tbuckley/cabot-search huggingface dataset:
Germline DNA repair gene mutations in Taiwan prostate cancer patients.
Authors: Wilson Huang, Shauh-Der Yeh
Journal: Journal of Clinical Oncology (2020)

e13640 Background: Genetic testing for inherited mutations in DNA-repair genes such as BRCA1, BRCA2, ATM, PALP2, FANCA has been proposed for high-risk and metastatic prostate cancer patients for personalized therapy and management. Although the prevalence of germline DNA-repair gene mutations among Caucasian populations are known, the frequency of such mutations in Taiwan prostate cancer patients has not been established. In this study, we performed next-generation sequencing (NGS) analysis of BRCA1, BRCA2, ATM, PALP2, and FANCA in 49 prostate cancer patients stratified according to the NCCN risk criteria using blood sample collected from a single hospital center. Methods: 4ml whole blood samples are collected in EDTA tube from prostate cancer patients of low-intermediate, high to very high, regional, and metastatic risks. The samples are subjected to buffy coat fractionation, genomic DNA extraction, library preparation, full-exon NGS, and comparative analysis with all known germline variants. We identified and correlated the frequency of germline DNA-repair gene mutations with patient’s age at diagnosis, Gleason grades, initial PSA, family history of prostate cancer, and NCCN risk. Results: A total of 49 blood samples were tested and analyzed for BRCA1, BRCA2, ATM, PALP2, and FANCA mutations. Among all cases, 6.1% (3/49, 95% confidence interval [CI]: - 0.6%-12.8%) carried pathogenic mutations: 2.0% (1/49) in BRCA1, 2.0% (1/49) in BRCA2, and 2.0% (1/49) in ATM. They were compatible with previously reported mutations and no new germline variants were detected. These mutations were associated with initial PSA and NCCN risk; all identified mutations belonged to Gleason grade 5 and high to very high risk subgroups. No clinical association was observed with patient’s age of diagnosis and family history. Conclusions: In this single hospital center study, we observed a modest incidence of DNA-repair gene mutations in the Taiwan prostate cancer cohort. Germline DNA-repair gene mutations were observed in high risk prostate cancer patients with the highest Gleason grade. Frequencies of the mutations did not differ significantly according to age at diagnosis or family history of prostate cancer. These results were similar to the reported findings in the Caucasian populations. Our findings confirmed the necessity of genetic testing in Taiwan prostate cancer patients. [Table: see text]
Role of AXL in metastatic melanoma and impact of TP-0903 as a novel therapeutic option for melanoma brain metastasis.
Authors: Eemon Tizpa, Hannah J Young, Kimberley-Jane C. Bonjoc, Chou-Wei Chang, Yilun Liu, Jason M Foulks, Ammar Chaudhry
Journal: Journal of Clinical Oncology (2020)

e22021 Background: Melanoma brain metastases (MBM) are common with a median overall survival of 4-5 months. Although immunotherapies have improved clinical outcomes and have doubled overall survival in MBM, there is a high incidence rate of relapse caused by drug resistance. AXL, a receptor tyrosine kinase (RTK), is associated with drug resistance and metastasis in many cancers. The activation of AXL via trans-phosphorylation regulates multiple signaling pathways that induce tumor survival, metastasis, drug resistance, and epithelial-to-mesenchymal transition (EMT). In MBM, AXL is upregulated and associated with disease progression, promoting cell invasion and migration. This suggests that targeting AXL can be a novel strategy to overcome treatment-related resistance in MBM. TP-0903, an investigational small molecule inhibitor of AXL, has shown efficacy in reversing the mesenchymal phenotype and re-sensitizing resistant cancer cells to targeted therapies in heme malignancies, pancreatic, and breast cancer. We aim to investigate the efficacy of TP-0903 in MBM. Methods: The Cancer Genome Atlas (TCGA) data was utilized to investigate the signaling pathways downstream of AXL that are upregulated in advanced melanoma. Nine signaling molecules including AKT1, mTOR, and PAK4 were analyzed to identify any correlation between gene expression levels and overall survival. Four metastatic melanoma cell lines were used to evaluate the effect of TP-0903 on cell viability and active AXL downregulation was assessed in vitro through MTS cell viability assays and Immunoblotting. Wound closure assays were executed to understand the functional consequences of AXL downregulation. Results: In all nine genes, high expression levels confer poor survival probability. Cell viability assays of four malignant melanoma cell lines showed that TP-0903 treatment resulted in IC 50 values ranging from 32 – 692 nM. Western blot analysis indicated that TP-0903 reduced the levels of phosphorylated AXL in malignant melanoma cell lines. In addition, increasing TP-0903 concentrations reduced the rate of cell migration in these malignant melanoma cell lines. Conclusions: AXL plays a role in EMT, treatment resistance, and metastasis in MBM, resulting in poor survival. Our findings suggest TP-0903 is effective in reducing cell migration, inhibit metastasis, and can be a potential therapeutic option in MBM.
Study in air-conducted and bone-conducted auditory brainstem responses in children with congenital external auditory canal atresia
Authors: Chen Wenxia, Xu Zhengmin, Wang Yan
Journal: BMJ (2016)

Objective
To study the clinical value of air- and bone-conduction auditory brainstem responses(ABRs) in children with congenital aural atresia.


Methods
Air- and bone-conduction click-evoked ABRs in 38 children with congenital external auditory canal atresia were compared to those in 34 normal-hearing children.


Results
ABR threshold were (65.0±8.7) dBnHL for air conduction and (10.6±7.0) dBnHL for bone conduction in children with congenital external auditory canal atresia; and (25.6±1.7) dBnHL and (9.7±6.7) dBnHL respectively in normal hearing children.There was statistically difference between the two groups in air-conduction ABR threshold(t'=21.59, P 0.05). While the air-bone ABR threshold gap was greater in children with external auditory canal atresia than in normal hearing children(t'=13.78, P 0.05).


Conclusion
Bone conduction ABR is valuable in assessing function of cochlea, auditory nerve and brainstem in individuals with congenital external auditory canal atresia.It has important clinical value in objective differential diagnosis of conductive deafness with combined application of air- and bone-conduction ABRs.


Key words: 
Ear, external; Congenital abnormalities; Auditory brainstem response
Analysis of risk factors related with hyperuricemia among 1420 youth and middle-aged adult health check-up residents in Guangzhou
Authors: Xuan Xiong, Xiao-shi Zhong, Xiao Xiao, Dan-ping Qing, Jian-guang Hu, Ying Zhang
Journal: BMJ (2013)

To survey the serum uric acid (SUA) levels and associated risk factors of hyperuricemia among youth and middle-aged residents in Guangzhou. A total of 1420 subjects, aged from 20 to 60 years, receiving health check-up at our hospital in 2010 were enrolled. The total prevalence of hyperuricemia was 22.04%, 32.01% in males and 14.07% in females. The average SUA was (388±78) μmol/L in males and (288±63) μmol/L in females. The prevalence of hyperuricemia in males was 30.11% before 40 years of age and 33.81% between 40 and 60 years of age. The average level of SUA in males was significantly higher than that of females. logistic regression analysis showed that BUN, body mass index (BMI) and hypertriglyceridemia were the independent risk factors of disease while HDL-C and gender (females) the protective factors.


Key words: 
Hyperuricemia; Risk factors
Phase I dose escalation study of immunoconjugate L-DOS47 in combination with pemetrexed/carboplatin in non-squamous non-small cell lung cancer (NSCLC) patients.
Authors: Afshin Dowlati, Chandra Prakash Belani, George R. Simon, Heman Chao, Sarina Anne Piha-Paul
Journal: Journal of Clinical Oncology (2020)

e21680 Background: L-DOS47, a cancer therapeutic designed to exploit the acidic tumour extracellular environment, consists of urease conjugated to an anti-CEACAM6 camelid monoclonal antibody. The antibody serves as a targeting agent to deliver urease to tumor sites, while the urease enzyme converts urea, an abundant natural metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells. An additive cytotoxic effect of L-DOS47 and pemetrexed/carboplatin has been observed against the A549 human lung adenocarcinoma cell line. L-DOS47 has been shown in a previous phase I clinical trial to be safe and well tolerated at doses up to 13.55 µg/kg. The current phase I study was designed to define the maximum tolerated dose of L-DOS47 in combination with pemetrexed/carboplatin. Methods: Stage IV (TNM M1a and M1b) histologically confirmed non-squamous NSCLC patients (aged ≥18 yrs, ECOG PS ≤1) received up to four cycles of L-DOS47 in combination with standard of care doses of pemetrexed/carboplatin. L-DOS47 was administered weekly over 21 days in each treatment cycle. Seven planned dosing cohorts (0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 μg/kg) employed a standard 3+3 design for the first two and the last two cohorts, and an accelerated 1 + 2 design for the middle three cohorts. Dose levels of L-DOS47 were escalated following a review of safety data by the Trial Steering Committee. Results: Fourteen (14) patients were enrolled across 6 dosing cohorts before recruitment was halted. Median age was 65.1 years, with 50.0% male and 78.6% Caucasian. 57.1% of patients had an ECOG score of 0, and 42.9% had an ECOG score of 1. The maximum tolerated dose (MTD) could not be determined as none of the patients experienced a dose limiting toxicity (DLT). 50.0% of patients experienced at least one treatment emergent adverse event (TEAE) assessed as study drug-related, with 14.3% of patients experiencing at least one grade 3/4 drug-related toxicity. Of 12 patients evaluable for efficacy, 5 patients (41.7%) had a partial response (PR), 4 patients (33.3%) experienced stable disease (SD) and 3 patients (25.0%) had progressive disease (PD). The objective response rate is 41.7%. The clinical benefit rate is 75.0%. Conclusions: L-DOS47, in combination with pemetrexed/carboplatin, appears to be well tolerated with promising anti-tumor activity against non-squamous NSCLC. Clinical trial information: NCT02309892.
Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma.
Authors: Eric Jonasch, Frede Donskov, Othon Iliopoulos, Wendy Kimryn Rathmell, Vivek Narayan, Benjamin Louis Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Sarah J. Welsh, Sanjay Thamake, Eric Kristopher Park, Naseem J. Zojwalla, Rodolfo F. Perini, W. Marston Linehan, Ramaprasad Srinivasan
Journal: Journal of Clinical Oncology (2020)

5003 Background: Patients (pts) with Von Hippel-Lindau disease (VHL) are at risk for several cancers, including clear cell renal cell carcinoma (ccRCC). Inactivation of VHL results in constitutive activation of the HIF-2α transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, has shown favorable safety and antitumor activity in a phase 1/2 study. We present initial results of the open-label phase 2 study of MK-6482 for treatment of VHL-associated ccRCC (NCT03401788). Methods: Adult pts with a pathogenic germline VHL variation, measurable localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS of 0/1 received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/pt decision to withdraw. Primary end point was ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent radiology review. Secondary end points were DOR, time to response (TTR), PFS, and safety and tolerability. Results: As of December 6, 2019, 61 pts were enrolled; median (range) age was 41 years (19-66) and most pts were male (52.5%) and had ECOG PS of 0 (82.0%). The most common lesions outside the kidney (non-RCC tumors) were CNS hemangioblastomas (80.3%) and pancreatic lesions (50.8%). Median (range) duration of treatment was 9.9 mo (1.9-18.2) and 95.1% of pts remain on therapy. Three pts discontinued (AE, n = 1; death [fentanyl toxicity], n = 1; pt decision, n = 1). There were 17 confirmed responses (ORR, 27.9% [95% CI, 17.1-40.8%]) and 8 (13.1%) unconfirmed (documented at 1 timepoint and to be confirmed at subsequent timepoint) responses; all responses were PRs. Of 61 pts, 53 (86.9%) had decrease in size of target lesions. In 17 pts with confirmed response, median (range) DOR was not reached (2.1-9.0 mo) and median (range) TTR was 5.5 mo (2.7-14.0). Responses were also observed in CNS, retinal, and pancreatic lesions. Median PFS was not reached; 12-mo PFS rate was 98.3%. Treatment-related AEs (TRAEs) occurred in 96.7% of pts, mostly grade 1 (44.3%) or grade 2 (42.6%) and primarily (≥20%) anemia (83.6%; considered an on-target-toxicity), fatigue (49.2%), and dizziness (21.3%). Grade 3 TRAEs occurred in 9.8% of pts, primarily fatigue (4.9%) and anemia (3.3%). There were no grade 4 or 5 TRAEs. One pt discontinued because of a TRAE (dizziness). Conclusions: MK-6482 showed promising efficacy and tolerability in pts with VHL-associated ccRCC and responses in other VHL-related lesions. These data support further investigation of MK-6482 in VHL disease. Clinical trial information: NCT03401788 .
Health coaching improves interventional effects in high-risk population of stroke
Authors: Qian Wang, Xiaoci He, Peng Wu, Kepin Sun, Yanfeng Wang, Xiaofen Li, Li Liu, Rongying Wang
Journal: BMJ (2019)

Objective
To assess the effect of health coaching on interventional effect in high-risk population of stroke.


Methods
A baseline survey was conducted among 897 residents aged 40 years and above selected by cluster sampling method in a community of Shijiazhuang city from January 2016 to June 2016, and 178 subjects were identified as high risk population of stroke. The high-risk subjects were randomly divided into two groups: the control group (n=89) was given routine health education, while the intervention group (n=89) received health coaching based on motivational interview for 13 months. The behavioral risk factors and self-efficacy scores were compared between two groups before and after intervention.


Results
There were no significant differences in behavioral risk factors between the two groups: for hypertension 72 vs. 74 cases (χ2=0.152, P=0.67), for hyperglycocemia 44 vs.48 cases (χ2=0.360, P=0.55), for dyslipidemia 62 vs. 60 cases (χ2=0.104, P=0.75), for smoking 35 vs.32 cases (χ2=0.215, P=0.64), for obesity 50 vs.52 cases (χ2=0.092, P=0.76), for lack of exercises 72 vs.70 cases (χ2=0.139, P=0.71), for atrial fibrillation 14 vs. 16 cases (χ2=0.160, P=0.19). And there was no significant difference in self-efficacy scores between the two groups [(5.3±1.2) vs. (5.6±2.0), t=0.997,P=0.32]. After intervention, there were significant differences between the two groups in behavioral risk factors: for hypertension 25 vs. 34 cases (χ2=19.984, P<0.05) , for hyperglycaemia 16 vs.32 cases (χ2=8.448, P<0.05) , for dyslipidemia 30 vs. 48 cases (χ2=13.216, P<0.05) , for smoking 20 vs.28 cases (χ2=7.583, P<0.05) , for obesity 18 vs.38 cases (χ2=14.158, P<0.05) , for lack of exercises 28 vs. 36 cases (χ2=10.235, P<0.01) , for atrial fibrillation 5 vs. 13 cases (χ2=6.451, P<0.05) . And the self-efficacy scores of intervention group were higher than those of control group[ (8.4±2.1) vs. (6.8±2.2), t=4.852, P<0.01].


Conclusion
Health coaching based on motivational interview is beneficial to reduce risk factors and improve self-efficacy in high risk population of stroke, which is worthy of popularization.


Key words: 
Health coaching; Stroke, high-risk; Community health services; Primary prevention
Efficacy of levothyroxine on benign thyroid nodules and its effect on blood lipids
Authors: Yifen Liu, Changheng Yin, Guangyuan Zhao, Jiuju Zhang, Linna Wang, Suhua Hou, Baoheng Zheng
Journal: BMJ (2019)

Three hundred and nine patients with thyroid nodules detected by physical examination in Harrison International Peace Hospital from October 2013 to October 2017 were divided into intervention group (155 cases) and control group (154 cases). Patients in intervention group received oral levothyroxine sodium 25 g/d for 12 months and those in control group had no treatment, patients were followed up every 3 months to 12 months. After treatment, the maximum diameter and thyroid nodule volume of the intervention group were (31.87±3.84) mm and (17.32±0.94) cm3, which were significantly smaller than those of the control group [(34.01±3.72) mm and (24.25±1.21) cm3, P<0.05]. TSH in intervention group was lower than that in control group [(2.24±0.41) vs. (2.52±0.58) mIU/L, P<0.05] and free T4 (FT4) was higher than that in control group [(25.64±3.85) vs. (16.39±3.28) pmol/L, P<0.05]. TC, TG and LDL-C in intervention group, were lower than those in the control group.The HDL-C level in intervention group was higher than that in control group (all P<0.05). After treatment, there were no malignant changes in the intervention group, while the malignant change rate in control group was 2.6% (4/154). It is suggested that levothyroxine treatment can reduce TSH level in patients with benign thyroid nodules, inhibit the growth of thyroid nodules.


Key words: 
Thyroxine; Thyroid nodule; Treatment outcome
厦门地区2型糖尿病患者生存质量多因素分析
Authors: 李学军, 杨叔禹, 赵能江, 王丽英, 郭灵祥, 吴洁, 周艺
Journal: BMJ (2009)

糖尿病已经成为全球第3位威胁人类健康的慢性非传染性疾病,其并发症多,治疗复杂,不仅影响患者身体健康,也影响患者的生存质量.厦门市地处我国沿海经济发达地区,属糖尿病高发区.为了解该地区2型糖尿病患者生存质量现状,探讨影响糖尿病患者生存质量的主要因素,本研究采用多元回归方法进行生存质量影响因素分析。
Hospitalization for complications due to systemic therapy in the United States.
Authors: Muni Rubens, Venkataraghavan Ramamoorthy, Anshul Saxena, Emir Veledar, Peter McGranaghan, Belinda Boulanger, Michael David Chuong, Matthew David Hall, Rupesh Kotecha, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2020)

7078 Background: Management of complications of systemic therapy for cancer involves significant healthcare burden for both patients and healthcare system. Aim of this study is to estimate trends as well as burden associated with these hospitalizations, using a nationally representative data. Methods: National Inpatient Sample data during 2005-2016 was used to identify complications of systemic therapy using ICD-9 and ICD-10 external cause of injury codes. Primary outcome was hospitalization rate while secondary outcomes were cost and in-hospital mortality related to these complications. Results: There were 443,222,223 hospitalizations recorded during the study period, of which 2,419,722 were due to complications of systemic therapy. The average annual percentage change of these hospitalizations was 8.1%, compared to -0.5% for general hospitalizations. The 3 most common causes for hospitalization were anemia (12.8%), neutropenia (10.8%), and sepsis (7.8%). During the study period, hospitalization rates had highest relative increases for sepsis (1.9 fold) and acute kidney injury (1.6 fold) and highest relative decrease for dehydration (0.21 fold) and fever of unknown origin (0.35 fold). Complications responsible for highest costs per hospitalization were sepsis ($16,834), acute kidney injury ($13,172), and pneumonia ($13,040). Leading causes of in-hospital mortality associated with systemic therapy were sepsis (15.8%), pneumonia (7.6%), and acute kidney injury (7.0%). Conclusions: During 2005-2016, hospitalization rates for systemic therapy complications increased by an annual rate of 8.1%, with anemia, neutropenia, and sepsis as the most common complications requiring hospitalization. Initiatives such as rule OP-35 by the Centers for Medicare and Medicaid Service, improving access and providing coordinated care, early identification and management of symptoms, and expanding urgent care access could decrease these hospitalizations and the burden on healthcare. [Table: see text]
Association of vitamin D level and vitamin D receptor gene FokI polymorphisms in pregnant women with fetal growth restriction
Authors: Zhihui Wang, Xinxiao Chen, Xuna Shen, Qinjian Yu, Wenjing Bai, Huanzheng Li, Zejiao Feng
Journal: BMJ (2019)

Serum vitamin D level and vitamin D receptor (VDR) gene FokI polymorphisms were detected in 200 single full-term pregnant women who gave birth in our hospital during 2016 to 2018. The newborns with birth weight 30 nmol/L carrying F allele (FF+Ff) were set as reference, the risk of FGR in pregnant women with serum 25(OH)D level ≤ 30 nmol/L carrying ff genotype was increased (OR=6.14, 95%CI: 2.13-13.23). The polymorphism of VDR gene FokI may be associated with the occurrence of FGR. In the case of vitamin D deficiency, the influence of ff genotype on FGR is more tangible.


Key words: 
Fetal growth retardation; Vitamin D; Receptors, vitamin D; Genes
A phase I safety and feasibility study of neoadjuvant chemoradiation plus pembrolizumab followed by consolidation pembrolizumab in resectable stage IIIA non-small cell lung cancer.
Authors: Christopher Lemmon, Gregory M.M. Videtic, Sudish C. Murthy, Kevin L. Stephans, Marc A. Shapiro, Usman Ahmad, Daniel Raymond, Vamsidhar Velcheti, Alejandro Bribriesco, Nathan A. Pennell
Journal: Journal of Clinical Oncology (2020)

9009 Background: Patients (pts) with resectable stage IIIA non-small cell lung cancer (NSCLC) have high rates of recurrence despite concurrent chemoradiation (CRT) followed by surgery. Immune checkpoint inhibitor consolidation has improved outcomes in unresectable stage III pts. Here we report the addition of concurrent neoadjuvant pembrolizumab (P) to CRT in stage IIIA patients to determine the safety and feasibility of this approach. Methods: Pts with stage IIIA NSCLC deemed resectable by a thoracic surgeon received neoadjuvant CRT consisting of cisplatin, etoposide, and concurrent P (200mg every 3 weeks x 3) with 45 Gy in 25 fractions. Pts without progression underwent resection followed by 6 months of consolidation P. The primary objective was feasibility and safety (defined as ≤30% grade 3 or higher pulmonary toxicity or any grade 4/5 nonhematologic toxicity). Ten pts were to be enrolled in Part 1, and if 2 or fewer pts had events then an additional 10 pts were to be enrolled. Secondary objectives were progression free survival (PFS), overall response rate (ORR), and pathologic complete response rate (pCR). Results: The median age of 9 enrolled pts was 66 years (range 49-76). 67% were female. 8 pts were assessable for radiographic response with an ORR of 75%. One pt came off study for progression prior to surgery and one had pleural metastases found during surgery so resection was aborted. Six pts underwent complete resection with a pCR rate of 67% (4/6). Consolidation P was started on 4 pts, with 3 completing treatment and 1 declined further treatment after 3 cycles. Median follow-up is 19.6 months and median PFS has not been reached. None of the patients who underwent resection have recurred. Serious adverse events were reported in all 9 pts with most significant being 2 grade 5 events: 1 due to pneumocystis pneumonia after resection but prior to consolidation, and 1 due to cardiac arrest during the neoadjuvant phase. Grade 3 events included 1 episode each of pneumonitis, bronchopleural fistula, acute kidney injury, colon perforation, and febrile neutropenia. Conclusions: The addition of P to neoadjuvant CRT in resectable stage IIIA pts resulted in a high pCR rate at resection. Although the relationship between grade 5 events and the addition of P was not clear, the stopping rule for infeasibility was met. As other larger studies are underway, the trial was halted rather than amended. This investigator initiated trial was funded by Merck. Clinical trial information: NCT02987998.