tbuckley/cabot-search huggingface dataset:
Effect of the 92-gene molecular classifier on therapeutic decision-making in cancers of uncertain primary.
Authors: Brock Schroeder, Catherine A. Schnabel, Mark G. Erlander, Benjamin Kim
Journal: Journal of Clinical Oncology (2013)

e15130 Background: Patients with metastatic cancer of uncertain primary site are at risk of suboptimal therapy if tumor type and subtype cannot be determined. Gene expression-based assays for tumor classification are utilized to complement clinicopathologic evaluation in cases with unknown primary sites of tumor origin or differential diagnoses; however, few studies have evaluated their clinical utility and effectiveness in real-world practice. The objective of this study was to evaluate the influence of a 92-gene molecular classification assay on clinical diagnosis and therapeutic decision-making. Methods: Medical oncologists who ordered the 92-gene assay as part of clinical care were invited to participate in a retrospective, questionnaire-based study. To minimize selection and recall biases, recruitment was based on consecutive cases: participating physicians were instructed to review the medical record of the first patient they ordered the 92-gene assay after a specified date and subsequently complete a 61-question survey. Results: Of 1,105 physicians invited, 103 (9.4%) completed the study (82% community practice; median practice time: 10 years). The majority of respondents had not initiated oncologic treatment before ordering the 92-gene assay: 31% had begun treatment, 24% had a specific regimen chosen but were waiting to begin treatment and 45% had not begun treatment or chosen a specific regimen. The 92-gene assay prediction was concordant with the final clinical diagnosis in 84% of cases; in one-third of these, the molecular diagnosis had not been clinically considered prior to molecular testing. Eighty-one percent of study participants reported that the 92-gene assay helped with therapeutic decision-making. Of these, the assay guided initial treatment choice in 52%, changed a considered treatment in 10%, excluded a potential treatment in 6%, and confirmed a previously determined treatment in 29% of cases. Conclusions: The results of this retrospective study demonstrate the clinical utility of molecular cancer classification: the molecular diagnoses provided by the 92-gene assay influenced therapeutic decision-making in the majority of cases.
Phase II study of mFOLFOX with bevacizumab (Bev) in metastatic gastroesophageal and gastric (GE) adenocarcinoma (AC).
Authors: Jia Li, Jeremy S. Kortmansky, Neal A. Fischbach, Stacey Stein, Xiaopan Yao, Howard S. Hochster, Jill Lacy
Journal: Journal of Clinical Oncology (2013)

4084 Background: The median survival for patients (pts) with metastatic GE AC in phase III studies is &lt;12 mos. Bev has demonstrated promising activity in metastatic GE AC when used in combination with cisplatin-based regimens in studies with patients from the Americas. We conducted a prospective phase II trial to investigate the efficacy of Bev in combination with mFOLFOX6 in pts with metastatic GE AC. Methods: Pts with previously untreated metastatic GE AC (gastric, GE junction, distal esophagus) received mFOLFOX6 (LV 400 mg/m 2 , 5-FU 400 mg/m 2 bolus and 2400 mg/m 2 over 46 hr continuous infusion, Ox 85 mg/m 2 ) and Bev 10 mg/kg q 2 wks. Response by RECIST was evaluated by CT q 8 wks. Primary objective was time to progression (TTP); secondary objectives were safety, response rate (RR), and overall survival (OS). Results: 39 pts were enrolled between 09/08 and 06/12. Pt characteristics are as follows: median age, 59 yo (range 27-79); M/F, 31/8; ECOG PS 0/1, 11/28; gastric/distal E and GEJ, 13/26; metastatic sites: lymph nodes 23, liver 19, lung 9, peritoneum 9; &gt;2 metastatic sites, 20; prior gastrectomy or esophagectomy, 7. Nine pts remain on study, and 15 pts are alive. Median # of cycles administered is 11 (range 4 - &gt;31). RR is 56.4% (4 CR, 18 PR). Median TTP is 8.2 mos. Median OS is 15.2 mos. Three pts survived &gt;24 mos. Grade 3/4 toxicities include neutropenia (13, 33.3%), neuropathy (8, 20.5%), DVT/PE (5, 12.8%), thrombocytopenia (3, 7.7%), anemia (1, 2.6%), hypertension (1, 2.6%), and proteinuria (1, 2.6%). We observed no GI perforations or grade 3/4 GI hemorrhagic events. Conclusions: FOLFOX6/Bev is well tolerated and associated with increased TTP and OS in pts with metastatic GE AC compared to historical data from similar populations treated without Bev. Our findings validate previous studies with Bev in combination with cisplatin-based regimens in pts from the Americas with metastatic GE AC. This study is supported by Genentech. Clinical trial information: NCT00673673.
Design of Noninferiority Trials for Hypofractionated vs Conventional Radiotherapy Among Patients With Cancer
Authors: Guosheng Yin, Zachary R. McCaw
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Corticospinal circuit remodeling after central nervous system injury is dependent on neuronal activity
Authors: Peter M. Bradley, Carmen K. Denecke, Almir Aljovic, Anja Schmalz, Martin Kerschensteiner, Florence M. Bareyre
Journal: The Journal of Experimental Medicine (2019)

The remodeling of supraspinal axonal circuits mediates functional recovery after spinal cord injury. This process critically depends on the selection of appropriate synaptic connections between cortical projection and spinal relay neurons. To unravel the principles that guide this target selection, we used genetic and chemogenetic tools to modulate NMDA receptor (NMDAR) integrity and function, CREB-mediated transcription, and neuronal firing of relay neurons during injury-induced corticospinal remodeling. We show that NMDAR signaling and CREB-mediated transcription maintain nascent corticospinal tract (CST)-relay neuron contacts. These activity-dependent signals act during a defined period of circuit remodeling and do not affect mature or uninjured circuits. Furthermore, chemogenetic modulation of relay neuron activity reveals that the regrowing CST axons select their postsynaptic partners in a competitive manner and that preventing such activity-dependent shaping of corticospinal circuits limits motor recovery after spinal cord injury.
Letter to the Editor: Prevalence of NAFLD in China: What Did We Learn From the Recent Meta‐Analysis?
Authors: Yuankai Wu, Yee Hui Yeo, Mindie H. Nguyen, Ramsey C. Cheung
Journal: Hepatology (2019)

Potential conflict of interest: Dr. Cheung received grants from Gilead. Dr. Nguyen has advised and received research grants from Bristol‐Myers Squibb, Janssen, and Gilead. She has advised Laboratory for Advanced Medicine, Exact Sciences, Intercept, Alnylam, Novartis, Eisai, Bayer and Spring Bank. She has received grants from the NCI and the B. K. Kee Foundation. To The Editor: We would like to congratulate Zhou et al.1 for performing the largest meta‐analysis to date on nonalcoholic fatty liver disease (NAFLD) in China. However, we have several concerns with their findings because of the methods they used to determine and report the prevalence. First, several of the more recent studies included in the meta‐analysis consisted only of patients without other liver disease. Prevalence of NAFLD in these studies is in the population without chronic hepatitis B and C and alcoholic liver disease, all of which are common liver diseases in China (7.18%,2 3.20%,2 and 4.34%‐11.11%,3 respectively). This can contribute to the higher prevalence in more recent years. Similarly, some of the studies included only highly selected populations (e.g., ethnic minority, male only), which again were not representative of the general population. Second, although study period data were included in the supporting table, the authors reported the prevalence according to the year of publication and not the study period (Table 1 in Zhou et al.). For example, reference 139 was published in 2015, but the prevalence of NAFLD was actually that of 2008 during entry into the study. This led to misclassification, and the conclusion that “the prevalence rapidly increased from 25.4% in 2008‐2010 to 32.3% in 2015‐2018” may not be supported by the results of this study analysis. The authors made no attempt to stratify the prevalence based on the actual study period. Third, the authors investigated the relationship between regional gross domestic products (GDPs) per capita and prevalence of NAFLD. The source of the GDPs was not explained in the paper, but it is likely that these values were the GDPs from a recent year without any adjustment. During the last two decades, China has experienced very rapid and uneven economic progress. For example, the regional GDPs per capita of Anhui and Guangxi provinces in 2005 were ¥8,670 (US $1,060) and ¥8,788 (US $1,074), respectively, but in 2017 the former (¥43,401 [US $6,425]) surpassed the latter (¥38,102 [US $5,640]).4 Therefore, analysis of NAFLD by regional GDP should be performed according to regional GDPs during the study period, including inflation, to more accurately reflect the association. Finally, the reported prevalence included data from duplicate or overlapping studies, which is against the conventional principle of meta‐analysis. For example, both references 163 and 261 were from the same cohort with the same study period (2011‐2012) and hence had almost identical numbers of subjects (7,893 and 7,896, respectively).
Prognostic implications of perineural invasion following radical cystectomy for urothelial carcinoma.
Authors: Manoj Rao, Ted Vellos, Guliz Barkan, Gopal Nand Gupta, Robert Charles Flanigan, Marcus Lee Quek
Journal: Journal of Clinical Oncology (2012)

e15014 Background: Perineural invasion(PNI) with urothelial carcinoma may be identified in radical cystectomy specimens, and its prognostic significance is controversial. We sought to determine the incidence and prognostic implications of PNI in a cohort of patients undergoing radical cystectomy for primary bladder cancer. Methods: From January 1996 to June 2011, 440 patients underwent radical cystectomy for urothelial bladder cancer with curative intent. Presence of PNI was determined in the cystectomy specimens, in addition to other histopathologic variables (grade, stage, surgical margins, lymphovascular invasion, concomitant variant secondary histologic subtypes, and presence of carcinoma-in-situ). Recurrence and survival data were analyzed to determine the prognostic significance of PNI in this cohort. Results: PNI was identified in 101 patients (23%) in our series. Those with extravesical primary tumors (61/128, 48%) and node-positive disease (34/86, 40%) were more likely to have PNI than organ-confined tumors (&lt;pT2; 10/183, 5%) (p&lt;0.001). Median follow-up was 2 years (range: 0.1 to 12.5 years). Compared to those with no evidence of PNI, recurrence-free survival was worse in the PNI-positive extravesical (p=0.01) and node-positive (p=0.02) tumors. Overall survival was also worse for PNI-positive patients (p&lt;0.001). On multivariate analysis, PNI was an independent risk factor for recurrence after radical cystectomy (p=0.01, RR=2.8: 95% CI 2.0-10.0). In the setting of PNI, adjuvant chemotherapy significantly improved overall survival(p=0.01). When analyzing PNI and lymphovascular invasion(LVI), there appears to be a worse recurrence-free survival for those who have both PNI and LVI than those with either alone(p&lt;0.001). Conclusions: PNI with urothelial carcinoma may be associated with a worse prognosis, especially for extravesical and node-positive disease following radical cystectomy. Adjuvant chemotherapy may benefit those patients who have PNI. Patients who have both PNI and LVI may be at higher risk for disease recurrence.
Concomitant Prostate Carcinoma and Follicular Lymphoma
Authors: Nattakorn Dhiantravan, Elizabeth Hovey, Annmarie Bosco, Eva Alina Wegner
Journal: Clinical Nuclear Medicine (2019)

Abstract We report a case of a 75-year-old man with concomitant metastatic prostate cancer and progressive follicular lymphoma and the utility of molecular imaging in differentiating these 2 conditions. 18 F-FDG PET/CT can offer accurate staging in many cancers, although its role in prostate cancer is limited. The role of 18 F-DCFPyL (PSMA) PET/CT in prostate cancer is evolving and has been demonstrated to have a higher sensitivity than conventional bone scan and CT scan. Together, FDG and PSMA PET/CT studies may offer a noninvasive approach to individually characterize concomitant malignancies, aiding optimization of management and follow-up.
Respiratory syncytial virus (RSV): a scourge from infancy to old age
Authors: James Andrew Coultas, Rosalind Smyth, Peter J Openshaw
Journal: Thorax (2019)

Respiratory syncytial virus (RSV) is the most common single cause of respiratory hospitalisation of infants and is the second largest cause of lower respiratory infection mortality worldwide. In adults, RSV is an under-recognised cause of deterioration in health, particularly in frail elderly persons. Infection rates typically rise in late autumn and early winter causing bronchiolitis in infants, common colds in adults and insidious respiratory illness in the elderly. Virus detection methods optimised for use in children have low detection rate in adults, highlighting the need for better diagnostic tests. There are many vaccines under development, mostly based on the surface glycoprotein F which exists in two conformations (prefusion and postfusion). Much of the neutralising antibody appears to be to the prefusion form. Vaccines being developed include live attenuated, subunit, particle based and live vectored agents. Different vaccine strategies may be appropriate for different target populations: at-risk infants, school-age children, adult caregivers and the elderly. Antiviral drugs are in clinical trial and may find a place in disease management. RSV disease is one of the major remaining common tractable challenges in infectious diseases and the era of vaccines and antivirals for RSV is on the near horizon.
A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing
Authors: Ye Cao, Mari J. Tokita, Edward S. Chen, Rajarshi Ghosh, Tiansheng Chen, Yanming Feng, Elizabeth Gorman, Federica Gibellini, Patricia A. Ward, Alicia Braxton, Xia Wang, Linyan Meng, Rui Xiao, Weimin Bi, Fan Xia, Christine M. Eng, Yaping Yang, Tomasz Gambin, Chad Shaw, Pengfei Liu, Pawel Stankiewicz
Journal: Genome Medicine (2019)

Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort.
Abstract P284: The Prospective Association Between Unprocessed Meat Consumption and Incident Cardiovascular Disease in Korean Adults
Authors: Kyong Park, Jakyung Son, Jiyoung Jang, Hye-Kyung Chung, Ryungwoo Kang, Kyong Won Lee, Min-Jeong Shin
Journal: Circulation (2017)

Introduction: Cumulative evidence has shown that total meat consumption is associated with the risk of cardiovascular disease (CVD) in Western societies. However, epidemiological information is limited regarding such associations in the Korean population whose consumption level of meat is much lower than the global average. Hypothesis: We hypothesized that higher intake levels of unprocessed total meat would not increase the overall risk of CVD incidence, and healthier alternatives to red meat (such as poultry) would have protective effects in middle-aged Korean population. Methods: Ansung-Anasan cohort 2001-12 analyses were conducted from 2001 to 2012 among 9,370 adults, aged 40-69 years, without CVD or cancer at baseline, from two communities, Ansan (urban) and Ansung (rural). Dietary information was ascertained at baseline and at the second follow-up visit. Total meat consumption was estimated as the sum of unprocessed red meat (sum of beef, pork, and organ meat) and chicken consumption. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: During a median follow-up of 7.8 years, 486 incident CVD cases were identified. In the fully adjusted Cox regression model, relative risks of CVD across increasing quintiles of total meat intake were 1.0 (reference), 0.72 (95% CI 0.55-0.95), 0.57 (95% CI 0.42-0.78), 0.69 (95% CI 0.51-0.95), and 0.69 (95% CI 0.48-0.97). Regarding specific types of meat, frequent chicken consumption was significantly associated with decreased risks of CVD, showing participants in the highest quintile of chicken intake were 1.5 times less likely to develop CVD than those in the lowest quintile (95% CI: 0.47-0.99), and this association showed a dose-response relationship for all statistical models ( P for trend &lt;0.05). Conclusion: Higher intakes of unprocessed total and red meat showed inverse associations with incident CVD in a large, prospective, population-based cohort study of middle-aged Koreans. These findings require further confirmation from other populations whose meat intake is relatively lower than the global average.
A phase II study of carboplatin (C) and weekly paclitaxel (P) with a selective cyclooxygenase-2 (COX-2) inhibitor, meloxicam, in advanced non-small cell lung cancer (NSCLC)
Authors: R. Suzuki, M. Yamamoto, H. Saka, H. Taniguchi, J. Shindo, Y. Tanikawa, S. Nomura, T. Oishi, Y. Hasegawa, K. Shimokata
Journal: Journal of Clinical Oncology (2007)

18007 Background: COX-2 overexpression is seen in many malignancies including lung cancer. Recent pre-clinical studies have shown that selective COX-2 inhibitors have demonstrated promising results when used with chemotherapy. Based on these observations, we are assessing the efficacy and tolerability of the combination chemotherapy consisting of C and P with meloxicam, a selective COX-2 inhibitor. Methods: Patients with stage IIIB or IV, ECOG PS 0 or 1, who had adequate organ function, were eligible. Patients received P 70 mg/m 2 weekly for 3 of 4 weeks with C (AUC 6) on day 1, as well as daily meloxicam (10 mg/day). Response rate was the primary endpoint. Secondary endpoints were overall survival, toxicity profile and QOL (Using EORTC QLQ-C30 and LC13). Results: From March 2005 until September 2006, forty-four patients were evaluated in this study. Gender M/F; 31/13, median age; 64 yr (range, 34–75), stage IIIB/IV; 11/33, PS0/1; 22/22, histology Ad/Sq/Others; 29/6/9. Partial response was observed in 19 patients (43%), and no complete response, yielding an overall response rate of 43% (95% confidence interval, 28.5%-57.8%). Nineteen patients (43%) had stable disease. Seven patients (16%) had grade (G) 3 and three (7%) had G4 neutropenia. Three patients (7%) had G3 thrombocytopenia. As for non-hematological toxicities, one G4 toxicity (perforation of jejunum) was observed, but the other toxicities were mild (one muscle pain, 2 liver dysfunction, 1 fatigue and 1 nausea G3). Grade 2 peripheral neuropathy was observed in only one patient. Using EORTC QLO questioner, the global health status did not changed significantly during this therapy (before and 4 and 8 weeks later). Median follow-up was 9.6 months (range, 1.8–22.7 months). At the time of the final analysis (January 2007), 16 patients had died. The one-year survival rate was 70% and MST was not reached till now. Conclusions: Meloxicam in combination with C and weekly P chemotherapy showed promising activity with encouraging survival. This therapy is relatively well-tolerated in advanced NSCLC. No significant financial relationships to disclose.
Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles
Authors: Richard M. Meade, David P. Fairlie, Jody M. Mason
Journal: Molecular Neurodegeneration (2019)

Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). All diseases are determined by αS aggregate deposition but can be separated into distinct pathological phenotypes and diagnostic criteria. Here we attempt to reinterpret the literature, particularly in terms of how αS structure may relate to pathology. We do so in the context of a rapidly evolving field, taking into account newly revealed structural information on both native and pathogenic forms of the αS protein, including recent solid state NMR and cryoEM fibril structures. We discuss how these new findings impact on current understanding of αS and PD, and where this information may direct the field.