tbuckley/cabot-search huggingface dataset:
A randomized phase II study of TS-1 plus cisplatin versus vinorelbine plus cisplatin with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC): WJOG 5008L.
Authors: Takashi Seto, Tomonari Sasaki, Takeharu Yamanaka, Naonobu Kunitake, Junichi Shimizu, Takeshi Kodaira, Makoto Nishio, Takuyo Kozuka, Toshiaki Takahashi, Hideyuki Harada, Naruo Yoshimura, Shinichi Tsutsumi, Hiromoto Kitajima, Masaaki Kataoka, Kazuhiko Nakagawa, Yasumasa Nishimura, Yoichi Nakanishi
Journal: Journal of Clinical Oncology (2015)

7512 Background: Cisplatin-based chemotherapy and concurrent radiotherapy is the standard treatments for LA-NSCLC. Thistrial evaluated two experimental regimens of chemotherapy with concurrent radiotherapy. Methods: Eligible patients with unresectable stage III NSCLC, 20 to 74 years of age, and ECOG PS of 0–1 were randomized to either Arm SP, S-1 (40 mg/m2/dose per oral, b.i.d, on days 1-14) and cisplatin (60 mg/m2 on day 1) repeated every 4 weeks or Arm VP, vinorelbine ( 20mg/m2 on day 1, 8) and cisplatin (80 mg/m2on day) repeated every 4 weeks with early concurrent thoracic radiotherapy of 60 Gy at 2 Gy per daily fraction. The primary endpoint was overall survival rate at 2-year (2yr-OS). A pick-the-winner design was used to identify the treatment regimen most likely to be superior. The planned sample size was 55 patients per arm, assuming in each arm that the null hypothesis for 2yr- OS was 50% versus an alternative hypothesis for 65% with one-sided alpha of 0.10 and power of 80% (Study ID: UMIN000002420). Results: One hundred eleven patients were registered between Sep 2009 and Sep 2012. Of 108 patients for efficacy analysis, the 2yr-OS was 76% (95% CI, 62-85%) for SP and 69% (95% CI, 54-79%) for VP. The hazard ratio (HR) of death between the two arms was 0.85 (0.48-1.49). The median progression-free survival (PFS) was 14.8 months for SP and 12.3 months for VP with a HR of 0.92 (0.58-1.44). 80% and 48% of patients completed the protocol treatment in SP and VP, respectively. Common grade 3-4 toxicities in SP v VP were neutropenia 33.3% v 75.9%, platelets 9.3% v 3.7%, hemoglobin 1.9% v 27.8%, febrile neutropenia 9.3% v 16.7%, diarrhea 5.6% v 0%. There were 4 and 5 treatment-related deaths in SP and VP, respectively. Conclusions: Both arms rejected the null hypothesis for 2yr-OS. In this study Arm SP was declared the winner in terms of 2yr-OS, PFS, treatment completion, and toxicity. Clinical trial information: 000002420.
Non-Follicular Low Grade B-Cell Lymphomas: Patterns of Presentation and Management with Comparative Prognostic Utility of IPI and FLIPI
Authors: Laura S. Jacobus, Julianne Lunde, Matthew J Maurer, Ahmet Dogan, Sergei I Syrbu, Cristine Allmer, Anne J. Novak, James R Cerhan, Grzegorz S. Nowakowski, Susan L Slager, Thomas E. Witzig, Carrie A. Thompson, George J. Weiner, Thomas M Habermann, Stephen M. Ansell, Brian K Link
Journal: Blood (2012)
Comparison of the postoperative prognostic value between old (6th edition) and new (7th edition) UICC TNM classification for renal cell carcinoma.
Authors: K. Kanao, M. Oya
Journal: Journal of Clinical Oncology (2010)

e15095 Background: In December 2009 the UICC has published a new TNM classification (7th edition) and a revision has proposed for renal cell carcinoma. To evaluate the performance of the new classification, we compare the postoperative prognostic vlaue of the seventh and sixth editions of the TNM classification of renal cell carcinoma. Methods: We retrospectively evaluated outcomes in 539 patients with renal cell carcinoma who underwent radical nephrectomy or nephron sparing surgery at our institution. Disease was advanced in 130 patients, including 29 with nodal and 46 with distant metastasis. Staging was performed according to the seventh and sixth edition of the TNM classification of renal cell carcinoma. Survival curves were calculated using the Kaplan-Meier method and Cox proportional hazards regression model was developed to predict cause specific survival. Likelihood of Cox proportional hazards regression model was used to compare the prognostic accuracy between two classifications. Results: Overall 1, 3 and 5-year patient survival was 95.2%, 92.0% and 89.9%, respectively. By use of new TNM classification, 59 patients of the previous T2 were divided into 45 of T2a and 14 of T2a. Eleven patients with contiguous extension into the ipsilateral adrenal gland transferred from T3a to T4. Five patients with tumor glossly extend into the renal vein transferred from T3b to T3a. According to the new classification cause specific survival of T2b that calculated by the Kaplan-Meier method was significantly shorter than T3a. In multivariate analysis there was also a reversal in the risk of survival between T2b and T3a, namely the T2b hazard ratio was significantly greater than that of T3a.There is no significance of likelihood between new and old TNM classification. Conclusions: According to the new TNM classification cause specific survival and the risk of survival were reversed between T2b and T3a. That suggests that further improvement may be necessary for the categorization among T2 and T3. No significant financial relationships to disclose.
Abstract 4319: Associations of dietary inflammation scores with incident, sporadic adenoma
Authors: Ashley C. Holmes, Roberd M. Bostick
Journal: Cancer Research (2016)

Abstract It is now well-accepted that inflammation is causal in colorectal carcinogenesis and that reducing inflammation reduces risk for colorectal neoplasms. The ability to characterize specific dietary components as having pro- or anti-inflammatory effects is a promising area of cancer prevention. To assess associations of diet with inflammation and diet-associated inflammation with cancer risk, we created a new food-based inflammation (FBI) score based on associations of whole food dietary components (processed meats, red meat, white meat, fish, nuts, coffee, tea, high- and low-fat dairy products, refined and whole grains, and 10 botanical categories) with a panel of biomarkers of inflammation (plasma C-reactive protein [CRP] and interleukins-6, -8, and -10) among 590 chronic disease diagnosis-free participants (47% male, 53% female, 57% white, 43% black) in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study. A previously reported Dietary Inflammation Index (DII) is a primarily nutrient-based score developed for the same purposes. We investigated associations of our new FBI score, a DII that includes contributions from foods and nutritional supplements (Food + Supplements DII), and a DII that includes contributions only from foods (Food-only DII) with incident, sporadic adenoma in a case-control study (CPRU; n = 2,195) conducted in the Twin Cities area of Minnesota from 1990 - 1994. Diet was assessed using a Willett food frequency questionnaire. Associations of the scores with adenoma were estimated using unconditional logistic regression models adjusted for age, sex, hormone replacement therapy use, family history of colorectal cancer, regular non-steroidal anti-inflammatory drug (NSAID) use, total energy intake, smoking, physical activity level, alcohol consumption, and body mass index (BMI). The multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) for those in the highest relative to those in the lowest score quartiles were 1.28 (95% CI 0.95, 1.72) for the FBI, 1.23 (95% CI 0.82, 1.85) for the Food + Supplements DII, and 1.14 (95% CI 0.85, 1.53) for the Foods-only DII. These results suggest that 1) a more pro-inflammatory diet may be associated with higher risk of colorectal adenoma, and 2) support further development and investigation of a food-based inflammation score for investigating associations of diet-related contributions to systemic inflammation with colorectal and other cancers and chronic diseases. Citation Format: Ashley C. Holmes, Roberd M. Bostick. Associations of dietary inflammation scores with incident, sporadic adenoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4319.
Dosage of isoniazid and rifampicin poorly predicts drug exposure in tuberculosis patients
Authors: Marieke G.G. Sturkenboom, Onno W. Akkerman, Richard van Altena, Wiel C.M. de Lange, Jos G.W. Kosterink, Tjip S. van der Werf, Jan-Willem C. Alffenaar
Journal: European Respiratory Journal (2016)

Treatment of tuberculosis (TB) has been increasingly challenged by the emergence of drug resistance, toxicity, relapse and nonresponse [1]. Pharmacokinetic variability is a major driver of emerging drug resistance [2]. Risk of treatment failure was almost nine-fold higher in patients with low drug exposure compared to patients with higher drug exposure [3]. Dosage poorly predicts isoniazid and rifampicin drug exposure in TB patients; TDM advocated in certain patients <http://ow.ly/37523023n23>
Immunotherapy with Long-Lived Anti-CD123 × Anti-CD3 Bispecific Antibodies Stimulates Potent T Cell-Mediated Killing of Human AML Cell Lines and of CD123+ Cells in Monkeys: A Potential Therapy for Acute Myelogenous Leukemia
Authors: Seung Y. Chu, Erik Pong, Hsing Chen, Sheryl Phung, Emily W. Chan, Nancy A. Endo, Rumana Rashid, Christine Bonzon, Irene W.L. Leung, Umesh S. Muchhal, Gregory L. Moore, Matthew J. Bernett, David E. Szymkowski, John R. Desjarlais
Journal: Blood (2014)
Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection
Authors: Tobias L. Lenz, Victor Spirin, Daniel M. Jordan, Shamil R. Sunyaev
Journal: Molecular Biology and Evolution (2016)

Deleterious mutations are expected to evolve under negative selection and are usually purged from the population. However, deleterious alleles segregate in the human population and some disease-associated variants are maintained at considerable frequencies. Here, we test the hypothesis that balancing selection may counteract purifying selection in neighboring regions and thus maintain deleterious variants at higher frequency than expected from their detrimental fitness effect. We first show in realistic simulations that balancing selection reduces the density of polymorphic sites surrounding a locus under balancing selection, but at the same time markedly increases the population frequency of the remaining variants, including even substantially deleterious alleles. To test the predictions of our simulations empirically, we then use whole-exome sequencing data from 6,500 human individuals and focus on the most established example for balancing selection in the human genome, the major histocompatibility complex (MHC). Our analysis shows an elevated frequency of putatively deleterious coding variants in nonhuman leukocyte antigen (non-HLA) genes localized in the MHC region. The mean frequency of these variants declined with physical distance from the classical HLA genes, indicating dependency on genetic linkage. These results reveal an indirect cost of the genetic diversity maintained by balancing selection, which has hitherto been perceived as mostly advantageous, and have implications both for the evolution of recombination and also for the epidemiology of various MHC-associated diseases.
Abstract 677: EML4-ALK fusion gene expressing transgenic mouse for lung cancer model
Authors: Kyoung-Ho Pyo, Hye Ryun Kim, Sun Min Lim, Mi Ran Yun, Sung-Moo Kim, Hwan Kim, Han Na Kang, Ji Min Lee, Sang Gyun Kim, Byoung Chul Cho
Journal: Cancer Research (2016)

Abstract Background: EML4-ALK is a fusion-type protein typrosin kinase that is generated in lung cancer. We have established transgenic mouse line. The surfactant protein C gene (SPC) is only expressed in alveolar epithelial cells. We applied SPC promoter on encoded human-EML4-ALK gene. Normally, EML4-ALK gene is silenced when LoxP-PGK-LoxP gene is turned on. When Cre recombinase is present with the specific inducer, tamoxifen, EML4-ALK gene is expressed in alveolar epithelial cell, and converses to lung cancer. Materials and Methods: For generation of EML4-ALK fusion transgenic mouse, a cDNA fragment encoding FLAG tagged EML4-ALK (variant 1) was ligated to end of the CMV-LoxP-PGK-LoxP. The expression cassette was injected into pronuclear-stage embryos of B6 mouse to generate Tg mouse. Transgenic mouse was prepared for interbreed with KI mouse (SPC-CreER2T-trTA-NeoR). The KI-Tg fusion mouse was confirmed by genotyping, then the mouse was injected with tamoxifen (cre recombinase inducer) intraperitoneally. The lung tumors were observed by MRI or CT. The lung pathology was analyzed by immunohistochemistry and hematoxylin &amp; eosin staining. For confirmation of EML4-ALK protein expression, western blot was performed in different organs. EML4-ALK tumor-bearing mouse was treated with ALK tyrosine kinase inhibitor (TKI) for 2 weeks and tumor shrinkage was measured. Results: EML4-ALK tumor was observed after one week. Tumor nodules were widely observed in all lung lobes. Pathologically, the histologic type was adenocarcinoma and had homology to patient tissue on H&amp;E stain. We confirmed EML4-ALK expression in different organs including lung, heart, liver, stomach, kidney, colon and brain. EML4-ALK (120kDa) was strongly expressed in lung, but not in other organs. Indeed, ALK and Flag expression were observed in tumor region by immunohistochemistry. The EML4-ALK tumor bearing mice were treated with ALK TKI for 2 weeks. The ALK TKI-treated mice showed dramatic shrinkage of tumors and showed gain in body weight. Conclusions: EML4-ALK Tg mouse was successfully established. The benefits of the model compared to a previous conditioned Tg mouse model are (1) no need to treat Cre inducer daily, and (2) short duration (approximately 1 week) of tumorigenesis. We confirmed dramatic tumor shrinkage after treatment with ALK TKI. This model provides a strong preclinical model for testing ALK TKIs in lung cancer. Citation Format: Kyoung-Ho Pyo, Hye Ryun Kim, Sun Min Lim, Mi Ran Yun, Sung-Moo Kim, Hwan Kim, Han Na Kang, Ji Min Lee, Sang Gyun Kim, Byoung Chul Cho. EML4-ALK fusion gene expressing transgenic mouse for lung cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 677.
Abstract 3598: Laser micro-irradiations of large amounts of cells for high content applications
Authors: Martin Mistrik, Eva Vesela, Tomas Furst, Ivo Frydrych, Jan Gursky, Jiri Bartek
Journal: Cancer Research (2016)

Abstract A new methodical approach for the evaluation of photo-manipulated samples is presented and tested in various biological setups. The method is based on an atypical setting of a standard laser-scanning microscope (LSM) and image-processing software solution. Newly, a whole population of several dozen of cells is simultaneously micro-irradiated by a laser beam in a precisely defined pattern of collinear rays. Such laser induced striation pattern is automatically analyzed by specialized software routine providing quantitative assessment of various photo-manipulations, such as DNA-damage induced protein translocations or modifications, in both live and fixed cells. Automation of the process reduces workload and opens new possibilities for various dynamic studies and/or high content experiments. Results obtained during the testing of the method are presented and offer an insight into several DNA damage recognition and response pathways. Citation Format: Martin Mistrik, Eva Vesela, Tomas Furst, Ivo Frydrych, Jan Gursky, Jiri Bartek. Laser micro-irradiations of large amounts of cells for high content applications. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3598.
Use of Antibiotics Among Patients Hospitalized for Exacerbations of Asthma
Authors: Peter K. Lindenauer, Mihaela S. Stefan, Laura C. Feemster, Meng-Shiou Shieh, Shannon S. Carson, David H. Au, Jerry A. Krishnan
Journal: JAMA Internal Medicine (2016)

Teaching Medical Students to Engage Meaningfully and Judiciously With Patient DataElectronic medical records (EMRs) are now ubiquitous and proficiency in their use is a necessary component of undergraduate medical education.Clerkship directors of medical schools have set national standards for how students should learn to access, document, and write orders in an EMR. 1 However, these standards minimally address how students might use their patients' electronic information after the clinical encounter concludes.In this issue of JAMA Internal Medicine, Brisson and Tyler 2 describe survey results in which 96.1% of medical students track patients electronically after direct patient care ends, largely to confirm diagnoses, check results of pending tests, and understand what happened during their subsequent clinical course.Although this is a single-institution survey, it is reasonable to imagine that resident and medical students across the country similarly track their former patients electronically to various degrees.When done well, medical student tracking via EMRs can benefit patients.On my inpatient teams, students who were tracking their patients were able to follow up on postdischarge diagnostic test results that altered their patients' courses.Also, tracking enriches learning, offering students feedback on clinical questions such as, "Did we really need to order that?" or "Did we estimate her prognosis well?," to help them develop deliberate practice patterns.However, there are 2 important problems with medical students tracking former patients via EMRs as it is currently practiced.First, patients do not explicitly provide consent to be tracked after their care ends, a problem that physicians and students could easily address through discussion with their patients.Second, some tracking is extracurricular.The Health Insurance Portability and Accountability Act likely only permits tracking of patients for education and quality assurance. 3However, 39.8% of medical students in the study by Brisson and Tyler 2 tracked former patients because they were curious about what had happened or liked the patient.Medical school informatics and EMR curricula need to teach students to engage meaningfully and judiciously with patients' data.
Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target
Authors: Alfredo Perales-Puchalt, Nikolaos Svoronos, Melanie R. Rutkowski, Michael J. Allegrezza, Amelia J. Tesone, Kyle K. Payne, Jayamanna Wickramasinghe, Jenny M. Nguyen, Shane W. O'Brien, Kiranmai Gumireddy, Qihong Huang, Mark G. Cadungog, Denise C. Connolly, Julia Tchou, Tyler J. Curiel, Jose R. Conejo-Garcia
Journal: Clinical Cancer Research (2016)

To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)-expressing ovarian cancer cells.FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic subtypes and 20 human healthy tissues. The effectiveness of human T cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T cells.FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T cells persisted as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor-transduced T cells away from targeted tumor cells.T cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries. Clin Cancer Res; 23(2); 441-53. ©2016 AACR.
Abstract 307: GPR120/FFAR4 activation by fatty acid 16:4(n-3) plays a key role in resistance to chemotherapy
Authors: Julia Houthuijzen, Ilse Oosterom, Brian Hudson, Akira Hirasawa, Laura Daenen, Chelsea McLean, Steffen Hansen, Marijn van Jaarsveld, Daniel Peeper, sahar Jafari Sadatmand, Jeanine Roodhart, Chris van de Lest, Trond Ulven, Kenji Ishihara, Graeme Milligan, Emile Voest
Journal: Cancer Research (2016)

Abstract Although chemotherapy is designed to eradicate tumor cells it also has a significant impact on normal tissues. These host-responses can have large effects on the efficacy of treatment and overall survival. Fatty acids are increasingly recognized to play important signaling roles. 12-S-HHT and 16:4(n-3) are two platinum-induced fatty acids (PIFAs) that induce systemic resistance to a broad range of DNA-damaging chemotherapeutics. PIFAs exert their chemoprotective effect on tumor cells via an indirect mechanism involving splenic F4/80+/CD11blow macrophages. Here we identified GPR120 on mouse and human splenic macrophages as the relevant receptor for 16:4(n-3). GPR120 (FFAR4) is a free fatty acid receptor that binds medium- to long-chain fatty acids and omega-3 fatty acids and is involved in anti-inflammatory response and metabolic control. Although both GPR40 (FFAR1) and GPR120 can be activated by 16:4(n-3) in vitro, only inhibition or genetic loss of GPR120 was able to block 16:4(n-3)-mediated chemoresistance in vivo. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA2 activity in splenic macrophages resulting in the production and secretion of resistance-inducing lysophosphatidylcholine 24:1 (LPC(24:1)). Taken together, we identified a novel function for GPR120. Activation by 16:4(n-3) leads to enhanced cPLA2 activity and production of LPC(24:1) resulting in chemotherapy resistance. Citation Format: Julia Houthuijzen, Ilse Oosterom, Brian Hudson, Akira Hirasawa, Laura Daenen, Chelsea McLean, Steffen Hansen, Marijn van Jaarsveld, Daniel Peeper, sahar Jafari Sadatmand, Jeanine Roodhart, Chris van de Lest, Trond Ulven, Kenji Ishihara, Graeme Milligan, Emile Voest. GPR120/FFAR4 activation by fatty acid 16:4(n-3) plays a key role in resistance to chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 307.
Internal Tandem Duplication Mutation Of FLT3 (FLT3/ITD) Induces Increased Homologous Recombination DNA Repair Activity, Drug Resistance and Sister Chromatid Exchanges In Acute Myeloid Leukaemia (AML)
Authors: Terry J Gaymes, David C Darling, Ghulam J. Mufti
Journal: Blood (2013)