tbuckley/cabot-search huggingface dataset:
Immune functional portraits of head and neck cancer using next generation sequencing.
Authors: Susan Raju Paul, Nikita Kotlov, Viktor Svekolkin, Felix Frenkel, Nava Almog, Maria Tsiper, Krystle Nomie, Nathan Hale Fowler, Derrick Lin, Laura Valine, Ann Sluder, Alexander Bagaev, Ravshan Ataullakhanov, Mark C Poznansky, Lori J. Wirth
Journal: Journal of Clinical Oncology (2020)

6561 Background: The addition of biomarkers as companion diagnostics and Next Generation Sequencing (NGS) have dramatically increased therapeutic efficacy and have aided precision medicine development. The unique genomic profile and tumor microenvironment (TME) composition of each patient can be ascertained through NGS. Using TCGA and Geo datasets, we characterized head and neck cancers (HNC) according to the cellular and functional state of their TME and conducted a pilot validation study using prospectively collected HNC tumors. Methods: To stratify the TME of HNC tumors into molecular functional portraits, we analyzed the sequencing data of 1,486 HNC tumor samples and 143 controls (normal, oral leukoplakia) from TCGA and GEO data sets. For the prospective pilot study, resected tissue from oropharyngeal carcinomas independent of HPV status were processed for whole exome (WES) and RNA-seq (n = 6; HPV-positive = 1). Results: To characterize the cellular composition and functional state of HNC tumors and their TMEs, we created 26 separate molecular signatures related to functional processes such as immune checkpoint inhibition, immune infiltration, immunosuppression, and stromal activities represented by angiogenesis and mesenchymal stromal cells. Unsupervised clustering of these signatures delineated tumors into 4 types: immune infiltration with increased stromal signatures (type A), immune infiltration with decreased stromal signatures (type B), no immune infiltration with increased stromal signature (type C), and no immune infiltration and decreased stromal signatures (type D). Most HPV-positive tumors were type B (p = 1e-27) and associated with increased survival compared to the HPV-negative tumors (types C and D; p = 3e-05). Type B HPV-positive tumors had reduced FAT1 and TP53 mutations, whereas type B HPV-negative tumors had increased caspase 8 mutations/loss. In the validation cohort, actionable mutations were found in PI3KCA and TSC2 in types A and B HPV-negative tumors. Moreover, while the HPV-positive tumor was classified as type C, we identified a caspase 8 homozygous deletion and absence of FAT1 and TP53 mutations, supporting the TCGA and GEO analysis. Conclusions: Exome and transcriptome analyses with cellular deconvolution from bulk RNA-seq enrich tumor characterization by including major TME components, providing a comprehensive biomarker profile for precision therapy and clinical decision making. Our prospective analysis identified TME parameters comparable with the large datasets and revealed targetable genomic alterations.
腹腔镜下宫壁切开治疗宫角妊娠
Authors: 闫文杰, 杨菁, 明蕾, 程丹
Journal: BMJ (2011)

患者女，19岁。因“清宫术后阴道不规则出血48 d”于2011年2月23日入本院。平素月经规律，末次月经2010年9月10日，停经108 d在当地医院行B超检查提示右侧宫角妊娠，于当地医院行清宫术，未清出妊娠组织。术后一直阴道间断性出血，量少，无腹痛。后于我院行盆腔三维彩超，提示右侧宫角可见2.2 cm× 1.9 cm混合性回声，查血人绒毛膜促性腺激素β( β-HCG)35.6 U/L(正常范围：0～10 U/L)。既往无特殊病史。未婚，孕1产0。体检：血压110/76 mm Hg(1 mm Hg =0.133 kPa)，心肺正常，腹平软，无压痛及反跳痛，移动性浊音阴性，四肢无水肿。妇科体检：子宫后位，鸭蛋大小，质软，活动可，宫体轻压痛，双侧附件未及异常。初步诊断为宫角妊娠（右侧）。 关键词：妊娠
A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab.
Authors: Manish R. Patel, Todd Michael Bauer, Antonio Jimeno, Ding Wang, Patricia LoRusso, Khanh Tu Do, Salomon M. Stemmer, Corinne Maurice-Dror, Ravit Geva, Sima Zacharek, Andressa S Laino, Jing Sun, Joshua Frederick, Honghong Zhou, William Randolph, Pamela Sarah Cohen, Robert S. Meehan, Ryan J. Sullivan
Journal: Journal of Clinical Oncology (2020)

3092 Background: mRNA-2752 is a novel mRNA-based therapeutic agent encoding OX40L T cell co-stimulator, IL-23 and IL-36γ pro-inflammatory cytokines. Here we present findings from a first-in-human study of iTu mRNA-2752 in solid tumor patients as monotherapy or in combination with durvalumab (durva). At the time of presentation, data will encompass the monotherapy escalation MTD/RDE along with the supporting translational work, and the available data in combination. Methods: iTu mRNA-2752 was administered every 2 weeks for up to 7 doses as monotherapy or in combination with durva in patients with advanced solid malignancy or lymphoma. Biomarker analyses include measurement of IL-23, IL-36γ and pro-inflammatory cytokine proteins in pre- and post-treatment tumor biopsies and plasma. PD-L1 immunohistochemistry was used to further characterize baseline status and changes to the TME with treatment. Results: As of 20 December 2019, 23 solid tumor patients have been treated either with mRNA-2752 alone (n = 14) or in combination (n = 9) and has been well tolerated with no dose limiting toxicities or related grade 3/4 toxicities. Of the 17 patients evaluated per RECIST and iRECIST, 1 had a PR (iRECIST), 6 had SD, and 10 had PD. The patient with a PR (52% tumor reduction) received 0.5 mg mRNA-2752 with durva, and had aPD-1/L1 naïve squamous-cell bladder carcinoma. Tumor shrinkage was observed in an additional 5 patients in injected and/or uninjected lesions in both monotherapy and combination. Preliminary biomarker data showed increased IL-23 and IL-36γ protein expression after 6-24 hours, and increased levels of downstream cytokines IL-22 and IL-6, respectively. Pro-inflammatory cytokines (e.g. IFN-γ, TNF-α) were also significantly increased at 1 day and 1-week post-treatment. Significant increases in PD-L1 expression predominantly in tumor-associated immune cells were observed after first dose and persisted up to 29 days after treatment. Conclusions: iTu mRNA-2752 given as monotherapy and in combination with durva is tolerable at all dose levels studied, and administration can be associated with tumor shrinkage. Analyses of tumor and plasma biomarkers suggest a sustained immunomodulatory effect of treatment that includes elevated IFN-γ, TNF-α, and PD-L1 levels. These data support the ongoing testing of the mRNA-2752/durva combination in the dose escalation part of the study. Clinical trial information: NCT03739931 .
浅谈加拿大的老年人服务
Authors: 王健, 祝墡珠, 潘志刚
Journal: BMJ (2008)

在加拿大,帮助老年人维护他们健康和独立性的计划多种多样,且大部分由政府资助,除了国家医疗保险计划所规定的公费医疗项目之外,各省和地区政府还为年满65岁者提供额外的公费医疗项目,包括凭处方购买的药物、牙医和眼医服务、足病医生和按摩师等提供的服务,有很完善的社区护理服务体系。
Combination of ticagrelor and cilostazol for patients with acute coronary syndrome complicated with upper digestive tract diseases following percutaneous coronary intervention
Authors: Dengfeng Ma, Zhiqiang Pei, Bingwei Li, Lijun Wu, Baoping Jia, Bing Yang, Jingbo Mu, Chen Wang, Zhenti Dang, Xin Su
Journal: BMJ (2018)

Objective
To evaluate the efficacy and safety of combined use of ticagrelor and cilostazol for patients with acute coronary syndrome (ACS) complicated with upper digestive tract diseases following percutaneous coronary intervention (PCI).


Methods
A total of 262 consecutive ACS patients complicated with upper digestive tract diseases followed-up for one-year after PCI were included in this study. The patients were allocated into control group (combined use of ticagrelor and aspirin, n=184) and cilostazol group (combined use of ticagrelor and cilostazol, n=78) for antiplatelet treatment. The basic characteristics of the patients, change of the treatment regimens, cardiovascular events and hemorrhagic events were compared between two groups.


Results
After one year of follow-up, 16.8%(31/184)patients in control group and 3.8%(3/78)in cilostazol group changed antiplatelet regimens(χ2=8.200, P=0.004). There was no statistical difference in use of statins and ACEI/ARB between two groups(P>0.05). The rate of proton pump inhibitor use in control group was significantly higher than that in cilostazol group [82.1% (151/184) vs. 52.6%(41/78), χ2=24.35, P=0.000]. However, the dosage of β-blockers in cilostazol group was significantly higher than that in control group [(39.1±12.4)mg vs. (28.6±10.1)mg, t=7.174, P=0.000]. No statistical difference was found in total cardiovascular events between two groups [21.7% (40/184) vs.12.8%(10/78), χ2=2.822, P=0.121]. The incidence of gastrointestinal hemorrhage in control group was significantly increased compared with cilostazol group [12.0%(22/184) vs. 2.6%(2/78), χ2=5.807, P=0.018], however, there was no significant difference in hemorrhagic events concerning the thrombolysis for myocardial infarction between two groups [17.4%(32/184) vs. 9.0%(7/78), χ2=3.063, P=0.089].


Conclusion
Combined use of cilostazol and ticagrelor is effective and safe for ACS patients with gastrointestinal hemorrhage or a higher risk of hemorrhage.


Key words: 
Acute coronary syndrome; Platelet aggregation inhibitors; Aspirin; Hemorrhage
<i>RAD51B</i><sub>me</sub> as predictive biomarker for PD-1 blockade response in non-small cell lung cancer.
Authors: Inês Maria Guerreiro, Daniela Barros-Silva, Paula Lopes, Ana Luísa Cunha, João Lobo, Luís Antunes, Ana Rodrigues, Marta Alexandra Silva Soares, Rui Henrique, Carmen Jerónimo
Journal: Journal of Clinical Oncology (2020)

e15235 Background: Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with likelihood of response to specific checkpoint inhibitors, prediction of response is rather imperfect and, thus, more accurate predictive biomarkers are mandatory. We examined the methylation profile of RAD51B, a DNA-repair gene, as candidate predictive biomarker for efficacy of anti-PD-1 therapy in patients with non-small cell lung cancer (NSCLC), correlating with patients’ outcome. Methods: PD-L1 immunoexpression and RAD51B me levels were analysed in samples of NSCLC obtained from patients not treated with anti-PD-1 blockade (testing cohort) and patients treated with anti-PD-1 (validation cohort). Results: Of a total of 127 patients assessed, 58.3% depicted positivity for PD-L1 (PD-L1 + ). RAD51B me levels significantly associated with PD-L1 immunoexpression. Patients with clinical benefit from immunotherapy disclosed higher RAD51B me levels (p = 0.04) and significantly higher median progression free survival (PFS) (p = 0.02). PD-L1 + was also associated with longer overall survival (p = 0.03). Conclusions: We demonstrated that RAD51B me levels might be combined with validated predictive biomarker PD-L1 immunostaining to select patients who will most likely experience clinical benefit from PD-1 blockade. The predictive value of RAD51B me should be confirmed in prospective studies.
Do differences in the microbiome explain early onset in colon cancer?
Authors: Ajaratu Keshinro, Chad Vanderbilt, Zsofia Kinga Stadler, Jinru Shia, Mithat Gonen, Ching-Tung Chen, Andrea Cercek, Robin B Mendelsohn, Rona Yaeger, Ahmet Zehir, Anita Bowman, Martin R. Weiser
Journal: Journal of Clinical Oncology (2020)

e16070 Background: Intestinal dysbiosis has been hypothesized as a possible etiology of the increasing incidence of early-onset colon cancer (EO-CC). Here, we compare the microbiome signature in nonmetastatic, microsatellite stable (MSS) EO-CC to average-onset colon cancer (AO-CC). Methods: Specimens from patients with resected stage I-III MSS colon cancer from 2014-2019 were sequenced by MSK-IMPACT, a large panel next generation sequencing (NGS) assay. A validated technique using non-human read sequences from NGS analysis was used to identify the microbial species in tumor tissue. The tumor microbial alpha diversity and differentially abundant microbiome were compared between patients younger than 40 years (EO-CC) with those older than 60 years (AO-CC). Results: Of 275 patients with MSS, 24 (mean 33.6, range 24-39) and 114 patients (mean 70, range 61-90) had EO-CC and AO-CC, respectively. There was no significant difference in clinicopathological features including gender, tumor stage and neoadjuvant treatment between the two groups. EO-CC was more likely to present with left sided disease compared to AO-CC (81% vs. 45%, p = 0.001). There was no significant difference in the tumor microbial diversity (alpha diversity) between the EO-CC and AO-CC (p Shannon = 0.95). Although there was a relative abundance of microbial species from bacterial phylum such as Actinobacteria, Deinococcus-Thermus, α-proteobacteria, γ-proteobacteria and δ-proteobacteria in EO-CC compared to AO-CC, this difference was not significant after controlling for multiple comparisons (Table). Conclusions: Our analysis did not reveal a significant difference between EO-CC and AO-CC in both the abundance and diversity of tumor microbial species, suggesting intestinal dysbiosis may not be a major driver in early onset colorectal cancer pathogenesis. However, additional studies with a larger sample size are warranted for further analysis and subgroup comparison. [Table: see text]
Changing HER2-status of the primary gastric tumor after neoadjuvant trastuzumab-based therapy.
Authors: Rashida Orlova, Natalia P. Beliak, Svetlana Kutukova, Natalia V. Zhukova, Inna Avramenko, Natalia V. Popova, Anastasia Ivanova, Alexandra Androsova, Ekaterina Zorina
Journal: Journal of Clinical Oncology (2020)

e16529 Background: Aproximetly 16 % of patients with metastatic gastric cancer (GC) have HER2+ tumors. With localized stages, the detection rate of HER2+ is known to be lower. Addition of trastuzumab (T) to chemotherapy (CT) improved survival in metastatic, HER2+ GC. Unlike the metastatic disease, Her-2 did not represent an independent prognostic biomarker for early stages during exploratory analysis of MAGIC trial. The aim of the study was to compare human epidermal growth factor receptor 2 (HER2) expression before and after trastuzumab-based chemotherapy in patients with locally advanced HER2-positive gastric cancer, to evaluate the contribution of trastuzumab to the effectiveness of neoadjuvant treatment in this rare patient population. Methods: We assessed HER2 expression using immunohistochemistry in pre-treatment biopsied specimens and post-treatment resected specimens obtained from 10 patients with locally advanced HER2-positive (3+) gastric cancer receiving trastuzumab-based neoadjuvant chemotherapy: 8 men (80%) and 2 women (20%), from 30 to 80 years old, the median age was 63,5 years. Included 7 patients with resectable adenocarcinoma of the stomach and 3 patients with adenocarcinoma of the esophageal-gastric junction. All patients received neoadjuvant therapy with trastuzumab (100%) + chemotherapy: FLOT (2 patients), FOLFOX (7 patients), XELOX (1 patient). All patients underwent R0 gastrectomy. Tumor regression grading (TRG) after treatment were determined according to Mandard system. Results: Two patients showed a complete pathomorphological response of the tumor (20%,TRG1), therefore, the determination of postoperative HER2 status was not possible. Two patients (20%) maintained the HER2-positive status and six patients (60%) had a change in HER2 expression from positive to negative. Three patients had a (y)pT3 and 5 had a (y)pN+ tumor. Basing on histological changes the tumor regression TRG3 ( &lt; 10% residual tumor cells) was observed in 5 patients (50%). TRG 4-5(preponderance of tumor cells/tumors without changes of regression) observed in 3 patients (30%). The follow-up period is too short for disease-free survival or overall survival to be assessed. Conclusions: HER2 expression can change after trastuzumab-based chemotherapy in patients with locally advanced HER2-positive gastric cancer. Continuous monitoring of HER2 expression after neoadjuvant treatments may be utilized to determine whether the continued use of trastuzumab is advisable.
Clinical utility of circulating genetically abnormal cells within low-dose computed tomography lung cancer screening: A correlative MCPND trial study.
Authors: Mingxiang Feng, Miao Lin, Haining Zhou, Yunhe Zhu, Baishen Chen, Xin Ye, Chuoji Huang, Juncheng Zhang, Chunxue Bai
Journal: Journal of Clinical Oncology (2020)

e15536 Background: Recent screening trial results using low-dose computed tomography (LDCT) have been shown to reduce lung cancer mortality in high-risk patients. However, high false-positive rates, inter-grader variability, and radiation injuries are challenging, and therefor highlight the necessity for complementary biomarkers. The diagnostic performance of circulating genetically abnormal cells (CACs) was respectively evaluated in samples collected from patients with pulmonary nodules before and after lung lobectomy within the Multicenter Chinese Pulmonary Nodule Detection (MCPND) trial. We also propose a deep learning that detects related genetically abnormal cells in excisions of symptomatic lesions to identify the source of CACs. Methods: 269 plasma samples (n = 179, before surgery; n = 90, after surgery) from 179 participants, including 125 patients with lung cancer and 54 donors with benign nodular lesions, were analyzed by using a FISH–based assay for 3p22.1, 3q29, 10q22_3 and CEP10. Diagnostic performance of CAC was evaluated in a blinded validation group. 109 paraffin-embedded specimens (45 benign nodular lesions, 64 malignancies) obtained from participants were tested in the same way to identify the genetically abnormal cells. Results: The diagnostic performance of CACs for lung cancer detection was 91% for sensitivity and 81% for specificity. For all participants, CACs had a positive predictive value of 92% and 80% for negative predictive value, respectively. Area under the ROC curve was 0.89 (P &lt; 0.01; 95%CI (0.82, 0.96)). 90 plasma samples were drawn from patients within 10 days after surgery. Of these samples, 58 participants’ CACs level reduced and 25 of them remained stable. Moreover, of 64 malignant specimens, genetically abnormal cells were detected in 60 specimens. However, only 4 specimens were detected having genetically abnormal cells in 45 benign nodular lesions. Conclusions: This validation study indicated that the number of genetically abnormal cells in circulation decreased after surgical resection, which suggested CACs could be released from lung cancer. CACs have diagnostic and prognostic value and could assist to improve the diagnostic accuracy in early stage lung cancer after low-dose computed tomography. Clinical trial information: ChiCTR1900026233.
小肠粪石梗阻三例
Authors: 任之洁
Journal: BMJ (2005)

例1 男,68岁,因腹痛1 d,伴频繁呕吐,而在外院急诊.体格检查:体温37℃,血压180/110 mm Hg(1mm Hg=0.133 kPa);腹胀,中上腹压痛,未见肠型.外周血白细胞13.5×109/L,中性分类0.88;胸片与腹部平片(立卧位)无异常,拟诊急性胃炎。
Adult lymphoma-associated hemophagocytic lymphohistiocytosis: A clinical case series in a predominantly Hispanic cohort from the University of Miami/Jackson Memorial Hospital.
Authors: Eduardo Edelman Saul, Amrita Desai, Jennifer Chapman, Lazaros J. Lekakis, Alexandra Stefanovic, Agustin Pimentel
Journal: Journal of Clinical Oncology (2020)

e20060 Background: Hemophagocytic Lymphohistiocytosis (HLH) is a systemic inflammation disorder secondary to immune dysregulation. Patients may present with fevers, splenomegaly, bone marrow failure, and hemophagocytosis, among other clinical and laboratory findings. Lymphoma Associated HLH (LA-HLH) is a puzzling diagnosis given both conditions overlapping presentation. There are currently no established treatment guidelines for LA-HLH. Methods: We conducted a retrospective search of the tumor registry and pathology database at the University of Miami/Jackson Memorial Hospital to identify adult patients with the combined diagnosis of Lymphoma and HLH between January 2008 and July 2018. Results: Data from nine LA-HLH patients were identified and reviewed. Median age was 53 years (range 19-73), with 78% of cases of Hispanic origin. Lymphoma subtypes consisted of six T-cell/NK-cell neoplasms - 2 Peripheral T-cell Lymphomas (PTCL), NOS; 2 EBV+ Extranodal NK/T-Cell Lymphomas; 1 EBV+, CD8+, PTCL, NOS; 1 EBV+, Post-Transplant Lymphoproliferative Disorder-Anaplastic Large Cell Lymphoma, ALK negative (PTLD ALCL ALK-); and three B-cell neoplasms - 1 EBV+ DLBCL; 2 DLBCL, NOS. HLH and Lymphoma were diagnosed simultaneously in 6/9 cases. Hemophagocytosis phenomena was demonstrated in 7/9 cases. Treatment consisted of combined HLH and Lymphoma therapies in 4 cases, while Lymphoma directed therapy was applied to four patients; another case was treated with a modified version of the HLH-1994 protocol. Overall, a total of five cases were exposed to HLH-directed regimens (HLH-1994/2004). Three patients had refractory LA-HLH and entered hospice care, whereas another 3 cases succumbed to treatment-related complications. Of the seven cases that were evaluable for Lymphoma response, four cases (57%) achieved CR, and three of them (43%) were alive with no evidence of recurrence at 10, 16, and 52 months as of last contact. Conclusions: Herein, we describe our unique experience of an LA-HLH case series in a predominantly Hispanic population in South Florida. The diagnosis is challenging, often delayed, and the prognosis is dismal in refractory cases despite currently available rescue therapies. Furthermore, we describe for the first time the association between HLH and PTLD ALCL.
Renal sympathetic denervation for treatment of resistant hypertension: a meta-analysis
Authors: Xin Yi, Dingsheng Jiang, Xiaoyan Li, Yi Guo
Journal: BMJ (2014)

Objective
To systematically evaluate the effectiveness and safety of renal sympathetic denervation (RSD) for treatment of patients with resistant hypertension.


Methods
English and Chinese literatures of controlled clinical trials on RSD in treatment of resistant hypertension were searched from the Cochrane Library, PubMed, Web of Science, Wanfang Database and CNKI up to February 2013.Meta-analysis was performed with the selected studies by using software Rev.Man 5.0.


Results
Seven studies involving 354 cases with RSD and 146 controls were included for analysis.Compared with control group, RSD significantly lower both systolic and diastolic blood pressure in patients with resistant hypertension (systolic, 1 month: MD=-18.04, 95%CI: -19.94--16.14, P<0.01; 3 months: MD=0.01, 95%CI: -28.10--17.98, P<0.01; 6 months: MD=-25.59, 95%CI: -34.08--17.11, P<0.01; diastolic, 1 month: MD=-7.53, 95%CI: -8.60--6.45, P<0.01; 3 months: MD=0.01, 95%CI: -12.5--4.47, P<0.01; 6 months: MD=-10.54, 95%CI: -16.44--4.63, P=0.000 5). In addition, there was no significant difference in adverse reactions between RSD treatment group and control group (OR=1.13, 95%CI: 0.34-3.76, P=0.84).


Conclusions
Renal sympathetic denervation can effectively reduce blood pressure in patients with resistant hypertension 1-6 months postoperatively, without increase of adverse reactions.The long-term efficacy and safety need to be further observed.


Key words: 
Sympathectomy; Hhypertension; Meta-analysis