tbuckley/cabot-search huggingface dataset:
Methylation profiling of hypomethylating agent response and treatment failure in pediatric and young adult MDS/AML.
Authors: LaQuita Marie Jones, Maureen Megan O'Brien, Erin Haag Breese, Michael Absalon, Karen Cristly Burns, Micheal Grimley, Benjamin Mizukawa, Lynn Hua Lee, John Peter Perentesis, Christine L. Phillips
Journal: Journal of Clinical Oncology (2020)

e22502 Background: Hypomethylating agents (HMAs) have favorable toxicity profiles and anti-leukemia activity in adult AML/MDS. We previously reported similar activity in eight pediatric patients (Phillips et al., British Journal of Hematology 2013), however, it remains unclear which factors influence outcome and sustainability of response. We sought to update our clinical experience and determine molecular correlates of HMA response and relapse with the goal of identifying potential biomarkers and physiologic insights. Methods: Clinical data was retrospectively collected through chart review from 2012 to 2017. Cryopreserved patient bone marrow was obtained from our institution’s biorepository under an IRB-approved protocol. Leukemic blasts were enriched by FACS, and genomic DNA was extracted and subjected to reduced representation bisulfite sequencing (RRBS). Differentially methylated regions (DMRs) were calculated using MethylKit. Results: Fourteen patients were treated with hypomethylating agents. Median age was 9.5 years (range 2-34). Two patients (14%) had germline TP53 mutations, secondary MDS/AML, and achieved complete response (CR). Four patients (29%) had monosomy 7, with 2 CR (50%) and 2 partial responses (PR). Contrarily, in the non-monosomy 7 patients, only 1 patient achieved a CR, 2 PR, and one had stable disease. DMRs were identified by comparing diagnostic and relapse samples, as well as responsive and refractory specimens. As expected, there was global DNA hypomethylation following treatment with HMAs. Pathway analysis of DMRs identified in relapse vs diagnostic samples revealed promoter hypomethylation in processes related to DNA binding, transcription factor activity, and RNA biosynthesis, as well as promoter hypomethylation of polycomb repressive complex 2 targets and gene sets classically associated with histone H3 K27 trimethylation. Gene set enrichment analysis (GSEA) of relapse versus remission marrow samples demonstrated reduced methylation of promoter regions regulating DNA repair, responses to DNA damage, and adaptive immune signaling. Conclusions: Our data suggests that HMA response and relapses after treatment may exhibit unique biological signatures reflected in methylation changes. These findings can inform further hypothesis generation and potentially combination therapies.
Correlation of CTCs with disease progression in Indian oral cancer patients.
Authors: Jayant Khandare, Burhanuddin Qayyumi, Atul Bharde, Gourishankar Aland, Sreeja Jayant, Swati Tripathi, Nitin Singh, Reecha Badave, Alain D'Souza, Balram Singh, Smriti Arora, Narendra Kale, Aravindan Vasudevan, Amrut Ashturkar, Kumar Prabhash, Pankaj Chaturvedi
Journal: Journal of Clinical Oncology (2020)

e15541 Background: Head and neck squamous cell carcinoma is leading cancer in the India with Oral squamous cell carcinoma (OSCC) as the most frequent subtype. OSCC is classified as a locoregional disease and its increased frequency is attributed to lack of good biomarkers compared to other epithelial cancers. At the time of diagnosis, above 50% of cases present the manifestation of advanced-stage disease, and are predisposed to disease failure in spite of appropriate treatment. Thus, early diagnosis of OSCC can significantly reduce the disease burden. Here we describe regulatory approved method to establish Circulating tumor cells (CTCs) presence in OSCC Indian patients and its positive correlation with various clinicopathological parameters, suggesting the potential use of CTCs as a significant parameter to stratify oral cancer with respect to the disease advancement. Methods: In a cross-sectional observational study, 230 OSCC patients at the different pathological stage of the disease and treatment mode were enrolled. CTCs were isolated using approved OncoDiscover liquid biopsy technology (Drug controller general of India approved), platform technology based on immunomagnetic CTC enumeration. CTCs were detected for CK18 presence and well-defined, DAPI-stained nuclei. Enumerated CTC subsequently analyzed for various clinic-pathological parameters such as pstage, extra-capsular spread (ECS), lymphovascular emboli (LVE), perineural invasion (PNI) and depth of invasion (DOI). CTC cut off values were obtained to differentiate early vs advanced stages with respect to different clinical stages and parameters. Results: CTCs of OSCC patients correlated positively with the cancer stages (clinical as well as pathological) as well as aggressive pathological features. The presence of aggressive pathological features that often suggest the poor outcome of the disease, we observed a 25-50 % increase in CTC number. Early stage, treatment naïve patients had lower number of CTCs. Mean CTC number in advanced-stage patients was 50 % higher than early-stage OSCC patients. Conclusions: Considering a positive correlation of CTC number with various pathophysiological features, CTC can be contemplated as a reliable parameter to predict the disease outcome in oral cancer. The consistent presence of CTC across all disease stages also suggests a probable nature of OSCC as a biological systematic disease. Clinical trial information: CTRI/2018/03/012905.
Bstronximab, a novel therapeutic antibody to treat metastatic testis cancer.
Authors: William Michael Schopperle
Journal: Journal of Clinical Oncology (2020)

e15621 Background: The treatment of metastatic testis cancer is by far the gold standard for treating metastatic solid cancers: over 90% of men diagnosis with metastatic testis cancer are completely cured with current therapies. What seems to be lost and somewhat surprising within this truly remarkable therapeutic cancer success in treating a metastatic cancer is the fact that in United States alone there are still over 400 young men who died from this disease because they do not respond to current therapies. Thus, despite the tremendous clinical success with treating this disease, there is still a strong unmet need to develop new treatments for men with metastatic testis cancer who fall outside the celebration of this disease as being completely cured. Methods: The human germ cell tumor embryonal carcinoma line, TERA-1. was used to generate purified testis cancer-specific cell membrane antigens to immunize mice and generated antibodies, by standard conventional mouse B cell hybridoma protocols. Isolated monoclonal antibodies where tested by ELISA and SDS-PAGE Western blotting to identify testis cancer specific antibodies. Testis cancer positive antibodies were further screen in an antibody-drug-conjugate screen to determine if the monoclonal antibody could function as a antibody-drug-conjugate therapeutic drug for metastatic testis cancer. Results: Dozens of monoclonal antibodies were generated with our antibody screen. Based on the screen results, a lead monoclonal antibody, named Bstrongomab, was selected for further development as a testis cancer therapeutic antibody. Bstrongomab is an IgG1 monoclonal antibody specific to the human embryonic cell marker, and testis cancer marker, TRA-1-60, a carbohydrate molecule which has been identified over 4 decades ago as a true human testis cancer marker. A human/mouse chimeric version of Bstrongomab was created - Bstrongximab - as a human therapeutic antibody. An antibody-drug-conjugate using Bstrongximab and the toxic payload MMAE (Monomethyl auristatin E) was developed and tested in pre-clinical human cancer testis in-vitro and in-vivo models and showed to be a powerful testis cancer therapeutic drug targeting TRA-1-60. Conclusions: Bstrongximab-MMAE is a novel therapeutic antibody-drug-conjugate which targets the testis cancer antigen TRA-1-60. TRA-1-60 is not expressed in normal tissues. Bstrongximab-MMAE is a new cancer drug ready to move into clinical trials for men with metastatic cancer that do not respond with current therapy protocols.
Early physician spillover responses to the oncology care model.
Authors: Brigham Walker
Journal: Journal of Clinical Oncology (2020)

e19393 Background: As Medicare increasingly seeks to transform beneficiary care through provider reimbursement incentives, there is a possibility that non-beneficiary care will change too. There is limited information on how the Oncology Care Model (OCM) has affected care in this way. This study seeks to analyze the early utilization and cost effects of the OCM on the non-Medicare population. Methods: This was a retrospective analysis of a large physician network comprised of OCM participants and non-participants alike. The data spanned July 1st, 2015 to June 30th, 2017 – one year before and after the launch of the OCM. Several states are represented, and this population includes about 20% of the non-hospital-based community oncology footprint. A difference-in-differences approach was used to compare primary first-year effects on the Medicare population with first-year spillover effects on the Medicare Advantage (MA), private, and Medicaid populations. The utilization and costs of care under management of the practices were evaluated. Effects of the OCM for breast, lung, colon, and prostate cancer among Medicare, MA, private, and Medicaid populations at the physician-by-month level are estimated. Results: The OCM appears to have reduced office visits for Medicare breast cancer and colon cancer. These effects look to have spilled over to the Medicaid breast cancer population, but not elsewhere. The OCM also modestly decreased overall costs for each sub-type but these reductions were not observed in the non-Medicare populations. Conclusions: This research was not randomized, so un-observable differences between groups unrelated to the OCM could drive these results. It is also limited to practice-based care and does not include hospital or pharmacy care. Finally, these are first year effects and the literature suggests that effects can develop for a few years after program launch. That said, this paper suggests that care patterns appear to have changed under the OCM for both Medicare and non-Medicare lives, but not uniformly.
The humanistic spririt of general practice should be concerned
Authors: 杨秉辉
Journal: BMJ (2006)

医学与人类的历史一样古老.当人们身体有病痛之时总会寻求解决的方法,尽管在远古时代医巫不分,当人们求助于巫祝之时,其目的仍在于医疗.在一些文明古国,医学较早地与巫术分家,形成其独立的体系,古希腊、阿拉伯、古印度以及我国皆是如此。
The AIM-HN and SEQ-HN study: A pivotal study evaluating the efficacy of tipifarnib in patients with head and neck squamous cell carcinoma (HNSCC) with <i>hras</i> mutations (AIM-HN) and the impact of <i>hras</i> mutations on response to first line systemic therapies for HNSCC (SEQ-HN).
Authors: Robert I. Haddad, Kevin Joseph Harrington, Lisa F. Licitra, Amanda Psyrri, Nabil F. Saba, Natasa Rajicic, Binaifer Balsara, Michael R. Kurman, Catherine Rose Scholz, Antonio Gualberto, Alan Loh Ho
Journal: Journal of Clinical Oncology (2020)

TPS6593 Background: HRAS mutations define a unique molecular subset of ~ 5% of HNSCC. Evidence suggests that these tumors respond poorly to standard systemic therapy but the impact of HRAS missense mutations on clinical outcomes has not been formally characterized. Tipifarnib is a potent and selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity. Phase 2 Proof of concept for tipifarnib in HRAS mutant HNSCC was recently achieved in study KO-TIP-001 (NCT02383927, Ho et. al. ESMO 2018). Methods: The AIM-HN and SEQ-HN Study (KO-TIP-007, NCT03719690) is an ongoing international, multicenter, open-label, 2 cohort (AIM-HN and SEQ-HN), pivotal trial designed to determine the Overall Response Rate (ORR) of tipifarnib in patients (pts) with HRAS mutant HNSCC (AIM-HN). SEQ-HN will retrospectively investigate how the ORR to first line treatment compares between the accrued HRAS mutant pts to matched-case control HRAS wild type (wt) HNSCC pts. Information on subsequent lines of therapy for HRAS mutant and wt pts will also be collected. AIM-HN will enroll at least 59 pts (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) who are refractory or have relapsed from at least one prior line of systemic platinum-based therapy and have measurable disease by RECIST 1.1. AIM-HN pts must have tumors with &gt;35% HRAS mutant variant allele frequency (VAF) or &gt;20% VAF if serum albumin is &gt;3.5 g/l. AIM-HN pts will receive treatment with tipifarnib at 600 mg bid on days 1-7 and 14-21 of 28-day cycles. Using Simon's Two-Stage Minimax design, if true ORR is &gt; 30%, the study will have 80% power to detect ORR &gt; 15% at 0.025 significance level. Both interim (after first 31 pts) and final analysis, 2-sided 95% CI on ORR, will be performed on the modified intent to treat population. The SEQ-HN observational cohort will enroll ~225 control pts who will receive standard of care treatment. A subset of SEQ-HN pts will be matched to the HRAS mutant AIM-HN pts according to defined patient characteristics and compared for responses to therapy. Clinical trial information: NCT02383927 .
Protein intake and breast cancer incidence and mortality.
Authors: Kathy Pan, Joseph C Larson, Rowan T. Chlebowski, Joanne E. Mortimer, JoAnn E Manson, Linda Van Horn, Thomas E Rohan, Dorothy Lane
Journal: Journal of Clinical Oncology (2020)

1569 Background: Associations between dietary protein intake and breast cancer are unclear, in part due to limitations of dietary self-report. Women’s Health Initiative (WHI) investigators compared the accuracy of food frequency questionnaire (FFQ) data on energy and protein intake with objective measures of dietary intake using biomarkers (doubly labeled water for energy and urinary nitrogen for protein [n=544]). Subsequently, regression equations incorporating participant characteristics were developed acknowledging differential reporting dietary data errors based on participant characteristics (Neuhouser Am J Epidemiol). FFQ findings were then used to determine biomarker- adjusted animal vs vegetable protein ratios. Methods: We examined associations of energy and protein intake with breast cancer incidence and mortality in Women’s Health Initiative (WHI) participants 50-79 years of age at entry between1993-1998, with breast cancers verified by medical record review and survival enhanced by serial National Death Index (NDI) searches through 2016. Associations between sources of protein intake (animal versus vegetable) quintiles and breast cancer incidence and mortality were estimated using multivariable Cox proportional hazards regression. Results: With 100,024 eligible participants, after 14 years follow-up, women with higher total protein intake had greater body mass index, were more likely White, menopausal hormone therapy users with higher total energy intake and fat intake. With 6,340 incident breast cancers, 764 deaths from breast cancer and 2,059 deaths after breast cancer, higher vegetable protein intake was associated with significantly lower breast cancer incidence (P for linear trend = 0.01) while higher animal protein intake was associated with significantly higher breast cancer incidence (P for linear trend = 0.03). Higher vegetable protein intake was also associated with significantly lower risk of death after breast cancer (P &lt;0.001) but not with lower risk of deaths from breast cancer (breast cancer followed by death attributed to breast cancer). Animal protein intake was not associated with deaths from breast cancer or deaths after breast cancer. Conclusions: Based on findings from biomarker-calibrated determination of protein intake by source, higher vegetable protein intake was associated with significantly lower risk of breast cancer incidence and of death after breast cancer while higher animal protein intake was associated with significantly higher risk of breast cancer incidence, but not mortality.
Prognostic role of mid-treatment PET/CT and plasma cytokines in patients undergoing chemoradiation for locally advanced non-small cell lung cancer (LA-NSCLC).
Authors: Jing Zeng, Ramesh Rengan, Christina S Baik, Keith D. Eaton, Bernardo H. L. Goulart, Sylvia Lee, Renato G. Martins, Rafael Santana-Davila, Daniel S Hippe, Paul D. Lampe, A. McGarry Houghton, Hubert Vesselle, Paul Kinahan, Stephen R. Bowen
Journal: Journal of Clinical Oncology (2020)

9040 Background: Patients with unresectable LA-NSCLC are treated with concurrent chemoradiation (CRT) and consolidation immunotherapy with survival that range from months to years or even decades. Early predictive biomarkers have potential to identify patients who are unlikely to benefit from continuing standard of care therapy and require a change in management. We investigated biomarkers that are widely available (PET/CT scan and plasma cytokine levels) to develop early predictors (mid-CRT) of survival in a phase II clinical trial of chemoradiation for LA-NSCLC. Methods: 37 Patients with AJCC v7 stage IIB-IIIB NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238) from 2016-9. All patients underwent chemoradiation; 18 also received adjuvant durvalumab. PET/CT exams were performed at week 3 of CRT and response status was pre-defined by published metrics. 21 patients consented to peripheral blood collection at baseline and week 3, and plasma levels of 43 common inflammatory cytokines were measured. Bootstrapping over 100 iterations of the least absolute shrinkage and selection operator (LASSO) was performed to reduce feature dimensionality and guard against false discoveries. Cox regression of selected cytokine levels and PET response status, as well as time-dependent receiver-operating characteristic (ROC) analysis, were evaluated for associations to overall survival (OS). Results: Median follow-up was 18 months with 1-year OS 81% and PFS 52%. Mid-CRT PET response (as determined by pre-defined metrics) was strongly associated with OS (HR 5.6 [1.4-22.0], p = 0.015) after adjusting for radiation target volume, with 1-yr OS 94% for responders vs. 68% for non-responders (p = 0.017). Plasma TNFα level was also prognostic for OS (HR 1.9 [1.1-3.5], p = 0.030). TNFα retained significance for OS (HR 2.3 [1.2-4.6], p = 0.016) after adjusting for PET response. Bivariate mid-CRT PET response and TNFα generated a parsimonious model to predict OS (AUC = 0.85, 18-month horizon). Conclusions: Risk stratification for long-term survival after chemoradiation in patients with LA-NSCLC may be achievable based on mid-chemoradiation assessment of widely available biomarkers (PET imaging and plasma TNFα level). Combined functional imaging and peripheral blood biomarkers will be validated in a larger sample of our trial cohort, along with other independent patient populations. Clinical trial information: NCT02773238.
Randomized phase II study of axitinib versus observation in patients with recurred or metastatic adenoid cystic carcinoma.
Authors: Bhumsuk Keam, Eun Joo Kang, Myung-Ju Ahn, Chan-Young Ock, Keun Wook Lee, Jung Hye Kwon, Yaewon Yang, Yoon Hee Choi, Min Kyoung Kim, Jun Ho Ji, Tak Yun, Byung-Ho Nam, Sung-Bae Kim
Journal: Journal of Clinical Oncology (2020)

6503 Background: Adenoid cystic carcinoma (ACC) does not respond to cytotoxic chemotherapy. Several anti-angiogenic agents were evaluated in single arm phase II trials. However, the role of chemotherapy is still controversial, because of natural stable disease course without chemotherapy and lack of randomized trial. We firstly conducted a randomized trial to evaluate the efficacy of axitinib compared to observation. Methods: In this multicenter, prospective phase II trial, we enrolled recurred, metastatic ACC patients who progressed within 9 months. Patients were randomly assigned either axitinib (5mg twice daily) or observation arm with 1:1 ratio. Crossover to the axitinib arm was permitted for patients in the observation arm who had disease progression. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), overall survival (OS), PFS, duration of response and adverse events. Results: A total of 60 patients randomly allocated to axitinib (N=30) and observation arm (N=30) and response evaluation was conducted in 57 patients. With a median follow-up of 25.4 months, the 6-month PFS rate was 73.2% (95% confidence interval [CI], 54.8 to 88.1%) in the axitinib arm and 23.2% (95% CI, 9.3 to 41.1%) in the observation arm (hazard ratio, 0.19; 95% CI, 0.08 to 0.45; P &lt; 0.001). Median PFS was 10.8 months in axitinib arm and 2.8 months in observation arm ( P &lt; 0.001). The ORR was 3.3% (95% CI, 0.1 to 17.2%) in the axitinib arm, and 0% (95% CI, 0 to 12.8%) in the observation arm. The disease control rate was 100% (95% CI, 88.4 to 100%) in the axitinib arm and 51.9% (95% CI, 32.0 to 71.3%) in the observation arm. After crossover, ORR of axitinib in the observation arm was 11.1% (95% CI, 2.4 to 29.2%). Median OS was not reached in axitinib arm, 28.5 months in observation arm ( P = 0.688). The most frequently reported adverse events of axitinib were grade 1 or 2 oral mucositis and fatigue. Detailed data of adverse events and mutational profile data will be presented. Conclusions: In this first randomized trial in patients with recurred or metastatic ACC, axitinib significantly increased 6-month PFS rate compared to observation. Clinical trial information: NCT02859012 .
Detection of ProGRP and CYFRA21-1 in differential diagnosis for hydrothorax
Authors: 刘运秋, 林江涛
Journal: BMJ (2006)

目的 探讨胸腔积液胃泌素前体释放肽片段31-98(ProGRP)及细胞角蛋白19(CYFRA21-1)单项及联合检测对肺癌所致恶性胸腔积液的诊断价值.方法将75例肺癌所致的恶性胸腔积液患者分为小细胞肺癌(SCLC)组36例和非小细胞肺癌(NSCLC)组39例,并以良性胸腔积液组37例进行对照.比较胸腔积液ProGRP、CYFRA21-1单项及联合检测对恶性胸腔积液的诊断价值.结果胸腔积液ProGRP在SCLC组、NSCLC组和良性胸腔积液组的阳性率分别为91.7%、2.6%和2.7%;CYFRA21-1在SCLC组、NSCLC组和良性胸腔积液组的阳性率分别为55.6%、82.1%和13.5%.胸腔积液ProGRP单项检测、CYFRA21-1单项检测、ProGRP+CYFRA21-1联合检测(按序列试验)和ProGRP+CYFRA21-1联合检测(按平行试验)诊断SCLC所致的恶性胸腔积液的敏感度分别为91.7%、55.6%、50.0%及94.4%,特异度分别为97.3%、86.5%、97.3%及83.8%,Youden指数分别为0.889 6、0.420 4、0.473 0和0.782 3.ProGRP单项检测、CYFRA21-1单项检测、ProGRP+CYFRA21-1按序列实验联合检测和按平行试验联合检测诊断NSCLC所致的恶性胸腔积液的敏感度分别为2.6%、82.1%、2.6%和82.1%,特异度分别为97.3%、89.2%、97.3%及86.5%,Youden指数分别为-0.001 4、0.712 4、-0.001 4和0.685 4.ProGRP单项检测、CYFRA21-1单项检测、ProGRP+CYFRA21-1按序列试验联合检测和按平行试验联合检测,诊断肺癌所致的恶性胸腔积液的敏感度分别为45.3%、69.3%、40.0%和98.7%,特异度分别为97.3%、86.5%、97.3%和83.8%,Youden指数分别为0.426 3、0.558 2、0.373 0及0.824 5.结论胸腔积液ProGRP和CYFRA21-1分别为SCLC和NSCLC所致的恶性胸腔积液患者首选的肿瘤标志物.按平行试验联合检测胸腔积液ProGRP和CYFRA21-1对肺癌所致的恶性胸腔积液鉴别诊断有很大的临床价值。
Contracted services of general practitioner improve management of primary hypertension in community
Authors: Zhao-hui Du
Journal: BMJ (2013)

Two hundred and forty patients with primary hypertension in Weifang Community were randomly sampled as contract group and another 240 hypertensive patients were sampled as control group. Patients in contract group signed service contract with general practitioners (GPs), who provided individualized service for hypertension management. Patients in control group receive conventional outpatient service for hypertension management. The clinical data of patients before and one year after contracted services were documented and compared with those in control group. The results showed that in contract group the average systolic pressure decreased from 134.60 mm Hg (1 mm Hg=0.133 kPa) to 130.62 mm Hg (P=0.000), reaching-the-target-BP rate increased from 56.3% to 85.5% (P=0.000), serum total cholesterol and triglyceride decreased significantly one year after receiving contracted services (P=0.000); while these indicators were not significantly changed in control group (all P>0.05). The results indicate that the contracted services of GPs can improve the effectiveness of hypertension management in community.


Key words: 
General practitioner; Disease management; Hypertension