tbuckley/cabot-search huggingface dataset:
Screening for Latent Tuberculosis Infection
Authors: Randall Reves, Charles L. Daley
Journal: JAMA Internal Medicine (2016)

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A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma
Authors: A.L. Ho, L. Dunn, E.J. Sherman, M.G. Fury, S.S. Baxi, R. Chandramohan, S. Dogan, L.G.T. Morris, G.D. Cullen, S. Haque, C.S. Sima, A. Ni, C.R. Antonescu, N. Katabi, D.G. Pfister
Journal: Annals of Oncology (2016)
Serendipitous Detection of Hodgkin Lymphoma by 18F-NaF PET/CT
Authors: Fuqiang Shao, Jingbo Wu, Zhanwen Huang, Fan Zhou, Yue Chen
Journal: Clinical Nuclear Medicine (2016)

A 17-year-old girl underwent F-NaF PET/CT to evaluate bone pain after an accident. The images did not identify any osseous lesion. However, there was a focally increased activity in the left upper chest, which corresponded to a partially calcified soft tissue mass in the mediastinum, suggestive of malignancy. The result led to subsequent F-FDG PET/CT imaging, which demonstrated intense activity in the mediastinal mass and in multiple cervical, supraclavicular, and mediastinal lymph nodes. Hodgkin lymphoma was diagnosed histopathologically following the biopsy.
The relationship among physical activity, QOL and self-efficacy of perioperative patients with gastric cancer
Authors: Masako Shomura, Emi Nakagawa, Kenji Nakamura, Kazuhito Nabeshima, Ryuji Kitazawa, Noriko Itou, Jun Tanaka, Midori Iso, Atsuko Otsuka, Yukiko Dozono
Journal: Annals of Oncology (2015)
Safety, pharmacokinetics, and preliminary activity of the α-specific PI3K inhibitor BYL719: Results from the first-in-human study.
Authors: Ana M. Gonzalez-Angulo, Dejan Juric, Guillem Argilés, Jan HM Schellens, Howard A. Burris, Jordan Berlin, Mark R. Middleton, Martin H. Schuler, Robin Van Geel, Thorunn Helgason, Douglas Bootle, Markus Boehm, Timothy K. Goggin, David Demanse, Cornelia Quadt, Jose Baselga
Journal: Journal of Clinical Oncology (2013)

2531 Background: BYL719 is an oral small-molecule inhibitor of the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which is encoded by the PIK3CA gene, one of the most commonly mutated genes in human cancers. BYL719 inhibits proliferation of PI3Kα-driven cancer cell lines in vitro and causes regression of PIK3CA-mutant tumor models in vivo. Methods: This Ph I study was performed in patients (pts) with advanced solid tumors carrying a somatic mutation of PIK3CA. Dose escalation used an adaptive Bayesian logistic regression model with overdose control. Following determination of the maximum tolerated dose (MTD), an expansion cohort was opened at the MTD to evaluate safety, pharmacokinetics (PK), and clinical activity in pts with PIK3CA-mutant advanced solid tumors, including estrogen receptor-positive (ER+) metastatic breast cancer (mBC). Results: During dose escalation 36 pts received doses up to 450 mg/d, where 4/9 pts had dose-limiting toxicities (DLTs). The MTD for once-daily dosing was declared as 400 mg/d. As of Nov 20 2012, DLTs were hyperglycemia, nausea, vomiting, and diarrhea. The most common BYL719-related adverse events (all grades, all cohorts, &gt;25%) were hyperglycemia (49%), nausea (45%), diarrhea (40%), decreased appetite (38%), vomiting (30%), and fatigue (27%). 39 pts are enrolled in the MTD dose-expansion cohort. Investigation of a twice-daily regimen is also ongoing. BYL719 has a favorable, approximately dose-proportional PK profile with a T max of 2h and a T ½ of 11h at the MTD. Partial responses were seen in 7 pts (in ER+ breast [2], cervical, trichilemmal, endometrial, ovarian, and head &amp;neck cancer [1 each]); 17 pts stayed on study for &gt;24 weeks. For 67 pts (76%) treated at doses of ≥270 mg/d, the median progression-free survival (mPFS) was 3.6 months (mo; 95% CI: 3.5–5.5 mo). mPFS in 15 ER+ HER2– mBC pts treated at ≥270 mg/d was 5.5 mo (95% CI: 3–7 mo). Conclusions: BYL719 displays dose-proportional and predictable PK. The safety profile is favorable, with mostly manageable on-target toxicities. At doses of ≥270 mg/d, tumor regression and prolonged disease control were observed in heavily pretreated pts with various tumor types carrying a PIK3CA mutation. Clinical trial information: NCT01219699.
Use of imaging studies for early-stage breast cancer at Cleveland Clinic.
Authors: Sanghee Hong, Leticia Varella, Katherine Tullio, Halle C. F. Moore, G. Thomas Budd, Stephen R. Grobmyer, Alberto J. Montero, Gary Schnur, Jame Abraham
Journal: Journal of Clinical Oncology (2016)

e18217 Background: Use of staging imaging (SI), including CT, PET and bone scans, is not routinely recommended in stage I-IIA breast cancer patients (ESBCP) in the absence of signs or symptoms of metastatic disease. Consistent with NCCN guidelines, the evidence-based Care Path developed at our institution discourages routine SI in this population. We reviewed the use of SI in ESBCP before and after implementation of Care Path. Methods: An IRB-approved retrospective review of newly diagnosed ESBCP seen at Cleveland Clinic between January 2013 and June 2015 was performed based on institutional cancer database. JMP10 was used for statistical analysis. All p-values were 2-sided. Results: We identified 345 ESBCP seen between January 2013 and December 2014 as the pre-Care Path group (Pre-CP) and 246 ESBCP seen between July 2014 and June 2015 as the post-Care Path group (Post-CP). We excluded 6 patients in each group due to ambiguity in the purpose of SI. Median age was 62 in the Pre-CP and 63 in the Post-CP; > 99% were female in both cohorts; most were stage IA in both cohorts. SI was performed in 19% of patients in Pre-CP and 16% of Post-CP. Only 8% of patients in Pre-CP (N = 26) and 6% in Post-CP (N = 12) had SI judged as “routine.” Specific indications included the presence of symptoms or lab abnormalities (4% in Pre-CP; 6% in Post-CP), follow-up of abnormal imaging studies done prior to diagnosis or after breast MRI (5% in Pre-CP; 2% in Post-CP), other indicated cancer screening/staging of concurrent cancer (1% in both groups), and surgical indications besides pre-surgical planning (1% in Pre-CP; < 1% in Post-CP). There were no statistical differences in SI between Pre-CP and Post-CP. Of SI done “routinely,” 11% (N = 4) had positive findings, all of which were later found to be false-positives. In total, 20% (N = 12) of imaging studies done for other indications were abnormal, with 17% (N = 2) of these abnormal findings confirmed as metastatic breast cancer. Conclusions: Our results support continued use of current imaging guidelines. The use of imaging studies for staging in ESBC was appropriately low before and after the implementation of Care Path in our institution, reflecting good compliance with current guidelines.
Animals in Research
Authors: B. Greenwold
Journal: JAMA (1988)

<h3>To the Editor.—</h3> As a physician in an academic institution, I feel compelled to offer a different perspective on animals in research from that of the commentary by Drs Smith and Hendee.<sup>1</sup>I want to clarify the pound seizure issue and to respond to the article's stated objective of organizing everyone from members of medical societies to patients to thwart animal protectionists' efforts before they jeopardize the health of mankind. Ninety percent of laboratory research animals are rodents, rabbits, and other small animals. Since dogs and cats make up less than 1% of research animals, the fate of animal research clearly doesn't hinge on their use. That research would be curtailed because of the much higher expense of buying dogs from breeders instead of from the pound is false. Pound-seizure advocates purposely underestimate the price of a pound animal and overestimate that of a dog bought from a dealer
Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide
Authors: Michael Wahl, Joanna J. Phillips, Annette M. Molinaro, Yi Lin, Arie Perry, Daphne A. Haas-Kogan, Joseph F. Costello, Manisha Dayal, Nicholas Butowski, Jennifer L. Clarke, Michael Prados, Sarah Nelson, Mitchel S. Berger, Susan M. Chang
Journal: Neuro-Oncology (2016)

Optimal adjuvant management of adult low-grade gliomas is controversial. Recently described tumor classification based on molecular subtype has the potential to individualize adjuvant therapy but has not yet been evaluated as part of a prospective trial. Patients aged 18 or older with newly diagnosed World Health Organization grade II low-grade gliomas and gross residual disease after surgical resection were enrolled in the study. Patients received monthly cycles of temozolomide for up to 1 year or until disease progression. For patients with available tissue, molecular subtype was assessed based upon 1p/19q codeletion and isocitrate dehydrogenase-1 R132H mutation status. The primary outcome was radiographic response rate; secondary outcomes included progression-free survival (PFS) and overall survival (OS). One hundred twenty patients were enrolled with median follow-up of 7.5 years. Overall response rate was 6%, with median PFS and OS of 4.2 and 9.7 years, respectively. Molecular subtype was associated with rate of disease progression during treatment (P<.001), PFS (P=.007), and OS (P<.001). Patients with 1p/19q codeletion demonstrated a 0% risk of progression during treatment. In an exploratory analysis, pretreatment lesion volume was associated with both PFS (P<.001) and OS (P<.001). While our study failed to meet the primary endpoint for objective radiographic response, patients with high-risk low-grade glioma receiving adjuvant temozolomide demonstrated a high rate of radiographic stability and favorable survival outcomes while meaningfully delaying radiotherapy. Patients with 1p/19q codeletion are potential candidates for omission of adjuvant radiotherapy, but further work is needed to directly compare chemotherapy with combined modality therapy.
The survival outcome after hepatic resection in patients with liver metastasis from gastric cancer.
Authors: Taichi Tatsubayashi, Yuichiro Miki, Wataru Takagi, Fumiko Hirata, Hayato Omori, Shinsaku Honda, Rie Makuuchi, Masanori Tokunaga, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Masanori Terashima
Journal: Journal of Clinical Oncology (2015)

161 Background: Optimal treatment strategy for patients with liver metastasis from gastric cancer (LMGC) has not yet been established. Although systemic chemotherapy remains mainstay of treatment for LMGC, complete resection of primary tumor and LMGC may improve survival outcome. Thus, the aim of this study is to investigate survival outcome and prognostic factors of patients who underwent hepatic resection for LMGC. Methods: From September 2002 to February 2014, 30 patients underwent hepatic resection for LMGC in our hospital. Indications of hepatic resection were as follows; (1) hepatic lesion is not more than three, (2) without extrahepatic metastasis other than lymph node metastasis, (3) adequate liver function. We investigated the overall median survival time (MST) and 5-year survival rate of all eligible patients. Univariate and multivariate analyses were performed to assess the association between each clinicopathological features and overall survival time. Results: There were 25 males and 5 females with a median age of 72 (range, 39-86). There were 16 synchronous LMGCs and 14 metachronous LMGCs. With respect to the number of LMGC, 22 patients had 1 lesion, 7 patients had 2 lesions, and 1 patient had 3 lesions. Overall MST and 5 year survival rates after hepatic resection were 2.8 years and 31.0%, respectively. The significant prognostic factors were age (70 years or older, p=0.029) and blood transfusion (p=0.013). Multivariate analysis showed that lymph node metastasis was an only independent indicator of poor prognosis (HR=6.13, p=0.026). Conclusions: Hepatic resection for patients with LMGC might be a promising treatment strategy, with 5-year survival rate of 31.0%. Lymph node metastasis was an only independent prognostic factor. A multi-institutional confirmatory study will be required to evaluate the role of hepatic resection in patients with LMGC.
Abstract LB-002: A novel c-Met/EGFR bispecific targeting antibody drug conjugate for NSCLC
Authors: Gang Chen, Lingna Li, Pia Muyot, Edwige Gros, Yanliang Zhang, Yingqing Sun, Hong Zhang, Yanwen Fu, Alice Lee, Jian Cao, Gunnar Kaufmann, Zhenwei Miao
Journal: Cancer Research (2015)

Abstract c-Met and EGFR are both widely and highly expressed, share and cross talk common signaling pathways in a variety of carcinomas including lung, breast, ovary, kidney, colon, thyroid, liver, and gastric carcinomas. Therapeutics like tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, targeting EGFR and c-Met are on the cutting-edge of cancer therapy. In preclinical studies and clinical trials, though these anti-c-Met and EGFR therapeutics showed promising anti-tumor activities but usually not sufficient for sustained treatment efficacy, their individual efficacies are limited due to the development of resistance. c-Met amplification has been considered to be a major escape route for EGFR-targeted therapies. We believe that antibody drug conjugates (ADCs) offer the promise and potential of delivering potent anti-tumor activity with the advantage of reduced side effects. We generated a novel bispecific antibody drug conjugate containing a proprietary human anti-c-Met antibody and anti-EGFR antibody, and a potent toxin by our novel C-lock conjugation method. The conjugate retained high binding affinity and targeting both c-Met and EGFR on tumor cell surface. The ADC showed potent cell killing in a lower nM range in a variety of c-Met and EGFR positive cell lines in vitro and strong in vivo anti-tumor efficacy in several c-Met and EGFR positive human NSCLC xenograft models without significant toxicity. The in vivo anti-tumor growth efficacy of bispecific c-Met/EGFR targeting antibody conjugates is superior to either single anti-c-Met or EGFR ADC. Citation Format: Gang Chen, Lingna Li, Pia Muyot, Edwige Gros, Yanliang Zhang, Yingqing Sun, Hong Zhang, Yanwen Fu, Alice Lee, Jian Cao, Gunnar Kaufmann, Zhenwei Miao. A novel c-Met/EGFR bispecific targeting antibody drug conjugate for NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-002. doi:10.1158/1538-7445.AM2015-LB-002
Error in Medicine
Authors: Fredrick K. Orkin
Journal: JAMA (1995)

<h3>To the Editor.</h3> —While noting that anesthesiology is the only specialty that has focused on and been successful in reducing errors in medicine, Dr Leape<sup>1</sup>misrepresents the temporal aspects of the improvement. Specifically, he writes, "Whereas mortality from anesthesia was one in 10 000 to 20 000 just a decade or so ago, it is now estimated at less than one in 200 000," citing my technology assessment of newer approaches to patient monitoring during anesthesia.<sup>2</sup>The improvement actually occurred over several decades, approaching the rate of one in 200 000 by the mid 1980s (Figure 1), just before standards for patient monitoring during anesthesia were promulgated by the specialty. It is doubtful that the efficacy of the anesthesia-monitoring standards can be proven because demonstrating changes in the preexisting low rates of severe adverse events (cardiac arrest and brain damage as well as death) due primarily to anesthetic
MicroRNA-21 Lowers Blood Pressure in Spontaneous Hypertensive Rats by Upregulating Mitochondrial Translation
Authors: Huaping Li, Xiaorong Zhang, Feng Wang, Ling Zhou, Zhongwei Yin, Jiahui Fan, Xiang Nie, Peihua Wang, Xiang-Dong Fu, Chen Chen, Dao Wen Wang
Journal: Circulation (2016)

BACKGROUND: Excessive reactive oxygen species generated in mitochondria has been implicated as a causal event in hypertensive cardiomyopathy. Multiple recent studies suggest that microRNAs (miRNAs) are able to translocate to mitochondria to modulate mitochondrial activities, but the medical significance of such a new miRNA function has remained unclear. Here, we characterized spontaneous hypertensive rats (SHRs) in comparison with Wistar rats, finding that micro RNA-21 (miR-21) was dramatically induced in SHRs relative to Wistar rats. We designed a series of experiments to determine whether miR-21 is involved in regulating reactive oxygen species generation in mitochondria, and if so, how induced miR-21 may either contribute to hypertensive cardiomyopathy or represent a compensatory response. METHODS: Western blotting was used to compare the expression of key nuclear genome (nDNA)–encoded and mitochondrial genome (mtDNA)–encoded genes involved in reactive oxygen species production in SHRs and Wistar rats. Bioinformatics was used to predict miRNA targets followed by biochemical validation using quantitative real-time polymerase chain reaction and Ago2 immunoprecipitation. The direct role of miRNA in mitochondria was determined by GW182 dependence, which is required for miRNA to function in the cytoplasm, but not in mitochondria. Recombinant adeno-associated virus (type 9) was used to deliver miRNA mimic to rats via tail vein, and blood pressure was monitored with a photoelectric tail-cuff system. Cardiac structure and functions were assessed by echocardiography and catheter manometer system. RESULTS: We observed a marked reduction of mtDNA-encoded cytochrome b (mt-Cytb) in the heart of SHRs. Downregulation of mt-Cytb by small interfering RNA in mitochondria recapitulates some key disease features, including elevated reactive oxygen species production. Computational prediction coupled with biochemical analysis revealed that miR-21 directly targeted mt-Cytb to positively modulate mt-Cytb translation in mitochondria. Circulating miR-21 levels in hypertensive patients were significantly higher than those in controls, showing a positive correlation between miR-21 expression and blood pressure. Remarkably, recombinant adeno-associated virus–mediated delivery of miR-21 was sufficient to reduce blood pressure and attenuate cardiac hypertrophy in SHRs. CONCLUSIONS: Our findings reveal a positive function of miR-21 in mitochondrial translation, which is sufficient to reduce blood pressure and alleviate cardiac hypertrophy in SHRs. This observation indicates that induced miR-21 is part of the compensatory program and suggests a novel theoretical ground for developing miRNA-based therapeutics against hypertension.
Phase I/II study of S49076, a multi-target inhibitor of c-MET, AXL, FGFR in combination with bevacizumab in patients with recurrent glioblastoma.
Authors: Khe Hoang-Xuan, Andreas Hottinger, Louis Royer-Perron, Agusti Alentorn, Julien Savatovsky, Rita De Micheli, Krisztian Homicsko, Sebastien Banquet, Jeanne Pauly, Isabelle Sudey, Roger Tell, Patrick Therasse, Maryline Barrie, Chantal Campello, Olivier L. Chinot
Journal: Journal of Clinical Oncology (2016)

2033 Background: There is no standard of care for the treatment of recurrent GBM (rGBM) and more effective treatments are clearly needed. S49076 is an orally bioavailable multikinase inhibitor of MET, AXL, FGFR1, 2, 3. The ability of S49076 to inhibit tumor growth in vivo was showed in a xenograft mouse model resistant to bevacizumab (BEV). Here, we report data from an ongoing Phase I study of S49076 in combination with BEV at first recurrence. Methods: Patients (pts) received escalating doses from 400 to 600 mg of S49076 orally, on a continuous once daily schedule of 28-day cycle, with BEV 10mg/kg on days 1 and 15. Primary objectives were to determine the Maximum Tolerated Dose (MTD), the Dose Limiting Toxicities (DLT) and to establish the Recommended Phase II Dose (RP2D) of S49076+BEV. Secondary objectives included pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity (assessed every each cycle using RANO criteria). Results: Thirteen rGBM pts were included. Overall 75% (9/12) were male, median age was 56 years (range 34-70), and median KPS was 90 (range 70-100). Three pts were respectively treated at the dose levels 400 mg and 500 mg and 6 patients at 600 mg (due to 1 DLT observed; G3 asymptomatic ejection fraction decrease). This dose level was considered as the RP2D. The reported adverse events (AE) related to S49076 were mainly of G1 or G2 (2 AE ≥ G3). No grade 5 S49076 and/or BEV related AE has been observed. Best responses for the 12 evaluable pts were: 4 partial responses (PR) confirmed and 2 unconfirmed, 5 stable disease (SD) including 2 SD ≥ 3 months, and 1 progressive disease. Similar S49076 PK profile in combination to BEV has been observed in the first-in-human study where S49076 was used in monotherapy. PD results showed high and moderate MET amplification assessed by FISH in 2 pts which were not predictive of clinical response. No expression of MET and AXL were observed by immunohistochemistry (IHC) in any of the pts. Conclusions: The combination of BEV and S49076 has been well tolerated at the dose levels tested. These preliminary data does not suggest an increase of activity by adding S49076 to BEV. Clinical trial information: 2013-003079-37.
Unusual Uptake of Radioiodine in a Subcutaneous Lipoma in a Patient With Differentiated Thyroid Cancer
Authors: Guohua Shen, Xiaolin Jing, Yuan Zhang, Anren Kuang, Rui Huang
Journal: Clinical Nuclear Medicine (2016)

A 68-year-old man underwent adjuvant radioiodine therapy for follicular variant papillary thyroid carcinoma. Post-therapeutic whole-body 131I scan showed abnormal radioiodine uptake on the right side of back. SPECT/CT localized this abnormal activity from a small subcutaneous lesion with fat density between the right 10th and 11th rib. Under ultrasound-guided autopsy, the lesion was confirmed as lipoma.
Effect of One Week of 8-Hour Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea on Glycemic Control in Type 2 Diabetes: A Proof-of-Concept Study
Authors: Babak Mokhlesi, Daniela Grimaldi, Guglielmo Beccuti, Varghese Abraham, Harry Whitmore, Fanny Delebecque, Eve Van Cauter
Journal: American Journal of Respiratory and Critical Care Medicine (2016)