tbuckley/cabot-search huggingface dataset:
Clinical use of RNA sequencing and oncobox analytics to predict personalized targeted therapeutic efficacy.
Authors: Elena Poddubskaya, Maxim Sorokin, Andrew Garazha, Alex Glusker, Alexey Moisseev, Marina Sekacheva, Maria Suntsova, Ella L Kim, Nurshat Gaifullin, Victor Tkachev, Alf Giese, Viktoria Barbara, Nikolay Borisov, Anton Buzdin
Journal: Journal of Clinical Oncology (2020)

e13676 Background: Analysis of mutation profiles in cancer patients does not provide clinical benefits in 80-90% of cases in the US (Marquart et al., 2018). Gene expression analysis potentially complements standard detection of clinically relevant mutations. Methods: 239 adult late-stage cancer patients. RNA gene expression sequencing completed on solid tumor samples using FFPE blocks. Patient mRNA profiles were analyzed using Oncobox bioinformatics, prioritizing target drugs according to their personalized predicted efficacy. Summary reports were provided to oncologists and resulting treatment selection and outcomes were assessed. Results: As of February 2020, feedback was received from participating doctors for 224 patients; 34 patients died before therapy prescription, 52 patients received treatment other than targeted therapy (chemo, surgery, radiation, or palliative care), 75 patients received at least one targeted therapy (single or combination therapy) predicted to be effective based on Oncobox analysis (“RNAseq cohort”). 63 patients received chemo or other drug therapy predicted to be potentially ineffective from Oncobox analysis (“other cohort”). Therapeutic response was obtained on 46 patients with biopsies collected no longer than 6 months prior to analysis who had no further surgery (30 in the RNAseq cohort and 16 in the other cohort). 63% of the RNAseq cohort obtained either partial response or stable disease using Oncobox guided therapies, compared to 44% of the other cohort (19% increase of disease control). The RNAseq cohort had higher mean prior therapies (1.3) compared to the other cohort (0.8) indicating more advanced disease. The similarly designed WINTHER trial reported ~8% increase of disease control using gene expression-guided vs mutation-guided therapeutics in a cohort of advanced cancer patients averaging three prior therapies (Rodon et al., 2019). Conclusions: Collectively these data suggest that gene expression profiling provides a more clinically relevant therapeutic match, and better response rates, than mutation guided therapeutic treatments. This potentially results in improved clinical outcomes for cancer patients. Clinical trial information: NCT03724097.
Diagnostic yield and clinical utility of germline genetic testing following somatic testing in breast cancer patients.
Authors: Stephen E Lincoln, Kingshuk Das, Nhu Ngo, Sarah M. Nielsen, Scott T. Michalski, Shan Yang, Daniel Esteban Pineda Alvarez, Robert Luke Nussbaum, Edward D. Esplin
Journal: Journal of Clinical Oncology (2020)

1092 Background: Germline genetic testing is recommended for breast cancer patients with specific presentations or family histories. Separately, tumor DNA sequencing is increasingly used to inform therapy, most often in patients with advanced disease. Recent NCCN and ESMO guidelines recommend germline testing following somatic testing, under specific circumstances and for specific genes. We examined the utility of germline findings in patients referred for both test modalities. Methods: We reviewed somatic and germline mutations in a consecutive series of patients who: (a) had a current or previous breast cancer diagnosis, (b) were referred for germline testing, and (c) previously received tumor sequencing. Diverse reasons for germline testing included: a tumor finding of potential germline origin, treatment or surgical planning, personal or family history, and patient concern. Results: 227 patients met study criteria of whom 88 (39%) harbored a pathogenic germline variant (PGV) in a high or moderate risk cancer predisposition gene. Mutations in certain genes were most likely to be of germline origin, and most PGVs were potentially actionable (Table). 13% of PGVs were not reported by tumor tests as either germline or somatic findings, usually a result of tumor test limitations. Of note, 27 of the patients with PGVs (31%) had these variants uncovered only after presenting with a second, possibly preventable, malignancy. Conclusions: Germline testing following tumor sequencing often yielded findings that may impact care. Indeed, the 39% PGV rate we observed suggests that such testing may be underutilized. We observed actionable PGVs missed by somatic tests, PGVs uncovered in patients’ second malignancies, and PGVs not within germline reflex testing criteria. These results reinforce the utility of germline testing separate from somatic testing in appropriate patients. [Table: see text]
Prevalence of BRCA1 and BRCA 2 and other mutations in Chilean population.
Authors: Carolina Selman, Mabel Hurtado, Badir Chahuan, Fabiola Mella, Hugo Marsiglia
Journal: Journal of Clinical Oncology (2020)

e13553 Background: Arturo López Pérez Foundation (FALP) is a Chilean Institution aimed to treatment of cancer patients. Since 2016 it has an Unit for Oncological Genetic Counseling (AGO) for patients with warning flags of potential cases of cancer of genetic origin AGO Unit is aimed to capture patients with warning flags and deliver information through pre-test counseling, offer possibility of a genetic test and post-test counseling. The purpose of this review is to provide relevant results of four years of this Unit. Methods: A descriptive study was carried out from patient care in the Oncological Genetic Counseling Unit of FALP between 2016 and 2019. It was considered those cases in which the process of pretest/post-test counseling was performed. Six "warningflags" were established: cancer in patients under 50 years of age, triple negative breast cancer, breast cancer in men, ovarian cancer, history of 2 or more primary cancers and a family history of cancer The number of test performed was analyzed. The results were expressed in positive pathogenic variants, uncertain variants and negative results. Results: 365 genetic counseling processes were carried out during the period. The average consultation age was 43.2 years (20.8 and 75.5) and 90.1% (329 attentions ) were female. Of the patients, 79.7% (294) perform the genetic test. 18.5% tested positive for a pathogenic variant, 6.5% for a pathogenic variant plus an uncertain variable, and 2.8% for two pathogenic variants. The mutations found were BRCA2 32.6% BRCA1 29.1%, ATM 10.1% RAD51C 6.7% CDKN2 A 5.6%, MUTYH 3.4% TP53 3.4%, MSH2 3.4% RAD51D 2.4%), NF1 1.1%, NTHL1 1.1%, RET 1.1% A 64.9% (237 patients) had cancer diagnosed at the time of the consultation, versus 33.1% of healthy care. 2% had no information. The type of cancer present was 79.7% breast cancer (189), 8.0% ovarian cancer, 2.1% thyroid cancer, 1.7% breast and ovarian cancer, 0.9% colon and/or endometrial cancer and 7.6% other cancers. The warning flags present were 41.2% age below 50 years, 26.2% family history, 15.4% relatives of people with positive results, 8.5% patients with triple-negative breast cancer, 5.3% patients with ovarian cancer, 2.8% patients with 2 or more primary cancers, and 0.6% male breast cancer patients. Conclusions: The highest percentage of patient care was for women with breast cancer, under 50 years of age. The overall test positivity rate is a cumulative 29%. Mutations in BRCA 1 and BRCA 2 were the most detected mutations, as reported in the literature. The slight predominance of BRCA 2 may be due to a familiar component. This is the largest report made in the Chilean population.
Expression of immune response markers in Arab patients with lung cancer.
Authors: Abdul Rahman Jazieh, Adda Bounedjar, Hanaa Bamefleh, Turki Al-Fayea, Hatim Q. Almaghraby, Ayed Belarabi, Wahiba Ouahioune, Zoubir Derbouz, Mohammad Alkaiyat, Khaled Alkattan, Moussab Damlaj, Walid Khalbuss
Journal: Journal of Clinical Oncology (2020)

e21543 Background: Programmed death-ligand 1 (PD-L1) is a marker for checkpoint inhibitors use in management of solid tumor especially non-small cell lung cancer (NSCLC). Our study aimed at determining the patterns of PD-L1 expression and CD8 immunostains in patients with NSCLC in Arab population. Methods: Archival tumor tissue form patients with confirmed diagnosis of NCSLC were obtained and stained for PD-L1 using antibody 22C3 by Dako using Immuno-histochemistry stain (IHC) and giving Tumor Proportion Score (TPS) a percentage number from 0 to 100% of stained tumor cells. Tumors were categorized into negative expressers (TPS&lt;1%), low positive (TPS 1-49%), and high positive (TPS 50% -100%). Correlation of expression with clinical and pathological features including CD8+ lymphocyte density was analyzed. Results: Two hundred NSCLC cases were included in the study from 6 centers in Saudi Arabia and Algeria. Median age was 65 years (28-93) and majority were males (75%) with stage 4 NSCLC (64%). The TPS was high in 37 patients (18%), low in 60 patients (30%), and negative in 103 patients (52%). In a univariate analysis, the following were significant predictors of any PD-L1 expression (&gt;1%): male gender, being Saudi national patients, high expression of CD8+ and the presence of tumor infiltrating lymphocytes. In the multivariate analysis, only high expression of CD8+ cells (&gt;2+) was significant with Odd Ratio (OR) of 4.4 (95% Confidence interval 1.5-12.9, p value of 0.003). Conclusions: PD-L1 expression in our population is similar to the published literature and correlated with the density of CD8+ cells. Validation of the predictive value of this marker in our population and identifying easier and reliable methods to test for it is warranted.
Anlotinib plus S-1 for patients with EGFR mutation-negative advanced squamous cell lung cancer with poor performance status after second or more -line treatment.
Authors: Xiaohong Xie, Fei Wang, Ming Liu, Xinqing Lin, Yinyin Qin, Zhanhong Xie, Jiexia Zhang, Ming Ouyang, Chengzhi Zhou
Journal: Journal of Clinical Oncology (2020)

e21665 Background: The study aimed to analyze the efficacy and safety of combination regimen of anlotinib and S-1 for Chinese patients with EGFR mutation-negative advanced squamous cell lung cancer (SqCLC) with poor performance status (PS, 2-3) after second-or-more-line treatment. Methods: Clinical data of 32 SqCLC patients with PS scores of 2-3 treated in the First Affiliated Hospital of Guangzhou Medical University between Jan.1, 2018 to Sep.31, 2019 who failed second-or-more-line treatment were analyzed retrospectively. The patients were divided into two treatment groups: anlotinib (12mg) plus S-1 (25mg) combination group and S1 (12mg) monotherapy group. The efficacy and adverse reactions of the two groups were compared. Results: In terms of the short-term efficacy, there was no significant difference in objective response rate (ORR) (16.7% vs 5.0%, p= 0.54), and disease control rate (DCR) (66.7% vs 55.0%, p= 0.713) between the two groups. As for the long-term efficacy, there was no significant difference in progression-free survival (PFS) between the two groups (5.19 ±1.13 months vs 3.17 ±0.42 months, p= 0.062). the overall survival (OS) of patients in the combination group was longer than S1 group (10.0 ±1.14 months vs 6.37 ±0.47 months, p= 0.042). Conclusions: SqCLC patients with higher PS scores still benefit from anlotinib and S-1 combination regimen, even after they failed second-line or above systemic treatment. [Table: see text]
复合型多发消化性溃疡合并带状疱疹一例诊治体会
Authors: 孙丽娜, 胡敏
Journal: BMJ (2012)

报道一例以“左上腹痛”为首发症状的消化性溃疡合并带状疱疹病例的诊治过程,提示在临床工作中,患者存在两种病症且症状有重叠时,容易因已确诊其中一种病而忽视了另一种病,以致漏诊.应避免临床思维的僵化、局限化。
“Being healthy and living life as if I never had cancer”: The meaning of “living well” from adolescents with cancer.
Authors: Katherine Schreiner, Daniel H. Grossoehme, Justin N. Baker, Jennifer Needle, Sarah Friebert, Maureen E Lyon
Journal: Journal of Clinical Oncology (2020)

e22532 Background: Extensive resources are devoted to discovering novel cancer treatments. Meanwhile, patient priorities and experiences must also be addressed. Specifically, among adolescents with cancer, patients’ definitions of “living well” may elucidate treatment preferences, guide care teams and families, and influence future behavioral interventions. The objective was to develop an empirical definition of “living well” for adolescents with cancer to enhance shared decision-making. Methods: Video recordings were analyzed from the Next Steps: Respecting Choices interviews with n = 30 adolescents ages 14-21 years with cancer and their families, a subsample of N = 126 adolescent/family dyads participating in a randomized clinical trial, FAmily CEntered (FACE) Advance Care Planning. Interviews were transcribed, verified and anonymized. A phenomenological analytic method was used to identify psychological meaning in participants’ statements. Results: Adolescents with cancer conceptualize living well as meaning maintaining physical, mental and emotional health, while engaging in purposeful, typical, adolescent-appropriate activities with people important to the adolescents. This has four components: living mindfully; living an identity as a healthy adolescent; spending time with friends and family; and living a purposeful life without depression. Living well means most often enjoying these activities while spending time with family and friends. An exemplary quotation is, “...being able to have a life where everything is going good, and being able to live healthy...gets rid of some of your worries not only for yourself but for your friends and family...less worries means a less stressful life...” Conclusions: By determining what “living well” means to adolescents with cancer, care teams and families can more easily understand patients’ priorities. A firm grasp on patients’ definitions of “living well” could relieve significant burden from families and increase families’ willingness to honor adolescent treatment preferences. Findings may guide future psychosocial interventions. Clinical trial information: NCT01670461.
Integrated biomarker study of neoadjuvant pepinemab and nivolumab in patients with resectable metastatic melanoma.
Authors: Michael C. Lowe, Brian Olson, Anthony Martinez, Jacklyn Hammons, Keith A. Delman, Melinda Lynne Yushak, Melanie Allor, Christine A. Reilly, Crystal L. Mallow, Elizabeth E. Evans, Terrence Lee Fisher, Gregory B. Lesinski, Ragini Reiney Kudchadkar
Journal: Journal of Clinical Oncology (2020)

10061 Background: SEMA4D has broad immunomodulatory effects in the tumor microenvironment (TME); blocking SEMA4D in combination with checkpoint inhibitors (CI) promotes immune infiltration, reduces recruitment of myeloid cells, enhances T cell activity, and promotes tumor regression. We hypothesized that adding pepinemab (VX15/2503), which targets SEMA4D, to CI would increase immunomodulatory effects and augment response in melanoma (NCT03769155). Methods: Patients with resectable stage IIIB/C/D melanoma were enrolled to control (no neoadjuvant therapy) or treatment cohorts (n = 8 in four cohorts of pepinemab plus nivolumab, ipilimumab, nivolumab/ipilimumab or alone). Here we report results from patients receiving two doses of nivolumab (360mg) and pepinemab (15mg/kg) every three weeks followed by surgery. Primary endpoint was T cell infiltration into the TME; secondary endpoints include pathologic response rates, peripheral immune profile, and safety. Results: Ten patients are reported: two were controls, eight received neoadjuvant therapy. Two patients had pathologic complete response, one had a near-complete pathologic response ( &lt; 1% viable tumor), one had a partial response (41% viable tumor) and four had stable disease (73-90% viable tumor). All neoadjuvant patients underwent surgery without delay; one patient experienced grade 3 post-operative cellulitis. There were two treatment-related grade 3 adverse events (weakness and arthralgia). Pharmacodynamic studies confirmed saturation of PD-1 and SEMA4D in peripheral and tumor-infiltrating T cells. T/B cell (CD8 + /CD20 + ) ratios, a surrogate for T cell infiltration, were higher in post-treatment tumors compared to pre-treatment and were higher in the tumor bed compared to normal adjacent tissue. Flow cytometric evaluation identified an increase in CD26 hi CD4 + and CD8 + tumor-infiltrating effectors in treated patients compared to controls and an increase in peripheral frequencies of the PD-1-responsive effector HLA-DR + CD38 + Ki67 + CD4 + and CD8 + T cells following treatment. Treatment increased infiltration of myeloid populations into the TME, increased expression of PD-L1 on TME myeloid populations, and increased expression of the SEMA4D receptor Plexin-B2 on the surface of TME CD45 − and M2 macrophages and MDSC. Conclusions: Neoadjuvant nivolumab and pepinemab results in increased T cell infiltration with excellent major response rate (38%) and expected safety profile. We continue to enroll patients using other rational combinations of pepinemab and CI. Clinical trial information: NCT03769155.
糖皮质激素性骨质疏松症诊疗指南(讨论稿)
Authors: 中华医学会骨质疏松和骨矿盐疾病分会
Journal: BMJ (2006)

一、概述 继发性骨质疏松症是由于疾病或药物等原因所致的骨量减少、骨微结构破坏、骨脆性增加和易于骨折的代谢性疾病.引起继发性骨质疏松症的病因很多,糖皮质激素性骨质疏松症在药物导致的骨质疏松症中最为常见。
Landscape of <i>IDH</i> mutations in patients with solid tumors: A pan-cancer analysis.
Authors: Xiaoxiang Guan, Hong Zhu, Junling Zhang, Kai Yuan, Dong Shen, Jing Zhao, Zhengyi Zhao, Longgang Cui, Yuzi Zhang, Guoqiang Wang, Shangli Cai, Yuezong Bai
Journal: Journal of Clinical Oncology (2020)

e13638 Background: Isocitrate dehydrogenase (IDH) is an enzyme family involved in cell aerobic metabolism of tricarboxylic acid cycle, including IDH1-3. Mutations in IDH family are common in glioma and hematologic malignancies. IDH inhibitors have shown promising efficacy not only in hematologic malignancies but also cholangiocarcinoma patients harboring IDH1 mutations. However, the landscape of IDH mutations in pan-cancer has not been fully characterized. Methods: Tissue or blood samples were subjected to NGS in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for detection the IDH mutation. Results: A total of 12,372 patients from more than 20 solid tumor species were analyzed, including biliary carcinoma (960 cases), liver cancer (1433 cases), lung cancer (3557 cases) and colorectal cancer (1310 cases). 105 cases (0.8%) with IDH mutations were identified. The average age for patients harboring IDH mutations was 59 years (range, 29-80 years). Among all the IDH mutations cases, 49 (47%) were biliary tract cancer, 25 (24%) were liver cancer, 16 (15%) were lung cancer and 7 (7%) were colorectal cancer. The most common IDH variant were IDH1 and IDH2 which were discovered in 84 cases and 21 cases, respectively. IDH1 R132C mutation represents 45.7% (n = 48) of all IDH mutations. Other mutations found affecting either IDH1 at Arg132 included R132L (n = 24), R132G (n = 5), R132H (n = 5) and R132S (n = 2) or IDH2 at Arg172 (R172K most frequently). In addition, IDH1/2 gene was most frequently co-mutated with TP53 and ARID1A. Conclusions: Somatic IDH1/2 mutations are found in multiple solid tumors and patients with IDH1/2 mutations may benefit from IDH1/2 inhibitors in the future.
Novel evidence synthesis system to support living systematic reviews and living guidelines for cancer immunotherapy.
Authors: Irbaz Bin Riaz, Samarth C Rawal, Rabbia Siddiqi, Noureen Asghar, Mahnoor Islam, Ognjen Gajic, Zhen Wang, Victor Montori, Vitaly Herasevich, Ronald S. Go, Chitta Baral, Hongfang Liu, Per Olav Vandvik, Tufia C. Haddad, Alan Haruo Bryce, S. Vincent Rajkumar, M. Hassan Murad
Journal: Journal of Clinical Oncology (2020)

2054 Background: Systematic reviews that summarize the toxicity of Immune checkpoint inhibitors (ICIs) become outdated very soon after publication. Therefore, we reported results of a toxicity meta-analysis at 2019 ASCO meeting and informed the intent to create a living systematic review (LSR). LSRs combine human and machine effort and support rapid evidence synthesis and living clinical practice guidelines. Now, we report our experience maintaining a LSR on toxicity of ICIs. Methods: Steps include quarterly literature searches to identify new clinical trials reporting ICI-associated adverse events (AEs), AI-enabled screening of new citations which meet the inclusion criteria, automated cumulative meta-analysis and an online reporting platform. Standard data formats and protocols were designed for inputting text, tables and graphics. Software was written to interpret these data and output the information in the appropriate format, such as a forest plot and summary tables. Finally, a dynamic interface that enables user inputs and displays the associated output was designed. Results: The LSR is continuously updated incorporating toxicity data from new clinical trials as it becomes available. We have screened 8000 relevant citations and summarized the odds of Grade 3 or higher AEs and AEs of special interest in patient receiving ICIs. The results are updated on quarterly basis and are available online. The results are updated on quarterly basis and will be available on a website at the time of publication. Prototype with dummy data is available at this link . This interface can also be manipulated via user input to organize and sort data tables and forest plots by type of cancer, name or mechanism (PD-1 or PD-L1) of ICI agent, single agent or combination, type of control arm, line of treatment and several other clinically relevant filters. For example, a user can instantaneously generate a meta-analysis summarizing the risk of colitis or pneumonitis in metastatic lung cancer trials with pembrolizmuab. Conclusions: This LSR engine can prospectively synthesize toxicity data from ICI trials in an efficient manner providing accurate and timely information for advanced clinical decision support at point-of-care. Efforts are ongoing to improve efficiency of screening, improve AI-enabled processes for automated screening and data abstraction, and test across multiple clinical questions.