tbuckley/cabot-search huggingface dataset:
Mechanical circulatory support programme – a one centre experience
Authors: Jure Samardzic, Mate Petricevic, Bojan Biocina, Bosko Skoric, Hrvoje Gasparovic, Maja Cikes, Daniel Lovric, Visnja Ivancan, Sanja Konosic, Davor Milicic
Journal: European Journal of Heart Failure (2012)
Case 28-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Patrick T. O'Gara, James F. Southern
Journal: New England Journal of Medicine (1987)

Presentation of CaseA 60-year-old man was admitted to the hospital because of facial swelling and cyanosis.There was a history of hypertension and impaired glucose tolerance that dated back 17 years. Seven years before admission the patient entered another hospital because of an inferior myocardial infarct complicated by a brief episode of cardiac arrest, from which he recovered uneventfully. On admission to that hospital the blood pressure was 190/100 mm Hg, and x-ray examination of the chest revealed no evidence of cardiac enlargement. Twenty-six months before entry he was readmitted to the same hospital because of the development of . . .
Prognostic value of circulating cytokines in colorectal cancer: A prospective study in sixty colorectal cancer patients in Tunisia.
Authors: Jihene Braham Ayari, Rania Guesmi, Mehdi Balti, Mouna Ben Azaiz, Aref Zribi, Sana Fendri, Sonia Ben Nasr, Ezzedine Ghazouani, Faida Agili, Sharif Ahmed Kullab, Abderrazek Haddaoui
Journal: Journal of Clinical Oncology (2019)

e15130 Background: Colorectal cancer is the third most common malignancy and fourth most common cause of cancer mortality worldwide. It is responsible for more than 600,000 deaths annually, and incidence rates are increasing in most of the developing countries. Pathophysiology implicates pro-inflammatory conditions that promote the tumor malignant progression, invasion, and metastasis. The aim of this study is to measure the level of circulating cytokines (IL1b, IL6, IL8, IL10, IL22, IL23 and TNFα) in sixty colorectal cancer patients in Tunisia and to evaluate their implication as prognostic factors. Methods: Serum samples were collected prospectively from a cohort of sixty colorectal cancer patients in Tunisia. Levels of circulating inflammatory cytokines, TNF-α, IL1b, IL6 and IL8 were measured using the technique of a solid-phase, two-site chemo-luminescent enzyme immune-metric assay (Immulite 1000, Simens, USA). Serum levels of IL10 were measured by enzyme-linked immunosorbent assays (ELISA) sandwich method. Results: The mean age of patients is 58 years (24–82 years), Thirty-sex among them were m and 24 women with sex ratio of 1.5. Twenty-five patients were at metastatic setting, and hepatic metastasis was found in 25% of cases. The mean level of cytokines Il6, IL10, TNFα, IL8 and IL1b were respectively 12.26 +/- 18.7 pg/ ml (min 2, max 117pg/ ml), 0.93 +/- 5.23 pg/ ml (min 0, max 39.35 pg/ml), 8.31 +/- 4.99 pg/ ml (min 4, max 27.20 pg/ ml), 61.9 +/- 159.71 pg/ml (min 5, max 1173 pg/ ml) and 1.13 +/- 3.34 pg/ ml (min 5, max 15.7pg/ml. We found a significant correlation between a high level of IL8 and metastatic disease (p=0.001), especially in mutant RAS cases (p=0.001). We found also a significant correlation between high level of IL1b and lymphovascular invasion (p=0.013) and young patients (p=0.01). On the other hand, there was significant correlation between IL8 and IL6 (r = 0.560, p = 0.00001); IL8 and TNFα (r = 0.404, p = 0.001); and IL10 with IL1b (r = 0.297, p = 0.021). Conclusions: Our results highlight the role of circulating IL8, TNFα, IL1b and IL10 as potential prognostic biomarkers in colorectal cancer patients. These cytokines could contribute to tumor growth and progression, namely for IL-8 level that was significantly correlated with poor prognosis and advanced stages. This correlation needs to be evaluated in large prospective trials and suggests a rational for the development and use of cytokine blockade in treatment of colorectal cancer patients.
Efficacy and safety of neoadjuvant PD-1 blockade with sintilimab in resectable squamous non-small cell lung cancer (sqNSCLC).
Authors: Ning Li, Jianming Ying, Xiuli Tao, Fan Zhang, Ziran Zhao, Yun Ling, Yushun Gao, Jun Zhao, Qi Xue, Yousheng Mao, Wendong Lei, Ning Wu, Shuhang Wang, Jianchun Duan, Yibo Gao, Zhijie Wang, Nan Sun, Jie Wang, Shugeng Gao, Jie He
Journal: Journal of Clinical Oncology (2019)

8531 Background: NSCLC patients who have potentially resectable disease often subsequently relapse after surgery. New therapy that prevents relapse after surgery is desperately needed. In this study, we tested the efficacy and safety of neoadjuvant sintilimab, an anti-PD-1 antibody, for patients with resectable sqNSCLC in China. Methods: All patients had treatment-naïve resectable sqNSCLC (stage IB-IIIA) that was confirmed by histopathology. Patients received two cycles of sintilimab (200 mg IV) on Day 1 and 22. Surgery was performed between Day 29-43. An enhanced PET/CT was obtained at baseline and seven days prior to surgery. Preliminary analysis of safety profile and efficacy was planned after at least 20 patients had received operation. Results: As of Jan. 28, 2019, 22 patients (20 males and 2 females) with sqNSCLC received two doses of sintilimab followed by radical resection. The median age was 61.5 yr (range, 48 to 70). Six (27.3%) and four (18.2%) patients experienced neoadjuvant treatment emergent adverse events (TEAEs) and neoadjuvant treatment-related AEs (TRAEs), respectively. Most of the TEAEs and TRAEs were grade 1 or 2. Three patients achieved radiological partial response: an ORR of 13.6% based on RECIST 1.1. Ten patients (45.5%) achieved a major pathologic response (MPR, ≤10% viable tumor cells), including four (18.2%) had complete pathologic response (no viable tumor cell). There was a direct correlation between pathological response and decrease in the standardized uptake values (SUV) in the primary tumor. Among nine patients with &gt; 30% decrease of SUV, eight had MPR, compared with no MRP response in the 11 patients with ≤30% decrease of SUV. Conclusions: Neoadjuvant sintilimab for sqNSCLC patients was tolerable and the 45.5% MRP rate is encouraging. A decrease in SUV may be predictive of pathologic response after PD-1 therapy in sqNSCLC. Clinical trial information: ChiCTR-OIC-17013726.
Atezolizumab plus bevacizumab in non-clear cell renal cell carcinoma (NccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (ccRCCsd): Updated results of activity and predictive biomarkers from a phase II study.
Authors: Ronan Flippot, Bradley Alexander McGregor, Abdallah Flaifel, Kathryn P. Gray, Sabina Signoretti, John A. Steinharter, Eliezer Mendel Van Allen, Meghara K. Walsh, Katy Gundy, Xiao X. Wei, Lauren Christine Harshman, Ulka N. Vaishampayan, Toni K. Choueiri, Rana R. McKay
Journal: Journal of Clinical Oncology (2019)

4583 Background: NccRCC and ccRCCsd are aggressive tumors associated with poor prognosis and response to therapy. Combination strategies co-targeting VEGF signaling and inhibitory immune checkpoints are highly active in clear-cell renal cell carcinoma, but data is lacking in NccRCC and ccRCCsd. We conducted a multicenter, open-label, single arm phase II trial of atezolizumab plus bevacizumab in NccRCC and ccRCCsd. Methods: Patients with NccRCC and ccRCCsd ( &gt; 20% sarcomatoid differentiation), and ECOG performance status of 0-2 were eligible. Prior systemic treatment was allowed with the exception of prior PD-1/PD-L1-directed therapy. Atezolizumab 1200mg and bevacizumab 15mg/kg were administered every 3 weeks until progression, unacceptable toxicity, or patient withdrawal. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Exploratory biomarker analyses included PD-L1 expression on tumor (TC) and immune cells (IC), and spatial analysis of the immune infiltrate. Results: Sixty patients received at least 1 cycle of treatment, among whom 56 were evaluable for response (17 ccRCCsd and 39 NccRCC). ORR was 34% in the overall population, 53% in ccRCCsd and 26% in NccRCC. Median progression-free survival was 8.4 months (95%CI, 6.9-16.5). Baseline tumor tissue was available for 36 patients. TC PD-L1 expression ≥1% was associated with improved ORR (9/14, 64%) compared to patients with PD-L1 expression &lt; 1% (4/20, 20%). Patients with TC PD-L1 expression ≥1% who experienced progressive disease as best response had shorter average distance between tumor cells and nearest neighboring immune cells at baseline. Further analysis of the immune tumor microenvironment on an expanded cohort, including IC PD-L1 expression and correlation with clinical outcomes, is ongoing and will be updated. Conclusions: The combination of atezolizumab plus bevacizumab is active in NccRCC and ccRCCsd. Candidate predictive biomarkers include PD-L1 expression in TC and topological analysis of the immune infiltrate. Clinical trial information: NCT02724878.
Whole-genome deep-learning analysis identifies contribution of noncoding mutations to autism risk
Authors: Jian Zhou, Christopher Y. Park, Chandra L. Theesfeld, Aaron K. Wong, Yuan Yuan, Claudia Scheckel, John J. Fak, Julien Funk, Kevin Yao, Yoko Tajima, Alan Packer, Robert B. Darnell, Olga G. Troyanskaya
Journal: Nature Genetics (2019)
Evaluation of survival by ADCC status: Subgroup analysis of SB3 (Trastuzumab Biosimilar) and reference trastuzumab in patients with HER2-positive early breast cancer at three-year follow-up.
Authors: Xavier Pivot, Mark D. Pegram, Javier Cortes, Diana Lüftner, Gary H. Lyman, Giuseppe Curigliano, Igor Bondarenko, Ye Chan Yoon, Younsoo Kim, Jae Yun Lim
Journal: Journal of Clinical Oncology (2019)

580 Background: SB3 is an approved biosimilar of reference trastuzumab (TRZ). At additional 2-year follow-up after completing neoadjuvant and adjuvant treatment, there was a difference in event-free survival (EFS), but no difference in overall survival (OS) between SB3 and TRZ. Upon monitoring quality attributes of TRZ, a marked downward shift in antibody-dependent cell-mediated cytotoxicity activities (ADCC) was observed in TRZ lots with expiry dates from Aug 2018 to Dec 2019. Some of the lots were used in the Phase III study. This is a post-hoc analysis of EFS and OS by ADCC status from a 3-year follow-up to investigate the difference in EFS between SB3 and TRZ. Methods: After completion of neoadjuvant and adjuvant therapy in patients with HER2 positive early breast cancer, patients from selected countries participated in a 5-year follow-up study (NCT02771795). Within the TRZ group, patients exposed to at least one shifted ADCC lot and those never exposed to shifted ADCC lot during neoadjuvant period were considered as “Exposed” and “Unexposed,” respectively. EFS and OS after 3-year follow-up was analyzed by ADCC status in the long-term follow-up set. Results: 367 patients (SB3, N = 186; TRZ, N = 181) were enrolled in the follow-up study. Within TRZ, 55 patients were Unexposed and 126 patients were Exposed. At a median follow-up duration of 40.8 months in SB3 and 40.5 months in TRZ, 3-year EFS rates were 92.5% in SB3, 94.5% in Unexposed, and 82.5% in Exposed and OS rates were 97.0%, 100%, and 90.6%, respectively. Exposed was associated with decreased EFS compared to Unexposed (HR 0.14, 95% CI 0.04-0.51, p= 0.003). There was a trend of decreased OS in Exposed compared to Unexposed, however, there was no significant difference (HR 0.14, 95% CI 0.02-1.15, p= 0.068). Between SB3 and Unexposed, no difference was observed in EFS (HR 1.06, 95% CI 0.33-3.44, p= 0.923), or OS (HR 0.54, 95% CI 0.05-5.44, p= 0.600). Conclusions: Within the TRZ group, Exposed showed significantly lower EFS compared to Unexposed, and a similar trend was observed in OS with no statistical significance. Between SB3 and Unexposed, no significant difference in EFS or OS was observed. Clinical trial information: NCT02771795.
Towards the noninvasive identification of pathologic responders to neoadjuvant pembrolizumab in muscle-invasive urothelial bladder cancer (MIBC).
Authors: Giuseppina Calareso, Marco Bandini, Daniele Raggi, Elena Farè, Andrea Gallina, Renzo Colombo, Maurizio Colecchia, Roberta Luciano Luciano, Andrea Salonia, Filippo Pederzoli, Jeffrey S. Ross, Russell Madison, Siraj Mahamed Ali, Jon Chung, Francesco Montorsi, Alberto Briganti, Antonella Messina, Andrea Necchi
Journal: Journal of Clinical Oncology (2019)

4540 Background: The possibility to predict the pathologic complete response (pT0) or pT≤1 after neoadjuvant immunotherapy may deeply impact the management of MIBC and orient clinical trials. The PURE01 study ( Necchi, JCO 2018) evaluated preoperative pembrolizumab before radical cystectomy (RC) in T2-3bN0MO patients (pts). The trial was amended to increase the sample size. Methods: Pts were assessed with bladder multiparametric magnetic resonance imaging (mpMRI: T2-weighted imaging, diffusion-weighted imaging, dynamic contrast enhancement [CE]) before and after treatment (3 cycles every 3 weeks) prior to RC. All mpMRI were made with bladder catheterization. We tested the following complete response (CR) definition: any measurable residual disease (T2W, morphology), but no residual restricted diffusion and no early CE signals. Exams were independently assessed by 2 senior radiologists and tested against the pT0/pT≤1 endpoints. Logistic regression models analyzed mpMRI and biomarker data on comprehensive genomic profiling (CGP) with FoundationONE CDx assay and PD-L1 combined positive score (CPS). Results: From 02/17 to 11/18, 84 pts were assessed before and after treatment (168 total mpMRI) and had the pathological response available from RC. Baseline CR (TURB effect) was observed in 14 (16.7%) pts. The mean overall percentage of agreement (OPA) across the mpMRI data was 98.2%. The sensitivity of post-therapy (PT) CR for pT0 response was 0.80 (95%CI: 0.61-0.92); the specificity for pT≤1 response was 0.94 (95%CI: 0.80-0.99). PT-CR was associated with both pT0/pT≤1 endpoints (p &lt; 0.001) after adjusting for clinical T-stage and histology. Baseline CPS≥10 and TMB≥20 mut/Mb were strongly associated with pT0 response (OR: 4.46 and 14.9). mpMRI CR post-pembrolizumab significantly improved the c-index of the CPS/TMB models: up to 0.81 and 0.87 for pT0/pT≤1 endpoints. Conclusions: In post-pembrolizumab MIBC, the proposed definition of radiological CR through mpMRI is endowed with limited inter-observer variability and high accuracy in predicting pT≤1. CPS/TMB-selected pts who achieve CR with mpMRI can be reliably spared any surgical treatment. Clinical trial information: NCT02736266.
Immune related adverse events (irAE) of mono-, combination, and sequential therapy regimens of ipilimumab (IPI), nivolumab (NIV), and pembrolizumab (PEM) for advanced melanoma.
Authors: Abdulaali Almutairi, Ali McBride, Srinath Sundararajan, Ivo Abraham
Journal: Journal of Clinical Oncology (2019)

e21011 Background: The immunotherapy agents IPI, NIV, and PEM have transformed the management of advanced melanoma but are associated with irAEs. We estimated the incidence of irAEs as observed in clinical trials of mono, combination , and sequential regimens of these agents in the advanced melanoma setting. Methods: We searched the Medline, Embase, and Cochrane databases; clinicaltrials.gov; and websites of regulatory agencies in USA, Europe, Australia, and Japan for phase 1-3 trials of IPI, NIV, and PEM in advanced melanoma. Random effect meta-analysis was utilized to estimate the incidence of irAEs (expressed as % with 95%CI) for all agents in mono-, combination, and sequential regimens. Results: 56 reports (32 published articles, 7 updates, 15 results published on clinicaltrials.gov and 2 regulatory documents) of 37 trials and relating unique and independent irAE data were included in the analysis. See Table. Conclusions: IPI mono had higher incidence rates of all grade and ≥ grade 3 hypophysitis and colitis but lower rates of all grade hypothyroidism, pneumonitis, and vitiligo than NIV or PEM mono. Combination and sequential regimens had higher irAE incidence rates compared to monotherapies except for grade ≥3 hypophysitis in PEM+IPI and NIV→IPI, and grade ≥3 vitiligo as well as all grade colitis and hypophysitis in IPI →NIV. Table. Incidence rates of select irAEs expressed as % with 95%CI (‡ all grade; * ≥ grade 3). [Table: see text]
COMPARISON OF OBJECTIVE CRITERIA AND EXPERT VISUAL INTERPRETATION TO CLASSIFY BENIGN AND MALIGNANT HILAR AND MEDIASTINAL NODES ON 18-F FDG PET/CT
Authors: Phan Nguyen, Manoj Bhatt, Farzad Bashirzadeh, Justin Hundloe, Robert Ware, David Fielding, Aravind Ravi Kumar
Journal: Journal of Thoracic Oncology (2013)
Profile of somatic mutations in young adults with pancreatic cancer.
Authors: Livia Munhoz Rodrigues, Simone Maistro, Maria Lucia Hirata Katayama, Rosimeire Aparecida Roela, Maria A. A. Koike Folgueira
Journal: Journal of Clinical Oncology (2019)

e15790 Background: Most pancreatic carcinomas (PC) occur in older people, however a few cases are detected in young adults. In this age group, the carcinogenic process is less well understood. Our goal was to identify and to characterize cancer driver genes in early age onset PC. Methods: Somatic variants of individuals affected by PC aged ≤45 years were searched in the COSMIC and CBioPortal databases. The variants were annotated using Oncotator, excluding the silent and intronic variants. Implication in cancer causality was evaluated in the Cancer Gene Census (CGC) and the Candidate Cancer Gene Database (CCGD). The most frequently mutated genes were identified and investigated to determine if they configured FrequentLy mutAted GeneS (FLAGs). Results: Whole genome (4) or exome (29) sequencing was available from 33 individuals (14 females and 19 males). A median of 31 (7-102) alterations per tumor, mainly represented by C &gt; T substitutions (median 16, 2-71), was detected. A median of 3 (0-11) truncated alterations, 4 (1-13) genes cataloged as CGC and 8 (1-22) genes cataloged as CCGD rank A or B was identified per tumor. The most frequently affected genes were those characteristic of tumor promotion in pancreatic cancer carcinogenesis, such as KRAS (79%), TP53 (64%), SMAD4 (18%), followed by RYR1 (15%) and TTN (12%) genes, the latter two classified as FLAGs and, finally, HERC2, GREB1 and DMBT1 (9%). Seventeen samples presented variants in both TP53 and KRAS (17/33), 9 and 4 presented only KRAS or TP53 variants, respectively. Three samples with mutations in neither of these genes presented mutations in genes such as BCLAF1, DCC, BRAF, CDH11 and CDKN2A, both CGCs. Three out of 9 samples carrying KRAS but not TP53 mutations presented variants in DNA homologous repair (HHR) genes. Among all the altered genes, the main biological processes were cell adhesion (139 genes involved) and anatomical structure formation involved in morphogenesis (127), while the most enriched pathways were Wnt (45) and Cadherin (30). Conclusions: TP53 and KRAS are the somatic mutations most frequently detected in PC. 10% of the samples showed no change in these genes, but showed changes in other CGCs. HERC2, GREB1 and DMBT1 are potential cancer drivers in young adult PCs.
Patterns of metastasis and second primary malignancies (SPM) in colorectal cancer: A perspective from Peru.
Authors: Jorge Leon, Fernando Namuche, Paola Catherine Montenegro, Claudio J. Flores
Journal: Journal of Clinical Oncology (2019)

e15068 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. Approximately 20% of patients with CRC already have metastases at diagnosis, and this figure has been stable over the last two decades. The lack of data makes it more difficult to manage our patients. The metastatic setting and patients with second primary malignancies are complicated scenarios. The objective of our study was to explore and describe the metastasis patterns and the second primary malignancies’ frequency in CRC patients. Methods: We retrospectively reviewed the electronic medical records of 609 patients with CRC from one specialized Peruvian cancer center between 2006 and 2016. For the evaluation of the metastasis pattern, we selected 198 patients with metastasis at debut and the patients who had relapse of the disease. Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. We evaluated the metastasis pattern according to primary tumour sidedness, age, CEA, histological grade, histological type. A survival analysis was performed with Kaplan Meier method, comparing the curves with Log Rank test for metastasectomy, biological therapy and number of sites with metastatic disease. A multivariate analysis was performed using the Cox regression model with the statistically significant variables found in the univariate analysis. Results: At the time of diagnosis, stage IV disease accounted for 15.3% (93) of all CRC cases. 105 (stage I-III) pts had relapse disease. Regardless of the primary tumor site, the most common site for metastatic spread was the liver (42.9%), lung (12.6%), carcinomatosis (18.2%). Pts who underwent metastasectomy presented a better OS [HR, 0.284; 95% CI, 0.123-0.657; p &lt; 0.05], as well as pts who received biologic therapy [HR, 0.641; 95% CI, 0.416-0.990; p &lt; 0.05] and a greater number of sites with metastatic disease had worst OS [HR, 1.878; 95% CI, 1.181-2.985; p &lt; 0.05] The incidence of SPM following CRC was 48/609 (7.8%), the more frequent localizations were: breast, prostate and lung with 14.6% each, then kidney 10.4%, bladder 8.3%. Conclusions: In mCRC metastasectomy, biological therapy and number of sites with metastatic disease play an important role in OS. The more frequent localizations with SPM were breast, prostate and lung.
M2 microglia-derived exosomes protect the mouse brain from ischemia-reperfusion injury via exosomal miR-124
Authors: Yaying Song, Zongwei Li, Tingting He, Meijie Qu, Lu Jiang, Wanlu Li, Xiaojing Shi, Jiaji Pan, Linyuan Zhang, Yongting Wang, Zhijun Zhang, Yaohui Tang, Guo-Yuan Yang
Journal: Theranostics (2019)

Rationale: Microglia play a critical role in modulating cell death and neurobehavioral recovery in response to brain injury either by direct cell-cell interaction or indirect secretion of trophic factors.Exosomes secreted from cells are well documented to deliver bioactive molecules to recipient cells to modulate cell function.Here, we aimed to identify whether M2 microglia exert neuroprotection after ischemic attack through an exosome-mediated cell-cell interaction.Methods: M2 microglia-derived exosomes were intravenously injected into the mouse brain immediately after middle cerebral artery occlusion.Infarct volume, neurological score, and neuronal apoptosis were examined 3 days after ischemic attack.Exosome RNA and target protein expression levels in neurons and brain tissue were determined for the mechanistic study.Results: Our results showed that the M2 microglia-derived exosomes were taken up by neurons in vitro and in vivo.M2 microglia-derived exosome treatment attenuated neuronal apoptosis after oxygen-glucose deprivation (p<0.05).In vivo results showed that M2 microglia-derived exosome treatment significantly reduced infarct volume and attenuated behavioral deficits 3 days after transient brain ischemia (p<0.05),whereas injection of miR-124 knockdown (miR-124k/d) M2 microglia-derived exosomes partly reversed the neuroprotective effect.Our mechanistic study further demonstrated that ubiquitin-specific protease 14 (USP14) was the direct downstream target of miR-124.Injection of miR-124k/d M2 exosomes plus the USP14 inhibitor, IU1, achieved comparable neuroprotective effect as injection of M2 exosomes alone.Conclusions: We demonstrated that M2 microglia-derived exosomes attenuated ischemic brain injury and promoted neuronal survival via exosomal miR-124 and its downstream target USP14.M2 microglia-derived exosomes represent a promising avenue for treating ischemic stroke.