tbuckley/cabot-search huggingface dataset:
Genomics and translational precision oncology for 803 patients with biliary tract cancer.
Authors: Jianzhen Lin, Xu Yang, Yinghao Cao, Guangyu Li, Songhui Zhao, Junping Shi, Jie Pan, Ke Hu, Lin Zhao, Mei Guan, Xinting Sang, Milind M. Javle, Kai Wang, Xiaoyue Wang, Hai-Tao Zhao
Journal: Journal of Clinical Oncology (2020)

4589 Background: Both incidence and mortality of biliary tract cancer (BTC) are increasing, and BTCs are characterized by poor prognosis and limited antitumoral treatments. There is no well-received regimen as the non-first-line treatment in patients with advanced BTCs, leading to the urgency of umbrella-setting personalized therapies according to genomic alterations. Methods: We performed genomic sequencing in a total of 803 BTCs, including 160 patients with whole-exome sequencing and 643 patients with hybrid capture–based comprehensive genomic profiling. Our molecular tumor board developed precise targeted therapies for patients with actionable targets. Results: Overall, the median tumor mutation burden was 3.0 (IQR: 0.8-6.1) Mut/Mb, with 10.5% patients of hypermutated BTCs. The most frequently mutated genes included TP53 (51%), KRAS (23%), ARID1A (16%) and SMAD4 (11%). The most common genes with significantly amplified oncogenes were CCND1 (6.97%), MET (6.72%) and MDM2 (6.6%), while the frequently deleted tumor-suppressor genes are CDKN2A (5.73%) and CDKN2B (5.35%). The mutational map of BTCs highlighted pathways of receptor-tyrosine kinase (RTK)/RAS and p53 signaling were frequently altered. Somatic truncating mutations of mismatch repair genes were identified in 6.1% (49/803) of patients, and germline pathogenic mutations in DNA damage response genes occurred in 8% (64/803) of BTCs. In addition, we demonstrate the amplified chromosomal focal at 7q31.2 was an oncogenic factor and it independently predicts both disease-free survival and overall survival of BTC patients. When molecular screening was linked to targeted therapies, 25.4% (204/803) of patients could match biomarker-assigned drug treatment (BADT). The frequent actionable biomarkers included amplifications of ERBB2 and MET, FGFR2/3 fusions and IDH1 mutations. For 46 patients with refractory BTCs received BADT, the objective response rate was 26.1%, with a median progression-free survival (mPFS) of 5.0 (95%CI: 3.5-6.5) months, and 56.8% patients achieved a ≥1.3 ratio of PFS2/PFS1. 4 of 6 (67%) patients with high microsatellite instability (MSI-H) BTCs had a responsive status after immunotherapy of PD1 inhibitor, confirming that MSI-H status was a robust biomarker of anti-PD1 treatments. Conclusions: Our study established the largest cohort in Chinese BTC patients to investigate the tumor mutational profiling and its translational clinical applications. Clinical trial information: NCT02715089 .
Hypomagnesemia is associated with an increased risk of early clinical failure in patients with Burkitt lymphoma.
Authors: Jennifer Gile, Gordon Ruan, Jithma P. Abeykoon, Molly McMahon, Thomas E. Witzig
Journal: Journal of Clinical Oncology (2020)

e20048 Background: No literature exists regarding whether hypomagnesemia at the time of diagnosis in Burkitt Lymphoma (BL) is associated with inferior survival. Methods: Patients with new diagnosis of BL who were seen at Mayo Clinic, MN from 2000-2019 with a serum magnesium level available prior to chemotherapy were included. Patients were allocated to two groups; Abnormal Magnesium Group (AMG), defined as a magnesium level &lt; 1.7 mg/dL and Normal Magnesium Group (NMG), defined as ≥ 1.7 – 2.3mg/dL. Two-sided Wilcoxon rank sum test and Chi square/Fischer’s exact test were used to compare the continuous and categorical variables, respectively. Kaplan-Meier and log-rank tests were used to perform all time to event analysis which were done from time of treatment. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards. Results: Of 90 patients with a diagnosis of BL, 42 patients had a magnesium level at or before time of diagnosis. The Table lists the baseline characteristics and significant findings of the AMG/NMG groups. The median follow-up was 30 months. Hypomagnesemia was predictive for inferior EFS at 30 months - 34.3% (95% CI: 8.7–74.0) for AMG and 79.3% (95% CI: 60.8-90.4) for NMG (p = 0.038). OS at 30 months for AMG was 42.9% (95% CI: 14.4-77.0) and for NMG was 93.7% (95% CI: 78.1-98.4%) (p = 0.002). Other parameters significant on univariate analysis included the Charlson Comorbidity Index (p = 0.034), creatinine (p = 0.009), and number of treatments (p = 0.048). In the multivariate analysis, creatinine (p = 0.005) and number of treatments (p = 0.004) were significant. Likelihood ratio testing of predictors associated with inferior OS were significant for hypomagnesemia (likelihood ratio 3.99, p = 0.046). Conclusions: Patients with hypomagnesemia at the time of BL diagnosis have inferior outcomes compared to BL patients with a normal magnesium level. Prospective studies are needed to confirm this finding and test Mg replacement strategies to mitigate the effects of hypomagnesemia. [Table: see text]
The prognostic impact of unplanned excision in primary STS of the extremities and trunk wall: Is re-excision always mandatory?
Authors: Maria Danieli, Francesco Barretta, Marco Fiore, Stefano Radaelli, Dario Callegaro, Marta Barisella, Claudia Sangalli, Silvia Stacchiotti, Elena Palassini, Rosalba Miceli, Paolo Giovanni Casali, Alessandro Gronchi
Journal: Journal of Clinical Oncology (2020)

e23557 Background: To investigate the outcome of patients affected by soft tissue sarcomas (STS) of the extremities and trunk wall who underwent unplanned excision (UE) and the prognostic impact of microscopic residual tumor at re-excision. Methods: All consecutive patients affected by primary STS of the extremity and trunk wall operated at Fondazione IRCCS Istituto Nazionale dei Tumori from Jan 1997 to Dec 2017 were included and divided in 3 groups: patients primarily resected at our institution (group A), patients undergoing re-excision after macroscopically complete UE (group B) and patients undergoing completion resection after macroscopically incomplete UE (group C). Inverse probability treatment weighted overall survival (OS), crude cumulative incidence of local relapse (CCI-LR) and of distant metastasis (CCI-DM) were calculated and compared. Histological subgroup curves were drawn and multivariable models were performed in group B. Results: 1965 patients were identified; 1079, 679 and 189 in group A, B and C respectively. Median follow-up was 84.41 months. 7-yrs OS was 0.74, 0.84 and 0.81 (p &lt; .001) for group A, B and C respectively; 7-yrs CCI-LR and DM were 0.05 and 0.25, 0.12 and 0.16, 0.14 and 0.29 (p &lt; .001 for both) for group A, B and C respectively. In group B, microscopic residual tumor was present in 26.9% of the surgical specimens, but this figure varied broadly among the histologic subtypes (being the lowest in Solitary Fibrous Tumor, 7.7%, and the highest in Myxofibrosarcoma [MFS], 46.5%). At multivariable analysis, age (for OS only), grade, size and histology were associated to OS and CCI-DM; while age, presence of residual tumor (p &lt; .001) and grade to CCI-LR. Of note, Myxoid liposarcoma (MLPS) and MFS showed the highest CCI-LR in presence of residual disease (18.6% vs 1.3% and 24.7% vs 7.2% respectively). Conclusions: Patients who underwent UE had a risk of LR twice as high as those primarily resected at a referral institution. However, this higher risk was not associated to a higher risk of DM or worse OS. In patients undergoing re-excision after macroscopic complete UE the presence of residual tumor was associated to a higher LR risk, again with no association with DM or OS. Despite the probable presence of a residual selection bias, it is possible that postponing re-excision after macroscopic complete UE doesn’t impact on the outcome. However, higher caution should be exerted for MLPS and MFS, given the higher probability of local relapse when microscopic residual tumor is found in the surgical specimen.
支气管哮喘的合理用药
Authors: 何权瀛, 郑俊永
Journal: BMJ (2010)

支气管哮喘是一种常见病、多发病,而且近年来发病率逐年增加.哮喘可以严重危害人民群众的健康和社会劳动力,并造成沉重的经济负担.实践表明只要认真贯彻相关哮喘诊治指南、合理规范治疗哮喘,就可以使哮喘达到良好的控制水平.然而目前国内防控哮喘中存在许多问题,诸如诊治不规范、用药不合理,甚至在某些地方假药泛滥,严重危害人民健康,必须尽早纠正。
Capecitabine therapy in recurrent/metastatic nasopharyngeal cancers.
Authors: Bader I Alshamsan, Maaz Kamal Alata, Ahmed Gad, Mashari J Alzahrani, Tusneem Elhassan, Jean Paul Atallah
Journal: Journal of Clinical Oncology (2020)

e18515 Background: A wide range of chemotherapeutic agents have demonstrated antitumor activity in patients with recurrent or metastatic Nasopharyngeal Cancers (NPC). These therapeutic agents have different efficacy and toxicity profile. Capecitabine monotherapy had activity in recurrent/metastatic NPC based on small previous retrospective studies. The primary objective is to evaluate the overall response rate and tolerability of capecitabine in recurrent/metastatic NPC. Methods: A retrospective electronic chart review performed for 51 cases of recurrent/metastatic NPC patients who received capecitabine 1000-1,250 mg/m² twice daily two weeks on, one week off between 2011 to 2019 at King Faisal Specialist Hospital &amp; Research Center (KFSH&amp;RC). The Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 was used. Results: The median age at diagnosis was 42 years. 98% had a non-keratinized undifferentiated squamous cell carcinoma (Grade III). The most common sites for metastases were Bone (58.3%), Lung (50.0%), and liver (45.8%). 95% of patients received platinum-based chemotherapy and radiation therapy as the primary treatment. Capecitabine was used as the second or third line of treatment in the metastatic setting 45.1% and 43.1%, respectively. The patients tolerated the standard dose for a median of 6 cycles; only 20.0% of patients required a 25% dose reduction. The best response for capecitabine was complete response in 8 patients (15.7%), partial response in 14 patients (27.5%), stable disease in 10 patients, (19.6%), with a clinical benefit achieved in 32 patients (62.7%), and progressive disease in 16 patients (31.4%). The overall response rate to capecitabine was 43.2%, which was consistent regardless of the site of metastasis. The median progression-free survival was seven months (95%.CI: 5.3 -8.8). The one and three-year survival rates were 79% and 53%, respectively. Capecitabine was generally tolerated, the most common grade I &amp; II adverse events were hand-foot syndrome (HFS) in 9 patients (20.5%), fatigue in 8 patients (15.7%), Diarrhea in 6 patients (11.7%), anemia in 5 patients (9.8 %), thrombocytopenia in 4 patients (7.8%) and neutropenia in 2 patients (4.0%). The most common grade III &amp; IV was HFS in 3 patients (6%) and fatigue in one patient (2%) that led to treatment discontinuation after the first cycle. Conclusions: Capecitabine in Recurrent/Metastatic NPC is an effective and well-tolerated oral agent; however, a randomized prospective trial to evaluate capecitabine efficacy in this setting still recommended.
Glasdegib (GLAS) plus low-dose cytarabine (LDAC) in AML or MDS: BRIGHT AML 1003 final report and four-year overall survival (OS) follow-up.
Authors: Michael Heuser, Tadeusz Robak, Pau Montesinos, Brian Leber, Walter M. Fiedler, Daniel Aaron Pollyea, Andrew Brown, Ashleigh O'Connell, Wendy Ma, Geoffrey Chan, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2020)

7509 Background: In newly diagnosed AML or high-risk MDS, primary analysis of the randomized phase 2 BRIGHT AML 1003 trial (data cutoff Jan 2017) showed superior OS for GLAS+LDAC vs LDAC alone. The trial then continued to predefined completion 4 years from randomization of all patients (pts), reached in Mar 2019 and presented herein. Methods: Pts with newly diagnosed AML or high-risk MDS and unsuitable for intensive chemotherapy were randomized 2:1 to GLAS+LDAC (n=88) or LDAC alone (n=44). For these groups, median (range) treatment duration was 83 (3-1575) and 47 (6-239) days; median follow-up for survival 47.6 and 48.1 months; 4 (4.5%) and 1 pt (2.3%) completed ≥4 years’ follow-up. Results: Consistent with the primary findings (OS HR 0.51; 80% CI 0.39, 0.67 p=0.0004), GLAS+LDAC prolonged OS vs LDAC alone (table). Results were consistent in AML pts and cytogenetic risk/disease history subgroups (table), as were analyses by pt characteristics and baseline risk factors (not shown). Survival probability was 39.5% vs 9.5% at 1 year and 18.0% vs 2.4% at 2 years. GLAS+LDAC induced higher complete remission (CR) rates overall (16/88 vs 1/44; RR 8.12, 95% CI 1.05, 62.78, p=0.010) and across subgroups. Notably, fewer pts discontinued GLAS+LDAC due to AEs (38.1% and 46.3%) and there was no increased sepsis or bleeding vs LDAC alone despite longer glasdegib treatment. With GLAS+LDAC, SMO-inhibitor-associated AEs included dysgeusia (25.0%), muscle spasms (22.6%) and alopecia (10.7%), with only 1 pt discontinuing due to dysgeusia. Conclusions: Consistent with primary analyses, GLAS+LDAC continued to have an acceptable safety profile and improved OS vs LDAC alone. HRs were consistent across cytogenetic risk subgroups and support use of GLAS+LDAC in de novo and secondary AML. Clinical trial information: NCT01546038 . [Table: see text]
An ultrasensitive amplicon-based sequencing panel for noninvasive molecular testing of hematological malignancies using blood.
Authors: Chae Yin Cher, Zi Yi Lim, Daryl Tan, Hae Tha Mya, Wichean Mongkonsritragoon, Min-Han Tan, Yukti Choudhury
Journal: Journal of Clinical Oncology (2020)

e19511 Background: Hematological malignancies, especially acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes (MDS), present with distinct genomic alterations relevant to prognosis. Bone marrow (BM) is the primary sample source for genetic testing, but is obtained by an invasive biopsy procedure which carries risk of infection. An alternative non-invasive sample type to profile disease-relevant genomic alterations at diagnosis and subsequently, is desired for clinical decision making. An ultrasensitive sequencing panel was applied to peripheral blood (PB) as an alternative to BM, to demonstrate its utility for disease profiling and monitoring. Methods: A total of 27 pairs of matched PB and BM samples were obtained from patients with hematological malignancies including leukemia (n = 21), lymphoma (n = 4), multiple myeloma (n = 1) and MDS (n = 1). The sequencing panel covers 45 genes commonly mutated in myeloid and lymphoid malignancies. The panel is based on amplicon-sequencing and includes error correction for variant detection with allele frequency (VAF) as low as 0.1%. Optimized bioinformatics pipeline and in-house sequencing noise removal was used for variant selection and clonal analysis. Results: Complete concordance was seen for mutations detected in 23 of 27 patient-matched BM and PB paired samples. The likely cause of discordance in the other 4 pairs is attributable to mutations with low VAF ( &lt; 0.5%). Overall, 91% of detected variants were concordant between PB and BM with strong correlation of VAFs (R = 0.9617). Serial testing trends correlated with stable disease with limited changes in VAFs (n = 2), and successful treatment response with rapidly falling VAFs (n = 5). In particular, 2 patients with FLT3-ITD and BCR-ABL1, respectively, identified at diagnosis had dramatic decrease in VAFs with respective targeted treatment. Conclusions: We report the utility of an ultrasensitive sequencing assay in PB with excellent concordance of mutations with BM, suggesting PB is a reliable alternative source for testing. In serial samples, the assay demonstrated value in treatment selection and response evaluation.
A genomic blood test (NETest) identifies neuroendocrine transformation of prostate cancer.
Authors: Kambiz Rahbar, Mark S. Kidd, Ignat A. Drozdov, Anna Malczewska, Lisa Bodei, Pawel Rajwa, Martin Boegemann, Christof Bernemann, Alexandra Kitz, Irvin Mark Modlin
Journal: Journal of Clinical Oncology (2020)

e17511 Background: Neuroendocrine-like differentiation (NELD) and an aggressive phenotype are key features of castration-resistant prostate cancer (CRPC). Current blood-based biomarkers cannot detect these treatment-refractory variants. Our aim was to evaluate the NETest, a blood-based 51-marker gene neuroendocrine detection tool, as a CRPC-diagnostic versus prostate cancer (PCA). Methods: In silico evaluation: NETest gene identification in the TCGA-PRAD ( n= 500 PCA) and CRPC RNAseq datasets (cBIOPortal: dbGap-phs000909.v.p1, tissue samples: n= 47, including 15 CRPC). Blood gene expression: PCA: n= 50, CRPC: n= 40, hormone-sensitive PCA: n= 75 and benign prostatic hyperplasia (BPH: n= 41). NETest assay: Normalized gene expression, algorithmically assessed and scored: 0-100. Cut-off 20. PSA: ECLIA diagnostic assay: cut-off 4ng/L, &gt; 10ng/ml = actionable value. Statistics: ANOVA, AUROC analyses and sensitivity/specificity metrics. Data is mean±SEM. Results: RNAseq: Two (4%) of the 51 NETest genes were identified in TCGA-PCA. In contrast, all 51 NETest genes (100%) were identified in CRPC tumors. Thirty-three (65%) were detected as upregulated (1.09-1425-fold vs. normal tissue). Blood-PCR: 49/51 (96%) NETest genes detected in CRPC blood. NELD-gene expression was significantly upregulated ( &gt; 2-fold, p&lt; 0.01) in CRPC vs. PCA ( TPH1, PNMA2, SSTR etc). NETest scores were elevated in CRPC (79±2.8) (ANOVA, p&lt; 0.0001) vs. PCA (22±2) and BPH (23±3). The AUC differentiating CRPC from PCA was 0.93 ( p&lt; 0.0001). NETest was elevated in 94% of CRPC vs. 13% PCA and 15% BPH (both p&lt; 0.001). The diagnostic sensitivities and specificities were 94% and 87%, respectively. PSA: PSA was elevated in CRPC (220±372ng/ml). This was different to PCA (14±20ng/ml, p&lt; 0.0001) and BPH (10.3±5.7ng/ml, p&lt; 0.003). The AUC for CRPC vs. PCA/BPH was 0.70 ( p= 0.10). PSA &gt; 10ng/ml occurred in 70% of CRPC, 60% of PCA ( p= NS) and 39% of BPH ( p&lt; 0.05). The AUC for NETest (0.93) was significantly better than PSA (z-statistic: 4.63, p&lt; 0.0001). Conclusions: The NETest is a liquid biopsy that detects neuroendocrine neoplasia genes in the blood and accurately identifies NELD in castration-resistant prostate cancer. We anticipate that the NETest could be used to provide real-time information relevant to the evolving neuroendocrine status of a PCA during therapy.
Respiratory Inflammation and Short-Term Ambient Air Pollution Exposures in Adult Beijing Residents with and without Prediabetes: A Panel Study
Authors: Xi Chen, Yiqun Han, Wu Chen, Yanwen Wang, Xinghua Qiu, Weiju Li, Min Hu, Yusheng Wu, Qi Wang, Hanxiyue Zhang, Tong Zhu
Journal: Environmental Health Perspectives (2020)

Background: Accumulating evidence suggests that individuals with glucose metabolism disorders are susceptible to mortality associated with fine particles. However, the mechanisms remain largely unknown. Objectives: We examined whether particle-associated respiratory inflammation differed between individuals with prediabetes and healthy control participants. Methods: Based on a panel study [A prospective Study COmparing the cardiometabolic and respiratory effects of air Pollution Exposure on healthy and prediabetic individuals (SCOPE)] conducted in Beijing between August 2013 and February 2015, fractional exhaled nitric oxide (FeNO) was measured from 112 participants at two to seven visits to indicate respiratory inflammation. Particulate pollutants—including particulate matter with an aerodynamic diameter of ≤2.5μm (PM2.5), black carbon (BC), ultrafine particles (UFPs), and accumulated-mode particles—were monitored continuously at a single central monitoring site. Linear mixed-effects models were used to estimate associations between ln-FeNO with pollutant concentrations at individual 1-h lags (up to 24 h) and with average concentrations at 8 and 24 h before the clinical visit. We evaluated glucose metabolism disorders as a potential modifier by comparing associations between participants with high vs. low average fasting blood glucose (FBG) and homeostasis model assessment insulin resistance (HOMA-IR) levels. Results: FeNO was positively associated with all pollutants, with the strongest associations for an interquartile range increase in 1-h lagged exposures (ranging from 21.3% for PM2.5 to 74.7% for BC). Associations differed significantly according to average HOMA-IR values when lagged 6–18 h for PM2.5, 15–19 h for BC, and 6–15 h for UFPs, with positive associations among those with HOMA-IR≥1.6 while associations were closer to the null or inverse among those with HOMA-IR<1.6. Associations between PM2.5 and FeNO were consistently higher among individuals with average FBG≥6.1 mmol/L vs. low FBG, with significant differences for multiple hourly lags. Discussion: Glucose metabolism disorders may aggravate respiratory inflammation following exposure to ambient particulate matter. https://doi.org/10.1289/EHP4906
北京某社区卫生服务站进行公司托管后的运营状况变化及思考
Authors: 曹杰, 代爱英, 崔静, 顾湲
Journal: BMJ (2004)

2002年11月～2003年4月北京顾邻康公司托管了东城区某医院社区卫生服务站,该站在所有权不变的情况下,经营管理权交给顾邻康公司,实行独立核算,人员工资与盈亏均由顾邻康公司承担,每月上交所属医院一定比例的流水营业额.将托管效果报告如下。
贫血(二)
Authors: 吴东, 陈嘉林
Journal: BMJ (2012)

一、贫血患者应常规检查网织红细胞计数网织红细胞是尚未完全成熟的红细胞,其内残存的细胞核成分经染色后呈网状结构,因此得名.在正常成人,网织红细胞约占外周血RBC总数的0.5％ -1.5％,该比例升高意味着骨髓造血旺盛.网织红细胞计数有利于贫血的鉴别诊断,还可用于评估贫血的疗效.对于前者,应结合贫血的严重程度进行分析,即计算网织红细胞指数(reticulocye index,RI)[1]。
Predictors of electronic patient-reported outcomes use in the survivorship setting.
Authors: Bridgette Thom, Stacie Corcoran, Jessica A. Lavery, Leon Sarpong, Alexandria Woodside, Deborah Korenstein
Journal: Journal of Clinical Oncology (2020)

e14038 Background: Patient-reported outcomes (PRO) offer insight into patient perception of health and symptom burden. Despite a shift toward electronic PRO (ePRO), optimal administration methods are unclear. Our institution recently began ePRO collection in survivorship clinics: patients are invited via email to complete a health survey on our online patient portal prior to annual visits, enabling clinician review of symptoms in advance of the visit. Patients who do not complete an ePRO survey at home are offered an iPad or paper survey at visit check-in. In the first year of ePRO, 87 patients inadvertently submitted multiple responses to the questionnaire, across two modalities. This study aimed to 1) assess determinants of ePRO completion across modalities (portal, iPad, paper); and, 2) among patients who submitted multiple surveys, compare consistency of responses in surveys completed within 30 days of each other. Methods: We reviewed records for 10194 patients seen in breast, thoracic, colorectal, and gynecologic survivorship clinics over one year. Demographics, disease/treatment details, and PRO responses (symptoms, health behaviors, etc.) were extracted. For aim 1, we used multivariate regression to determine predictors of completion method. For aim 2, we calculated Cohen’s kappa coefficients to compare responses based on completion modality. Results: Most patients (65.6%) completed the survey on an iPad in clinic; 16.7% on the portal, 17.7% on paper in clinic. Younger age (p &lt; .001), white race (p &lt; .001), less fatigue (p = .01), and English as primary language (p &lt; .001) were associated with portal use in multivariate analyses. In general, Cohen’s Kappa analyses revealed high agreement between surveys. Conclusions: Our findings highlight demographic gaps in ePRO acceptance. Although most patients completed an ePRO (portal or iPad), few completed it at home in advance of their visit, which has implications for clinic flow and clinician preparation for visits. However, our finding of consistent symptom reporting across mode and location of completion is reassuring. Future work should seek to improve comfort with ePRO completion at home among groups less likely to accept it and explore the implications of symptom burden on ePRO acceptance.