tbuckley/cabot-search huggingface dataset:
Characteristics of probands with mutations predisposing to gynecologic cancers enrolled in a facilitated cascade testing protocol.
Authors: Kristina Hwang, Katherine Baumann, Allison Brodsky, Kathleen Lutz, Deanna Gerber, Jessica Martineau, Ophira M. Ginsburg, Julia Anne Smith, Douglas A. Levine, Bhavana Pothuri
Journal: Journal of Clinical Oncology (2020)

e13682 Background: We sought to evaluate the feasibility of obtaining genetic testing (GT) for first- or second-degree (1°, 2°) family members of a proband known to have actionable germline mutation associated with endometrial and/or ovarian cancer through a coordinated referral system. Here we characterize the initial probands and discuss the time frame of their enrollment in facilitated cascade testing (CT). Methods: Patients with pathogenic mutations associated with gynecologic cancers were determined from cancer genetics and gynecologic oncology clinics. Consenting patients completed a RedCap survey on personal cancer history and history of GT. They were then asked to contact 1° and/or 2° relatives regarding their GT results. Relatives were advised to contact our team. Relatives who consented to the study were referred for GT and contacted for follow up to ascertain whether they received GT and/or took action to reduce cancer risk. Results: From 3/2019- 1/2020, this study has accrued 39 probands. The median age was 39 years (range: 25-68). The most commonly expressed gene mutations were BRCA1 or BRCA2 (87.18%, n=34). Other mutations included BRIP1, MLH1, MSH2, MSH6, and PMS2. The majority (62%) of probands had no personal history of cancer. Among those who had a history of cancer (n=15), 80% had breast and/or ovarian cancer, and 80% reported their genetic mutation was discovered at or after the time of their cancer diagnosis. Median age at time of enrollment in CT was 49 years (range: 29-66) for patients with a history of cancer and 32 years (range: 25- 68) for those without, (p=0.009). Among all probands, the median time between mutation identification and enrollment in CT was 2 years (range=0 to 11). There was no significant difference in time between mutation identification and enrollment in CT when comparing those with and without cancer histories (p=0.5). Conclusions: These results suggest that patients with pathogenic mutations predisposing to gynecologic cancer are willing to undergo CT even if they have no personal history of cancer. Patients with a history of cancer tend to be older at time of enrollment in CT, likely because most discover their genetic mutation at or after the time of cancer diagnosis. With an average of 2 years elapsed between time of mutation identification and enrollment in CT, there is need for expansion of CT accessibility. Increased education and awareness among patients and providers in identifying those who may benefit from CT, screening, and risk reducing surgery to prevent cancer is needed.
The perils of premature phenotyping in COVID-19: a call for caution
Authors: Lieuwe D.J. Bos, Pratik Sinha, Robert P. Dickson
Journal: European Respiratory Journal (2020)

<b>By prematurely phenotyping patients with COVID-19, we and our patients are exposed to considerable and preventable risk. If data-driven phenotypes are not insisted upon, our cognitive biases guarantee that we9ll end up with phenotype-driven data.</b>https://bit.ly/2ZM8wZV
Development and validation of a novel ten-gene prognostic signature for hepatocellular carcinoma.
Authors: Taicheng Zhou, Zhihua Cai, Ning Ma, Wenzhuan Xie, Chan Gao, Mengli Huang, Yuezong Bai, Yangpeng Ni, Yunqiang Tang
Journal: Journal of Clinical Oncology (2020)

e16665 Background: Hepatocellular carcinoma (HCC) remains a major challenge for public health worldwide and long-term outcomes remained dismal despite availability of curative treatment. We aimed to construct a multi-gene model for prognosis prediction to inform clinical management of HCC. Methods: RNA-seq data of paired tumor and normal tissue samples of HCC patients from the TCGA and GEO database were used to identify differentially expressed genes (DEGs). DEGs shared by both cohorts along with patients’ survival data of the TCGA cohort were further analyzed using univariate Cox regression and LASSO Cox regression to build a prognostic 10-gene signature, followed by validation of the signature via ICGC cohort and identification of independent prognostic predictors. A nomogram for prognosis prediction was built and Gene Set Enrichment Analysis (GSEA) was performed to further understand the underlying molecular mechanisms. Results: Of 571 patients (70.93% men and 29.07% women; median age [IQR], 65 [56-72] years), a signature of 10 genes was constructed using the training cohort. In the testing and validation cohorts, the signature significantly stratified patients into low- vs high-risk groups in terms of overall survival across and within subpopulations with stage I/II and III/IV disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 0.13 [95% CI, 0.07-0.24; P &lt; 0 .001] to 0.38 [95% CI, 0.2-0.71; P &lt; 0.001]) after adjusting for clinicopathological factors. Prognosis was significantly worse in the high-risk group than in the low-risk group across cohorts (P &lt; 0.001 for all). The 10-gene signature achieved a higher accuracy (C-index, 0.84; AUCs for 1-, 3- and 5-year OS, 0.84, 0.81 and 0.85, respectively) than 8 previously reported multigene signatures (C-index range, 0.67 to 0.73; AUCs range, 0.68 to 0.79, 0.68 to 0.80 and 0.67 to 0.78, respectively) for estimation of survival in comparable cohorts. A nomogram incorporating tumor stage and signature-based risk group showed better predictive performance for 1- and 3- year survival than for 5 year survival. Moreover, GSEA revealed that the pathways related to cell cycle regulation were more prominently enriched in the high-risk group while the low-risk group had higher enrichment of metabolic process. Conclusions: Taken together, we established a robust 10-gene signature and a nomogram to predict overall survival of HCC patients, which may help recognize high-risk patients potentially benefiting from more aggressive treatment.
Prevalence and temporal trends of prescription drug use in cancer survivors: A population study, 2001 to 2016.
Authors: Elisa Liu, Sylvia Christine Kurz, Jiyoung Ahn, Erik P. Sulman
Journal: Journal of Clinical Oncology (2020)

12023 Background: The burden of prescription drug use is higher in cancer survivors than the general population. We examined the prevalence and temporal trends of prescription drug use among cancer survivors, with an emphasis on central nervous system (CNS) active medications used to manage long-term cancer sequelae. Methods: Adult respondents with (n=3207) and without (n=40,440) a prior cancer diagnosis from 8 cycles (2001-2016) of the National Health and Nutritional Examinational Survey (NHANES) were evaluated for prescription drug usage. Cross-sectional analyses and temporal trends across cycles were evaluated and weighted to represent the US adult population. Results: Cancer survivors report higher rates of prescription drug usage (85.1% vs 54.3%, p&lt;0.001, and 75.8%, p&lt;0.001) and polypharmacy (27.8% vs 10.7%, p&lt;0.001, and 22.7%, p&lt;0.001) than both unadjusted and age-adjusted controls. Younger survivors report greater usage of CNS (36.8% vs 13.1%, p&lt;0.001), psychotherapeutic (18.4% vs 7.7%, p&lt;0.001), hormonal agents (19.1% vs 10.1%, p=0.003), and gastrointestinal (10.7% vs 4.7%, p=0.02) than controls, while differences are attenuated in older cohorts. Among broad drug categories, the usage of cardiovascular (p-trend&lt;0.001), metabolic (p-trend&lt;0.001), and immunologic agents (p-trend=0.01) has increased. Among CNS active subclasses, the usage of anticonvulsants (p-trend&lt;0.001), anxiolytics (p-trend =0.02), narcotics (p-trend=0.02) and GABA analogs (p-trend&lt;0.001) has increased. When comparing respondents with and without a history of cancer, the increased usage of anti-depressant prescription medications (18.3% vs 1.5% p&lt;0.001), including SSRIs (11.2% vs 1.0%, p&lt;0.001), SSNRIs (3.5% vs 0.3%, p&lt;0.001), tricyclics (2.8% vs 0.1%, p&lt;0.001), among cancer survivors was disproportionate compared to the increased proportion of positive depression screens (9.2% vs 7.0%, p=0.006). Conclusions: Cancer survivors report higher prescription drug use for both chronic conditions and late effects of cancer. The usage of CNS active medications, many of which are used on and off label for their pain management properties, has increased. The higher rates of pharmaceutical use may result in unanticipated long-term toxicities and financial burdens.
The study on the effect of depression on breast cancer incidence through IDO/kynurenine pathway.
Authors: Yanmei Zhang, Ling Zhu, Dandan Chen, Rui Xu, Liping Ren, Xiaoqing Wei, Fan Tang, Yuzhu Zhang, Qianjun Chen
Journal: Journal of Clinical Oncology (2020)

e13569 Background: Psychosocial factors have been considered as the most common causes for women with breast cancer. However, it remains unclear whether mental stress can influence cancer incidence and progression. This study aims to investigate the relationship between them and the potential molecular mechanism. Methods: Depression model was established by restricting MMTV-PyMT mice in a 50ml-fixator for 4 h per day for 21 consecutive days. Behavioral tests including light-dark box test, open-field test and force swimming test were performed. Then blood, brain and mammary samples were collected at the indicated time points. ELISA was used to detect the concentration of neurotransmitters serotonin, epinephrine and norepinephrine and inflammatory factors IL-6, TNF-a and IL-1β in brain tissue and serum. Real-time quantitative qPCR and western blot were used to detect indoleamine 2, 3-dioxygenase (IDO) expression. The level of tryptophan was measured by high performance liquid chromatography(HPLC). Flow cytometry was used to evaluate the exhaustion of CD8 + T cells. Besides, the correlation between IDO expression detected by immunohistochemistry and the severity of mammary tumors was analyzed in the tumor specimens. Results: We observed that chronic stress caused depression-like behaviors, abnormal secretion of neurotransmitters serotonin, epinephrine and norepinephrine and promoted the development of breast cancer in MMTV-PyMT mice. Depression elevated the secretion of inflammatory factors IL-6, TNF-a and IL-1β in brain tissue and serum, which upregulated the expression of IDO and decreased the level of tryptophan in mice. Furthermore, T cells are sensitive to low tryptophan concentration, so elevated IDO expression suppressed and exhausted CD8 + T cells, ultimately promoting cancer incidence. Administration of xiaoyao pill (a well-known Chinese herbal formula for treating depression) or IDO inhibitor reversed the depression-like behaviors in mice and slowed the development of breast cancer. At the same time, the analysis of clinical samples showed that depression identified by Hamilton Depression Scale(HAMD) and IDO expression in mammary tumor tissues were positively correlated with the severity of mammary tumors. Conclusions: Altogether, our results suggest that depression can promote tumor immune privilege and cancer occurrence through inducing upregulated IDO expression.
Validation of RecurIndex (RI) for patients with early-stage breast cancer enrolled in a Taiwanese multicenter study.
Authors: Yi-Hsuan Lee, Nicolas Pennarun, Ling-Ming Tseng, Po-Sheng Yang, Ji-An Liang, Chia-Ming Hsieh, Yuan-Ching Chang, Ming-Yang Wang, Kuan-Hui Shih, Skye Hung-Chun Cheng, Chiung-Sheng Huang
Journal: Journal of Clinical Oncology (2020)

3560 Background: Numerous prospective studies, predominantly in Caucasian population, have proven the clinical utility of using multigene expression tests to prevent overtreatment in early breast cancer (EBC) patients. Since racial and ethnic disparities exist in genetic and biological factors that could influence the disease, the primary purpose of this study is to access the clinical utility of RecurIndex, a recurrence risk test, that is based on a genomic profiling derived from Asian women. Methods: A total of 298 patients with EBC, luminal subtype (85.6%), HER2 subtype (7.7%) and triple-negative subtype (6.7%), were enrolled in a retrospective study across Taiwan medical centers. Kaplan Meier and Cox Proportional Hazards model were used to, respectively, identify independent prognostic factors and calculate the survival rates. The prediction model was then tested using the area under the receiver operating characteristic curve (AUC). The primary endpoint was distant recurrence-free survival (DRFS). Results: The 10-year DRFS was significantly higher in the good-prognosis group than the poor-prognosis group (92.0% [95% CI, 86.1-98.2] versus 63.0% [95% CI, 49.9-79.5]) (Table). The overall hazard ratio for distant recurrence was 1.031 (95% CI, 1.017±1.046) per RI score increment. In addition, in a subset of 179 cases (60.1%), the model yielded an 82.3% correct classification rate for predicting DR with a sensitivity of 87.0%, a specificity of 68.6% and negative predictive values of 97.3%. Conclusions: The present study provides robust evidence of the clinical utility of RI-DR to predict clinical outcomes. RecurIndex could be used to determine the utility of chemotherapy in Asian patients, especially in hormone-receptor positive and HER2 negative disease, leading to a meaningful reduction in adjuvant chemotherapy recommendations. [Table: see text]
Clinical features of adult-onset Still's disease patients with pulmonary complications
Authors: Jian Li, Lin Tang, Min Shen
Journal: BMJ (2016)

Objective
To review the clinical characteristics of adult-onset Still's disease (AOSD) patients with special pulmonary complications.


Methods
Medical records of 506 AOSD inpatients, who were admitted in Peking Union Medical Hospital from October 1997 through March 2015, were retrospectively reviewed. The clinical features, biochemical parameters, radiology, pulmonary function tests, ultrasound, treatments and prognosis of AOSD patients with special pulmonary complications were analyzed.


Results
The incidence of special pulmonary complications in AOSD inpatients was 2.2% (11/506), including 3 cases of interstitial lung disease and 8 cases of pulmonary artery hypertension. All 11 patients had common manifestations of AOSD, including fever (11/11), arthralgia/arthritis (11/11), rash (9/11), lymphadenopathy and/or splenomegaly (8/11), serositis (10/11), abnormal liver function (9/11), neutrophilia (11/11), and hyperferritinemia (11/11). The patients with interstitial lung disease had no or mild symptom, and were diagnosed by HRCT and pulmonary function test. The patients with pulmonary artery hypertension had various symptoms including dyspnea of exertion (8/8), cough (4/8), chest suppression (2/8), and chest pain (2/8). Four patients died from severe infection, including 3 cases of pulmonary artery hypertension and 1 case of interstitial lung disease.


Conclusions
Interstitial lung disease and pulmonary artery hypertension are life-threatening complications of AOSD patients. Earlier recognition and prompt treatment should be made to improve patient outcomes.


Key words: 
Still's disease, adult-onset; Lung disease; Signs and symptoms
武汉某高校新生结核菌感染和肺结核患病情况调查
Authors: 陈丽萍, 胡永峰
Journal: BMJ (2005)

对华中科技大学校本部2004级10 833名新生免费实施结核菌素纯蛋白衍化物(PPD)试验和胸部X线检查,结果表明,新生结核菌感染率为53.2%,PPD强阳性反应率为9.5%;活动性肺结核患病率为212.3/10万,现患病例发现率为39.1%.有卡痕新生结核菌感染率、PPD强阳性率比无卡痕新生高,研究生结核菌感染率、PPD强阳性率比本科生高。
Pharmacokinetic (PK)-pharamcodynamic (PD) analysis and receptor occupancy data to support every other week maintenance dosing of magrolimab in combination with azacitidine in MDS/AML patients.
Authors: Balaji Agoram, ChaoYu Jin, Roy Maute, Chris H.M. Takimoto, Mark Chao, David Andrew Sallman
Journal: Journal of Clinical Oncology (2020)

e15098 Background: Magrolimab (Hu5F9-G4) is a monoclonal IgG4 antibody that binds to CD47 receptor and blocks its interaction with SIRPA, thereby enabling tumor cell phagocytosis and activation of an anti-tumor T-cell response. Magrolimab has shown encouraging efficacy and tolerable safety profiles in treatment-naïve myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) patients on an every week (QW) maintenance dosing schedule. Reduced dosing frequency (e.g. every other week – Q2W) is desired to enhance patient convenience and quality of life. Methods: Interim pharmacokinetic (PK) and CD47 receptor occupancy (RO) data from study 5F9005 (Clinical Trial: NCT03248479) were used for this analysis. A previously developed population PK (PopPK) model of magrolimab was verified with observed PK data from study 5F9005. The PK model was linked to peripheral blood and bone marrow blast CD47 RO. The model-predicted RO was validated with observed RO data. Simulations of PK and RO were conducted to justify the proposed reduced dosing frequency of Q2W starting in Cycle 3 onward. Simulations were compared with preliminary observed RO data from the ongoing 5F9005 study after switching to Q2W dosing. Results: The results showed that observed magrolimab PK in study 5F9005 was consistent with model predictions. Model predicted RO was aligned with observed RO data. PK and RO simulations based on the model indicated &gt; 99% RO in peripheral blood and ~90% RO in bone marrow are expected after switching to Q2W dosing regimen from Cycle 3 onward. Preliminary observed RO data confirmed these predictions. Conclusions: Magrolimab PK in AML/MDS is consistent with other patient populations including solid tumors and lymphomas. Model-based simulations and preliminary RO data support Q2W dosing of magrolimab from Cycle 3 onward as optimal RO is expected with the proposed dosing regimen. Clinical trial information: NCT03248479 .
A prospective phase I trial of dendritic cell-based cryoimmunotherapy in metastatic castration-resistant prostate cancer.
Authors: Liv Cecilie Vestrheim Thomsen, Alfred Honoré, Lars Anders Reisæter, Bjarte Almås, Kristina Førde, Einar Kleboe Kristoffersen, Guro Kristin Melve, Martin Biermann, Svein Inge Helle, Waqas Azeem, Ole Johan Halvorsen, Lars Akslen, Duke Bahn, Klaus Pantel, Sabine Riethdorf, Haakon Ragde, Bjørn T. Gjertsen, Anne Margrete Øyan, Karl-Henning Kalland, Christian Beisland
Journal: Journal of Clinical Oncology (2020)

3029 Background: Dendritic cell (DC)-based cryoimmunotherapy (CryoIT) was used to treat metastatic castration-resistant prostate cancer in a Phase I clinical trial. Primary objective was safety of treatment. Secondarily, clinical, radiological and immunological treatment responses were investigated. Methods: In 18 patients cryoablation by a freeze-thaw process under general anesthesia was performed, followed by intratumoral autologous immature DC injection. In the last 9 patients checkpoint inhibition of either CTLA-4 or PD-1 was added. Subjects had minimum 46 weeks follow-up. Adverse events (AEs) and blood analyses were registered at all visits. Disease progression was determined by three imaging modalities according to (i)RECISTv1.1 and progression-free survival (PFS) by Kaplan-Meier method. Circulating tumor cells (CTC/7.5 mL, CellSearch) and ultradeep T-cell receptor (TCR) b-chain sequences (TCRSafe) were enumerated. Patients were separated by CTC into none (n=10), 1-4 (n=4) and ≥ 5 (n=4). Health related quality of life (HRQoL) measured by EORTC-QLQ C30 questionnaire were answered at inclusion, and 10, 22 and 46 weeks post CryoIT. Scores were calculated according to the EORTC manual. Results: Subjects progressing within 22 weeks had higher PSA (p=0.03). AE profile of the total cohort (n=18) was comparable with interim reports (n=13); of 20 possible DC-related AEs one was severe (urinary retention) and 19 mild-to-moderate, and spread independent of treatment regime. Maximum tolerated dose of DC was not reached. By 46 weeks, imaging showed 6 patients partial response or stable disease. Median PFS was 150 days in total cohort. Pretreatment CTC counts ≥5 indicated higher progression rates and recurring CTC. Ultradeep TCR-sequencing showed more prevalent and higher expressed (&gt;5-fold) new TCR clonotypes at 2-6 weeks in men without progression. Participants reported high and stable HRQoL scores throughout the study. However, presence of CTC was associated with worse HRQoL scores at week 10 (p=0.031) and 22 (p=0.005). Conclusions: DC treatment seems safe and well tolerated, also combined with checkpoint inhibitors. Effect is indicated in subjects with moderate pre-treatment PSA levels. Immune responses are suggested by higher number of novel TCR clonotypes in men with non-progressive disease. Clinical trial information: NCT02423928 .
Evaluation of the fully automated Idylla EGFR Mutation Assay in Chinese patients with lung adenocarcinoma.
Authors: Tian Qiu, Li Junling, Bo Zheng, Jianming Ying
Journal: Journal of Clinical Oncology (2020)

e21716 Background: Epidermal growth factor receptor ( EGFR) mutation testing is nowadays an essential part of lung adenocarcinoma diagnosis. Its rapid detection is of utmost significance in order to ensure that patients receive timely and appropriate treatment. However, the current techniques for EGFR examination in China, ARMS-PCR and NGS, often take 3~7 days to deliver the final results. In contrast, the fully automated Idylla EGFR assay could detect 51 EGFR mutations directly from formalin-fixed, paraffin-embedded (FFPE) samples within 2.5 hours with &lt; 2 minutes of hands-on time. The test has proven both accurate and robust among Caucasian lung adenocarcinoma patients but has never been clinically validated in Chinese patients. Methods: FFPE samples were retrospectively collected from 94 lung adenocarcinoma patients followed by EGFR testing using the Idylla system. Seventy-eight samples were also previously assessed with ARMS-PCR, 9 with NGS and 7 with both. In case of discordance, repeat testing was performed on the same tissue block with a third method. The sensitivity and specificity of the Idylla EGFR assay were evaluated against ARMS-PCR or NGS. Mutations beyond the scope of detection by the Idylla EGFR assay were not included in the analyses. Results: Of the 94 tumors enrolled, 77 were stage I-II. The Idylla system was consistent with ARMS-PCR or NGS for the EGFR mutational profiles of 92 tumors: 80 positive and 12 negative. Among the 2 cases of discrepancy, one was wild-type using Idylla but were found to harbor G719X/S768I using ARMS-PCR (and confirmed by NGS), while the other one carried L858R according to Idylla, as confirmed by ARMS-PCR, but was discovered to have an additional mutation L861Q using NGS. The Idylla EGFR test had a sensitivity of 97.6%, a specificity of 100% and an overall concordance of 97.9%. Conclusions: The Idylla system provides a rapid, accurate and user-friendly solution to EGFR characterization, especially in time-sensitive scenarios where special expertise and staff training could be a challenge.
吻合器环形痔切除术结合血栓取出术治疗急性嵌顿性环状混合痔38例
Authors: 鲁兵, 傅传刚, 张钧, 周坤, 王赭, 陈勇, 刘玉祥
Journal: BMJ (2006)

吻合器痔上黏膜环形切除术(PPH)治疗Ⅲ～Ⅳ度痔已为大家所认同.[1,2],我们采用PPH结合血栓取出术治疗急性嵌顿性混合痔38例,报告如下. 1.对象与方法:38例患者为2004年1月至2005年8月收治的病例,其中男性22例、女性16例,年龄31～78岁,中位年龄57.5岁.符合国家中医药管理局中医病环状混合痔的诊断疗效标准.痔嵌顿时间1～3 d,痔核嵌顿于肛门外口难于还纳,或还纳后痔核很快再次脱出于肛门外口,疼痛剧烈.痔核水肿明显,嵌顿痔核内有不同程度的血栓形成,脱出的黏膜部分有坏死脱落。