemotherapy or had DCIS were excluded. With regard to diagnostic criteria, HER2 positivity was defined as either 3+ by IHC or FISH analysis amplification ratio of ≥2.2. In addition, if in any cases which CNB samples or surgical specimens showed HER2-positive had defined true HER2-positive cases, we assessed the false-negative results of the HER2 test via IHC using CNB samples and surgical specimens. Results: In a matched cohort of 262 patients, 59 cases showed HER2-positive (five cases were CNBs negative to surgical specimens positive, 14 cases were CNBs positive to surgical specimens negative, and 40 cases were both positive). If we decide for selection of trastuzumab target cases by CNBs only, we make mistakes in indications of trastuzumab for five (8.5%) of 59 HER2-positive cases who were CNBs negative to surgical specimens positive. Conclusions: There are quite a few cases show false negatives for HER2 testing in CNB samples. In cases of considering the indication for trastuzumab in the neoadjuvant chemotherapy, even if the CNB samples resulted in negative, we consider that retesting with FISH analysis should be carried out.
MEK/MELK inhibition and blood–brain barrier deficiencies in atypical teratoid/rhabdoid tumors
Authors: Michaël H Meel, Miriam Guillén Navarro, Mark C de Gooijer, Dennis S Metselaar, Piotr Waranecki, Marjolein Breur, Tonny Lagerweij, Laurine E Wedekind, Jan Koster, Marianne D van de Wetering, Netteke Schouten-van Meeteren, Eleonora Aronica, Olaf van Tellingen, Marianna Bugiani, Timothy N Phoenix, Gertjan J L Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2019)

Atypical teratoid/rhabdoid tumors (AT/RT) are rare, but highly aggressive. These entities are of embryonal origin occurring in the central nervous system (CNS) of young children. Molecularly these tumors are driven by a single hallmark mutation, resulting in inactivation of SMARCB1 or SMARCA4. Additionally, activation of the MAPK signaling axis and preclinical antitumor efficacy of its inhibition have been described in AT/RT.We established and validated a patient-derived neurosphere culture and xenograft model of sonic hedgehog (SHH) subtype AT/RT, at diagnosis and relapse from the same patient. We set out to study the vascular phenotype of these tumors to evaluate the integrity of the blood-brain barrier (BBB) in AT/RT. We also used the model to study combined mitogen-activated protein kinase kinase (MEK) and maternal embryonic leucine zipper kinase (MELK) inhibition as a therapeutic strategy for AT/RT.We found MELK to be highly overexpressed in both patient samples of AT/RT and our primary cultures and xenografts. We identified a potent antitumor efficacy of the MELK inhibitor OTSSP167, as well as strong synergy with the MEK inhibitor trametinib, against primary AT/RT neurospheres. Additionally, vascular phenotyping of AT/RT patient material and xenografts revealed significant BBB aberrancies in these tumors. Finally, we show in vivo efficacy of the non-BBB penetrable drugs OTSSP167 and trametinib in AT/RT xenografts, demonstrating the therapeutic implications of the observed BBB deficiencies and validating MEK/MELK inhibition as a potential treatment.Altogether, we developed a combination treatment strategy for AT/RT based on MEK/MELK inhibition and identify therapeutically exploitable BBB deficiencies in these tumors.
Study on activation of the IGF-1R mTOR pathway in neuroendocrine tumours (NETs).
Authors: Oriol Casanovas, Alex Teule, Carles Villabona, Teresa Serrano, Joan Fabregat, Ramon Salazar
Journal: Journal of Clinical Oncology (2013)

4139 Background: NETs are a heterogeneous group of rare neoplasms. Preclinical studies have shown that IGFR overestimulation can lead to constitutional activation of mTOR pathway. The main objective of this study is to describe the activation status of IGF1R-mTOR pathway by immunohistochemistry in a series of NETs and to assess the association with IGF1R expression. Methods: We studied 69 paraffin tumour blocks: 28 pancreatic NETs (pNETs) (2 gastrinomas, 1 glucagonoma, 4 insulinomas and 21 non-functioning (nf) pNETs), 32 GI NETs (4 stomach, 8 colorectum, 18 ileum and 2 dudodenum) and 9 NETs from other origins (2 anterior mediastinum, 2 ovary, 3 bile duct and 2 kidney). The expression of IGF1R, phosphorylated (p) mTOR and (p)S6 has been determined by immunohistochemistry using anti-IGF1Rβ (sc-713), anti-Phospho-mTOR (S2448) (49F9, Cell Signaling) and anti-Phospho-S6 Ribosomal Protein (S235/336)(91B2, Cell Signaling). Results: Expression of IGF1R has been observed in 46 of 69 (66%) samples with the highest expression in 2/4 (50%) insulinomas, 5/21 nf pNETs (23%) and 3/18 ileum (17%). We have observed activation of the mTOR pathway by immunodetection of (p)mTOR in 14 of 69 samples (20%): 2/21 nf pNETs (9.5%), 1/8 colorectum (12.5%), 8/18 ileum (44%), 1/2 anterior mediastinum, 1/2 ovary, 1/3 biliar tract. We haven’t detected any (p)S6 activation in these samples. Consistent IGF1R-mTOR pathway activation was detected in 11/14 (78%) samples with mTOR positivity that also showed expression of IGF1R. The most relevant finding is that all of the 8 samples from ileum with activation of mTOR showed some degree of expression of IGF1R. Conclusions: 2/3 of NETs show varying levels of expression of IGF1R, but only 16% demonstrate activation of the IGF1R-mTOR pathway. While the positivity of (p)mTOR in pNETs is lower than expected, we have identified a subgroup of ileal NETs with consistent activation of both IGF1R and (p)mTOR which could help stratify patients in clinical trials involving modulation of this pathway. In contrast, none of the 69 samples studied was positive for (p)S6 which suggests this marker is not valid to be used in the clinic. Further validation studies are required to help clinical stratification for therapies against IGF1R mTOR pathways.
International guidelines for antithrombotics in cancer patients.
Authors: Dominique Farge, Philippe Debourdeau, Marielle Beckers, Harry Buller
Journal: Journal of Clinical Oncology (2012)

e13062 Background: Venous thromboembolism (VTE), defined as deep-vein thrombosis (DVT) or pulmonary embolism (PE), including those related to indwelling central venous catheter (CVCT), is reported in 15 to 20% of patients with cancer. To date, VTE impact on oncology patients remains elusive and the increased incidence of cancers and of CVC for chemotherapy leads to an increased number of VTE. Methods: Heterogeneity in clinical practices worldwide, and lack of international recommendations led us to establish international guidelines for the management of VTE in cancer patients according to the GRADE methodology. These international guidelines were elaborated under the auspices of the International Society of Thrombosis and Haemostasis (ISTH) following an initiative from the “Groupe Francophone Thrombose et Cancer” (GFTC,www.thrombose-cancer.com) with the collaboration of the Academic Medical Centre (AMC), Amsterdam, The Netherlands, and the methodological support and quality control of the French national cancer institute (INCa). A literature review of the studies published on this topic between 1996 and 2011 was performed. A first version of the guidelines was established based on the corresponding levels of evidence derived from analysis of the selected studies. The recommendations were classified as Strong or Weak according to GRADE and Best Clinical Practices based on international expert’ agreement in the absence of literature data. In the absence of data we provided guidance based on experts opinion. The document was then peer-reviewed by a group of 200 international independent experts. Results: The main topics of the guidelines are the treatment and the prophylaxis of VTE with heparins and vitamin K antagonists in medical and surgical cancer patients, including CVC related thrombosis. Recommendations on the use of vena cava filters, thrombolysis and VTE treatment in patients with intracranial malignancies as well as for prophylaxis in the ambulatory setting are also proposed. Conclusions: These first international guidelines, the methodological steps, the data analysis and critical appraisal, the conclusions with their levels of evidence and the argued judgement of the experts will be available on the GTC, INCa and ISTH web sites
Choosing oncology as specialization: Medical students' perception after clinical rotation in cancer center.
Authors: Omar Orlando Castillo Fernandez, Maria Lim, Lilian Hayde Montano, Gaspar Perez-Jimenez, Jhonattan Camaño, Enrique Mendoza, Yamileth Pereira
Journal: Journal of Clinical Oncology (2019)

10528 Background: Cancer is a leading cause of death worldwide and the demand for oncologist and palliative care specialists is increasing dramatically. Two years ago, The Universidad de Panama incorporated Oncology in the curriculum in order to face the shortage of professionals involved in cancer care. Little information is available concerning young medical students desire to pursue a career in oncology.The aim of this study is to evalute medical students perception about Oncology as a specialization field. Methods: An electronic survey was sent to medical students from Universidad de Panama after finishing Oncology rotation the last 2 years. Chi square and Mann Whitney U tests were used to compare variables. Results: 145 questionnaries were responded (40%). 60% female and 40% male. Median age was 25 years old. Clinical rotation during Oncology practices were: 37% in Medical Oncology, 24% in Surgical Oncology, 21% in Radiation Oncology and 18% in Palliative Care. 20% (29) of students are highly motivated to pursue a career in Oncology. 8 in Radiation Oncology. 8 in Surgical Oncology, 8 in Medical Oncology and 5 in Palliative Care. Variable associated with a oncology preference were: male gender (p=0.007), lack of human resources (p=0.009), contact with patients and family (p=0.005), good experience with mentor (p=0.002), nature and complexity of disease (p&lt;0.001). Potential emotional burden was negatively asssociated (p=0.004) with oncology preference. 66% of students acknowledged that clinical rotation changed positively their perception about cancer patient care and a third of students haved not rule out the possibility to choose Oncology in the near future. Conclusions: Early exposition to medical student to cancer care might help to reduce the global shortage of oncologist and palliative specialists.
Mobile Photoplethysmographic Technology to Detect Atrial Fibrillation
Authors: Yutao Guo, Hao Wang, Hui Zhang, Tong Liu, Zhaoguang Liang, Yunlong Xia, Li Yan, Yunli Xing, Haili Shi, Shuyan Li, Yanxia Liu, Fan Liu, Mei Feng, Yundai Chen, Gregory Y.H. Lip, Yutao Guo, Gregory Y.H. Lip, Deirdre A. Lane, Yundai Chen, Liming Wang, Jens Eckstein, G Neil Thomas, Liu Tong, Feng Mei, Liu Xuejun, Li Xiaoming, Shan Zhaoliang, Shi Xiangming, Zhang Wei, Xing Yunli, Wen Jing, Wu Fan, Yang Sitong, Jin Xiaoqing, Yang Bo, Bai Xiaojuan, Jiang Yuting, Liu Yangxia, Song Yingying, Tan Zhongju, Yang Li, Luan Tianzhu, Niu Chunfeng, Zhang Lili, Li Shuyan, Wang Zulu, Xv Bing, Liu Liming, Jin Yuanzhe, Xia Yunlong, Chen Xiaohong, Wu Fang, Zhong Lina, Sun yihong, Jia shujie, Li Jing, Li Nan, Li shijun, Liu huixia, Li Rong, Liu Fan, Ge qingfeng, Guan tianyun, Wen Yuan, Li Xin, Ren Yan, Chen xiaoping, Chen ronghua, Shi Yun, Zhao yulan, Shi haili, Zhao yujie, Wang quanchun, Sun weidong, Wei Lin, Esther Chan, Shan Guangliang, Yao Chen, Zong Wei, Chen Dandi, Han Xiang, Xu Anding, Fan Xiaohan, Yu Ziqiang, Gu Xiang, Ge Fulin
Journal: Journal of the American College of Cardiology (2019)