tbuckley/cabot-search huggingface dataset:
A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2-positive advanced gastric cancer (Ni-HIGH study): Safety evaluation.
Authors: Daisuke Takahari, Hirokazu Shoji, Keiko Minashi, Hiroki Hara, Keisho Chin, Akira Ooki, Mariko Ogura, Izuma Nakayama, Ken Kato, Satoru Iwasa, Hidekazu Hirano, Yusuke Amanuma, Naoki Ishizuka, Narikazu Boku, Kensei Yamaguchi
Journal: Journal of Clinical Oncology (2020)

4525 Background: Addition of an anti-PD-1 antibody to trastuzumab (Tmab) reportedly enhances ADCC activity of Tmab, leading to an additive antitumor effect. We investigated the safety and tolerability of nivolumab (Nivo) plus Tmab combined with S-1 or capecitabine (Cape) and oxaliplatin (Ox) for pts with HER2-positive (+) advanced gastric cancer (AGC). Here, we report the safety evaluation results. Methods: This open-label, phase 1b study was conducted at four centers in Japan. The study consisted of safety (n = 12) and expansion (n = 24–30) parts. Chemotherapy-naïve pts aged ≥ 20 years with histopathologically confirmed HER2+ AGC and measurable lesions were eligible. In the safety evaluation, pts were assigned to cohort 1 or 2 in sequence. Pts received Nivo (360 mg, day 1), Tmab (course 1: 8 mg/kg; course 2–: 6 mg/kg, day 1), Ox (130 mg/m 2 , day 1) and either S-1 (40 mg/m 2 bid, days 1–14; cohort 1) or Cape (1000 mg/m 2 bid, days 1–14; cohort 2) every 3 weeks until disease progression or unacceptable toxicity. The primary purpose of the safety evaluation was to determine the toxicity and tolerability of this combination therapy. An independent data and safety monitoring committee assessed the tolerability of the study treatments before starting the second treatment course. A preliminary evaluation of tumor response on the cut-off date (December 16, 2019) was also performed. Results: From November 2018 to August 2019, 12 pts with HER2+ AGC were enrolled in the safety part (six pts each in cohorts 1 and 2). During the 1st course, all 12 pts experienced at least one adverse event (AE). The most common AEs were peripheral sensory neuropathy (PSN) (n = 4) and leukocytopenia (n = 3) in cohort 1 and PSN (n = 5) and anorexia (n = 4) in cohort 2. AEs of grade ≥ 3 were observed in only one pt in cohort 1 (grade 3 neutropenia). No pt suspended or discontinued study treatments due to AEs. One pt in cohort 1 reduced dose of S-1 due to grade 2 erythema and continued the subsequent courses with the dose. After a median follow-up of 6.1 (range, 3.1–13.3) months, one pt from cohort 1 achieved a complete response, eight pts (four in each cohort) achieved a partial response, and three pts (one in cohort 1 and two in cohort 2) showed stable disease. No progressive disease was observed. Conclusions: Both Nivo plus Tmab and either S-1 or Cape plus Ox are tolerable in pts with HER2+ AGC. Both cohorts 1 and 2 have progressed to the expansion part of the study. Clinical trial information: 000034222 .
Effect of live education targeted to genetic counselors on knowledge and competence.
Authors: Vanessa Carranza, Susan H. Gitzinger, Bryan Carson Taylor, Joan B. Fowler
Journal: Journal of Clinical Oncology (2020)

11035 Background: Rapid advancements in genomics and sequencing technologies have presented a growing need for experts in the field of genetics to translate results and optimize patient care. As knowledge regarding DNA mutations and the technology to properly detect them continuously advances, it will be vital that genetic counselors play a larger role in the oncology healthcare team. Methods: These activities were designed to target genetic counselors involved in the diagnosis, management and genetic counseling of patients who have or are at risk for DDR-mutated cancers, attending live symposia at the 2018 &amp; 2019 American College of Medical Genetics &amp; Genomics Annual Meeting. Learning and knowledge was objectively assessed by analyzing pre- and post-test results before and after the educational activities. To determine retention of knowledge over time, follow-up assessments were sent to participants after each live activity. Assessment questions in the form of case studies were utilized to gauge whether participants translated knowledge into practice at follow-up. Statistical testing between pre- and post-tests and from pre-test to follow-up were conducted via chi square analysis with a priori significance set at 0.05. Results: Evaluations were collected from N = 275 (onsite) participants. Improved learners, as determined by significant ( P &lt; 0.05) increases in correct responses, were observed in several specific topic areas: When to consider germline testing (2018 participants: 53.33% pre-test vs. 87.5% post-test; 2019 participants: 42.55% pre-test vs. 84.72% post-test). Patients most likely to benefit from a PARP inhibitor based on genetic testing results (2018 participants: 50% pre-test vs. 93.75% post-test; 2019 participants: 75.49% pre-test vs. 94.37% post-test). However not all improvement was sustained at follow-up: When it is appropriate to consider germline testing (2018 participants: 64.44% at follow-up – not significant ( P= 0.138); 2019 participants: 85% at follow-up ( P&lt; 0.001). Patients most likely to benefit from a PARP inhibitor based on genetic testing results (2018 participants: 68.89% at follow-up – not significant ( P= 0.140); 2019 participants: 65% at follow-up – not significant ( P= 0.329). Conclusions: This analysis shows that live accredited education can significantly improve the knowledge and competence of genetic counselors in multiple areas surrounding the use of germline testing to guide treatment recommendations. Results also suggest that ongoing education in clinically appropriate scenarios is warranted.
ctDNA levels before treatment predict survival in non-small cell lung cancer patients treated with a tyrosine kinase inhibitor.
Authors: Mariano Provencio-Pulla, Roberto Serna, Fernando Franco, Alfredo Sanchez, Carlos García Girón, Manuel Domine, Carlos Camps, Jose Miguel Sanchez Torres, Juana Maria Oramas Rodriguez, Luis Enrique Chara Velarde, Ana Laura Ortega, María Ángeles Sala, Berta Hernandez, Maria Sereno, Joaquim Bosch-Barrera, Airam Padilla, Jose Balsalobre Yago, Remei Blanco, Javier De Castro, Atocha Romero
Journal: Journal of Clinical Oncology (2020)

9542 Background: Currently there is an intense debate concerning therapeutic strategies in EGFR positive NSCLC patients with advance disease. Osimertinib is superior to standard EGFR Tyrosine Kinase Inhibitors (TKIs) as first line treatment. However, it is yet unclear whether this option is superior to sequential treatment of a 1 st or 2 nd generation TKI followed by osimertinib. In order to clarify this issue it is important to identify which patients are at high risk of progression disease. Methods: This is a prospective, multicentre, cross-sectional study promoted by Spanish Lung Cancer Group. 698 plasma samples from 196 advanced NSCLC patients with tumors harboring an EGFR activating mutation and treated with a first line TKI (afatinib, gefitinib, erlotinib or osimertinib) were analyzed. Plasma samples were prospectively collected before treatment (T0), after 3 months of treatment (T3), after 6 months of treatment (T6) and at first disease progression. EGFR mutations were analyzed by dPCR. Multivariate Cox proportional hazards analysis was used to determine the significance of ctDNA in the prediction of prognosis. Results: The median follow up was 19.8 months. At baseline patients with plasma EGFR sensitizing mutations at allele frequency (AF) ≥ 10% had worse OS and PFS than patients in which the opposite occurred (HR = 1.86; 95 %CI: 1.09-3.17, and HR = 1.65; 95 %CI: 1.07-2.58, respectively). Noteworthy, median OS and PFS time were 18.6 and 8.8 months respectively, in patients with plasma AF≥10% before treatment initiation compared to 37.9 and 12.4 months for patients with plasma AF &lt; 10%. Similar results were obtained when a cutoff of AF≥ 5% was used (HR = 1.73; 95%CI: 1.02-2.94 for OS, and HR = 1.72; 95%CI: 1.13-2.61 for PFS). Patients who remained ctDNA-positive after 3 months of treatment exhibited also poorer outcomes (HR = 3.24; 95%CI: 1.77-5.94 for OS, and HR = 3.1; 95%CI: 1.91-5.03 for PFS). In the same way, detectable levels of ctDNA after 6 months of treatment predicted shorter OS and PFS (HR = 3.3; 95%CI: 1.53-7.13 and HR = 2.62; 95%CI: 1.62-4.25, respectively). Conclusions: ctDNA levels significantly predict survival. Moreover, ctDNA levels before treatment initiation can be useful to assess patient’s progression risk which is not possible to assess otherwise facilitating treatment decision making.
Efficacy and hepatotoxicity of Infliximab in resolving steroid-refractory immune-related adverse events (irAEs) in a real-world setting.
Authors: Thiago Pimentel Muniz, Daniel Vilarim Araujo, Anjie Yang, Hadas Sorotsky, Sareh Keshavarzi, Marcus O. Butler, Samuel Saibil, Anna Spreafico, David Hogg
Journal: Journal of Clinical Oncology (2020)

e15227 Background: Infliximab is used to treat steroid-refractory immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICI). Current dogma holds that infliximab is contraindicated in immune hepatitis; steroid refractory disease should be managed with mycophenolate mofetil (MMF). This is based on anecdotal reports of infliximab-induced hepatotoxicity in patients with rheumatologic diseases who received multiple infusions of the drug. In this series of 56 consecutive cases of infliximab-treated patients, we assessed the efficacy of infliximab in resolving specific steroid-refractory irAEs and evaluated the risk of hepatotoxicity from this drug. Methods: We reviewed consecutive patients treated with infliximab for steroid-refractory irAE at a tertiary cancer center between January 2010 and February 2019. To judge hepatotoxicity, we used the Wilcoxon signed rank test to compare the mean value of ALT, AST and total bilirubin (BT) between 0-4 weeks before and after infliximab therapy. We compared factors associated with infliximab efficacy by logistic regression. A p value &lt; 0.05 was considered statistically significant. Results: Mean age was 61.9 years. The majority had a diagnosis of melanoma (62%); 45% had a combination of two ICI before toxicity onset, of whom 73% received an anti-PD1 and an anti-CTLA-4. Colitis was the most common toxicity (66%), followed by pneumonitis (11%). Infliximab was used to treat immune related hepatitis (ir-hepatitis) in 1 patient (2%). Median number of infliximab doses was 1 (1-3), with resolution of toxicity in 76% of patients. Colitis was likely to resolve with infliximab in comparison to other irAE [OR 0.2(95% CI 0.05-0.73)]. Univariate logistic regression did not demonstrate statistical difference in toxicity outcome when ICI were given either as monotherapy (p = 0.3) or combination (p = 0.97). Mean BT, ALT and AST levels before and after infliximab were not statistically different (see table), with no evidence of infliximab-induced hepatotoxicity. The patient treated for ir-hepatitis had a complete recovery, with no further hepatotoxicity. Conclusions: Infliximab was effective in treating irAE and was not associated with hepatotoxicity in this dose-limited setting. Infliximab may be an alternative to MMF in steroid-refractory ir-hepatitis and should be tested prospectively in a randomized trial. [Table: see text]
A novel XNA-based NGS panel for cancer diagnostics.
Authors: Qiang Gan, Zhen Cui, Simin Tang, Michael Joseph Powell, Aiguo Zhang, Michael Y. Sha
Journal: Journal of Clinical Oncology (2020)

e16142 Background: Identification of genetic variants with low allelic frequency using NGS method is confounded by the complexity of the human genome sequence and by bias and errors that arise during library preparation, sequencing and analysis. To overcome this, we developed a novel NGS approach employing a modified backbone nucleic acid molecule, Xenonucleic Acid (XNA) to enrich the target mutant before the sequencing. XNA enables to efficiently and selectively suppress wild type targeted DNA amplification but amplify targeted mutant alleles. Methods: We developed this XNA-based NGS for detection of mutations in lung and colorectal cancer which includes 8 genes (KRAS, NRAS, EGFR, BRAF, PIK3CA, APC, CTNNB1 and TP53) and 19 hotspots. Results: With as low as 10 ng input DNA, low allelic frequency mutant analysis powered by the XNAs in the library preparation increased the sensitivity of detection dramatically. There were, on average, 32, 24, 25 and 18-fold enrichment in variant allele frequency (VAF) for samples with original 0.10%, 0.25%, 0.50% and 1.25% VAF mutants, respectively. The analytical specificity is about 92% and analytical sensitivity (LOD) can be down to 0.10% VAF with 1000-2000X on Illumina MiSeq. The reproducibility results were obtained for intra-assays, inter-assays and inter-operator assays, and the CVs of detected VAF% were investigated. These 19 actionable mutants were validated by testing cfDNA and FFPE. Preliminary clinical sensitivity for FFPE sample is about 100% for lung cancer and colorectal cancer samples respectively, comparing to without XNA NGS about 85.7% for lung cancer and 70% for colon cancer. For cfDNA sample its clinical sensitivity is about 100% for lung and colon cancer, but without XNA mediated enrichment NGS is only about 70% for lung cancer and undetectable for early colon cancer. Conclusions: The result demonstrated that XNA can selectively block amplification of wild type alleles and leads to enrich of mutants read, and significantly increases the assay sensitivity without the requirement for NGS deeper sequencing.
Evaluation of spatiotemporal heterogeneity of tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) at baseline diagnosis and after chemotherapy.
Authors: Katherine I. Zhou, Bryan Peterson, Anthony Serritella, Natalie Reizine, Yan Wang, Daniel V.T. Catenacci
Journal: Journal of Clinical Oncology (2020)

4546 Background: Tumor mutational burden (TMB) may be a predictive marker for response to anti-PD1/PDL1 agents (IO). Molecular heterogeneity of various biomarkers for GEA has been established. To characterize heterogeneity of TMB and its clinical relevance, we compared TMB in primary (1 0 ) &amp; metastatic (met) tumors at baseline newly diagnosed stage IV advanced GEA (aGEA), and before &amp; after chemotherapy treatment (tx) for stage II–IV GEA. We assessed the prognostic relevance of TMB in aGEA. Methods: We retrospectively reviewed a cohort of 127 patients (pts) diagnosed with GEA in 2012–2019, for a total of 280 tumor samples with TMB data. TMB level was defined as low (≤5/Mb), intermediate (int) ( &gt; 5/Mb, ≤15/Mb), or high (hi) (≥15/Mb), determined by Foundation One. Analysis was performed by Fisher’s exact test for PDL1/TMB, McNemar’s test for paired TMB, and univariate Cox proportional-hazards model for overall survival (OS). Results: Of 280 tumors, 50% (140/280) had low TMB, 45% (125/280) int TMB, &amp; 5% (15/280) hi TMB. TMB ranged 0–58.6/Mb (median 5.3/Mb). Of tumors with hi TMB, 53% (8/15) were MSI-Hi, while of MSI-Hi tumors, 100% (8/8) were TMB hi. TMB level did not correlate with PDL1 status ( p= 0.83). Concordance between TMB levels of paired baseline 1 0 and baseline met tumors was 66% (29/44) (Table). TMB level was lower in the met than in the 1 0 in 23% (10/44) of cases, and higher in the met in 11% (5/44). Of 4 TMB hi baseline 1 0 tumors, 2 were not TMB hi in the met; of 40 TMB low/int baseline 1 0 tumors, 0 were TMB hi in the met ( p= 0.16). Post-tx tumors exhibited 71% (42/59) concordance of TMB levels compared to pre-tx 1 0 tumors. Of 2 TMB hi baseline tumors, 1 was not TMB hi in the post-tx tumor; of 57 TMB low/int baseline tumors, 0 were TMB hi in the post-tx tumor ( p= 0.32). In pts with aGEA at diagnosis, OS did not significantly differ depending on baseline 1 0 tumor TMB level (median OS of 21.4 [95% CI 15.4–27.9] months for TMB low, 14.6 [10.9–23.5] months for TMB int, and 9.6 [3.9–NA] for TMB hi; p= 0.3), nor depending on baseline met TMB level. Conclusions: Notable baseline spatial discordance of TMB was observed, particularly TMB hi 1 0 to low/int met. Discordance was also observed before &amp; after tx, without significant increase towards TMB hi temporally. Spatiotemporal heterogeneity may impact the role of TMB as a predictive biomarker &amp; warrants further study. [Table: see text]
Estimation of absolute benefit of S-1 postoperative therapy for ER-positive, HER2-negative breast cancer: Exploratory analysis of the phase III potent trial.
Authors: Masahiro Takada, Shigeru Imoto, Takanori Ishida, Yoshinori Ito, Hiroji Iwata, Norikazu Masuda, Hirofumi Mukai, Shigehira Saji, Takafumi Ikeda, Hironori Haga, Toshiaki Saeki, Kenjiro Aogi, Tomoharu Sugie, Takayuki Ueno, Shinji Ohno, Hiroshi Ishiguro, Chizuko Kanbayashi, Takeshi Miyamoto, Yasuo Ohashi, Masakazu Toi
Journal: Journal of Clinical Oncology (2020)

532 Background: Estimation of risk of recurrence is critical for adjuvant therapy decision making in patients with primary breast cancer. The POTENT trial examined outcomes associated with standard postoperative endocrine therapy with/without S-1 in patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer (Toi et al, San Antonio Breast Cancer Symposium 2019). The aim of this study was to investigate absolute treatment effect across recurrence risk score to individualize indication for the concurrent administration of standard postoperative endocrine therapy with S-1. Methods: The POTENT trial included 1930 patients with ER-positive and HER2-negative breast cancer. The primary end point was invasive disease-free survival (iDFS). A continuous, composite measure of recurrence risk for each patient was determined from a Cox model incorporating age, tumor size, nodal status, grade, estrogen receptor, and Ki-67 expression levels. Absolute treatment effect of S-1 was estimated in each risk group defined by the composite risk score. Results: Of 1930 patients, we included the data from 1897 patients without unavailable data. Tumor grade, ER expression, and Ki-67 expression were available from central assessment. A Cox proportional hazards model for iDFS was estimated in standard endocrine therapy only group (N = 954). Age was excluded from the model because it did not add prognostic information. 5-year iDFS estimates were 91.6%, 82.0%, and 67.2% for low, intermediate, and high composite risk group, respectively. Absolute improvement in 5-year iDFS by the addition of S-1 to standard endocrine therapy were 0.9%, 6.7%, and 8.1% for low, intermediate, and high composite risk group, respectively. Hazard ratio for S-1 in each risk group were 0.86 (95%CI: 0.45-1.63, P = 0.642), 0.51 (95%CI: 0.34-0.78, P = 0.001), and 0.71 (95%CI: 0.49-1.02, P = 0.064), respectively. Continuous value of composite risk was also prognostic in a Cox proportional hazards model stratified by S-1 and neoadjuvant/adjuvant chemotherapy use (HR 2.58, 95%CI: 2.13-3.11, P &lt; 0.0001). Conclusions: Patients with ER-positive and HER2-negative disease, and intermediate to high risk, defined by clinicopathological factors, experienced absolute improvement of about 7-8% in 5-year iDFS with addition of S-1 to standard endocrine therapy, while improvement was minimal in those at low risk. Clinical trial information: 000003969 .
浦东新区人群血糖水平和血糖变异性分布状况研究
Authors: 冯波, 赵秀丽, 李栩, 黄亦文, 乐秀康, 富明, 陈明慧, 倪亚芳, 赵竹芳, 周凤英, 孟仲莹, 王惠玲, 姚国良, 张容, 刘昊, 张小倩
Journal: BMJ (2005)

为了解社区自然人群血糖变异特点及其分布情况,对浦东新区的1 628人进行调查,检测空腹血糖和75 g葡萄糖负荷后2 h血糖,并计算两者之间的血糖变异系数.结果显示血糖代谢异常发生率较高,其中糖耐量低减者占较大比例.血糖变异系数与空腹血糖、75 g葡萄糖负荷后2 h血糖呈正相关.血糖代谢异常与年龄、体重指数和高血压等因素相关。
经皮肾镜取石术后急性肺栓塞合并脑栓塞一例
Authors: 刘仁水, 刘湘群, 陈琼
Journal: BMJ (2009)

患者男,50岁.因反复右腰部疼痛4年入院.既往有原发性高血压1级病史3年,未服用过降压药物.入院体查:血压125/95 mm Hg(1 mm Hg=0.133 kPa),体重92 kg,营养过剩,重度肥胖体形,双肺呼吸音清晰,未闻及干湿啰音,心率73次/min,律齐,心音有力,各瓣膜区未闻及病理性杂音,腹部各项无异常.腹部彩色超声:右肾多发性结石并轻度积水.心电图正常。
A phase I, open-label, dose-escalation trial of BI 1701963 as monotherapy and in combination with trametinib in patients with KRAS mutated advanced or metastatic solid tumors.
Authors: Eelke Gort, Melissa Lynne Johnson, Jimmy J. Hwang, Shubham Pant, Ulrich Dünzinger, Kathrin Riemann, Thomas Kitzing, Pasi A. Janne
Journal: Journal of Clinical Oncology (2020)

TPS3651 Background: Activating mutations of KRAS drive many types of cancer. Activation of KRAS relies on guanine nucleotide exchange factors, such as SOS1, to mediate exchange of GDP for GTP. BI 1701963 is a small-molecule protein–protein interaction inhibitor that prevents the interaction between KRAS and SOS. Binding of BI 1701963 to the catalytic site of SOS1 inhibits binding of SOS1 to RAS–GDP, thereby hindering the exchange from RAS–GDP (inactive form) to RAS–GTP (active form). In preclinical studies this has been shown to lead to cytostasis in cancer cells addicted to KRAS signaling. Methods: NCT04111458 is a first-in-human trial of BI 1701963 in patients aged ≥18 years with tumors harboring KRAS mutations. Primary objectives are to determine the maximum tolerated dose (MTD) and recommended Phase II dose of BI 1701963 as monotherapy and in combination with trametinib, based on dose-limiting toxicities (DLTs). Secondary objectives are to evaluate safety, tolerability, pharmacokinetics/-dynamics and preliminary efficacy. The study will have two arms (mono- and combination therapy), and be divided into dose escalation (Part A), confirmation (Part B) and expansion (Part C, combination only) phases. Inclusion criteria include activating KRAS mutation, ≥1 evaluable lesion (RECIST 1.1), ECOG PS ≤1 and adequate organ function. Exclusion criteria include history of: RAS, MAPK or SOS1 targeting therapies; retinal vein occlusion; retinal pigment epithelial detachment; and decreased cardiac function. Parts B and C will be conducted in patients with advanced NSCLC. Treatment will continue until confirmed clinical benefit, defined toxicities, or withdrawal of consent. The primary endpoints are: Part A, the MTD, and the number of patients with DLTs during Cycle 1; Part B (monotherapy), the number of patients with DLTs; Part C, objective response (OR, RECIST 1.1). Starting doses of BI 1701963 in Part A will be 50 mg once daily (QD) orally (monotherapy) and 100 mg QD (combination, once proved safe as monotherapy) and will be escalated until the MTD is reached. The starting dose of trametinib will be 1 mg QD, escalated to the MTD or a max. of 2 mg QD. Dose cohorts will include ≥3 patients, with two therapeutic relevant doses (TRDs) established in each arm. In Part B, patients will be randomized to groups receiving one of the TRDs. If an OR is observed at a TRD in the combination arm, additional patients will be recruited into expansion cohorts receiving the relevant dose. As of Feb 11, 2020 three patients have been treated. Clinical trial information: NCT04111458 .