tbuckley/cabot-search huggingface dataset:
Inhibition of SETMAR–H3K36me2–NHEJ repair axis in residual disease cells prevents glioblastoma recurrence
Authors: Ekjot Kaur, Jyothi Nair, Atanu Ghorai, Saket V Mishra, Anagha Achareker, Madhura Ketkar, Debashmita Sarkar, Sameer Salunkhe, Jacinth Rajendra, Nilesh Gardi, Sanket Desai, Prajish Iyer, Rahul Thorat, Amit Dutt, Aliasgar Moiyadi, Shilpee Dutt
Journal: Neuro-Oncology (2020)

Abstract Background Residual disease of glioblastoma (GBM) causes recurrence. However, targeting residual cells has failed, due to their inaccessibility and our lack of understanding of their survival mechanisms to radiation therapy. Here we deciphered a residual cell–specific survival mechanism essential for GBM relapse. Methods Therapy resistant residual (RR) cells were captured from primary patient samples and cell line models mimicking clinical scenario of radiation resistance. Molecular signaling of resistance in RR cells was identified using RNA sequencing, genetic and pharmacological perturbations, overexpression systems, and molecular and biochemical assays. Findings were validated in patient samples and an orthotopic mouse model. Results RR cells form more aggressive tumors than the parental cells in an orthotopic mouse model. Upon radiation-induced damage, RR cells preferentially activated a nonhomologous end joining (NHEJ) repair pathway, upregulating Ku80 and Artemis while downregulating meiotic recombination 11 (Mre11) at protein but not RNA levels. Mechanistically, RR cells upregulate the Su(var)3-9/enhancer-of-zeste/trithorax (SET) domain and mariner transposase fusion gene (SETMAR), mediating high levels of H3K36me2 and global euchromatization. High H3K36me2 leads to efficiently recruiting NHEJ proteins. Conditional knockdown of SETMAR in RR cells induced irreversible senescence partly mediated by reduced H3K36me2. RR cells expressing mutant H3K36A could not retain Ku80 at double-strand breaks, thus compromising NHEJ repair, leading to apoptosis and abrogation of tumorigenicity in vitro and in vivo. Pharmacological inhibition of the NHEJ pathway phenocopied H3K36 mutation effect, confirming dependency of RR cells on the NHEJ pathway for their survival. Conclusions We demonstrate that the SETMAR-NHEJ regulatory axis is essential for the survival of clinically relevant radiation RR cells, abrogation of which prevents recurrence in GBM.
Hormone-replacement therapy may be associated with increased incidence of luminal breast cancer: Results from a large-scale health maintenance organization (HMO) analysis.
Authors: Nava Siegelmann-Danieli, Vered Rosenberg, Avital Bareket-Samish, Gabriel Chodick, Varda Shalev
Journal: Journal of Clinical Oncology (2020)

e13599 Background: Trends in breast cancer (BC) incidence may be impacted by potentially competing variables (e.g., mammography rates, hormone-replacement therapy [HRT] use). Methods: This observational retrospective study examined trends/associations between BC incidence, mammography rates, and HRT use among female members of the Maccabi Healthcare Services (the second largest HMO in Israel).BC subtypes were determined based on therapies received by patients diagnosed after 2006 (following trastuzumab approval in the adjuvant setting). Results: Between 2002 and 2014, 14,092 BC cases (88% invasive, 12% in-situ) were identified. The age-adjusted incidence rate of invasive BC peaked in 2005, consistent with increased mammography screening that year, and decreased thereafter. HRT use among all female members aged≥45 years decreased from 13.2% in 2002 to 4.6% in 2014, consistent with the global trend after the Women's Health Initiative publication. Analysis by BC subtype involved 6,218 invasive BC patients diagnosed between 2007 and 2014 (luminal A, 47.5%; luminal B1 without human epidermal growth factor receptor 2 [HER2] over-expression, 25.7%; luminal B2 with HER2 over-expression, 7.7%; estrogen receptor [ER]-negative/HER2+, 4.9%; triple negative, 8.3%; unknown, 6.0%). Overall, 75-86% of patients across all subtypes did not have any HRT exposure vs 14-25% who were current users (within 1 year before the BC diagnosis), recent users (within 2-5 years), or past users ( &gt; 5 years). Current and recent use of HRT was statistically significantly higher in luminal BC vs ER-negative tumors: rates in luminal A/B1/B2, 15.3%/12.1%/11.1% vs ER-negative HER2+/triple-negative/unknown, 8.9%/9.7%/7.7% ( P&lt; 0.001). In BC patients (≥45 years) with HRT exposure, the preparations used were estrogen plus progesterone (62%), estrogen alone (24%), and tibolone (14%). In non-BC cases (≥45 years), the respective values were similar: 61%, 26%, and 13%. Conclusions: HRT current/recent exposure may contribute to increased incidence of luminal BC tumors.
Early-stage breast cancer (BC) patients: Factors associated with aromatase inhibitor-induced musculoskeletal symptoms.
Authors: Simran Arora Elder, Yamin Sun, Seungyoun Jung, Candace Bavette Mainor, Shruti Murali, Paula Rosenblatt, Katherine H. R. Tkaczuk
Journal: Journal of Clinical Oncology (2020)

525 Background: Hormone receptor positive (HR+) breast cancer comprises the largest subgroup of breast cancer. Aromatase Inhibitors (AI) are a key treatment for HR+ BC patients (pts) and reduce mortality. Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), defined as myalgias, arthralgias, or joint stiffness, occur in up to 50% of pts leading to low adherence to and often discontinuation of therapy. Little is known of the mechanism of AIMSS or its predisposing risk factors. This study aims to identify risk factors associated with AIMSS development in BC patients on AI therapy. Methods: We conducted a medical record review of pts with non-metastatic HR+ BC on adjuvant AI therapy between January 2009 and June 2017 at the University of Maryland Comprehensive Cancer Center. This study included 194 ptswho were free of arthralgia prior to AI therapy. We analyzed pts’ demographics, lifestyle factors, reproductive history, tumor characteristics, medications, cancer treatment, co-morbidities, AI type, onset and severity of AIMSS. Severe AIMSS was defined as requiring change in AI therapy or discontinuation. Multivariable-adjusted logistic regression was used to identify risk factors for severe AIMSS. Results: The mean age of participants was 61. The mean BMI at diagnosis was 30 kg/m 2 . 41% of pts were White, 40% were Black, 7% other and 12% unknown. Most (79%) did not have a history of tamoxifen and 16% were on GnRH agonists. Most (71%) used letrozole as initial AI therapy; 18% anastrozole; and 11% exemestane. 56% experienced AIMSS while on AI therapy and 20% required change or hold of AI therapy. 4% permanently discontinued AI due to AIMSS severity. BMI at diagnosis was significantly positively associated with risk of AIMSS. Multivariate odds ratio (95% confidence intervals) comparing the highest to lowest tertile of body mass index (BMI) at diagnosis was 4.01 (1.07-10.90; P trend : 0.05). There were no significant associations with race, smoking, reproductive factors, type of AI therapy, tamoxifen use prior to AI therapy, medication use, experience of other cancer treatments, and tumor characteristics. Conclusions: 56% of BC pts on adjuvant AI therapy experienced AIMSS. 24% of these changed, held or discontinued AI regimen due to severe AIMSS. Higher BMI at diagnosis was associated with a higher risk of AIMSS. Our results confirm clinical significance of AIMSS among BC pts on AI therapy and suggest BMI as a modifiable factor for AIMSS. A larger study is warranted to replicate our findings and seek other possible risk factors for AIMSS.
在社区进行高血压健康教育的体会
Authors: 胡林
Journal: BMJ (2012)

高血压是社区的常见病,在社区进行高血压健康教育,可大大提高患者对高血压的知晓率、服药率、控制率,具有重要意义.1.应纠正患者将血压与症状混为一谈,以自我感觉来衡量血压的高低等错误观念:社区患者如果没有症状一般不会主动就诊或测量血压,进行健康教育时要提醒社区居民注意测量血压.同时告知患者血压高低并不代表高血压的危险程度,也不能区分高血压究竟是原发还是继发,发现患有高血压时需要进行必要的辅助检查来判断高血压的危险分层,区分高血压是原发还是继发,必要时需要转诊至上级医院来明确。
Sudden deaths caused by cardiac tamponade due to rupture of aortic dissecting: autopsy of 5 cases
Authors: Yu-hua Zhang, Lian-shan Zhang, Zhi-hong Li, Guang Ma
Journal: BMJ (2013)

A retrospective analysis was made on clinical manifestations and autopsy results of 5 sudden deaths from aortic dissecting (AD). Sudden deaths from AD were almost induced by type Ⅰ and Ⅱ of DeBakey Typing. Most patients had a history of hypertension and prodromal symptoms of either chest pain, abdominal pain or back pain. Most common cause of death was cardiac tamponade induced by rupture of the ascending aorta. The clinicians should further recognize of AD so as to achieve the objective of early diagnosis and early treatment.


Key words: 
Aortic rupture
Application of problem-based learning in residency training of general medicine
Authors: Yan Wang, Yan-hong Gao, Zhi-hong Pan, Shu-yan Chen
Journal: BMJ (2012)

Problem-based learning (PBL) is a student-centered pedagogy in which a subject is approached in the context of realistic problems.We have applied PBL into intemnal medicine of general medicine for up to three years.The results suggest that the PBL method could promote the clinical competencies and self-learning capacities of students.However there is still room for improvement.

Key words: 
Teaching methods; General practice
Daratumumab-based three drug regimens for high-risk multiple myeloma: A meta-analysis.
Authors: Arafat Ali Farooqui, Muhammad Tariq, Shaha Nabeel, Aqsa Ashraf, Zahoor Ahmed, Muhammad Salman Faisal, Mohammad Ammad Ud Din, Zartashia Shahab, Alireza Setarehaseman, Faiz Anwer
Journal: Journal of Clinical Oncology (2020)

e20549 Background: Efficacy of daratumumab (D) based regimens in high risk multiple myeloma (MM) (i.e, ISS stage II/III and t(4;14) or (del17p)) has not been thoroughly investigated. The aim of this study was to assess the efficacy of D based 3-drug regimens compared to non-D based regimens in high risk MM. Methods: A systematic review of literature was performed to identify randomized controlled trials (RCTs) which reported overall response rates (ORR) and progression free survival (PFS) of MM patients (pts) with D based 3-drug regimens. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using RevMan v.5.3 to report the efficacy of D based 3-drug regimens. A random effects model was employed only when there was significant heterogeneity among studies ( &gt; 40%, as assessed by I-squared). Results: Screening of 604 studies yielded 04 RCTs (n = 2,234 pts). D was evaluated with lenalidomide (L), carfilzomib (C), bortezomib (B) and dexamethasone (d). DLd regimen was studied in 649, DCd in 312 and DBd in 240 pts. Total 1201 pts were evaluated with D. D based 3-drug regimens proved to be of improved efficacy versus non-D 2-drug regimens in the pooled analysis i.e., PFS (HR 0.46, 95% CI 0.33-0.63; p &lt; 0.00001; I 2 = 81%) and ORR (OR 2.83, 95% CI 2.06-3.88; p &lt; 0.00001; I 2 = 44%). Relapsed/refractory MM (n = 833) also showed improved ORR (OR 2.79, 95% CI 1.78-4.36; p &lt; 0.00001; I 2 = 62%). In high risk group, addition of D decreased the risk of progression to 42% (HR 0.58, 95% CI 0.39-0.85; p = 0.005; I 2 = 3%). In standard risk pts, D decreased the risk of progression/death to 66% (HR 0.34, 95% CI 0.23-0.51; p &lt; 0.00001; I 2 = 74%). D increased the risk of neutropenia (OR 1.88, 95% CI 1.54-2.31; p &lt; 0.00001; I 2 = 0%), respiratory tract infections (OR 1.87, 95% CI 1.49-2.35; p &lt; 0.00001; I 2 = 0%) and diarrhea (OR 1.83, 95% CI 1.46-2.29; p &lt; 0.00001; I 2 = 23%) in the study population. Conclusions: Daratumumab based 3-drug regimens appear to abrogate high risk features in MM compared to 2 drug regimens.
Long-term outcomes among BCG-treated high-risk non-muscle invasive bladder cancer patients in an equal access setting.
Authors: Stephen B. Williams, Lauren Howard, Meagan Foster, Zachary William Abraham Klaassen, Jan Sieluk, Haojie Li, Kentaro Imai, Eric Sbar, Amanda M. De Hoedt, Stephen J. Freedland
Journal: Journal of Clinical Oncology (2020)

e17031 Background: Management of high-risk non-muscle invasive bladder cancer (HR NMIBC) represents a clinical challenge due to high failure rates despite prior bacillus Calmette-Guérin (BCG) therapy. We describe real-world patient characteristics, long-term outcomes, as well as the economic burden in the HR NMIBC population. Methods: We identified a random sample of 412 HR NMIBC patients who received ≥ 1 dose of BCG within Veterans Affairs (VA) centers across the United States from January 1, 2000, to December 31, 2016. HR NMIBC was defined as high-grade Ta (TaHG), T1, and/or carcinoma-in-situ (CIS). We analyzed the number of BCG instillations received, as well as used the Kaplan-Meier method to estimate event-free survival for cystectomy and bladder cancer-specific death. All-cause expenditures were summarized as medians with corresponding interquartile ranges (IQR) and adjusted to 2019 USD. Results: The median (IQR) age at diagnosis was 67 years (61-74), with most patients being white (84%) and male (81%). At HR NMIBC diagnosis, 69 (17%) patients had CIS +/- T1 or TaHG, and 341 (83%) had TaHG or T1, no CIS. The vast majority of patients [n = 363, (90%)] received six BCG instillations (range: 1-7) within 365 days of the first dose. The total follow-up was 2,694 person-years. From BCG initiation to end of follow-up, the median all-cause expenditures per patient were $358,593 (257,699 – 652,853). Conclusions: In this equal access setting, the vast majority of HR NMIBC patients received 6 instillations of BCG within 1 year, although the interval over which the instillations were given varied among patients. Patients with CIS appeared to have a worse prognosis, as 24% underwent cystectomy, and 13% died of bladder cancer at 10 years of follow-up. These findings also highlight the considerable economic burden of HR NMIBC. [Table: see text]
Activity and safety of third-line BRAF-targeted therapy (TT) following first-line TT and second-line immunotherapy (IT) in advanced melanoma.
Authors: Victoria Atkinson, Kathleen Batty, Georgina V. Long, Matteo S. Carlino, Geoffrey David Peters, Prachi Bhave, Maggie A. Moore, Wen Xu, Lauren Julia Brown, Melissa Arneil, Megan Lyle, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2020)

10049 Background: Patients with advanced melanoma who progress on 1 st line TT and 2 nd line IT have limited treatment options. We explored the safety and efficacy of re-treatment with 3 rd line TT. Methods: was pooled from 6 centers in Australia from 2009-2018. Eligible patients with BRAF V600 mutant melanoma had 1 st line therapy with a BRAF/MEK inhibitor, 2 nd line IO and were re-challenged with a BRAF/MEK inhibitor. Results: 90 patients were included; median age 61 years, 78% BRAF V600E, 89% ECOG 0-1 at baseline. 1 st line TT was combination BRAF/MEK inhibitors in 80%, predominately dabrafenib/trametinib. Response to 1st line therapy was CR 20%, PR 41%, SD 17% and PD 13% and median duration of therapy was 7.2 months (0-33 months). 70% stopped for progressive disease, 9% toxicity and 16% had a planned switch to immunotherapy. For 2 nd line IT, 49% had PD-1 alone, 33% had PD-1+CTLA-4, 14% had CTLA-4 alone. Only median duration on IT was 67 days (0-23 months), 81% ceased for PD, 14% for toxicity. Of patients who had a planned switch to IO before 1 st line TT progression, one patient responded to second line IO with SD as BORR, there were no other responses to 2 nd line IO in the planned switch group. At 3 rd line TT re-challenge, 54% were AJCC stage IVd, 34% IVc, 51% had elevated LDH, 59% ECOG 0-1. 47% were re-challenged with dabrafenib/trametinib, 33% vemurafenib/cobimetinib, 11% encorafenib/binimetinib. BORR was 28%, with median duration on 3 rd line TT 81 days. The OS was 1.7 years, with 34% alive at time of analysis. Conclusions: Despite progression on 1 st line TT and 2 nd line IT, patients may experience meaningful response and on re-challenge TT.
Concordance of provider treatment patterns with NCCN oncology treatment guidelines (NCCN Guidelines) for metastatic non-small cell lung cancer (mNSCLC).
Authors: Brian S. Seal, Meghan Mooradian, Candice Yong, Amy L Schroeder, Dana Macher, Biruk Bekele, Allison Petrilla
Journal: Journal of Clinical Oncology (2020)

e21574 Background: mNSCLC clinical treatment guidelines are rapidly evolving, however, their influence on prescriber use of anti-cancer treatment regimens is not known. This retrospective study evaluated whether US patients with mNSCLC received first line (1LOT), second (2LOT), or third (3LOT) line treatment regimens that were concordant with NCCN Category 1-2A recommendations. Methods: mNSCLC patients who initiated treatment between 2014-2017 were identified using medical and pharmacy claims from the 100% Medicare Fee-for-Service (FFS) Part A/B/D sample and multi-payer Inovalon MORE 2 Registry. Claims-based algorithms identified mNSCLC and LOT following diagnosis; patients with other primary cancers or &lt; 6 months follow-up were excluded. Treatment regimens were compared to active NCCN Guidelines at time of treatment to determine if regimen was concordant with Category 1-2A recommendations. Genetic mutation/biomarker status was not available. Results: 6,523 patients with mNSCLC met criteria for analysis (FFS/Medicare Advantage:78.6%; commercial:14.0%, managed Medicaid:7.4%; mean age:69.3 [SD:9.2]). For 1LOT, 81% received platinum-based doublet regimens; most common monotherapy included erlotinib, nivolumab, and pembrolizumab; 18% of 1LOT patients received maintenance therapy. For 2LOT, approximately one-third received nivolumab monotherapy, one-third received platinum-based doublets, and remainder received other regimens. Most common 3LOT included monotherapy nivolumab, pemetrexed, paclitaxel, and docetaxel. NCCN Guidelines concordance varied: 1LOT (90.5%), 2LOT (58.5%), 3LOT (71.9%). Non-concordant regimens included nivolumab as 1LOT and early adoption of platinum agent+(pemetrexed or paclitaxel) in 2LOT, and chemotherapy as 2LOT in anaplastic lymphoma kinase rearrangement-positive or epidermal growth factor receptor mutation-positive disease. Conclusions: In Medicare and non-Medicare patients with mNSCLC, 1LOT closely followed NCCN Guidelines. Most variability was observed in 2LOT where 58.5% regimens were concordant with Category 1-2A recommendations. Non-concordance may be driven by lack of effective second-line regimens and early adoption of innovative therapies.
Clinical efficacy of adefovir dipivoxil combined with anti-tuberculosis drugs inn treatment for chronic hepatitis B complicated with pulmonary tuberculosis
Authors: Jie Jiang, Jian-chun Zhang, Deng-sen Ding, Lin Li, Guo-qing Liu
Journal: BMJ (2009)

Objective It is purposed to evaluate clinical efficacy of adefovir dipivoxil combined with anti-tuberculosis (TB) drugs in treatment for chronic hepatitis B (HB) complicated with pulmonary TB. Methods Ninety-four eases of pulmonary TB complicated with chronic HB receiving anti-TB drug treatment at Liaocheng Hospital for Infectious Disease during September 2006 to September 2008 were divided into treatment and control groups matched on their pulmonary TB lesion, damage in liver function and HB virus (HBV) DNA load. Forty-seven cases in the treatment group were administered with anti-TB drugs, i.e., isoniazid (INH) 0. 3 g daily, rifapentine (RFT) 0.45 g twice a week, pyrazinamide (PZA) 1.5 g daily, streptomycin (SM) 0. 75 g daily or ethambutol (EMB) 0. 75 g daily, and regular liver-protection drags, as well as oral adefovir dipivoxil 10 mg daily for eight months, and another 47 cases in the control group were administered with the same anti-TB drugs and regular liver-protection drugs as the treatment group. Two to eight weeks after treatment, clinical symptoms, liver function, HBV DNA load, negative conversion of acid-fast staining bacteria in sputum smear, and absorption of pulmonary TB lesion were evaluated for all the patients in both groups. Data were analyzed with U-test and χ2-test, respectively. Results After treatment, damage in liver function worsened in three cases (6.4%), as compared to that in 47.3 percent of the control group (P<0.05). Clinical symptoms, including tiredness, loss of appetite, abdominal distension, uncomfortable in upper abdomen, and so on, appeared in three cases of the treatment group (6.4%) during anti-TB treatment, as compared to those in 18 cases of the control group (47.3%) (P<0.05). HBV DNA conversed to negative (less than 1.0×103 lg copies/ml) in 24 cases of the treatment group (51.1%), HBV load went down to 1.0×103-1.0×104 lg copies/ml in 23 cases (48. 9%), sputum smear bacteria conversed to negative in 41 cases (87. 2%) and pulmonary lesion absorbed in 45 cases (95.7%), all with statistically significance as compared to those in the control group (47. 3% , 0. 0% , 2. 6% , 39. 5% and 50. 0% , respectively, P <0. 05). Renal function was all in normal in both groups and no patient with drug resistant variant HBV was found during and after treatment, and no obviously adverse reaction was found in patients with adefovir dipivoxil. Conclusion Adefovir dipivoxil has a good safety and can reduce laver damage in anfi-TB drug treatment for patients of chronic hepatitis B complicated with pulmonary TB.

Key words: 
Hepatitis B, chronic;  Tuberculosis,pulmonary;  Antitubercular agents
Morbidity survey of blindness and low vision among senior residents in Huaihai communities of Shanghai
Authors: Bin Shen, Jian-feng Zhu, Feng Xu
Journal: BMJ (2013)

A cluster sampling method was used to select 5 Huaihai communities of Shanghai. All individuals were aged ≥60 years. Visual acuity without correction and presenting acuity with their habitual distance correction were measured separately for each eye. The prevalence of blindness and low vision was 0.49% and 1.65% respectively. The leading causes of blindness in a descending sequence included macular degeneration, cataract and retinal vascular disease.


Key words: 
Blind; Prevalence
Langerhans cell sarcoma: The Mayo Clinic experience with an extremely rare disease.
Authors: Muhamad Alhaj Moustafa, Liuyan Jiang, Han W. Tun
Journal: Journal of Clinical Oncology (2020)

e19543 Background: Langerhans cell sarcoma (LCS) is a very rare cancer with the reported incidence of 2 per 100,000,000. It originates from antigen presenting cells belonging to the dendritic cell/macrophage family. Methods: Following IRB approval, we identified LCS patients treated at the Mayo Clinic Cancer Center. Medical charts were reviewed to extract clinical data. Results: Our cohort consists of 5 patients with confirmed diagnosis of LCS. The median age at diagnosis was 34 years (range, 11-75) with 60% (3/5) females. One female was an African American and the rest were Caucasians. ECOG performance status at the time of diagnosis was 0 in 4 patients and 3 in 1 patient. Four patients had disseminated disease at diagnosis. 3/5 patients had moderate splenomegaly at diagnosis. 2/5 patients presented with a bulky mediastinal tumor and 1/5 patients presented with bulky intraabdominal disease. Predominant sites of disease are summarized in the table. BRAF mutation was negative in all 3 tested patients. The median follow up for the whole cohort was 25 months (range; 5, 41). Three patients relapsed after the initial treatment. Patient # 4 received allogeneic stem cell transplantation after the 4 th relapse and is in CR 14 months later. Patient # 5 had PD-L1 expression &gt; 95% and was started on pembrolizumab with sustained response for 1 year. Conclusions: LCS is extremely rare and is associated with unfavorable outcomes after currently available therapeutic interventions. More studies on the genetic and molecular basis of LCS are necessary to develop targeted therapies. [Table: see text]