tbuckley/cabot-search huggingface dataset:
Morphologic and molecular analysis of early-onset gastroesophageal adenocarcinomas.
Authors: Namrata Setia, Cindy Wang, Angela Lager, Steven Brad Maron, Bryan Peterson, Nicole Arndt, Joseph Misdraji, Changqing Ma, Sonia Kupfer, John Hart, Daniel V.T. Catenacci
Journal: Journal of Clinical Oncology (2020)

4547 Background: The incidence of early-onset gastroesophageal adenocarcinomas (EO-GEA) is increasing, and these tumors now constitute &gt; 30% of all gastroesophageal cancers. Besides hereditary gastric cancer syndromes, which form ~3% of EO-GEA, the morphologic and molecular spectrum of these tumors is not well-studied. Methods: Next-generation sequencing (NGS) data obtained from routine clinical care from patients with EO-GEA, defined as age ≤50 years, from 3 tertiary care centers was evaluated and compared with tumor profiles of 2,081 patients with GEA from cBioPortal for Cancer Genomics. Available histologic slides were reviewed, and the tumors were classified into Lauren and WHO subtypes. Tumor-detected pathogenic variants of potential germline origin were identified from the NGS data. Results: The study cohort was formed by 79 patients with gastroesophageal (42%) and gastric (58%) adenocarcinoma. The most commonly mutated genes included TP53 (28.5%), CDH1 (10%), ARID1A (5%), KRAS (3.9%) and PIK3CA (3.9%). EO-GEA were less likely to harbor TP53 (28.5% vs. 57.5%, p 0.003) and ARID1A (5% vs. 20.6%, p 0.002) mutations when compared with cBioPortal data. Based on the Lauren scheme, the tumors were classified into intestinal (40%), diffuse (24%), mixed (12%), and indeterminate (15%) subtypes. Driver mutations in CDH1, TP53, FBXW7, BAP1 genes were seen in diffuse/mixed subtype, and TP53, ARID1A, KRAS, PIK3CA, APC, ATM, NBN, MUTYH genes in intestinal subtype. The indeterminate subtype showed TP53 mutations and additional alterations, including SMARCB1/ SMARCA4 loss leading to rhabdoid/undifferentiated morphology. ERBB2 amplification was more likely to be present in intestinal and indeterminate subtypes (p = 0.003). CD274 amplification/PD-L1 expression was more likely to be present in indeterminate subtype (p &lt; 0.0001). Potential germline variants included mutations in gastric cancer susceptibility genes such as CDH1 (2.5%) and APC (1%), and other cancer susceptibility genes such as ATM (4%), NBN (1%), MUTYH (1%) and POLD1 (1%). Conclusions: The molecular profile of EO-GEA is distinct from traditional gastric cancers. Histologic subtypes of EO-GEA correlate with distinct genomic alterations. Our findings also support multigene germline panel testing in parallel for patients with EO-GEA.
Carbon dioxide combining power/potassium ratio in etiological diagnosis of Cushing's syndrome
Authors: Jingxia Guo, Jingtao Dou, Lele Li, Jia Cui, Weijun Gu, Guoqing Yang, Jin Du, Kang Chen, Li Zang, Lijuan Yang, Zhaohui Lyu, Jianming Ba, Juming Lu, Yiming Mu
Journal: BMJ (2016)

Objective
To evaluate carbon dioxide combining power/potassium ratio (CO2CP/K)in etiological diagnosis of Cushing's syndrome.


Methods
The clinical data 489 patients with pathohistologically confirmed Cushing's syndrome treated in PLA General Hospital between 1993 and 2015 were retrospectively reviewed. Among 489 patients, there were 246 cases of adrenocorticotropic hormone(ACTH) nondependent Cushing's syndrome and 243 cases of ACTH dependent Cushing's syndrome, including 214 cases of Cushing's disease (CD) and 29 cases of ectopic ACTH syndrome (EAS). Receiver operating characteristic(ROC) curve was used to evaluate efficacy of CO2CP/K for etiological diagnosis and the cut-off value and corresponding sensitivity and specificity were analyzed.


Results
Blood potassium levels were lower in ACTH nondependent group than those in ACTH dependent group[(3.46±0.77) vs.(3.69±0.57)mmol/L, t=3.433, P=0.001]. Bicarbonate, base excess and CO2CP/K (10.0±5.5 vs. 7.6±2.1) were higher in ACTH nondependent group than those in ACTH dependent group (t=-3.612, P=0.000). There was no significant difference in serum sodium, carbon dioxide binding force and pH value between two groups (P>0.05). Blood potassium [(2.47±0.63) vs.(3.62±0.67)mmol/L] and chlorine levels were lower in EAS group than those in CD group. Bicarbonate, base excess and CO2CP/K (15.6±8.0 vs. 7.8±2.4) were higher in EAS group than those in CD group (t=- 10.145, P=0.000). There was no significant difference in serum sodium, carbon dioxide binding force and PH value between two groups (P>0.05). Taking 8.95 as cut-off value the sensitivity and specificity of CO2CP/K in diagnosis of ACTH dependent Cushing's syndrome were 0.34 and 0.85, while taking 9.09 as cut-off value the sensitivity and specificity of CO2CP/K in diagnosis of EAS were 0.89 and 0.78, respectively.


Conclusions
The value of CO2CP/K is limited in distinguishing between ACTH dependent and non-ACTH independent Cushing, s syndrome. It may distinguish CD from EAS to some extent, indicating that it might be used as the screening method for etiological diagnosis.


Key words: 
Cushing's syndrome; Hypokalemia; Etiology; Diagnosis; Adrenal gland neoplasms
Abstract 15: Multicenter Kawasaki Disease Study In Children Of Argentina
Authors: Pablo A Melonari, Luis H Llano Lopez, Marisa Olguín, Anahí Albano, Andrea Gajo Gané, Luciana Bellone, Alicia Aletti, Alejandro Ellis, Miriam Calvari, Aldo Cancellara, Norberto de Carli, Cristina Euliarte, Virginia Bonardo, Mannino Leonardo, Gaiano Alejandra, Brusadín Mariana, Santillán Alejandro, Tonetto Ivana, Juan Petricca, Lazarte Gustavo, Flynn Luis, Adrián Collia, Vilca Iris, Battagliotti Cristina, María T Apaz, Rubén Cutica, Héctor J Abate, Pablo A Melonari
Journal: Circulation (2015)

Introduction: Kawasaki disease (KD) is a vasculitis that affects vessels of small and medium caliber. Objectives: 1 Determine clinical and epidemiology of KD in children in 22 pediatric referral centers in Argentina. 2 Identify risk factors for coronary complications (CC). Material and Methods: A retrospective and analytical study from 01/01/2010 to 31/12/2013. Variables: age, sex, heart rate (HR), clinic features, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), leukocytes (Gb), neutrophils, hemoglobin (Hb) and CC. Color Doppler echocardiography: acute phase and 4-6 weeks. Results: Subjects: 191, age (Md) 29 months (R: 2-144) .Ratio v / m: 1.8 / 1. Clinical: fever 100% (191/191) more frequent and adenopatía: 57% (110/191) less frequent. CC: 15.7% (30/191). Mortality: 0.52% (1/191 cases). Increased risk of CC: leukocytosis&gt; 20,000 / mm3 Odds ratio (OR) = 4.235 (95% CI 1704-10529). Hematocrit &lt;30, OR = 6.042. (95% CI 2469-14782) p &lt;0.0002; Hb &lt;10 OR = 5.056 (95% CI 2163-11814) p 100 mm / 1h OR = 3.725 (95% CI 1642-8447) p 100 mg / dl OR = 6.417. (95% CI 2441-16869) p &lt;0.0002 and other heart affections.OR = 7.964. (95% CI 2459-25794) p &lt;0.0010. Children from the West of the country have 2.7 times greater risk of CC OR = 2.714 (95% CI: 1228-5997) p &lt;0.019 compared to the rest. Conclusions: Increased frequency in males. Increased risk of CHD in subjects from western Argentina. Low mortality. Increased risk of CC: low hematocrit and hemoglobin; leukocytes, neutrophils, ESR, CRP, FC, high, Presence of other heart alterations and more days of fever at the time of establishing of treatment. Risk factors for coronary involvement
由一例高血压自然发展病程看高血压致肾功能损害及患者教育
Authors: 任京媛, 姚崇华
Journal: BMJ (2009)

高血压是常见的心血管疾病之一.目前我国高血压患者约2.0亿,但对高血压的知晓率、治疗率及控制率均很低.许多患者尤其是青壮年患者认为血压升高时吃两片药就行了,不需要去医院就诊.笔者遇到1例高血压患者发现高血压3年.因为没有及时治疗导致高血压的肾损害发生,使预后较单纯高血压相差一个等级的病例,教训深刻,与大家交流如下。
BRAF fusion in lung cancer.
Authors: Jun Zhao, Renhua Guo, Xinghao Ai, Lianke Liu, Lin Li, Mingjiu Chen, Xingxiang Pu, Min Zhang, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2020)

e21598 Background: BRAF was a part of RAS/MAPK pathway, which regulated the proliferation, differentiation, migration, and apoptosis of cells. BRAF V600E was a potential treatment target for non-small cell lung cancer and other tumors. While BRAF fusion was rare in lung cancer. Here we focus on BRAF fusion in lung cancer. Methods: We retrospectively reviewed next-generation sequencing (NGS) results of lung cancers, with or without treatment history. The samples were subjected to NGS using 59 or 1021-gene panel, which enables simultaneously assess snv, indel, rearrangements and cnv variations. Patients with BRAF fusion were collected and used to analysis. Results: We found eighteen lung cancers have BRAF fusion from about twelve thousand patients, 13 are females. The median age at diagnosis was 47-year old (range 28 to 70). Tested samples included 13 tissues, 5 plasma, and 2 pleural effusion. BRAF fusion could occur in different stage, 12 stage Ⅳ and 1 stage Ⅰ, other were unknown. There were 14 lung adenocarcinoma, 1 squamous cell carcinoma and 1 adenosquamous carcinoma, other two patients were unknown. The partner genes of BRAF fusion were distinctly among the patient, TRIM24 was relatively common. The median tumor mutation burden (TMB) was 4.8muts/Mb (range 0 to 15.4), with low TMB-H frequency (10.5%, defined 9 as cutoff value). Seven patients had no system treatment history, and 1 had concurrent EGFR L858R mutation. Nine patients received EGFR-TKI therapy, 1 received ALK-TKI therapy, and 1 received chemotherapy. Among the EGFR-TKI treated patients, 7 received first and third generation TKI sequential therapy, the median TTD (time to discontinue) of TKIs was 26 months (range 17 to 46). The EGFR mutation still exist when EGFR-TKIs resistance, included EGFR primary mutation, T790M, and C797S, concurrent with BRAF fusion. Except for BRAF fusion, there also had other complex resistance mechanism occurred, like HER2 mutation, KRAS mutation, etc. Conclusions: BRAF fusion had low frequency in lung cancer and occurred at different stage during disease development. BRAF inhibitors maybe a potential strategy for BRAF fusion lung cancers. As TKIs resistance mechanism, BRAF fusion is a huge clinical challenge, indicate the importance of further research.
CYAD-101: An innovative non-gene edited allogeneic CAR-T for solid tumor cancer therapy.
Authors: Hans Prenen, Jeroen Dekervel, Sébastien Anguille, Alain Hendlisz, Alexandre Michaux, Panagiota A Sotiropoulou, David Edward Gilham, Sébastien Mauen, Sarah Snykers, Emilie Cerf, Caroline Lonez, Anne Flament, Frederic Lehmann, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2020)

3032 Background: In contrast to autologous CAR-T cell therapies, allogeneic donor-derived CAR-T cells can be banked and used in a timely fashion overcoming the critical time delay of just in time autologous cell manufacture. CYAD-101 is an allogeneic CAR-T that uses a non-gene edited peptide-based technology (TIM) to control graft versus host disease (GvHD) combined with a NKG2D-based CAR. Pre-clinical studies confirmed that CYAD-101 maintained CAR-directed anti-tumor activity in the absence of the induction of GvHD. Clinical grade CYAD-101 cells were produced for the phase 1 alloSHRINK trial (NCT03692429). Methods: A bank of clinical grade CYAD-101 cells was generated through two production runs using a single donor apheresis. Together, the bank generated &gt; 53 billion CYAD-101 cells suitable for the entire dose escalation segment and short expansion phase of the trial (15 patients in total). Both runs showed high consistency with the CYAD-101 product generated composed mainly of CD4 + T cells (&gt;85%) with a transduction level of &gt; 92%, low relative expression of CD69/CD25 and largely absent expression levels of PD-1/LAG-3. The CYAD-101 cells were predominantly (&gt;80%) CD45RA − / CD62L − / CD27 − suggestive of an effector memory T cell population. Results: Upon co-culture with target K562 cells, CYAD-101 readily produced IFN-γ that was blocked by a NKG2D blocking antibody confirming specificity of the CAR. CYAD-101 cells showed in vitro cytotoxicity against tumor cells and produced an array of Th1 (IFN-γ, IL-2 and TGF-β) and Th2 (IL-4, IL-5) cytokines. Importantly, minimal IFN-γ was produced upon TCR stimulation while stimulation with a non-TCR mitogen (PMA + ionomycin) lead to high levels of IFN-γ. Together, these data show that clinical grade CYAD-101 cells were able to functionally respond through the CAR but showed minimal TCR-driven activation. Fifteen refractory metastatic CRC patients who had previously failed at least one line of oxaliplatin—containing therapy were treated with three doses of CYAD-101 cells given on Day 3 of three successive FOLFOX chemotherapy cycles. Updated clinical results continue to demonstrate an encouraging clinical activity (2 patients with partial response and 9 with stable disease) and the absence of GvHD in the context of CYAD-101 cell engraftment. Conclusions: These early clinical results demonstrate the safety and tolerability of a non-gene edited predominantly CD4 + CAR-T therapeutic approach. The initial observations of clinical activity in metastatic CRC patients warrants the continued development of this therapy. Clinical trial information: NCT03692429 .
Wire-guided over-the-scope clip method for closing gastrobronchial fistula
Authors: Bulent Odemis, Dilara Turan Gökçe
Journal: Endoscopy (2020)

Gastric fistula is a significant complication that develops in 0.9 % – 2.6 % of cases after bariatric surgery [1]. Although gastrobronchial fistula (GBF) is a rare gastric fistula, it can generally be treated with thoracotomy and laparotomy but with high mortality rates.
Escalated dosing schedules of CC-486 for patients experiencing first acute myeloid leukemia (AML) relapse: Results from the phase III QUAZAR AML-001 maintenance trial.
Authors: Hartmut Dohner, Andrew Wei, Pau Montesinos, Hervé Dombret, Farhad Ravandi, Hamid Sayar, Kimmo Porkka, Irwindeep Sandhu, Francesco Passamonti, Fabrizio Pane, Tadeusz Robak, Jose F. Falantes, Andre C. Schuh, Gert J. Ossenkoppele, Ignazia La Torre, Barry Skikne, Keshava Kumar, Qian Dong, C. L. Beach, Gail J. Roboz
Journal: Journal of Clinical Oncology (2020)

7513 Background: A goal of AML maintenance therapy is to decrease the risk of relapse by suppressing growth of residual leukemic cells post-induction. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules ( &gt;7 days [d]/28d cycle) to sustain therapeutic activity. In the QUAZAR AML-001 trial (NCT01757535), CC-486 maintenance treatment (Tx) significantly prolonged overall (OS) and relapse-free survival vs. placebo (PBO) in pts with AML in first remission following induction chemotherapy (IC), who were not candidates for hematopoietic stem cell transplant (HSCT). Pts initially received CC-486 or PBO for 14d/cycle, but pts who relapsed with 5–15% blasts could receive escalated 21d/cycle dosing. We review outcomes of pts who received 21d dosing in QUAZAR AML-001. Methods: Pts were aged ≥ 55 years, with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and had achieved first CR/CRi after IC ± consolidation. Within 4 mo of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO QD on d 1–14 of 28d Tx cycles. CR/CRi status was assessed every 3 cycles. Pts relapsing with 5%–15% blasts in blood or bone marrow could receive study drug for 21d/cycle at the investigator’s discretion. Tx could continue until &gt; 15% blasts, unacceptable toxicity, or HSCT. Results: 91 patients (CC-486, 51/238 [21%]; PBO, 40/234 [17%]) were assigned to ≥ 1 21d/cycle dosing schedule. Median time to dose escalation was 9.2 mo (range 1.0-52.7) for CC-486 and 6.0 mo (0.5-19.3) for PBO. Median number of 21d dosing cycles was 2.0 (range 1-45) in the CC-486 arm and 2.0 (1-16) in the PBO arm; 43% and 18% of pts, respectively, received &gt; 3 cycles of 21d dosing. Among 78 evaluable pts, 10/43 (23%) CC-486 pts and 4/35 (11%) PBO pts regained CR/CRi (central review) during dose escalation. Median OS from randomization was 22.8 mo vs. 14.6 mo with CC-486 vs. PBO, respectively (HR 0.66 [95%CI 0.42, 1.0]; P = 0.073), and 1-year survival rates were 80.4% vs. 59.5% (+20.9% [95%CI 2.1%, 39.7%]). The most common AEs with first onset during 21d dosing were febrile neutropenia (CC-486 24%, PBO 3%), thrombocytopenia (22%, 23%), anemia (22%, 20%), and neutropenia (20%, 10%). Conclusions: Escalated 21d CC-486 dosing was well tolerated and resulted in prolongation of OS and restoration of remission in approximately one-fourth of pts. Hematologic AEs first reported during escalated dosing in both Tx arms may be due in part to disease relapse. A 21d dosing schedule should be considered for pts receiving CC-486 who experience relapse with 5–15% blasts. Clinical trial information: NCT01757535 .
Circulating exosome DANCR correlated to the recurrence of hepatitis C virus-related hepatocellular carcinoma.
Authors: Shu-Chi Wang, Jee-Fu Huang, Chia-Yen Dai, Wan-Long Chuang, Ming-Lung Yu
Journal: Journal of Clinical Oncology (2020)

e13688 Background: Long non-coding RNAs (lncRNAs) have been associated with various types of neoplasms. Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) has high risk of recurrence. Methods: Differentially-expressed candidate lncRNAs relevant to HCV-HCC were identified by RNA-seq in Screening set, validated by qPCR in Validation set, and confirmed in external Test cohort. Target lncRNAs in tissue and serum exosome were applied to predict HCC recurrence of HCV-HCC after curative surgical resection in a large Application cohort. Pathogenetic mechanisms of target lncRNA were explored by using JFH1-infectious cells. Results: Of the top ten differentially-expressed lncRNAs relevant to HCV-related HCC identified in Screening set, differentiation antagonizing non-protein coding RNA (DANCR), which was upregulated by HCV infection and identified as the most relevant lncRNA to HCV-HCC, was overexpressed in tumor than in adjacent non-tumor (ANT) tissues. Of 183 HCV-HCC patients followed for 10 years after curative HCC resection, tumor DANCR, tumor/ANT DANCR ratio and circulating exosome DANCR levels were positively associated with HCC recurrence. Circulating exosome DANCR levels by droplet digital PCR provided the best predictive power of HCC recurrence with area under the curve of 0.88, when compared to tumor DANCR levels, tumor/ANT DANCR ratio, and alfa-fetoprotein. Exosome DANCR &gt; 50 copies/ml was the most predictive factor associated with HCC recurrence and mortality (hazard ratio/95% confidence intervals: 7.0/4.3-11.6 and 2.7/1.5-5.1 respectively, Cox regression model). Cell experiments showed that DANCR, positively associated with mesenchymal-associated β-catenin expression, promoted cell migration and invasion ability. Conclusions: lncRNA-DANCR was highly relevant to disease progression of HCV-HCC. Circulating exosome DANCR could serve as a non-invasive prognostic biomarker for HCV-HCC.
Detection of ALK and ROS1 fusion transcripts in FFPE samples of non-small cell lung cancer patients using a novel RT-PCR based assay and targeted RNA sequencing.
Authors: Marc G. Denis, Audrey Vallee, Christine Sagan, Guillaume Herbreteau, Sandrine Theoleyre, Jaya Rajamani, Michael Lee, Ellen Ordinario
Journal: Journal of Clinical Oncology (2020)

e21695 Background: Detection of genomic rearrangements like ALK and ROS1 fusions are mandatory in non-small cell lung cancer (NSCLC) as those alterations can be targeted by an increasing number of drugs. Fluorescence in-situ hybridization (FISH) has been so far the gold standard but multiplexed technologies would allow analysis of many potential targets simultaneously. We have evaluated a novel RT-PCR based assay and a targeted RNA sequencing solution for the detection of ALK and ROS1 rearrangement in NSCLC patients. Methods: 41 patients with late stage NSCLC were included in the study. ALK and ROS1 status were screened on FFPE tissue sections using immunohistochemistry and confirmed with FISH. Total nucleic acids were extracted from tissue sections using the Maxwell RSC RNA FFPE kit (Promega). Detection of rearrangements was performed by RT-PCR using the prototype ALK/RET/ROS1 Fusion Panel assay (Roche), which detects 7 ALK fusion variants, 13 ROS1 variants and 6 RET variants. For RNA sequencing, the libraries were prepared with the QIAseq Targeted RNAscan Lung Cancer Panel (Qiagen). Sequencing was performed on a MiSeq instrument (Illumina). Results: We tested 16 ALK FISH+ tumors, 4 ROS1 FISH+ tumors, and 21 samples that were either IHC- or IHC+/FISH-. The RT-PCR assay detected 15 of the 16 ALK FISH+ tumors, and 3 of the 4 ROS1 FISH+ tumors. In the 21 IHC- or IHC+/FISH- samples, 1 additional ROS1 fusion and 1 RET fusion were detected. The remaining 19 assays samples were negative. 2 fusions were missed by RT-PCR because the assay design does not cover these rearrangements (KLC1-ALK and CTNND1-ROS1). With targeted RNA sequencing, we were able to detect 14 of the 16 ALK FISH+ tumors and all 4 of the ROS1 FISH+ tumors. We also identified 1 additional ROS1 fusion and 1 RET fusion in the 21 IHC- or IHC+/FISH- samples. 17 patients were negative and 2 tests were not contributive. Overall, using FISH as a reference, the sensitivity of both assays was 90% (18/20). Conclusions: Using limited amount of biological material, both RT-PCR and targeted RNA sequencing were able in one assay to detect the overwhelming majority of ALK and ROS1 fusions identified with FISH. These approaches also allowed us to detect gene rearrangements that were missed by the initial IHC/FISH screening. The RT-PCR assay requires less RNA (as little as 3 ng) and has a much faster turn-around time. The RNA sequencing approach allowed us to identify the fusion partners, but it requires much more RNA and is rather difficult to implement in routine practice.
Correlation of levels of extracellular vesicles in peripheral and pulmonary blood plasma with pathological stages of lung cancer patients.
Authors: Hyun Koo Kim, Byeong Hyeon Choi, Yu Hua Quan, Jiyun Rho, Sunghoi Hong, Yong Park, Yeonho Choi, Ji-Ho Park, Hwan Seok Yong, Kook Nam Han, Young Ho Choi
Journal: Journal of Clinical Oncology (2020)

e15558 Background: Exosome concentration is known to be higher in cancer patients than in healthy individuals. In this study, we observed that the levels of exosomes differ in tumor-draining pulmonary blood and in peripheral blood in animal models and human subjects at different pathological stages of lung cancer. Methods: Ten rabbits and 40 humans formed the study cohorts. Blood was collected from a peripheral vein in all groups, and pulmonary blood was collected intraoperatively from all groups, except the healthy human controls. Quantitative analysis of exosomes was performed by nanoparticle tracking assay, CD63 enzyme-linked immunosorbent assay, and western blotting. Results: The peripheral blood of lung cancer-bearing animals and patients with lung cancer carried higher amounts of exosome than that from healthy controls ( p &lt; 0.01 and p &lt; 0.001, respectively). Moreover, pulmonary blood from lung cancer-bearing animals and patients had significantly higher exosome levels, compared to preoperative peripheral blood ( p &lt; 0.01 and p &lt; 0.0001, respectively). In patients, pulmonary exosome levels showed higher correlation with pathological stages of lung cancer than the peripheral exosome levels. Conclusions: Exosome levels increased with increasing grade of lung cancer, and this trend was more prominent in the pulmonary than in the peripheral blood.