A Novel NFIX-STAT6 Gene Fusion in Solitary Fibrous Tumor: A Case Report

Solitary fibrous tumor is a rare subtype of soft-tissue sarcoma with a wide spectrum of histopathological features and clinical behaviors, ranging from mildly to highly aggressive tumors. The defining genetic driver alteration is the gene fusion NAB2–STAT6, resulting from a paracentric inversion within chromosome 12q, and involving several different exons in each gene. STAT6 (signal transducer and activator of transcription 6) nuclear immunostaining and/or the identification of NAB2–STAT6 gene fusion is required for the diagnostic confirmation of solitary fibrous tumor. In the present study, a new gene fusion consisting of Nuclear Factor I X (NFIX), mapping to 19p13.2 and STAT6, mapping to 12q13.3 was identified by targeted RNA-Seq in a 74-year-old female patient diagnosed with a deep-seated solitary fibrous tumor in the pelvis. Histopathologically, the neoplasm did not display nuclear pleomorphism or tumor necrosis and had a low proliferative index. A total of 378 unique reads spanning the NFIXexon8–STAT6exon2 breakpoint with 55 different start sites were detected in the bioinformatic analysis, which represented 59.5% of the reads intersecting the genomic location on either side of the breakpoint. Targeted RNA-Seq results were validated by RT-PCR/ Sanger sequencing. The identification of a new gene fusion partner for STAT6 in solitary fibrous tumor opens intriguing new hypotheses to refine the role of STAT6 in the sarcomatogenesis of this entity

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors

A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men

Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD

Pharmacogenetic Profiling in High-Risk Soft Tissue Sarcomas Treated with Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are sub-stantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chem-otherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to es-tablish their clinical utility

Research priorities in prehabilitation for patients undergoing cancer surgery: an international Delphi study

Background Recently, the number of prehabilitation trials has increased significantly. The identification of key research priorities is vital in guiding future research directions. Thus, the aim of this collaborative study was to define key research priorities in prehabilitation for patients undergoing cancer surgery. Methods The Delphi methodology was implemented over three rounds of surveys distributed to prehabilitation experts from across multiple specialties, tumour streams and countries via a secure online platform. In the first round, participants were asked to provide baseline demographics and to identify five top prehabilitation research priorities. In successive rounds, participants were asked to rank research priorities on a 5-point Likert scale. Consensus was considered if > 70% of participants indicated agreement on each research priority. Results A total of 165 prehabilitation experts participated, including medical doctors, physiotherapists, dieticians, nurses, and academics across four continents. The first round identified 446 research priorities, collated within 75 unique research questions. Over two successive rounds, a list of 10 research priorities reached international consensus of importance. These included the efficacy of prehabilitation on varied postoperative outcomes, benefit to specific patient groups, ideal programme composition, cost efficacy, enhancing compliance and adherence, effect during neoadjuvant therapies, and modes of delivery. Conclusions This collaborative international study identified the top 10 research priorities in prehabilitation for patients undergoing cancer surgery. The identified priorities inform research strategies, provide future directions for prehabilitation research, support resource allocation and enhance the prehabilitation evidence base in cancer patients undergoing surgery

Effects Of Selected Process Parameters In Extrusion Of Yam Flour (dioscorea Rotundata) On Physicochemical Properties Of The Extrudates.

Raw yam (Dioscorea rotundata) flour was cooked and extruded in a Brabender single-screw laboratory scale extruder. Response surface methodology using an incomplete factorial design was applied with various combinations of barrel temperature [100, 125, 150 degrees C], feed moisture content [18, 22, 26%] and screw speed [100, 150, 200 rpm]. Initial viscosity at 30 degrees C, water solubility index, expansion and hardness were determined. The highest values of initial viscosity were at the highest barrel temperatures and the highest moisture contents. At high feed moisture content and high barrel temperatures the yam extrudate flour showed the greatest values of water solubility index. The physical properties of the extruded product showed that at high temperature the lower the moisture content the greater the expansion index. Hardness was influenced directly by moisture content and inversely by extrusion temperature. The extrusion of yam flour led to the production of snacks and pre-gelatinized flours of diverse properties. Also extruded yam flour can be successfully used in the preparation of 'futu' (pre-cooked compact dough), a yam-based food, popular in Western Africa.4429610

Effects of selected process parameters in extrusion of yam flour (Dioscorea rotundata) on physicochemical properties of the extrudates

Raw yam (Dioscorea rotundata) flour was cooked and extruded in a Brabender single-screw laboratory scale extruder. Response surface methodology using an incomplete factorial design was applied with various combinations of barrel temperature [100, 125, 150 degrees C], feed moisture content [18, 22, 26%] and screw speed [100, 150, 200 rpm]. Initial viscosity at 30 degrees C, water solubility index, expansion and hardness were determined. The highest values of initial viscosity were at the highest barrel temperatures and the highest moisture contents. At high feed moisture content and high barrel temperatures the yam extrudate flour showed the greatest values of water solubility index. The physical properties of the extruded product showed that at high temperature the lower the moisture content the greater the expansion index. Hardness was influenced directly by moisture content and inversely by extrusion temperature. The extrusion of yam flour led to the production of snacks and pregelatinized flours of diverse properties. Also extruded yam flour can be successfully used in the preparation of 'futu' (pre-cooked compact dough), a yam-based food, popular in Western Africa.4429610

Development of extruded snacks using jatoba (Hymenaea stigonocarpa Mart) flour and cassava starch blends

The use of the jatoba trees (Hymenaea stigonocarpa Mart) by the timber industry poses an ecological problem in Brazil. The objective of this research was to investigate the use of jatoba flour for the production of snacks by the thermoplastic extrusion of a composite flour consisting of jatoba and cassava starch. Chemical analysis showed that the jatoba fruit provides high-fibre flour (486 g kg(-1)) with 66 g kg(-1) protein, and 398 and 88 g kg(-1) of insoluble and soluble fibre, respectively. Such flour is of potential use for the production of high-fibre snacks, allowing for the economical exploitation of the jatoba while preserving the tree. Composite flours with jatoba flour and cassava starch mixtures (150:850, 300:700, 450:550), conditioned to moisture levels of 170, 200 and 230 g kg(-1) were processed in a Brabender single-screw extruder. The extrusion conditions were 150 rpm screw speed, 4 mm die diameter and 125, 150 and 175 degrees C of barrel temperatures. The snacks produced were evaluated as to their sensory characteristics and response surface methodology was used to optimise the extrusion process. Response surface and contour diagrams revealed that all mixtures conditioned to 170 g kg(-1) moisture and extruded at 150 degrees C produced snacks of acceptable quality, higher levels of jatoba flour leading to significant quality losses with respect to sensory characteristics. (C) 1998 Society of Chemical Industry.781596