tbuckley/cabot-search huggingface dataset:
Comparison of recurrence patterns after surgery and radiation therapy with 68Ga-PSMA-11 PET/CT in nonmetastatic castrate-sensitive prostate cancer patients: A single-center post-hoc retrospective analysis in 787 patients.
Authors: Wesley R Armstrong, Pan Thin, Kathleen Nguyen, Rejah M. Alano, Kiara M Booker, Jeannine Gartmann, Vincent Lok, Stephanie Lira, Johannes Czernin, Amar Upadhyaya Kishan, Nicholas George Nickols, Jeremie Calais
Journal: Journal of Clinical Oncology (2020)

3577 Background: 20 to 50% of prostate cancer (PCa) patients undergoing radical prostatectomy (RP) or definitive radiation therapy (dRT) will experience disease recurrence. However, anatomical recurrence patterns may differ depending on the therapeutic approaches. The aim of this post-hoc retrospective analysis was to investigate if the relapse pattern as assessed by 68Ga-PSMA-11 PET/CT was different depending on the type of local pelvic therapy (RP, dRT, salvage RT (SRT), pelvic lymph node dissection (PLND), pelvic lymph node RT (PLNRT)) in patients with non-metastatic castrate sensitive (nmCS) recurrent disease after primary definitive therapy. Methods: Patients who underwent a 68Ga-PSMA-11 PET/CT for nmCS PCa recurrent disease after primary definitive therapy were screened from a database of 4 prospective studies (NCT02940262, NCT03515577, NCT04050215, NCT03582774). Patients who underwent primary staging (n = 95), without definitive therapy (n = 68), with known metastatic disease (M1) (n = 68) or with castrate resistant (CR) disease (n = 291) were excluded. We examined the relationship between recurrence patterns as assessed by 68Ga-PSMA-11 PET/CT (PROMISE criteria) and prior local treatments: i) RP, ii) dRT, iii) RP + SRT. Results: 787 patients were included in the analysis. Positive scan rates were 60%, 94% and 75% in RP, dRT and RP + SRT populations, respectively. Median pre-scan PSA levels were 0.50 (0.02-72.5) ng/ml, 4.4 (0.1-202) ng/ml, and 1.07 (0.04-33) ng/ml for patients who underwent RP (n = 464), dRT (n = 109) and post-RP SRT (n = 214). Median time to first recurrence was 27.7 after RP and 54.6 months after dRT (p = &lt; 0.0001). Patients who underwent RP had lower local recurrence (LR) pattern (T+) rates by PSMA PET than those with dRT (99/464; 21% vs 69/109; 63%; p = &lt; 0.0001). Nodal metastasis (N1) positivity rate was similar between RP and dRT (179/464; 39% vs 43/109; 39%; p = 0.87). Extrapelvic metastasis (M1) positivity rate was lower for RP than dRT (93/464; 20% vs 51/109; 47%; p = &lt; 0.0001). Median time from post-RP SRT to second recurrence was 22.3 months. In patients who had a second recurrence after RP and SRT the positivity rate of LR (T+), N1 disease and M1 disease by PSMA PET/CT was 12% (24/214), 46% (99/214) and 44% (95/214). Conclusions: In this cohort of patients with nmCS PCa recurrent disease after primary definitive therapy, the patterns of failure differ based on prior local treatments.
老年人上消化道大出血致急性心肌梗死三例
Authors: 党小红, 郭文玲
Journal: BMJ (2005)

2001年7月至2002年7月我科收治153例上消化道出血患者,60岁以上的有61人,其中3例67岁以上老年患者在上消化道大出血救治过程中出现急性心肌梗死(AMI),符合WHO关于AM1的诊断标准.3例患者既往无冠心病病史,均为男性。
Pembrolizumab (pembro) plus olaparib in patients (pts) with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort A efficacy, safety, and biomarker results.
Authors: Evan Y. Yu, Jose Maria M. Piulats Rodriguez, Gwenaelle Gravis, Brigitte Laguerre, Jose Angel Arranz Arija, Stephane Oudard, Peter C.C. Fong, Michael Paul Kolinsky, Marinela Augustin, Tilman Todenhöfer, Audrey E. Kam, Howard Gurney, Ali Tafreshi, Margitta Retz, William R. Berry, Nataliya Mar, Haiyan Wu, Ping Qiu, Charles Schloss, Johann S. De Bono
Journal: Journal of Clinical Oncology (2020)

5544 Background: Pembro + olaparib has shown antitumor activity and acceptable safety in docetaxel-pretreated pts with mCRPC enrolled in cohort A of the phase I/II KEYNOTE-365 study (NCT02861573). Updated results with new biomarker data are reported. Methods: Pts with docetaxel-pretreated mCRPC who progressed within 6 mo of screening received pembro 200 mg IV Q3W + olaparib 400-mg capsule or 300-mg tablet PO BID. Pts might have received 1 other chemotherapy and ≤2 second-generation androgen-receptor targeted therapies. Primary end points: PSA response rate (decrease ≥50% from baseline, confirmed by a second value ≥3 wks later), ORR per RECIST v1.1, and safety. Key secondary end points: DCR, DOR, rPFS, and OS. Biospecimens (eg, blood, tissue) were collected for biomarker analysis (tissue PD-L1 expression, androgen receptor variant 7 [AR-v7] expression in circulating tumor cells [CTCs], and a T-cell–inflamed gene expression profile [GEP]). ctDNA was analyzed by Guardant Health 360 (GH360) and Omni (GH Omni) assays. FFPE tissue was analyzed by FoundationOne CDx (F1CDx) assay. Results: 84 of 87 enrolled pts were treated; 48/84 (57.1%) had measurable disease. Median (range) time from enrollment to data cutoff was 3.6 mo (0.0-29.2) for all pts and 26.7 mo (21.2-29.2) for 41 pts with ≥27 wks’ follow-up. Confirmed PSA response rate was 9% (95% CI, 3.5-16.8) in 82 pts with a baseline PSA assessment. Median time to PSA progression: 3.8 mo (95% CI, 2.9-4.4). In 24 pts with measurable disease and ≥27 wks’ follow-up, ORR was 8.3% (95% CI, 1.0-27.0; 2 PRs) and DCR ≥6 mo was 20.8% (95% CI, 7.1-42.2). Median (range) DOR was NR (12.0+ to 21.4+ mo); 2 pts had DOR ≥12 mo. In all pts, median rPFS was 4.3 mo (95% CI, 3.4-7.7) and median OS was 14.4 mo (95% CI, 8.1-18.5). Grade ≥3 TRAEs occurred in 29 pts (35%); 2 pts died of TRAEs (1 myocardial infarction, 1 unknown). Overall, 26% had PD-L1 + tumors (combined positive score ≥1). Of 31 pts with CTC data, 12.9% were AR-v7 + . No BRCA1/2 mutation was detected by GH360 (n=42). Of 57 pts analyzed by GH Omni, 2 had BRCA2 mutations, 1 had a BRCA1 mutation, 4 had ATM mutations, 1 had a CHEK1 mutation, and 6 had CDK12 mutations. Of 49 pts analyzed by F1CDx, 4 had BRCA mutations; 1 pt had a copy number loss mutation not detected by ctDNA analysis. GEP was not associated with ORR or PSA response. Conclusions: Pembro + olaparib continued to show activity and acceptable safety in pts with docetaxel-pretreated mCRPC. A phase III study of this combination is ongoing (KEYLYNK-010, NCT03834519). Clinical trial information: NCT02861573 .
Studying human reproductive biology through single-cell analysis and in vitro differentiation of stem cells into germ cell-like cells
Authors: Lin Li, Risako Yang, Chenghong Yin, Kehkooi Kee
Journal: Human Reproduction Update (2020)

Understanding the molecular and cellular mechanisms of human reproductive development has been limited by the scarcity of human samples and ethical constraints. Recently, in vitro differentiation of human pluripotent stem cells into germ cells and single-cell analyses have opened new avenues to directly study human germ cells and identify unique mechanisms in human reproductive development.The goal of this review is to collate novel findings and insightful discoveries with these new methodologies, aiming at introducing researchers and clinicians to the use of these tools to study human reproductive biology and develop treatments for infertility.PubMed was used to search articles and reviews with the following main keywords: in vitro differentiation, human stem cells, single-cell analysis, spermatogenesis, oogenesis, germ cells and other key terms related to these subjects. The search period included all publications from 2000 until now.Single-cell analyses of human gonads have identified many important gene markers at different developmental stages and in subpopulations of cells. To validate the functional roles of these gene markers, researchers have used the in vitro differentiation of human pluripotent cells into germ cells and confirmed that some genetic requirements are unique in human germ cells and are not conserved in mouse models. Moreover, transcriptional regulatory networks and the interaction of germ and somatic cells in gonads were elucidated in these studies.Single-cell analyses allow researchers to identify gene markers and potential regulatory networks using limited clinical samples. On the other hand, in vitro differentiation methods provide clinical researchers with tools to examine these newly identify gene markers and study the causative effects of mutations previously associated with infertility. Combining these two methodologies, researchers can identify gene markers and networks which are essential and unique in human reproductive development, thereby producing more accurate diagnostic tools for assessing reproductive disorders and developing treatments for infertility.
高血压的社区管理
Authors: 唐新华
Journal: BMJ (2009)

近年国内外大量循证医学结果表明,高血压病仅仅依靠医院门诊治疗是远远不够的,必须重视并加强社区人群防治和对患者的管理,走预防为主、防治结合的社区综合防治道路,而且社区管理具有资源丰富、人群集中和成本效益高的独特优势[1]。
Prognostic value of baseline elevated red cell distribution width in DLBCL.
Authors: Akiva Diamond, Kirsten M Boughan, Marcos J.G. De Lima, Paolo Fabrizio Caimi
Journal: Journal of Clinical Oncology (2020)

e20031 Background: Elevated red cell distribution width (RDW) has been associated with all-cause mortality, risk of developing cancer and cancer mortality in large retrospective studies. The underlying mechanism may be due to inflammatory and nutritional abnormalities. We hypothesized DLBCL patients with an elevated RDW at the time of diagnosis would have a worse prognosis. Methods: A retrospective single-institution study included 541 DLBCL patients diagnosed between 2001 and 2016. RDW over 14.5% was considered high, as this was the upper limit of normal at our institution. The overall and progression free survival was estimated using Kaplan-Meier methods, and the difference between groups was compared using the log-rank test. Univariate and multivariate analyses were performed with Cox proportional hazards regression. Results: We identified 410 DLBCL pts with available baseline RDW, 229 (56%) had RDW &gt; 14.5. Median follow up from diagnosis was 60 months. The complete response rate was 63.8% in the group with high RDW (n = 152) and 88.4% in the normal RDW group (n = 216, p &lt; 0.0001) . For patients with high RDW, 1-year overall survival (OS) was 65% (95%CI 0.58-0.72) vs 90% (95%CI 0.87-0.94) for pts with normal RDW &lt; / = 14.5; 2-year OS was 57% (95%CI 0.50-0.65) vs 84% (95%CI 0.79-0.89), respectively (p &lt; 0.0001). This difference remained statistically significant when the analysis was restricted to patients treated with anthracycline-containing regimens given with curative intent (2y OS = 66% vs. 87.5%, p &lt; 0.0001). Univariate analysis revealed that R-IPI, high RDW, elevated LDH, albumin &lt; 3.5mg/dl, Hgb &lt; 10g/dl, advanced stage disease, bulky disease, extra nodal disease, and ECOG performance status 3-4 were associated with worse OS. In multivariate analysis, older age (HR 2.07, 95%CI 1.38-3.1), high RDW (HR 1.68, 95%CI 1.15-2.5), albumin &lt; 3.5mg/dl (HR 1.76, 95%CI 1.18-2.6) and ECOG 3-4 (HR 2.47, 95%CI 1.47-4.2) were independent prognostic factors for OS. Conclusions: High RDW is associated with worse response rates and independently associated with worse OS in patients with DLBCL. Based on our study, DLBCL patients with high RDW at diagnosis should be considered at higher risk of mortality and treatment failure. Further research is needed to clarify the underlying mechanism and to evaluate the utility of incorporating RDW into prognostic indices.
Predictors of response to upfront bortezomib, lenalidomide and dexamethasone (VRd) in multiple myeloma.
Authors: Amany Keruakous, Silas Day, Azra Borogovac, Jennifer L. Holter, Adam Steven Asch, Carrie Yuen
Journal: Journal of Clinical Oncology (2020)

e20507 Background: Achievement of response to less than very good partial response (VGPR) after initial induction is an adverse prognostic factor for progression free survival (PFS) in multiple myeloma (MM). Triplet regimen has been demonstrated to be more effective as compared to doublets, with VRd being the preferred induction regimen in newly diagnosed multiple myeloma (NDMM) based on SWOG077 (43.5% VGPR or better). However, recent studies using quadruple combination, daratumumab-VRd, has shown deep response with 63% reached stringent complete remission (sCR) and CR. Balancing efficacy and toxicity in selecting induction regimen in treatment of MM is a challenge due to advanced age and comorbidity. Biomarkers that guided selection based on prediction for efficacy would be clinically useful. In this study we hypothesized that there is a subgroup of patients with MM that would not benefit from upfront VRd could be identified by biologic factors. Methods: For this retrospective study, we selected a cohort of patients with NDMM who were treated with upfront VRd to be evaluated for response after 3-6 cycles of treatment. We identified variables of risk classification that included cytogenetics, ISS stage, immunoglobulin subtype, light chain restriction, pre-treatment albumin level, bone marrow disease burden, end-organ involvement (hypercalcemia, anemia, renal insufficiency and lytic bone lesions), and presence of extra medullary disease. We analyzed the correlation between variables and response to therapy using Chi Square (Fisher’s Exact) test. Results: Among 175 patients treated in our institution starting April 2011 through May 2018, 120 patients received bortezomib-based regimen with 80% (96 subjects) received VRd and 20% (24 subjects) received Vd, with median age of 60.5 (39-74). After 3-6 cycles of VRd, 50% of patients achieved VGPR or better (48/96), 43% achieved partial response (PR) (43/96), 5% did not respond (5/96). Our data showed that immunoglobulin subtype has statistical significant impact on response to VRd; with increased incidence of VGPR or better in IgA myeloma (79%) as compared to IgG myeloma (37%) (P-Value &lt; 0.0006). In IgG myeloma, we showed increased proportion of patients with PR (56%). Additionally, all 5 patients who did not respond to VRd had IgG myeloma. Other variables did not show statistically significant impact to response to upfront VRd. Conclusions: We conclude that IgG subtype MM predicts suboptimal response with VRd. Thus other regimens or four-drug regimen should be considered for upfront therapy in IgG subtype of MM.
对膝关节炎患者社区干预46例
Authors: 吴剑峰, 邢海英, 张卫, 张建宝, 李俊海, 王庆甫, 黄沪, 周政新, 孙滨, 王辉
Journal: BMJ (2004)

选择已经确诊的膝关节炎患者92例,以分层随机抽样分为干预组和对照组各46例,医生对干预组患者进行社区干预,对照组在门诊治疗.6个月后干预组患者膝关节的骨关节炎严重指数低于对照组(P<0.01)。
Geospatial immune variability illuminates differential evolution of lung adenocarcinoma
Authors: Khalid AbdulJabbar, Shan E. Ahmed Raza, Rachel Rosenthal, Mariam Jamal-Hanjani, Selvaraju Veeriah, Ayse Akarca, Tom Lund, David A. Moore, Roberto Salgado, Maise Al Bakir, Luis Zapata, Crispin T. Hiley, Leah Officer, Marco Sereno, Claire Rachel Smith, Sherene Loi, Allan Hackshaw, Teresa Marafioti, Sergio A. Quezada, Nicholas McGranahan, John Le Quesne, Charles Swanton, Yinyin Yuan
Journal: Nature Medicine (2020)
Inhaled corticosteroid use and risk of pneumonitis in patients treated with immune checkpoint inhibitors.
Authors: Mingjia Li, Daniel Spakowicz, Songzhu Zhao, Sandip H. Patel, Andrew Johns, Madison Grogan, Abdul Miah, Marium Husain, Kai He, Erin Marie Bertino, Peter G. Shields, Lai Wei, David Paul Carbone, Gregory Alan Otterson, Carolyn J Presley, Dwight Hall Owen
Journal: Journal of Clinical Oncology (2020)

3140 Background: The identification of risk factors for immune-related adverse events (irAEs) is an important area of research. Among irAEs, pneumonitis carries one of the highest morbidities. There is a lack of strong predictors for pneumonitis in patients (pts) treated with ICI. We sought to identify predictors for the development of pneumonitis, and whether the use of inhaled corticosteroids (ICS) at time of ICI could be protective. Methods: Pts with advanced cancer treated with ICI from 2011 and 2018 were included in this retrospective study. Pneumonitis attribution to ICI was determined by treating physician at time of diagnosis. Time to pneumonitis was defined as days from the start of ICI to pneumonitis diagnosis. Pts who never had pneumonitis were censored at the time of last follow up or death. Predictors of pneumonitis were assessed by univariate Cox proportional hazard models at a significance threshold of alpha = 0.05. Results: A total of 837 pts were identified, and 30 (3.6%) pts developed any grade pneumonitis (12 grade 2, 14 grade 3, 1 grade 4, 3 grade 5) after receiving ICI (Table). Pts with age ≥65 years (y) had increased risk of developing pneumonitis over pts with age &lt; 65y (HR 2.1, 95 CI: 1.02-4.4, p=0.041). 82 (9.7%) of the total cohort were on inhaled corticosteroid (ICS) at time of ICI, and 9 (11%) developed pneumonitis. Rather than being protective, pts on ICS had higher risk of pneumonitis (HR 4.2, 95 CI: 1.9-9.2, p=0.001). Pts with lung cancer had an increased risk for pneumonitis compared to pts with other cancers (HR 3.2, 95 CI: 1.5-6.4, p =0.003). Other risk factors included performance status, smoking history, line of therapy, or prior treatment including radiation were not statistically significant. Conclusions: Rather than a protective effect of ICS, our analysis found a higher risk of pneumonitis in pts treated with ICS. We confirmed an increased risk of pneumonitis for lung cancer pts compared to pts with other cancers, and higher risk of pneumonitis in pts age &gt;65y. We hypothesize that the increased inflammatory status in chronic lung inflammation may predispose pts to pneumonitis that was not ameliorated by ICS. Future study is needed in prospective cohorts to further clarify the underlying inflammatory mechanism. [Table: see text]
Inhibiting fatty acid synthase in operable triple negative breast cancer.
Authors: Sagar D. Sardesai, Alexandra Thomas, Christopher Gallagher, Filipa Lynce, Yvonne Lynn Ottaviano, Tarah Jean Ballinger, Bryan P. Schneider, Anna Maria Storniolo, Amber Bauchle, Sandra K. Althouse, Susan Perkins, Jian-Ting Zhang, Kathy Miller
Journal: Journal of Clinical Oncology (2020)

584 Background: Fatty acid synthase (FASN) is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and is associated with poor prognosis. In vitro, FASN overexpression induces drug resistance to DNA damaging agents. Proton pump inhibitors (PPI) selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells. We report the results of a single arm phase II study of high dose omeprazole (OMP) in combination with anthracycline- taxane (AC-T) based neoadjuvant chemotherapy. Methods: Patients (pts) with operable TNBC independent of baseline FASN expression; and no prior PPI use within 12 months were enrolled. Pts began OMP 80 mg PO BID for 4-7 days prior to AC-T; carboplatin was allowed per physician discretion. OMP was continued until surgery. Paired biopsy samples were obtained before and after OMP monotherapy. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive disease in breast or axilla, in pts with baseline FASN expression (FASN+) assessed using immunohistochemistry. Relevant secondary endpoints included pCR in the intent to treat population, change in FASN expression, enzyme activity and downstream target gene expression after OMP monotherapy; safety and limited OMP pharmacokinetics. We targeted a pCR rate of 60% in FASN+ pts (null pCR ~ 40%) with 80% power and alpha of 0.10. Results: A total of 42 pts were recruited from 5 US sites. Median age was 51y (28-72). Most pts had &gt;cT2 (33, 79%) and ≥N1 (22, 52%) disease. 14 (33%) were African American. FASN expression prior to AC-T was identified in 28 (85%) samples available for analysis. The pCR rate was 71.4% (95% CI 51.3 to 86.8) in FASN+ pts and 71.8 %( 95% CI 55.1 to 85.0) in all enrolled pts. Fifteen pts (36%) received carboplatin with AC-T; pCR in this subset was 73%. Peak OMP concentration was significantly higher than IC 50 observed during preclinical testing; FASN positivity significantly decreased with OMP monotherapy from 0.53(SD 0.25) at baseline to 0.38(SD 0.30; p = 0.02). OMP was well tolerated with no known grade (G) 3 or 4 toxicities. Chemotherapy toxicity was similar to prior studies using AC-T with G3 or 4 neutropenia (19%), febrile neutropenia (7%) and peripheral neuropathy (7%) being the most common. Conclusions: Consistent with previous studies, FASN is frequently expressed in early stage TNBC. OMP can be safely administered in doses that inhibit FASN. The addition of high dose OMP to neoadjuvant AC-T yields a promising pCR rate without adding toxicity. Funded by the Breast Cancer Research Foundation. Clinical trial information: NCT02595372 .
Clonal lineage analysis of CLL research samples by IGH chain sequencing to reveal novel CLL subgroups defined by ongoing class-switch recombination and somatic hypermutation.
Authors: Timothy Looney, Graeme Quest, Harriet Feilotter, Zadie Davis
Journal: Journal of Clinical Oncology (2020)

e20001 Background: B cell somatic hypermutation (SHM) and class switch recombination (CSR) are mechanistically related but distinct processes requiring precisely targeted generation and repair of single and double strand DNA breaks. Within the context of chronic lymphocytic leukemia (CLL), the presence of ongoing SHM or CSR may reveal the functionality of DNA damage repair pathways, with potential relevance to therapeutic strategies involving the generation of DNA breaks or inhibition of DNA repair machinery. Here we apply clonal lineage analysis of IGH chain sequencing data to evaluate CSR and SHM in a cohort of CLL and splenic marginal zone lymphoma (SMZL) research samples. We present evidence of ongoing CSR and SHM in a significant subset of samples. Methods: Multiplex primers targeting the IGH framework 1 region and isotype region (Oncomine IGH-LR assay; detection of all nine isotypes) were used for IGH repertoire sequencing via the Ion Gene Studio S5 from 25ng peripheral blood total RNA derived from 63 individuals with CLL and 4 individuals with SMZL. Clonotyping and clonal lineage analysis was performed by Ion Reporter, whereby clonal lineages are defined as sets of unique rearrangements having a shared variable and joining gene, the same CDR3 length, and a minimum CDR3 nucleotide similarity of 85%. Ongoing CSR was defined as the presence of IgM/IgD and at least one switched isotype (IgG, IgA, or IgE), or a combination of switched isotypes, within the same lineage. Ongoing SHM was defined as the presence of subclones that differ within the VDJ region sequence compared to other clonal lineage members. Results: 11/68 cases showed evidence of ongoing CSR or SHM. Of the 57 cases showing no evidence of ongoing CSR or SHM, variable gene mutation analysis revealed the presence of three distinct subgroups having either no SHM, intermediate SHM (average 98% sequence identity) or high SHM &lt; 94% identity). 3 of 4 SMZL cases showed evidence of ongoing CSR or SHM. Conclusions: These results reveal previously underappreciated heterogeneity within CLL and suggest the subdivision of CLL based on a combination of IGHV mutation level and presence of ongoing SHM or CSR. The described heterogeneity may serve as a valuable criterion for stratifying CLL patients in the future.