tbuckley/cabot-search huggingface dataset:
Radiotherapy in localized gastric cancer management: To be or not to be?
Authors: Amany Hussein, Khaled Al Saleh, Mustafa El-Sherify, Nashwa Nazmy, Jitendra Shete
Journal: Journal of Clinical Oncology (2020)

e16511 Background: Gastric adenocarcinoma still have dismal outcome in spite of the progress made in systemic treatment in last 2 decades. In localized disease, treatment outcome still suboptimal, with up to 88% suffer from recurrence/metastasis. Hence, improvement in radical initial treatment is mandatory. Recent trials showed survival benefit of adding radiotherapy (preoperative or adjuvant) with favorable toxicity profile when using current advances radiation techniques. Methods: We retrospectively analyzed impact of radiotherapy in management of localized gastric cancer in Kuwait. 87 adult patients with newly diagnosed gastric cancers were treated and followed up at Kuwait Cancer Control Center (KCCC) between 2009-2015, 12 were excluded due to inoperability. 13 patients were excluded as they had early disease and underwent only surgery. Finally, 62 patients were submitted in study 48 patient received radiotherapy (RT group) as part of treatment (44 postoperative, 3 postoperative after induction Chemotherapy, 1 preoperative). 14 patients did not receive radiotherapy (NRT group); five received perioperative chemotherapy, nine received postoperative chemotherapy). Survival analysis was done using Kaplan-Meier, and comparison was done according to clinicopathological features. Results: The median age at diagnosis was 55 (range 25-70). Men represented 65.5%. Asian were 17 patients and Caucasian were 70 patients. 68.9% were nonsmoker while 31% were smoker. Median follow up was 45 months (1-89). 2 year Overall survival in the NRT group was 50% while in RT group was 79.1%. 3 year OAS was 42.8% and 64.5% in NRT group and RT group respectively. Median overall survival for NRT group was 82 months. While for the RT group median survival was not reached at time of analysis with p value (0.025). 2 year DFS in NRT group was 50% while in RT group was 66.6%. 3 year DFS was 42.8% and 54.1% in NRT group and RT group respectively. Median DFS not reached in both groups p value (0.04). On correlation of prognostic clinicopathological features with benefits of adding radiotherapy it was noticed that high grade, positive margins statistically benefit more from local radiotherapy and had better local control. Distal tumours behave badly whether received radiotherapy or not. Interestingly benefit of adding radiotherapy was not significantly affected by nodal status. Conclusions: Radiotherapy should be part of management in postoperative locally advanced gastric cancer especially with high grade tumours and positive margins. However still ongoing trials to clear the role of radiotherapy in preoperative setting.
Blood serum amyloid A as potential biomarker of pembrolizumab efficacy for patients affected by advanced non-small cell lung cancer (NSCLC) overexpressing PD-L1: Early results of the FoRECATT Study.
Authors: Vincenzo Di Noia, Ettore D'Argento, Sara Pilotto, Carmine Carbone, Emanuele Vita, Giovanni Luca Ceresoli, Giordano D. Beretta, Giampaolo Tortora, Emilio Bria
Journal: Journal of Clinical Oncology (2020)

9598 Background: Identifying the patients who may benefit the most from immune checkpoints inhibitors remains a great challenge for clinicians. The tumor-derived Serum Amyloid A (SAA) inhibits the immune-response in melanoma patients. Here we present the early results of FoRECATT study investigating on blood SAA as biomarker of response to upfront pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC). Methods: In this prospective study, patients with PD-L1 ≥ 50% receiving upfront pembrolizumab (P cohort) and with PD-L1 0-49% treated with chemotherapy (CT cohort), were evaluated for blood SAA and radiological response at baseline and every 9 weeks. Primary endpoint was response rate (RR) according to Response Evaluation Criteria in Solid Tumors 1.1; secondary endpoints were progression-free (PFS) and overall survival (OS). The most accurate SAA cut-off to predict response was established with ROC-analysis in the P cohort. Results: In the P Cohort (n = 42), the overall RR was 38%. After a median follow-up of 18.5 months (mo), baseline SAA ≤ the ROC-derived cut-off (29.9 mg/L; n = 14/42, 33%) was significantly associated with higher RR (53.6 versus 7.1%; OR 15, 95%CI 1.72-130.7, P= 0.009), longer PFS (17.4 versus 2.1 mo; P&lt; 0.0001) and OS (not reached versus 7.2 mo; P&lt; 0.0001) compared with SAA &gt; 29.9 mg/L. In multivariate analysis, low SAA positively affects PFS ( P= 0.001) and OS ( P= 0.048) irrespective of ECOG PS, number of metastatic sites and pleural effusion. SAA monitoring (n = 40) was also significantly associated with survival endpoints: median PFS 17.4 versus 2.1 mo and median OS not reached versus 7.2 mo when SAA remained low (n = 14) and high (n = 12), respectively. In the CT Cohort (n = 30), RR was not significantly affected by SAA level, while low SAA at baseline (n = 17) was associated with better PFS (HR = 0.42, 95%CI 0.16-1.10, P= 0.02) and OS (HR = 0.16, 95% CI 0.04-0.55, P= 0.0004). Conclusions: Low SAA predicts a higher likelihood of response to upfront pembrolizumab only and good survival outcomes irrespective of treatment in advanced NSCLC patients. Therefore, a simple blood test might be useful to identify patients likely to derive better outcomes from immunotherapy. A further study (FoRECATT-2) is ongoing to confirm the results in a larger validation cohort and to assess the potential effect of SAA on immune response in vitro assays.
Subcellular partitioning of Kaiso (ZBTB33) as a biomarker to predict overall breast cancer survival.
Authors: Sandeep K Singhal, Donald Sens, Mary Ann Sens, Jung Byun, Ryan Yancey, Ambar Caban, Heike Boisvert, Stephanie Hennek, Mark Bobrow, Shakir Ahmed, Jason White, Andrew Aukerman, Clayton Yates, Rami Vanguri, Rohan Bareja, Romina Lenci, Adriana De Siervi, Anna Napoles, Nasreen A. Vohra, Kevin Gardner
Journal: Journal of Clinical Oncology (2020)

3534 Background: The epigenetic transcriptional regulator, Kaiso (ZBTB33) has been identified as a member of the C2H2 zinc finger proteins containing a BTB/POZ -zinc finger family of transcription factors that are implicated in development of cancer. Although, our understanding of clinical relevance of subcellular distribution (cytoplasmic/nuclear) Kaiso in the growth and survival of human Breast cancer (BC) is limited. Methods: We examined a cohort of 555 BC patients who underwent surgery for their primary BC in Greenville, NC using AI and SM approach. Results: The sub-classification BC shows, cytoplasmic Kaiso is differentially enriched in ER- BC (p=0.001) compared nuclear Kaiso (p=0.8) and is significantly enriched in the more aggressive classes LumB (p=0.0017), HER2+ (p=0.05) and TNBC (p=6.1e-07) with respect to LumA BC patients. Additionally, the survival analysis of different compartments of Kaiso demonstrates that high cytoplasmic Kaiso (HR = 16.29 (7.6 – 34.8), p = 5.5e−13) is much more predictive of poor survival compared to nuclear Kaiso (HR = 2.83 (2.02 – 3.8), p = 6.1e−11). At gene expression level, ZBTB33 mRNA levels do not correlate with either nuclear (Spearman correlation: -0.03157, p= 0.7267) or cytoplasmic levels (Spearman correlation: -0.03526, p= 0.6962) of Kaiso. Surprisingly, ZBTB33 mRNA abundance is predictive of poor overall BC survival as demonstrated in two independent publicly available BC cohorts Metabric (HR = 2.14 (1.49 − 3.08), p = 2.7e−05) and Gyorffy B et al. (HR = 1.81 (1.55 − 2.12), p = 2.5e−14). Nuclear and cytoplasmic levels of Kaiso do not show significant differences based on race p=0.27 and p=0.1 respectively. Conclusions: Our data suggest subcellular distribution of high Kaiso is associated with poor prognosis of BC survival and subcellular localizations of Kaiso may play differential biological roles in BC prognosis.
Genomic landscape of angiosarcoma: A targeted and immunotherapy biomarker analysis of 143 patients.
Authors: Andrea P. Espejo Freire, Andrew Elliott, Yamac Akgun, Philippos Costa, Maryam Alasfour, Andrew Rosenberg, Julio Diaz-Perez, Ty Subhawong, Junaid Arshad, Wolfgang Michael Korn, Don S. Dizon, Margaret von Mehren, Moh'd M. Khushman, Atif Mahmoud Hussein, Kirsten Leu, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2020)

11545 Background: Targeted therapies for angiosarcoma (AS) patients have limited efficacy. Although significant responses to immunotherapy (IO-therapy) have been observed in cutaneous AS, its efficacy across all types of AS is not known. Herein, we describe genetic and molecular biomarkers of AS in order to propose potential therapeutic options. Methods: We retrospectively reviewed 143 AS tumors profiled by Next-Generation Sequencing (NGS) 592-gene panel (Caris Life Sciences,Irving, TX, USA). Whole transcriptome sequencing (WTS) was performed on 53 tumors. Mutations and copy number amplifications (CNAs) were analyzed and grouped by pathway. Biomarkers potentially associated with response to IO-therapy (TMB-High [≥10/Mb], MSI-High, and PD-L1 [IHC ≥ 2+ and 5%]) were also analyzed. AS subtypes based on primary tumor site were compared. P-values were corrected using a Benjamini &amp; Hochberg method. Results: Sample median age was 67 (range 22-89), 61% were female, and 29% were classified as metastatic/recurrent. The most commonly mutated genes were TP53 (29%), ARID1A (17%), POT1 (16%), and ATRX (13%); MYC CNA was found in 23% of cases. IO-therapy markers were present in 36.4% of cases (TMB-High in 26%, PD-L1+ 21.8%, MSI-High 0.7%). Pathway alterations were detected in 86% of AS cases. By pathway, TP53 was altered in 31%, cell cycle 30%, DNA damage repair (DDR) 21%, RAS 18%, PI3K 15% and chromatin remodeling 14%. By site, head/neck (HN) AS had the highest rate of IO-therapy markers (65%, p &lt; 0.05) [TMB-High (63%, p &lt; 0.0001)], TP53 mutation (51%, p = 0.07), and POT1A mutation (41%, p &lt; 0.01). MYC CNA was highest in breast (63%) and extremity (40%) AS (p &lt; 0.0001). DDR alterations were present in 56% (p = 0.09) of cutaneous AS and ranged from 12-27% in other subtypes (not significant, NS). RAS and PI3K alterations ranged from 6-27% across all subtypes (NS). Conclusions: Our findings suggest differential angiosarcoma biology across primary sites. HN AS had more frequent markers of potential IO-therapy response, as well as DDR alterations. Next in frequency, we found ARID1A which is possibly associated with overactive EZH2, a target of tazemetostat. MYC amplification suggests a role targeting cell cycle via cyclin-dependent kinase or bromodomain inhibitors in breast and extremity ASs. Finally, RAS and PI3K are mutated in a low percentage of cases, explaining the limited benefit of tyrosine kinase inhibitors in AS. Future AS clinical trials should be designed with consideration of primary site, IO-therapy response biomarkers, and activated pathway.
中青年男性冠心病患者代谢综合征危险因素分析
Authors: 贺军, 张艳红, 李晨, 杨晨
Journal: BMJ (2006)

近年来冠心病的发病年龄逐渐提前,且以男性患者多见,因此,代谢综合征(metabolic syndrome MS)与中青年男性冠心病发病的关系值得探讨.我们旨在分析中青年男性冠心病患者中MS危险因素的分布与聚集状况,为早期临床干预提供依据。
Evaluation of the incidence of pneumonitis in United States veterans with non-small cell lung cancer receiving durvalumab following chemoradiation.
Authors: Theodore Seth Thomas, Suhong Luo, Eric Marshall Knoche, Kristen Marie Sanfilippo, Jesse W. Keller
Journal: Journal of Clinical Oncology (2020)

9034 Background: Locally advanced, unresectable non-small cell lung cancer is commonly treated with concurrent chemoradiation therapy (CRT). Durvalumab is a PD-L1 immune checkpoint inhibitor (ICI) administered following completion of CRT. Pneumonitis is a known toxicity of ICI therapy. In the landmark PACIFIC study the incidence of pneumonitis in patients receiving durvalumab was 33.9% (any grade) and 3.4% (grade 3/4) compared to placebo 24.8% and 2.6% ( Antonia et al, NEJM 2017). The incidence of pneumonitis is thought to be higher in real-world populations. This study evaluated the incidence of pneumonitis in a cohort of U.S. Veterans. Methods: Durvalumab recipients were identified using VA Informatics and Computing Infrastructure databases. Using pharmacy records we confirmed durvalumab and corticosteroid prescriptions. Clinical information was obtained via the electronic medical record. The primary outcome was the development of pneumonitis. We defined asymptomatic pneumonitis as the presence of new radiographic findings consistent with pneumonitis without documented clinical symptoms. We recorded pneumonitis grade as reflected in clinical documentation. If not specifically graded, we used Common Terminology Criteria for Adverse Events (CTCAE v4.0) to assess severity. Logistic regression analysis evaluated associations between pneumonitis and age, comorbidities, radiation dose and stage. Cox proportional hazards analysis evaluated associations between pneumonitis and risk of death. Results: A total of 123 veterans received durvalumab through 3/31/2019 (with follow up through 11/15/2019). Asymptomatic radiographic infiltrates occurred in 49 (39.8%) patients. There were 26 cases of clinically important pneumonitis Grade 2: 9(7.3%), Grade 3: 14 (11.4%), Grade 4: 2(1.6%), and grade 5: 1 (.08%). Acute hypersensitivity reactions occurred in five (4.1%) patients. Reported reasons for discontinuation of durvalumab included: disease progression [38 (31%)], toxicity [30 (24.3%)], and patient death [1 (1.6%)]. There was no association between age, time from radiation end to durvalumab initiation, radiation dose, smoking history, chemotherapy used or disease stage on development of pneumonitis. Cox analysis did not demonstrate an association between pneumonitis and risk of death. Conclusions: Clinically significant pneumonitis was more frequent in this cohort than reported in prior clinic trial populations. Further studies to identify pneumonitis risk factors are needed.
Comprehensive genomic profiling of 216 Chinese patients with renal cell carcinoma.
Authors: Congwang Zhang, Chunhe Yang, Jie Chen, Xiaohong Xu, Lingyu Wang, Rongbo Lin, Yining Yang
Journal: Journal of Clinical Oncology (2020)

3532 Background: Renal cell carcinoma (RCC), a global public health problem, has exhibited a gradual rise in incidence. Unfortunately, the scarcity of effective biomarkers in the clinical became a major limitation of the progress of biological therapies. Therefore, it is imperative to accurately comprehend RCC genomic profiling for exploring its clinical treatment strategies. Methods: Formalin Fixed Paraffin Embedded (FFPE) tumor and matched blood samples of 216 Chinese RCC patients were obtained for next-generation sequencing (NGS)-based 620 cancer genes panel assay and RCC genomic profiling was evaluated. Results: In our Chinese RCC cohort, multiple histological subtypes, encompassing clear cell (96/216, 44.44%), papillary (14/216, 6.48%), chromophobe (2/216, 0.93%), and undefined subtypes (104/216, 48.15%) were included. The top ranked genomic alterations in Chinese RCC patients were VHL (45.83%), PBRM1 (17.1%), BAP1(13.89%), TP53 (10.65%), SETD2 (9.29%), MTOR (8.67%), ARID1A (5.6%), PTEN (5.09%). Interestingly, BAP1, PBRM1 were co-mutated with VHL, and MET, NF2 were mutually exclusive with VHL (all p &lt; 0.05). Of these patients, 87.9% (190/216) of RCC patients had at least one genomic alteration, indicating the potential clinical benefits of targeted therapies. Out of 15 most common canonical pathways, potentially targetable genomic alterations were mainly identified in HIF (45.83%), chromatin remodeling (42.59%), PI3K/AKT (24.07%), DNA damage response (19.44%), RTK-RAS (18.06%), TP53 (15.74%), NOTCH (9.72%), Hippo (9.72%), and WNT (5.56%) pathway. Additionally, HIF pathway was commonly co-altered with chromatin remodeling pathway, and WNT and NOTCH pathways were significantly co-altered with TP53 pathway. Rare mutation types such as CDKN2A-DMRTA1 and HOOK1-ALK were also detected. Across samples, the median TMB was 2.2 (0-18.6) mutations/Mb. Only 2 Chinese RCC patients had TMB-high (&gt; 10 mutations/Mb). Conclusions: Our results displayed the landscape of genomic alterations in 216 Chinese RCC patients. The genomic alterations identified in our study may provide an opportunity to discover potential strategies for targeted and immunotherapy in RCC. Future studies should account for these genomic alterations.
新生儿脑梗死一例
Authors: 鲁丽, 王东辉, 韩桂珍, 艾丽新
Journal: BMJ (2009)

患儿男,出生6h.因阵呼吸暂停3次、右侧肢体抽搐2 h于2007年2月11日入院.系第1胎第1产,胎龄39周,因头盆不称行剖宫产分娩,出生时无窒息,Apgar评分1分钟8分、5分钟10分.患儿于生后1h无明显诱因突然出现呼吸暂停,颜面青紫,经刺激足底,拍背约30 s缓解.给予吸氧观察,于生后1.5h和3 h再次出现呼吸暂停,颜面青紫,给予吸氧、清理呼吸道颜面转红润.于生后4h出现惊厥,表现为右侧肢体抽搐.父母健康,非近亲结婚。
Heterodimeric IL-15 delays tumor growth and promotes intratumoral CTL and dendritic cell accumulation by a cytokine network involving XCL1, IFN-γ, CXCL9 and CXCL10
Authors: Cristina Bergamaschi, Hrishikesh Pandit, Bethany A Nagy, Dimitris Stellas, Shawn M Jensen, Jenifer Bear, Maggie Cam, Antonio Valentin, Bernard A Fox, Barbara K Felber, George N Pavlakis
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Interleukin-15 (IL-15) promotes growth and activation of cytotoxic CD8 + T and natural killer (NK) cells. Bioactive IL-15 is produced in the body as a heterodimeric cytokine, comprising the IL-15 and IL-15 receptor alpha chains (hetIL-15). Several preclinical models support the antitumor activity of hetIL-15 promoting its application in clinical trials. Methods The antitumor activity of hetIL-15 produced from mammalian cells was tested in mouse tumor models (MC38 colon carcinoma and TC-1 epithelial carcinoma). The functional diversity of the immune infiltrate and the cytokine/chemokine network within the tumor was evaluated by flow cytometry, multicolor immunohistochemistry (IHC), gene expression profiling by Nanostring Technologies, and protein analysis by electrochemiluminescence and ELISA assays. Results hetIL-15 treatment resulted in delayed primary tumor growth. Increased NK and CD8 + T cell tumoral infiltration with an increased CD8 + /Treg ratio were found by flow cytometry and IHC in hetIL-15 treated animals. Intratumoral NK and CD8 + T cells showed activation features with enhanced interferon-γ (IFN-γ) production, proliferation (Ki67 + ), cytotoxic potential (Granzyme B + ) and expression of the survival factor Bcl-2. Transcriptomics and proteomics analyses revealed complex effects on the tumor microenvironment triggered by hetIL-15 therapy, including increased levels of IFN-γ and XCL1 with intratumoral accumulation of XCR1 + IRF8 + CD103 + conventional type 1 dendritic cells (cDC1). Concomitantly, the production of the chemokines CXCL9 and CXCL10 by tumor-localized myeloid cells, including cDC1, was boosted by hetIL-15 in an IFN-γ-dependent manner. An increased frequency of circulating CXCR3 + NK and CD8 + T cells was found, suggesting their ability to migrate toward the tumors following the CXCL9 and CXCL10 chemokine gradient. Conclusions Our results show that hetIL-15 administration enhances T cell entry into tumors, increasing the success rate of immunotherapy interventions. Our study further supports the incorporation of hetIL-15 in tumor immunotherapy approaches to promote the development of antitumor responses by favoring effector over regulatory cells and by promoting lymphocyte and DC localization into tumors through the modification of the tumor chemokine and cytokine milieu.
A case of brucellosis presenting lymphadenitis as prominent symptom
Authors: Lihua Lu
Journal: BMJ (2020)

布氏杆菌病是由布氏杆菌引起的一种人兽共患性传染病，临床症状不典型，常导致多系统损害，极易误诊。报道1例以发热、淋巴结炎为突出症状的非流行区误诊病例资料，以提高临床医生对布氏杆菌病的认识。
Developing a performance matrix for multidisciplinary teams.
Authors: Lynleigh Evans, Yiren Liu, Terence Kwan, James Callister, Karen Byth, Simon Poon, Paul R. Harnett
Journal: Journal of Clinical Oncology (2020)

e19200 Background: While multidisciplinary teams (MDTs) are considered the “gold standard” of care for cancer patients, their performance varies widely. This study aimed to develop a user friendly, reliable and valid self-assessment tool for MDTs to evaluate their performance and monitor improvement over time. Methods: Using maturity modelling methodology, key themes from the literature were developed into a 2-dimensional matrix comprising 17 indicators (within 6 components) across 5 levels of performance. A modified Delphi methodology (where 38 MDT members each assigned the contents to components and performance levels using card sorting software) was used to establish face and content validity. A 10 minute on-line version of the matrix was piloted across 11 MDTs. Each participant estimated where they thought the MDT performed for each indicator. Correlation and factor analyses examining convergent and discriminant validity were conducted using SPSS. Cronbach alpha was used to measure internal consistency and evaluate reliability. Ease of use and usefulness were also examined. Results: A total of 109 members completed the matrix, with representation from medical, nursing and allied health professionals. The mean results for each indicator are shown below (maximum 5). Overall results for the different teams varied from 1.2 to 4.2, with standard deviations ranging from 0.4 to 0.8. Conclusions: This matrix has the potential to be a simple, valid and reliable tool for MDTs to measure their performance and monitor improvement over time. The tool will now be refined and then disseminated to a wider audience for further validation and feedback. [Table: see text]
Impact of relacorilant, a selective glucocorticoid receptor antagonist, on the immunosuppressive effects of endogenous cortisol.
Authors: Andrew Greenstein, Pamela N. Munster, Jasgit C. Sachdev, Gini F. Fleming, Andreas Grauer, Stacie Peacock Shepherd
Journal: Journal of Clinical Oncology (2020)

3091 Background: Cortisol, an endogenous glucocorticoid receptor (GR) agonist, controls a broad transcriptional program that affects T-cell activation, pro-inflammatory cytokine secretion, and immune cell trafficking. By selectively antagonizing GR, relacorilant may reverse the immunosuppressive effects of cortisol in solid tumor cancers. Methods: Immune cells and GR expression were assessed by IHC and calculated based on The Cancer Genome Atlas (TCGA) data. Human PBMCs were stimulated with αCD3+IL-12 +/- cortisol or cortisol + relacorilant. EG7 tumor-bearing mice were treated with anti-PD1 (RMP1-14) ip Q5D +/- relacorilant QD. Whole blood mRNA was measured via Nanostring, hematology was performed using standard complete blood count assays, and cytokines were assessed by immunoassays in study NCT02762981. Results: GR expression was observed in human tumor and immune cells. Its abundance was positively correlated with tumor infiltration of T H 2, Treg, and PDL1 + cells ( P&lt; .001) and negatively correlated with T H 1 cells ( P&lt; .001). In PBMCs, cortisol inhibited, and relacorilant restored, CD8 + T-cell activation ( P&lt; .001) and pro-inflammatory cytokine secretion (TNFα P= .006, IFNγ P&lt; .05). In the EG7 syngeneic model, relacorilant increased αPD1 efficacy ( P= .007) and decreased circulating IL-10 ( P&lt; .002). In patients with advanced solid tumors, relacorilant + nab-paclitaxel systemically suppressed the expression of canonical GR-controlled genes ( ptgs2 P&lt; .001) and genes encoding candidate-immunomodulatory drug targets ( cxcl8, ptger4, ido1; P&lt; .001). In a small subset of patients (n = 11), sustained clinical response was associated with increased T-cell count ( P= .06) and IFNγ ( P= .03), as well as decreased Tregs ( P= .06) and IL-10 ( P= .03). Conclusions: Evidence of T-cell activation by relacorilant was observed in PBMCs, syngeneic mouse tumors, and patients with sustained response in a Phase 1 study. This supports the hypothesis that relacorilant can reverse immune suppression by endogenous cortisol in solid tumor cancers. Clinical studies with immune checkpoint inhibitors and relacorilant are planned.