bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of novel fumarate hydratase gene alterations in prostate cancer.
Authors: Millis Sherri Z. , Marsh Sydney , Pecci Cristina , Boddupalli Sai-Sridhar , Ross Jeffrey S. , Stephens Phil , Miller Vincent A. , Ali Siraj Mahamed , Wang Jue 
Published: July 2017

11585 Background: Fumarate hydratase (FH), an enzyme involved in the Krebs cycle, plays a crucial role in the generation of energy and oxygenation of cells. Genomic alterations (GAs) of FH, a tumor suppressor gene, have been shown to cause chronic hypoxia that encourages tumor formation and have been linked to hereditary leiomyomatosis and renal cell cancer. Only few reports have associated FH mutations with other cancers, and none in prostate cancer. Methods: Identification of an FH V435M pathogenic alteration, which likely changes fumarate binding kinetics, in a prostate cancer patient, with negative family history for renal cancer and cutaneous leiomyomatosis, led to review of a database of 1781 prostate cancer patients, whose tissue was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling identified 49 prostate adenocarcinoma patients (3%) with FH gene alterations, 2 of which harbored the V435M GA identified in the original prostate patient. Ten of 40 alterations were H476_k477 insertions, in the C terminus domain, and 14 were amplifications. The rest were variants of unknown significance (VUS). Conclusions: A FH GA, known to impact other cancers, found in a prostate cancer, led to the discovery of a frequency that suggests deregulation of metabolic pathway activation may contribute to prostate cancer pathogenesis for a subset of patients. The somatic FH GA’s are likely to be substantially more common than germline mutations, and identifying metabolic-enzyme mutations that are pathogenic in prostate cancer could lead to pharmacologic manipulations that are more effective and less toxic than existing therapies. No FDA approved therapies currently exist for this patient’s tumor type nor of any other tumor type with FH GA’s. In our case, alterations in the C-terminal binding domain of FH might inform drug development.
A clinical and genomic profile of inflammatory myofibroblastic tumors.
Authors: Daniel Sugganth , Gay Laurie M. , Vergilio Jo-Anne , Ross Jeffrey S. 
Published: July 2017

1538 Background: Inflammatory Myofibroblastic Tumors (IMT) are tumors that morphologically traverse the neoplastic and inflammatory realms. With a predilection for children and young adults, many patients present with systemic symptoms and the tumors demonstrate local invasiveness and even metastasis. IMTs are composed of fascicles of myofibroblastic spindle cells with a marked lymphoplasmacytic infiltrate. Methods: Integrated genomic profiling of DNA and RNA from IMTs in 30 patients was performed using a hybrid capture, paired-end NGS sequencing method and customized pipeline analysis. Results: 23 patients were children or young adults ( < 30y), overall the age ranged from 7 months to 72 years. The tumor was clinically aggressive in 10 patients; 3 metastatic, 5 multifocal and 2 locally invasive. Epithelioid morphology was documented in 2 cases, one demonstrated the ALK-RANBP2 fusion. ALK rearrangements were detected in 13 patients, with 7 different fusion partners. ALK IHC or FISH was performed in 23 patients and were all concordant with the genomic results. 22 gene fusions were detected in 21 patients, 4 tumors had ROS1-TFG fusions, 2 had NTRK3-ETV6 fusions. 3 had novel fusions in JAK1-PML, PDGFRB-NOTCH1 and MUTYH-TESK2 respectively. Intact tyrosine kinase domains (TKD) in JAK1 are transposed to the promoter coiled-coil motif in PML, in the rearrangement. While the TKDs are preserved in the PDGRB and TESK2 rearrangements, the functional roles of their partners are yet to be elucidated. The prevalence of rearrangements was higher in patients below 30 years of age (20/23) compared to that above 30y (3/7). All 10 aggressive tumors were detected to have rearrangements. Conclusions: IMTs are seen predominantly in younger age groups. Gene rearrangements are seen more frequently in patients with younger age and also in more aggressive tumors, in a statistically significant manner. Alterations in genes associated with hematopoietic neoplasms such as JAK1 among others, are interesting, given the hematologic component of the lesion, and the presence of novel tyrosine kinase rearrangements warrant further investigations to elucidate mechanistic models.
Comprehensive genomic profiling (CGP) of advanced papillary renal cell carcinoma (PRCC) to reveal distinctions from TCGA dataset.
Authors: Pal Sumanta K. , Geynisman Daniel M. , Ali Siraj Mahamed , Yakirevich Evgeny , Stephens Phil , Ross Jeffrey S. , Miller Vincent A. , Chung Jon , Choueiri Toni K. 
Published: July 2017

4517 Background: Biologic characterization of PRCC by TCGA reveals alterations in MET in type 1 disease, and CDKN2Asilencing, SETD2 mutations and TFE3 fusions in type 2 disease. A limitation of TCGA data is that of 161 pts analyzed, 73% and 3% had M0 and M1 disease, respectively. We present the gene alterations (GA) identified in pts with advanced PRCC.Methods: FFPE tissue was obtained from 169 patients with PRCC. Diagnosis and PRCC subtyping was centrally confirmed by 2 board-certified pathologists. DNA was extracted and comprehensive genomic profiling (CGP) was performed (median coverage, 648X) in a CLIA-certified central laboratory. Results: Of 169 pts with advanced PRCC, 39 (23%) were type 1, 108 (64%) were type 2 and 22 (13%) were unclassified. 66 samples (39%) were from a metastatic site biopsy, and 103 were from the kidney (61%). An average of 2.4 GA/tumor were detected. In type 1 pts, commonly altered genes were MET (33%: 8 activating mutations, 5 amplifications), TERT (30%), CDKN2A/B (13%), and EGFR (8%). In type 2 pts, commonly altered genes were CDKN2A/B (18%), TERT (18%), NF2 (13%) and FH (13%); METGAs (5 mutations, 3 amplifications) were observed in 7.4% of type 2 pts. MET GA was significantly associated with type 1 PRCC (p = 0.0002) and NF2 GA and alterations in SWI/SNF complex genes were both significantly associated with type2 PRCC (p = 0.02 and p = 0.007, respectively). Overall, frequent alterations were found in genes involved in SWI/SNF complexes (25%), chromatin modification (23%) and cell cycle regulation (22%). RAS/RAF pathway (9%) and PI3K/mTOR pathway (8%). Notable differences with TCGA include higher frequencies of MET and NF2 GAs, association of GAs in the SWI/SNF with type 2 PRCC, and frequent CDKN2A/B alteration in both type 1 and type 2 disease. MET alteration was lower in metastases vs primary (type 1: 15% vs 38%; type 2: 4% vs 10%). Conclusions: In a cohort of PRCC patients slightly larger than the TCGA experience, key differences in CRGA frequency were observed. These likely underscore the marked difference in stage distribution between datasets. Results of this study may inform trials of relevant targeted therapy in metastatic PRCC.
NTRK1-3 point mutations in poor prognosis thyroid cancers.
Authors: Iniguez-Ariza Nicole M. , Bible Keith Christopher , Morris John C. , Chintakuntlawar Ashish V. , Shridhar Vijayalakshmi , Smallridge Robert C. , Menefee Michael E. , Hilger Crystal , Severson Eric Allan , Ryder Mabel M 
Published: July 2017

6087 Background: NTRK1-3 fusions, identified in pediatric radiation-associated thyroid cancers, are low frequency oncogenic drivers that can trigger constitutive activation of TrK1-3 tyrosine kinase domains with responsively heightened downstream signaling through RAS-MAPK, PI3K-AKT, and/or PLCγ-PKC. NTRK point mutations are rare and of largely uninvestigated oncogenic potential, but some appear oncogenic. Methods: Advanced thyroid cancer (TC) patients (pts) requiring systemic therapy at Mayo Clinic sites underwent tumor genetic interrogation using Foundation One analyses with the goal of informing salvage therapeutic strategies. In this IRB-approved study, data from pts with TCs bearing NTRK point mutations were retrospectively analyzed, as this occurrence was unexpected but potentially of prognostic and/or therapeutic relevance. Results: Five of 55 pts (9%) with advanced TCs subject to Foundation One tumor interrogation had NTRK1-3 point mutations (allele frequency, AF, 15-49%); none had fusions. All 5 tumors had microsatellite stability; 4/5 had low tumor mutation burden (2-5 mutations/megabase). NTRK mutations in 3 anaplastic TC (ATC) pts (15% prevalence) were: NTRK3 I749M (AF 15%; overall survival, OS, 15 mos), NTRK1 R744H (AF not available; OS 9.5 mos), and NTRK1 R583H (AF 20.1%; OS > 4.9 mos); NTRK2 S167Y (AF 49%; OS > 51 mos) or NTRK1 R6W (AF 42%; OS > 60 mos) were found in one papillary (PTC) and one Hürthle cell (HCC) TC pt respectively (summary table below). Conclusions: NTRK point mutations, but not fusions, were unexpectedly identified in 9% of assessed advanced TCs - but remarkably in 15% of ATCs. Mutated NTRKs, along with oncogenic p53 and TERT, may contribute to TC progression, especially in ATC, consequent to downstream activation of MAPK and PI3K-AKT pathways. We posit that NTRK point mutations may have therapeutic implications for treatment of refractory disease. [Table: see text]
Clinical and genomic alterations features of patients with advanced colitis associated cancers (CAC).
Authors: Kelsen David Paul , Miller Vincent A. , Tang Laura H. , Capanu Marinela , Balasubramanian Sohail , Ross Jeffrey S. , Stephens Philip J. , Yaeger Rona 
Published: July 2017

e15010 Background: CAC are a catastrophic complication of inflammatory bowel disease. The spectrum of genomic alterations (GA) in CAC is different than that of sporadic colorectal cancer (CRC) (Yaeger et al PMID 27063727). While the prognosis for CAC patients (pts) may be worse than that of sporadic CRC pts, there is little data regarding outcome for metastatic CAC pts treated with standard chemotherapy regimens. We reviewed demographic features and clinical outcome for pts with metastatic CAC in the context of somatic tumor GA. Methods: We identified small and large bowel CAC cases seen at Memorial Sloan Kettering between 2003 and 2015 with tissue available for study. Hybrid capture based next-generation sequencing analysis of over 300 cancer-related genes was used to comprehensively characterize GA. The electronic medical record of each patient was reviewed. Demographic and clinical data was extracted and outcome reviewed in the context of somatic tumor GA. Results: Clinical features for 17 pts with metastatic CAC are shown below. All pts with initial stage III CAC received FOLFOX adjuvant therapy. First-line treatment for metastatic disease included FOLFOX/FOLFIRINOX/FU-LV in 10 previously untreated pts and FOLFIRI after adjuvant therapy. Median duration of survival from time of metastatic disease was 14.8 months, (95% CI 5.7-24.3;range 2-68+ months), substantially less than that expected for pts with Stage IV CRC. Only 4 patients survived for > 24 months. GA were identified in TP53 (87%) and KRAS (33%); potentially targetable alterations were found in 8 pts ( IDH1 (1), EML4-ALK(1), ERBB2 (1); FGFR1/2 (3); BRAF (1); PIK3CA(1). 2 pts received a targeted agent based on GA; 1 partial response to a FGFR inhibitor is ongoing. No patient had a hyper-mutated tumor. Conclusions: Metastatic CAC pts have an exceedingly poor prognosis, with survival well below that expected for sporadic CRC. BRAF mutations associated with poor outcome in sporadic CRC are rare in CAC. 47% of CAC pts had potentially targetable GA. [Table: see text]
Feasibility of collaborative precision medicine oncology between academic- and community-based hospitals.
Authors: Rodriguez-Rodriguez Lorna , Krasna Mark , Hirshfield Kim M. , Rojas Veronica , Riedlinger Gregory , Ali Siraj Mahamed , Miller Vincent A. , Ganesan Shridar 
Published: July 2017

e18015 Background: The Rutgers Cancer Institute of New Jersey (CINJ) is conducting an ongoing, prospective, observational clinical trial that is evaluating use of comprehensive genomic profiling (CGP) and molecular tumor board (MTB) review to assist in caring for patients with rare or refractory cancers. As part of this precision medicine approach to cancer care, CINJ has formed a partnership with community hospitals (Meridian Health) to enroll patients in this study, and to actively participate in MTB meetings. The purpose of this cohort analysis is to evaluate the feasibility of using CGP to identify clinically-relevant genomic alterations as an aid to guiding point-of-care management in a community hospital setting. Methods: Meridian Health staff was trained in patient selection, enrollment, and follow-up. CGP was performed by Foundation Medicine, Inc. The patient case’s clinical history, pathology, and CGP results were presented at an MTB meeting. The enrolling physicians (n = 11) were invited to attend the MTB in person or through web-accessible video conferencing. A letter listing MTB consensus recommendations on potential treatment options was sent to the referring physician, and patient follow-up was scheduled at regular intervals. Results: 35 patients were enrolled by Meridian Health. Gyn and GI cancers were the most common types at enrollment (each 26%, 9 out of 35), followed by breast cancer (20%, 7 out of 35). At study enrollment, the mean KPS was 91%, and 23 patients (66%) had stage IV disease. The median duration between study enrollment and MTB presentation was 44 days. 3 patients were excluded because of deteriorated clinical status at the time of the MTB. MTB-based treatment options were implemented in 9 of 32 patients (28%). This result is similar to those reported in published analyses of patients enrolled at CINJ. Conclusions: Collaborations between an academic cancer center and a community hospital is a feasible approach to facilitating access to precision medicine for cancer patients treated in the community. A larger cohort is needed to determine the impact on patient’s outcomes.
Incidence and Prevalence of Cancer in Colombia: The Methodology Used Matters
Authors: Valencia Omaira , Lopes Gilberto , Sánchez Patricia , Acuña Lizbeth , Uribe Daniel , González Jaime 
Published: July 2017

Purpose Incidence and prevalence are important factors in policy making and planning in health care systems. The aim of this study was to compare two different estimates of the incidence and prevalence of cancer in Colombia—real-world data from the health care system and estimates from cancer registries. Materials and Methods Data from all providers were aggregated by the High-Cost Diseases Office (Cuenta de Alto Costo [CAC]). The real-world, age-standardized observed incidence (OI) and observed prevalence (OP) rates were calculated using the number of patients with a diagnosis of cancer who were cared for in the national health system between 2014 and 2015. The registry estimated incidence (EI) and estimated prevalence (EP) were extracted from GLOBOCAN population fact sheets for 2012, which use data from four Colombian city-based registries and extrapolate survival using the average for Asian countries, together with registries from Uganda and Zimbabwe. Results A total of 130,441 patients were analyzed. The OI of cancer in Colombia was 69.2 and the OP was 479 (per 100,000 people) in early 2015, whereas the EI was 175.2 and the 5-year EP was 501.2 (per 100,000 people), showing a higher estimate from GLOBOCAN data for 2012 than was observed in early 2015 by the CAC. Some differences were higher in specific cancers. Conclusion Because of differences in methodology, the EI and the EP are not comparable to the OI and the OP. Policymakers need robust and current information to prioritize disease prevention and control programs. In Colombia, the OI and the OP—calculated by the CAC with data from the whole country—offer an opportunity for a more precise real-world estimation of patients with cancer in Colombia.
Verapamil Use Is Associated With Reduction of Newly Diagnosed Diabetes Mellitus
Authors: Yin Ti , Kuo Shu-Chen , Chang Yea-Yuan , Chen Yung-Tai , Wang Kai-Wei Katherine 
Published: July 2017

Abstract

Objective:
The mechanism of the beneficial effect of calcium-channel blockers (CCBs), especially verapamil, on the development of type 2 diabetes mellitus (T2DM) has been described. This study compared the incidence of T2DM in adults prescribed oral verapamil and propensity score–matched adults prescribed other oral CCBs.

Methods:
This retrospective population-based cohort study used Taiwan’s National Health Insurance Research Database from 2000 to 2011. T2DM was defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification.

Results:
During follow-up periods of 41,958 and 42,118 person-years, 269 of 4930 patients in the verapamil cohort and 340 of 4930 patients in the matched cohort, respectively, developed T2DM. The incidence rates were 6.41 and 8.07 per 1000 population per year among verapamil and other CCB users, respectively. The adjusted hazard ratio (HR) for T2DM associated with use of verapamil (vs. other CCBs) was 0.80 [95% confidence interval (CI), 0.68 to 0.94; P = 0.006]. After exclusion of patients followed for &lt;180 days or &lt;365 days (to avoid bias derived from delayed diagnosis), adjusted HRs remained significant [0.79 (95% CI, 0.67 to 0.93; P = 0.005) and 0.77 (95% CI, 0.65 to 0.91; P = 0.002), respectively]. Only the interaction term for age was significant (P = 0.009). Verapamil had a more prominent effect on patients aged older than 65 years (P &lt; 0.001).

Conclusions:
In patients with no known history of diabetes mellitus, oral verapamil use was associated with a decreased incidence of T2DM compared with other CCBs.
Role of Sigma-1 Receptor/p38 MAPK Inhibition in Acupoint Catgut Embedding–Mediated Analgesic Effects in Complete Freund’s Adjuvant-Induced Inflammatory Pain
Authors: Du Kairong , Wang Xue , Chi Laiting , Li Wenzhi 
Published: July 2017

BACKGROUND:
The endoplasmic reticulum chaperone protein Sigma-1 receptor (Sig-1 R) and mitogen-activated protein kinases (MAPKs) are involved in the mechanism of pain. Acupoint stimulation exerts an exact antihyperalgesic effect in inflammatory pain. However, whether Sig-1 R and MAPKs are associated with the acupoint stimulation-induced analgesic effects is not clear. This study investigated the analgesic effect of acupoint catgut embedding (ACE) and the inhibition of Sig-1 R and MAPKs in ACE analgesia.

METHODS:
Rats were prepared with intrathecal catheter implantation. ACE was applied to bilateral “Kunlun” (BL60), “Zusanli” (ST36), and “Sanyinjiao” (SP6) acupoints in the rat model of inflammatory pain (complete Freund’s adjuvant [CFA] intraplantar injection). Then, Sig-1R agonist PRE084 or saline was intrathecally given daily. The paw withdrawal thresholds and paw edema were measured before CFA injection and at 1, 3, and 5 day after CFA injection. Western bolt was used to evaluate the protein expression of spinal Sig-1R, p38MAPK, and extracellular signal-regulated kinase (ERK), and immunohistochemistry of Sig-1R was detected at 1, 3, and 5 days after CFA injection.

RESULTS:
ACE exhibited specific analgesic effects. ACE increased paw withdrawal thresholds and markedly decreased CFA-induced paw edema at 1, 3, and 5 days. ACE downregulated the protein expression of Sig-1R, which was increased significantly at 1, 3, and 5 days after CFA injection. ACE decreased the expression of p38 MAPK and ERK at 1 and 3 days but not at 5 days. However, an injection of Sig-1R agonist PRE084 markedly reversed these alterations, except ERK expression.

CONCLUSIONS:
The present study demonstrated that ACE exhibited antihyperalgesic effects via the inhibition of the Sig-1R that modulated p38 MAPK, but not ERK, expression in the CFA-induced inflammatory pain model in rats.
Review of Vasia Lekka’s, The Neurological Emergence of Epilepsy: The National Hospital for the Paralysed and Epileptic (1870–1895)
Authors: Ioannidis Stavros 
Published: July 2017

Vasia Lekka. The Neurological Emergence of Epilepsy: The National Hospital for the Paralysed and Epileptic (1870-1895). New York: Springer, 2015. xiii + 209 pp.
Decision Structure and Performance of Networked Technology Supply Chains
Authors: Wang Jingqi , Wu Xiaole , Krishnan Viswanathan 
Published: July 2017

Supply chains in key growth industries increasingly commercialize a critical piece of technology invented by an upstream technology supplier. The focal technology is licensed to specialist design firms and designed into products, which are fabricated by dedicated large-scale manufacturers. We examine a technology supplier’s licensing decision in such emerging multiparty networked supply chains in which a downstream design firm’s capability may not be publicly known. We find that the supply chain and firm profits are critically affected by whether or not a license agreement between a technology supplier and a design firm is kept confidential from a manufacturer. Instead of licensing to two downstream firms, a technology supplier may also license to an integrated firm with both design and manufacturing capabilities, which forms a conventional vertical supply chain. We compare a networked supply chain with a vertical supply chain and show that the network model can, under some conditions, outperform the integrated configuration and increase profits for all supply chain entities. In particular, a downstream firm can be better off decentralized, with design and manufacturing functions taken by different firms. Our research helps explain the emergence of such networked supply chains and offers insights on how to structure them to improve outcomes. The online appendix is available at https://doi.org/10.1287/msom.2017.0619 .
The front-line general surgery consultant as a new model of emergency care
Authors: Navarro AP , Hardy EJO , Oakley B , Mohamed E , Welch NT , Parsons SL 
Published: July 2017

Introduction Emergency general surgery services in England are undergoing rapid structural change with the aim of improving care. In our centre, the key issues identified were high numbers of admissions, inappropriate referrals, prolonged waiting times, delayed senior input and poor patient satisfaction. A new model was launched in January 2015 to address these issues: the surgical triage unit (STU). This study assesses the success of the new service. Methods All emergency general surgical admissions during a five-month period before introduction of the STU were compared with those of a comparable five-month period after its introduction. Process, clinical and patient experience outcomes were assessed to identify improvement. Results Attendance fell from 3,304 patients in the 2014 cohort to 2,830 in the 2015 cohort. During the 2015 study period, 279 more patients were discharged on the same day. Resource requirement fell by 2,635 bed days (23%). The number of true surgical emergencies remained consistent. Rates for reattendance (7.8% for 2014 vs 8.1% for 2015) and readmission (5.7% for 2014 vs 5.7% for 2015) showed no significant difference. Patient experience data demonstrated a significant improvement in both net promoter score (64.1 vs 82.2) and number of complaints (34 vs 5). Clinical outcomes for low risk procedures remained similar. Emergency laparotomy in-hospital mortality fell (11.4% vs 10.3%) despite preoperative risk stratification suggesting a risk burden that was significantly higher than the national average. Conclusions This novel model of emergency general surgery provision has improved clinical efficiency, patient satisfaction and outcomes. We encourage other units to consider similar programmes of service improvement.