tbuckley/cabot-search huggingface dataset:
PIK3 mutation as a predictor of immune checkpoint inhibitor response.
Authors: Aasems Jacob, Jianrong Wu, Aman Chauhan
Journal: Journal of Clinical Oncology (2020)

e15257 Background: Although several biomarkers predicting response to immune checkpoint inhibitor (ICI) therapy have been evaluated, the emerging data is conflicting. There is a lack of real-world data that might help identify biomarkers in diverse populations. Methods: Patients with solid tumors who received ICI and underwent tumor tissue next generation sequencing (NGS) in our institution between 2016-2019 were included in the study. Response to ICI was assessed based on RECIST 1.1 and median progression free survival (mPFS), radiologic response and immune-related adverse events (IRAEs) were analyzed in relation to various molecular biomarkers. Results: 69 patients had complete NGS and RECIST 1.1 data required for analysis. Study cohort included 14 different cancer types. 78% of the patients were smokers. TP53 (62%), CDKN2A (44%), NOTCH1/2 and PIK3 (33%) were the most common mutations identified. 42% patients had CR/PR with ICI and mPFS was 38 weeks (w). A statistically significant improvement in PFS was observed in patients with PIK3 mutated cancers (mPFS 123 weeks vs. 23 weeks, p = 0.012). These patients also had a higher percentage of response (60.9% vs 39.1%, p = 0.5), and were also associated with increased risk of immune related adverse events (IRAEs) (73.9% vs. 37%, p = 0.004). PIK3 mutation had no association with PDL1 status or tumor mutational burden (TMB). Mean TMB was 12.59, and 29% patients had positive PDL1 expression. There was significant difference in mPFS between high (≥20mut/Mb) and low/intermediate TMB (0-19mut/Mb) (mPFS 18w vs. 65 w, p = 0.049) as well as PDL1 positive and negative tumors (40w vs. 18w, p = 0.059). BRAF mutation was associated with early progression in all cancers (mPFS 17w vs 39w, p = 0.033). Conclusions: Conventionally, a marker of poor survival and chemotherapy response, PIK3 mutation was associated with positive ICI response in our study. High incidence of IRAEs in PIK3 mutants also point towards increased ICI activity. High TMB, as expected was associated with ICI response.
Advance in research of vertigo medicine
Authors: Xizheng Shan, Entong Wang
Journal: BMJ (2018)

回顾近年来眩晕医学研究的进展，阐述良性阵发性位置性眩晕研究取得的3个里程碑式的突破，国际权威机构研究发布的多项眩晕类疾病的诊断标准和诊疗指南促进了眩晕诊疗的规范化，提示眩晕类疾病诊疗水平全面提升的发展态势和眩晕诊疗的多学科团队模式已经形成。中国的眩晕医学专业化是眩晕诊疗的新模式，也是提高眩晕类疾病诊疗水平的必然趋势。
Updated results from the phase IIIb complement-1 study of ribociclib (RIB) plus letrozole (LET) in the treatment of HR+, HER2-advanced breast cancer (ABC).
Authors: Michelino De Laurentiis, Simona Borstnar, Mario Campone, Ellen Warner, Javier Salvador Bofill, William Jacot, Susan Faye Dent, Miguel Martin, Alistair E. Ring, Paul H. Cottu, Janice M. Lu, Eva Ciruelos, Hamdy A. Azim, Sanjoy Chatterjee, Katie Zhou, Jiwen Wu, Nii Ankrah, Claudio Zamagni
Journal: Journal of Clinical Oncology (2020)

1055 Background: Real-world evidence is important as it complements data from randomized controlled trialse report updated results from CompLEEment-1, a Phase IIIb trial evaluating RIB+LET in an expanded population, the largest CDK4/6i trial in ABC to date. Methods: Patients (pts) with HR+, HER2– ABC, ≤ 1 line of prior CT and no prior ET for ABC received RIB+LET. Study design has been reported previously (De Laurentiis, et al. ASCO 2019). Primary endpoints were safety and tolerability. Results: 3,246 pts received ≥ 1 dose of study treatment. Median duration of follow-up was 25.4 months (mos) (15 additional mos since interim analysis [De Laurentiis, et al. ABC5 2019]). Median treatment exposure was 17.8 mos. Baseline characteristics indicated a diverse population, including men (1.2%), premenopausal women (22.2%), and pts aged ≥ 70 years (19.5%); 112 (3.5%) pts had an ECOG PS of 2, 194 (6.0%) pts received prior CT for ABC, and 51 (1.6%) pts had stable CNS lesions. The most common adverse events (AEs) were neutropenia (61.1%), nausea (35.9%), and fatigue (23.4%). Grade 3/4 hematologic abnormalities ( &gt; 5.0 %) were decreased neutrophils (54.8%), leukocytes (25.9%), and lymphocytes (12.6%). Grade 3/4 biochemical abnormalities ( &gt; 5.0 %) were increased ALT (9.1%) and AST (6.7%). An increase of &gt; 60 ms in QTcF interval from baseline occurred in 189 (5.9%) pts, while post-baseline QTcF of &gt; 480 to ≤ 500 ms and &gt; 500 ms occurred in 59 (1.8%) and 42 (1.3%) pts, respectively. Treatment-related AEs led to treatment discontinuation in 418 (12.9%) pts. Of 74 (2.3%) on treatment deaths, 38 (1.2%) were due to breast cancer. Median time to progression was 27.1 mos (95% CI, 25.7-NE), overall response rate was 43.6% (95% CI, 41.5-45.8%), and clinical benefit rate was 69.1% (95% CI, 67.1-71.1%) for pts with measurable disease at baseline. Conclusions: This analysis confirms the safety and efficacy of RIB+LET in a large, diverse cohort of pts with HR+, HER2– ABC (with no previous ET for ABC), closely resembling real-world clinical practice. Safety and efficacy data were consistent with those observed in the MONALEESA trials, supporting the use of RIB+LET in the first-line setting. NCT02941926. Clinical trial information: NCT02941926 .
Correlation of LINE-1 hypomethylation with size and dysplasia in colorectal tubular adenomas, and risk for synchronous and metachronous CRC.
Authors: Alice Jiang, Stephanie Sutherland, Lela Buckingham, Joshua Melson
Journal: Journal of Clinical Oncology (2020)

e16083 Background: Conventional adenomas (tubular or tubulovillous adenoma; TA) are frequently detected in patients undergoing average risk screening colonoscopy. Risk stratification of adenomas is currently limited to histologic features and size. Molecular features of TA could help further determine risk for development of CRC. Here, we report whether size of TA, high grade dysplasia, and synchronous or metachronous CRC associate with LINE-1 methylation. Methods: LINE-1 methylation was assessed by pyrosequencing of bisulfite-converted DNA. We compared LINE-1 methylation in TA among varying sizes, in the presence of high or low grade dysplasia, and between patients with synchronous and metachronous colorectal cancer. Results: LINE-1 methlyation was found to progressively decrease in TA of increasing size and with high grade dysplasia. TA &lt; 5mm in size (n = 45) had higher LINE-1 methylation levels compared to TA 5-9mm in size (n = 42), and &gt; = 10mm (n = 32) (72.31 ± 6.11 vs 67.50 ± 7.00 vs 66.75 ± 11.89, p = 0.013). TA with high grade dysplasia (n = 26) had lower LINE-1 methylation levels compared to low grade dysplasia (n = 135) (59.86±7.93 vs 67.16±9.20, p &lt; 0.001). Tumor tissue (n = 36) had the lowest levels of LINE-1 methylation at 50.36±8.40. There were lower levels of LINE-1 methylation in TA of patients with synchronous CRC compared to those without (53.07+4.5 vs 59.95+5.4 vs, p &lt; 0.001). LINE-1 methylation was lower in normal tissue from cancer patients compared to that from patients without any neoplasia (50.36 ± 8.40 vs 71.50 ±6.47, p &lt; 0.001). LINE-1 methylation levels were higher in patients with initial low risk TA who developed metachronous high risk TA (n = 31) compared to those who did not (n = 35) (75.78±2.45 vs 64.84±4.58, p = 0.001). LINE-1 methylation levels were not different in patients with initial TA who developed metachronous CRC (n = 2) compared to those who did not (n = 89) (70.00±5.65 vs 66.85±8.20, p = 0.69). Conclusions: High-grade dysplasia and increasing size of conventional TA were associated with greater LINE-1 hypomethylation. This is supportive of a hypothesis that greater LINE-1 hypomethylation of tubular adenomas indicates advancement along the CRC tumorigenesis pathway. Greater LINE-1 hypomethylation in TA was also seen in patients with synchronous CRC compared to those without, though no difference was found in those who developed metachronous CRC. Higher LINE-1 methylation was seen in patients with initial low risk TA, who developed metachronous high risk TA compared to those who did not.
A phase III randomized clinical trial of diclofenac versus tramadol for mucositis-related pain in head and neck cancer patients undergoing concurrent chemoradiation.
Authors: Sachin Babanrao Dhumal, Vanita Noronha, Vijay Maruti Patil, Amit Joshi, Nandini Sharrel Menon, Parmanand Jain, Kumar Prabhash
Journal: Journal of Clinical Oncology (2020)

e24124 Background: Oral mucositis related pain during CTRT in head and neck cancers is a common problem. Unfortunately, in spite of it being common, there is limited evidence for selection of systemic analgesic in this situation. Hence, this study was designed to compare the analgesic effect of an NSAID (diclofenac) versus a weak opioid (tramadol). Methods: This was an open-label, parallel design, superiority randomized controlled study. In this study head and neck cancer patients undergoing radical or adjuvant chemoradiation, who had grade 1 or above mucositis (in accordance with CTCAE version 4.03) and had pain related to it were randomly assigned to either diclofenac or tramadol for mucositis related pain control. The primary endpoint was analgesia after the 1st dose. The secondary endpoints were the rate of change in analgesic within 1 week, adverse events, and quality of life. Results: 128 patients were randomized, 66 in diclofenac and 62 in tramadol arm. The median AUC for the diclofenac arm and the tramadol arm were 348.936 units (Range 113.64-1969.23) &amp; 420.87 (101.97-1465.96) respectively (p = 0.05619). Five patients (8.1%) in the tramadol arm and 11 patients (16.7%) in the diclofenac arm required a change in analgesic within 1 week of starting the analgesic (p = 0.184). There was no statistically significant difference in any adverse events between the 2 arms. However, the rate of any grade of renal dysfunction was numerically higher in diclofenac arm (10.6% versus 4.8%, p = 0.326). Conclusions: In this phase 3 study, evaluating diclofenac and tramadol for Chemoradiation induced mucositis pain, the analgesic efficacy of both analgesics was found to be similar but diclofenac was associated with a higher rate of renal dysfunction. Clinical trial information: CTRI/2016/09/007302 .
A phase II study of induction PD-1 blockade in subjects with locally advanced mismatch repair-deficient rectal adenocarcinoma.
Authors: Andrea Cercek, Zsofia Kinga Stadler, Jenna L. Cohen, Jill A Weiss, Michelle F. Lamendola-Essel, Asha Krishnan, Rona Yaeger, Neil Howard Segal, Louise Catherine Connell, Imane H. El Dika, Nancy E. Kemeny, Leonard B. Saltz, Jesse Joshua Smith, Garrett Michael Nash, Philip Paty, Julio Garcia-Aguilar, Martin R. Weiser, Luis A. Diaz
Journal: Journal of Clinical Oncology (2020)

TPS4123 Background: The treatment of patients with locally advanced rectal cancer includes total neoadjuvant therapy with chemotherapy, chemoradiation followed by surgery. While most rectal cancers respond to combination induction chemotherapy, patients with mismatch repair deficient (dMMR) or MSI-H tumors have a significantly higher chance of progression with this treatment regimen. dMMR or MSI-H tumors have shown remarkable responses to PD-1 blockade, but the effect of neoadjuvant checkpoint inhibition has not been well studied. In this trial we will determine the pathologic complete response rate (pCR) of neoadjuvant anti-PD-1 blockade followed by standard chemoradiation in dMMR or MSI-H locally advanced rectal cancer. We hypothesize that treatment naïve dMMR or MSI-H rectal cancers will achieve a robust clinical response to PD-1 blockade and that the total neodjuvant therapy with PD-1 blockade followed by chemoradiation will improve pCR rates. Methods: Eligible patients ≥18 years of age with Stage II (T3-4, N-) or Stage III (any T, N+) histologically confirmed dMMR or MSI-H (by NGS) rectal adenocarcinoma will be enrolled. Patients will receive TSR-042 (500mg IV) every 3 weeks for a maximum of 8 cycles (6 months of treatment). Imaging, internal endoscopic exam and ctDNA blood draw will be performed at 6 weeks and every 3 months during induction anti-PD-1 treatment. Adverse events and surgical complications will be graded according to the NCI CTCAE v5 and the Clavien-Dindo classification, respectively. Following neoadjuvant checkpoint blockade, patients will undergo conventional chemoradiotherapy followed by surgical resection. The primary endpoint is pathologic complete response compared with historical control in pMMR patients. Patients will be followed up every 6 months for assessment of disease-free survival for up to five years. Clinical trial information: NCT04165772 .
Application of next generation sequencing (NGS) in gastrointestinal stromal tumor (GIST).
Authors: Bin Li, Jun Bai, Lingjun Zhu, Sen Zhang, Guihua Wang, Pingping Dai, Jiaojiao Huan, Wei Gao, Xuefeng Xia, Yan-Fang Guan, Xin Yi, Ling Yang
Journal: Journal of Clinical Oncology (2020)

e13675 Background: The majority of GISTs harbor activating mutations in KIT or PDGFRA. However, the clinical relevance of other genomic alterations, tumor mutation burden(TMB), microsatellite instability(MSI) as well as ctDNA-based clinical utility were poorly examined. Methods: A total of 106 samples obtained from 92 patients (Table) were sequenced by NGS with 1021 cancer-associated gene panel. Results: In 62 treatment naïve patients, the most common primary localization was stomach (29), followed by small intestine (22). KIT mutations were found in 52 (89.0%) cases. The most frequent alterations occurred in exon 11(48/55), followed by exon 9(6/55) and then exon 17(1/55). The primary foci of GIST patients harboring KIT exon 9 mutations was small intestine mainly. There was one patient presented with PDGFRA mutation in exon 18 (1.9%,1/62). All these cases were absent of BRAF, RAS, PIK3CA mutations, while actionable mutations detected from other genes, including CDKN2A(6/62), NF1(4/62) TSC1(2/62), PTEN(2/62) and BRCA2(2/62). Six (6/62, 10.0%) patients were KIT/ PDGFRA wild type and two of them (33.3%) detected pathogenic mutation in NF1 gene, with diagnosed age at 36 and 38 years old respectively. TMB and MSI status were analysed in 30 GIST using NGS method and no TMB-H or MSI-H sample found. Thirty-six patients who resistance to imatinib or sunitinib were screened. Nine (47.4%) and four patients (16.0%) harbored resistant mutations in KIT gene detected from tumor and blood sample cohort, concurrent sensitive and resistance mutations remain the major subtype (Table). The low percent of ctDNA detection were consistent with previous studies that clinical characteristics (tumor size, Ki67, etc.) could influence the results. Conclusions: Panel-based NGS could comprehensively elucidated the landscape of GIST and identified more tumor-specific genetic alterations which can be managed by targeted therapy. But immunotherapy and liquid biopsies remains challenging and needs further investigation from our results. [Table: see text]
Derivation and validation of a scoring system to assess pre-test probability of being COVID-19 positive
Authors: A. Borghetti, A. Ciccullo, M. Paratore, F. Rovedi, L. Stella, A. Marchetti, P. Cattani, L. Zileri Dal Verme, R. Cauda, A. Gasbarrini, S. Di Giambenedetto
Journal: Journal of Infection (2020)
VEGF-A and TGF-β in bioptates of oral squamous cell carcinoma reflect tumor response to chemotherapy and monoclonal antibodies (cetuximab).
Authors: Liubov Yu Vladimirova, Elena M. Frantsiyants, Irina V. Neskubina, Aza A. Lyanova, Elena V. Shalashnaya, Oleg I. Kit, Marina A. Engibaryan, Natalia A. Abramova, Irina L. Popova, Ludmila A. Ryadinskaya, Natalia M. Tikhanovskaya, Maria A. Teplyakova, Kristina A. Novoselova, Valeriya S Myagkova, Marina M. Sergeeva, Yuriy A. Fomenko
Journal: Journal of Clinical Oncology (2020)

e18563 Background: Cetuximab is a monoclonal antibody directed against the EGFR receptor, able to block the EGFR signaling pathway and also indirectly affect the secretion of some growth factors. The search for biomarkers responsible for cetuximab resistance is an urgent task. The purpose of the study was to analyze VEGF-A and TGF-β levels in tumor tissue bioptates in patients with squamous cell carcinoma of the oral cavity receiving chemotherapy (CT) and cetuximab. Methods: The study included 30 patients with HNSCC St III-IV, T3-4N0-1M0. All patients received 2 cycles: cisplatin 100 mg/m 2 , intravenously, day 1, 5-fluorouracil 1000 mg/m 2 /day, intravenously, 96-hour continuous infusion, in combination with targeted therapy cetuximab 400 mg/m2 on day 1 in a loading dose, then 250 mg/m2 on days 8 and 15). Patients were divided into two groups: with response to cetuximab and CT (partial regression and stabilization) n = 17 and progression considered (resistance to the treatment) n = 13. Levels of VEGF-A and TGF-β were determined in tumor tissue bioptates by ELISA using standard test systems (Bender Med System, Austria). Statistical processing of results was performed using the Statistica 6.0 program (Stat-Soft, 2001). Results: CT and cetuximab in patients with resistance did not result in statistically significant changes in levels of VEGF-A, TGF-β and the VEGF-A/TGF-β ratio in tumor tissue bioptates, compared to the initial values. The studied markers in tumor tissue bioptates in patients with response to CT were statistically significantly different from the initial values: VEGF-A was decreased by 1.46 times, TGF-β by 2.96 times, while the VEGF-A/TGF-β ratio was twice elevated (p &lt; 0.05). Conclusions: The results on levels of VEGF-A and TGF-β and the VEGF-A/TGF-β ratio are of a prognostic value and can be used for evaluating the efficacy of cetuximab and CT in patients with HNSCC.
Reply to “COVID-19 in persons with haematological cancers”: a focus on myeloid neoplasms and risk factors for mortality
Authors: Bruno Fattizzo, Juri Alessandro Giannotta, Mariarita Sciumè, Daniele Cattaneo, Cristina Bucelli, Nicola Stefano Fracchiolla, Francesco Onida, Luca Baldini, Wilma Barcellini, Alessandra Iurlo
Journal: Leukemia (2020)
帕金森病误诊28例分析
Authors: 马顺天
Journal: BMJ (2005)

帕金森病(parkinson disease,PD)也称震颤麻痹,是一种由于黑质和纹状体变性、多巴胺含量显著减少而引起的神经系统疾病.而继发性脑炎、药物中毒等帕金森样症状和病理改变者则称为帕金森综合征.静止性震颤、肌张力增强、运动减少和位置反射障碍是本病的主要临床特征[1].我院自1996年1月至2003年12月PD误诊患者共28例,现对误诊类型、原因及防范措施分析如下。
Sorafenib as an adjuvant therapy for hepatocellular carcinoma with microvascular invasion after radical resection: A prospective multicenter nonrandomized controlled study.
Authors: Li Xu, Yuhao Tang, Hua Li, Jie Zhou, Zhongguo Zhou, Yaojun Zhang, Minshan Chen
Journal: Journal of Clinical Oncology (2020)

e16685 Background: Hepatocellular carcinoma (HCC) with microvascular invasion (MVI) is established with poorer outcome and more frequent postoperative recurrence. Sorafenib is the first target drug that successfully prolongs the survival of advanced HCC, but it failed to prolong the survival of HCC after radical resection or ablation in the STORM study. After that, series studies revealed that sorafenib could improve the survival of HCC with MVI after surgery, while most studies with positive results were retrospective ones. Methods: A multicenter, prospective non-randomized, open-label study was performed in pts undergoing radical resection, postoperative pathology confirming HCC with MVI (BCLC A or B stage; T2 or part T3aN0M0). Pts in the treatment group (S group) started sorafenib within 4-6 postoperative weeks at the dose of 400mg per day at most 2 years, and the control group (C group) never received sorafenib. The primary endpoint is recurrence-free survival (RFS) rate at the 2nd postoperative year, and the secondary endpoints include postoperative median time to recurrence (TTR), 1-year postoperative RFS, pts’ overall survival (OS), and safety. This study was approved by Ethical Committee of Sun Yat-sen University Cancer Center, and registered at ClinicalTrials.gov with number NCT02867280. Results: Between 1 June 2015 and 31 August 2019, 154 eligible pts from 3 academic hospitals in China were enrolled (83 in C group and 53 in S group). Baseline demographics were balanced between the two groups. The 2-yr RFS rate was 56.1% in the S group vs. 55.7% in the C group, respectively ( P = 0.955), and the median RFS was 15.5 vs. 16.0 months ( P = 0.827).The recurrence rates at the 1st postoperative year were 38.6% vs. 34.0% ( P = 0.568), and the median TTR was the same as the RFS. There were 31 pts (54.4%) of the S group experienced treatment-related adverse events (AEs). The most common AE was hand-foot syndrome (HFS, 19/57, 10 pts ≥ grade-2). Other AEs included diarrhoea (15/57, 26.4%), alopecia (11/57, 19.3%), hypertension (5/57, 8.8%) and decreased platelet (3/57, 5.3%), and gastric ulcer with bleeding (1/57, 1.8%). Sorafenib was interrupted or discontinued in 7 pts due to AEs. Recruiting of this study was closed according to the results of the planned mid-term analysis, and all pts were followed on schedule to observe the other survival data. Conclusions: Postoperative sorafenib treatment with dose of 400mg once daily was well tolerated, but did not improve the RFS and TTR of Chinese HCC pts with MVI. Clinical trial information: NCT02867280 .
Genomic landscape and clinicopathological characteristics of lung cancer in young Chinese patients.
Authors: Jiexia Zhang, Xiaoling Tong, Hua Bao, Xue Wu, Xiaonan Wang, Yang Shao
Journal: Journal of Clinical Oncology (2020)

e13520 Background: Approximately 2-3% of lung cancer (LC) was found in very young patients (≤ 45 years old) and they were reported to have different clinical characteristics and genetic profiles when compared to older patients. However, it is still lack of large-scale genomic studies that could provide deep insights into the tumorigenesis, precision treatment and prognosis for this particular population. Methods: Clinically annotated data of targeted next generation sequencing (NGS) on 7858 tumor tissue specimens from LC patients were analyzed. For all specimens, a total of 422 or 425 cancer-related genes were interrogated with a mean coverage depth greater than 500x. Results: Of 7858 LC cases, 814 of them were younger than 45 (age at diagnosis), which were compared to 7044 old LC cases ( &gt; 45 years old). Clinical information showed that young LC are more prevalent in female, to be more advanced disease and to have more adenocarcinoma in histology. Somatic genomic data analysis revealed that compared to old LC, young LC has significantly higher ALK/ROS1/RET fusions, ERBB2 mutations and 5q amplification(FDR &lt; 0.1), but lower mutational frequencies in KRAS, CDKN2A, ERBB4, FAT1, NF1, lower copy number gain (CNG) of PIK3CA, MDM2, FGFR1, and less 5q deletion(FDR &lt; 0.1). Interestingly, in young LC, genetic differences between female and male are not significant, with TP53 and EGFR being most frequently mutated in both sexes. Similarly, the differences between young and old female LC are also limit, with young female LC having more ALK fusions (13.43% vs. 5.1%, FDR &lt; 0.01), less EGFR mutations and MDM2 CNG than old female. On the contrary, male patients demonstrated much wide disparity between young and old LC: young LC was enriched with ALK/ROS1/RET/ERBB2 fusions and mutations in EGFR, ERBB2 and SMAD2, while old LC have more mutations in KRAS, TP53, CDKN2A, and CNG of PIK3CA (all FDR &lt; 0.1). We also found that EGFR exon19 deletion (19del) was significantly enriched in young LC, especially in male, while p.L858R showed preference in old LC. Conclusions: The data suggest that the prevalence of different genetic alterations is both age and sex related. The high level of ALK/ROS1/RET fusions and less CNV in young LC could potentially lead to more effective treatment and better prognosis. We also noted that genomic alterations in young LC were not significantly different across sexes, but the disparity by sex was enormously enlarged in old LC, which might be correlated to their life-long exposures, such as smoking, life styles and sex-affected factors.