tbuckley/cabot-search huggingface dataset:
INTRAMYOCARDIAL FAST-SENC CMR STRAIN IS LESS IMPACTED BY COMPENSATORY MECHANISMS THAN ECHOCARDIOGRAPHY IN MONITORING CARDIOTOXICITY: THE PREFECT STUDY
Authors: Henning Steen, Moritz Montenbruck, Blaz Gerzak, Arne Kristian Schwarz, Sebastian Kelle, Sorin Giusca, Grigorios Korosoglou, Susan Dent, Daniel Lenihan
Journal: Journal of the American College of Cardiology (2020)
Brain metastasis in a series of NSCLC: Egyptian experience.
Authors: Salah Eldeen Elmesidy, Mahmoud Abdelsalam, Husam Zawam
Journal: Journal of Clinical Oncology (2012)

e18001 Background: Incidence of cerebral metastasis is increasing among lung cancer patients. Many factors have been reported associated with increase risk of brain metastasis. The aim of this retrospective analysis is to investigate the predictive factors for the development of brain metastasis in lung cancer patients. Methods: We retrospectively analyzed histologically proven lung cancer patients radiologically diagnosed of having brain metastases who presented to Kasr Al-Eini Center for Oncology (NEMROCK) in the period from 2004 till 2010, with follow up period of 6 months at least. The following factors were analyzed: age, gender, PS, smoking history, tumor size &amp; grade preceding development of brain metastasis. Results: Our study included 403 patients. 67 patients (16.6%) experienced brain metastasis during the course of their disease. 40 (10%) patients had brain metastasis among other sites of distant spread at first presentation which represent 88.9% of patients presented with metastatic disease. In a median follow-up of 17.1 months (6-77) the time to develop brain metastasis (TTBM) for the whole group was 5 months (range 2-22 months) (95% CI : 4.3-7.7). The most important factor affecting the TTBM was the use of chemotherapy before developing brain metastasis with a median TTBM of 5.9 months (95%CI : 3.2-6.8) among those who received chemotherapy compared to 2 months among the patients who didn't receive chemotherapy (P= &lt;0.0001). The second factor was PS at time of initial diagnosis (P= 0.027). The median OS after brain metastasis was 6 months (95% CI : 4.26-7.74). On univariate analysis, PS and use of chemotherapy after developing brain metastases showed statistically significant difference affecting OS. Conclusions: We concluded that PS as well as use of chemotherapy are the 2 main factors associated with shorter time to develop brain metastasis. PS and use of chemotherapy after developing brain metastases showed longer OS after developing brain metastases. Keywords: NSCLC, Brain metastasis, Egypt
ASSOCIATION BETWEEN WORLD HEALTH ORGANIZATION FUNCTIONAL CLASS AND PULMONARY ARTERY PRESSURE AFTER BALLOON PULMONARY ANGIOPLASTY IN PATIENTS WITH CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION
Authors: Nobutaka Ikeda, Shuji Kubota, Toru Okazaki, Raisuke Iijima, Hidehiko Hara, Yukio Hiroi, Masato Nakamura
Journal: Journal of the American College of Cardiology (2020)
Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer
Authors: Kyungsoo Kim, Seyeon Park, Seong Yong Park, Gamin Kim, Su Myeong Park, Jae-Won Cho, Da Hee Kim, Young Min Park, Yoon Woo Koh, Hye Ryun Kim, Sang-Jun Ha, Insuk Lee
Journal: Genome Medicine (2020)

Abstract Background T cells exhibit heterogeneous functional states in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) can reinvigorate only the stem cell-like progenitor exhausted T cells, which suggests that inhibiting the exhaustion progress will improve the efficacy of immunotherapy. Thus, regulatory factors promoting T cell exhaustion could serve as potential targets for delaying the process and improving ICI efficacy. Methods We analyzed the single-cell transcriptome data derived from human melanoma and non-small cell lung cancer (NSCLC) samples and classified the tumor-infiltrating (TI) CD8 + T cell population based on PDCD1 (PD-1) levels, i.e., PDCD1 -high and PDCD1 -low cells. Additionally, we identified differentially expressed genes as candidate factors regulating intra-tumoral T cell exhaustion. The co-expression of candidate genes with immune checkpoint (IC) molecules in the TI CD8 + T cells was confirmed by single-cell trajectory and flow cytometry analyses. The loss-of-function effect of the candidate regulator was examined by a cell-based knockdown assay. The clinical effect of the candidate regulator was evaluated based on the overall survival and anti-PD-1 responses. Results We retrieved many known factors for regulating T cell exhaustion among the differentially expressed genes between PDCD1 -high and PDCD1 -low subsets of the TI CD8 + T cells in human melanoma and NSCLC. TOX was the only transcription factor (TF) predicted in both tumor types. TOX levels tend to increase as CD8 + T cells become more exhausted. Flow cytometry analysis revealed a correlation between TOX expression and severity of intra-tumoral T cell exhaustion. TOX knockdown in the human TI CD8 + T cells resulted in downregulation of PD-1, TIM-3, TIGIT, and CTLA-4, which suggests that TOX promotes intra-tumoral T cell exhaustion by upregulating IC proteins in cancer. Finally, the TOX level in the TI T cells was found to be highly predictive of overall survival and anti-PD-1 efficacy in melanoma and NSCLC. Conclusions We predicted the regulatory factors involved in T cell exhaustion using single-cell transcriptome profiles of human TI lymphocytes. TOX promoted intra-tumoral CD8 + T cell exhaustion via upregulation of IC molecules. This suggested that TOX inhibition can potentially impede T cell exhaustion and improve ICI efficacy. Additionally, TOX expression in the TI T cells can be used for patient stratification during anti-tumor treatments, including anti-PD-1 immunotherapy.
Utility of 2D-speckle tracking echocardiography in early identification of left ventricular dysfunction in antineoplastic therapy-induced cardiotoxicity.
Authors: Carmela Coppola, Carlo G. Tocchetti, Giovanna Piscopo, Clemente Cipresso, Carlo Maurea, Maria Cristina Lombari, Domenica Rea, Piera Maiolino, Maria Gaia Monti, Luigi Tarantini, Giulia Russo, Giovanni Cioffi, Francesco Giotta, Stefano Oliva, Immacolata Capasso, Rosario Vincenz Iaffaioli, Claudio Arra, Nicola Maurea
Journal: Journal of Clinical Oncology (2013)

631 Background: ErbB2 is overexpressed in about 25% of breast cancers; in the heart, it modulates myocardial development and function. Trastuzumab (T), an anti-ErbB2 inhibitor, has improved the prognosis of patients with breast cancer, but is related to an increased risk of asymptomatic left ventricular (LV) dysfunction (3-34%) and heart failure (2-4%). Conventional measures of ventricular function, such as fractional shortening (FS) and ejection fraction (FE) are insensitive in detecting early cardiomyopathy induced by antineoplastic therapy. Aim of this study is to evaluate whether myocardial strain by 2D-speckle tracking (ST) is able to identify early LV dysfunction in mice treated with doxorubicin (D) and T, alone or in combination (D+T) and to relate data of cardiac function with tissue alterations. Methods: Cardiac function was measured with FS, by M-mode echocardiography, and with radial myocardial strain with ST in sedated C57BL/6 mice (8-10 wk old) at time 0, 2 and 6 days of daily administration of D, T, D+T and in a control group. In excised hearts, we evaluated TNFα and CD68 by immunohistochemistry; interstizial fibrosis was analyzed with picrosirius red staining. Results: FS was reduced in group D and D+T at 2 days (52+0.2% and 49+2% respectively), both p&lt;0.001 vs 60+0.4% (sham), while in group T it decreased only at 6 days (49+1.5% vs 60+0.5%, p=.002). In contrast, after 2 days, myocardial strain was already reduced not only in D and D+T, but also in T alone: 43+3%, 49+1%, and 44+7%, respectively, all p&lt;0.05 vs sham (66+0.6%). Cardiotoxicity was associated with significant alterations in extracellular matrix remodeling as confirmed by an increase of interstizial collagen with D (4.56%), T (2.17%) and D+T (3.77%)at 6 days p&lt;0.05 vs sham (1.17%) and by increased cardiac inflammation in fact the myocytes were positive for TNFα and CD68 cells/mm 2 at 6 days in group D (16.46% and 155 respectively), in group T+D (12.35% and 74.16) and in group T (5.65% and 72.32) p&lt;0.01 vs sham (0.56% and 2.3). Conclusions: Myocardial strain identifies LV systolic dysfunction earlier than conventional echocardiography and can be a useful tool to predict cardiotoxicity in this setting.
Open label phase II studies of modified vaccinia ankara expressing the tumor antigen 5T4 given in conjunction with IFL and FOLFOX chemotherapy regimens: Final analysis of safety and immunogenicity of MVA 5T4 given before, during and after chemotherapy
Authors: R. Harrop, R. Hawkins, A. Anthoney, N. Steven, N. Habib, R. Griffiths, A. Melcher, H. Wassan, S. Naylor
Journal: Journal of Clinical Oncology (2006)

2527 Background: 5T4 is a tumour associated antigen that is widely expressed on the surface of most human adenocarcinomas, including colorectal, but rarely in normal cells. Modified Vaccinia Ankara (MVA) has been employed as a vaccine vector to deliver 5T4. Previously, MVA-5T4 has been evaluated in a phase I/II clinical trial in stage IV colorectal cancer patients. MVA-5T4 was shown to be safe and well tolerated and induced 5T4 specific immune responses in most patients. Furthermore, 5T4 specific antibody titres correlated with clinical benefit. Methods: Two open label phase II clinical trials were initiated in which patients with advanced colorectal cancer received MVA-5T4 in conjunction with either 5-FU/leukovorin and irinotecan (TV2-IFL; n=19 patients) or 5-FU/leukovorin and oxaliplatin (TV2-FOLFOX; n=17 patients). MVA-5T4 was administered up to 6 times, 2 prior to, 2 during and 2 post-chemotherapy. The primary objectives were to assess the safety and immunogenicity of MVA-5T4 given in combination with chemotherapy. Results: Recruitment to both trials is complete and MVA-5T4 was well tolerated in all ITT patients, with no serious adverse events being associated with MVA-5T4. 5T4-specific cellular and humoral immune responses were monitored before, during and after chemotherapy in all 23 per protocol patients (n=12 for TV2-IFL and n=11 for TV2-FOLFOX). Following vaccination, all 23 patients mounted 5T4 cellular and/or humoral responses. Immune responses were detectable during chemotherapy in the majority of patients. IFNγ ELISPOT responses to 5T4 peptides revealed precursor frequencies as high as 1 in 1000 PBMCs. Assessment of clinical responses in all PP patients demonstrated an overall response rate of 65% across both trials. Conclusions: MVA-5T4 is safe and well tolerated when administered in conjunction with IFL and FOLFOX chemotherapy regimens. Furthermore, 5T4 specific immune responses are induced in all per protocol patients and can be boosted or maintained during chemotherapy. Encouraging clinical responses have been observed and 5T4 immune responses shown to correlate with clinical benefit. [Table: see text]
PATHOLOGY OF NEOATHEROSCLEROSIS IN THREE CURRENT STANDARD DRUG-ELUTING STENTS IN HUMANS
Authors: Rahul R. Bhoite, Hiroyuki Jinnouchi, Atsushi Sakamoto, Yu Sato, Maria Romero, Frank D. Kolodgie, Renu Virmani, Aloke V. Finn
Journal: Journal of the American College of Cardiology (2020)
Trends in Emergency Department Visits and Inpatient Admissions for Hyperglycemic Crises in Adults With Diabetes in the U.S., 2006–2015
Authors: Stephen R. Benoit, Israel Hora, Francisco J. Pasquel, Edward W. Gregg, Ann L. Albright, Giuseppina Imperatore
Journal: Diabetes Care (2020)

OBJECTIVE To report U.S. national population-based rates and trends in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) among adults, in both the emergency department (ED) and inpatient settings. RESEARCH DESIGN AND METHODS We analyzed data from 1 January 2006 through 30 September 2015 from the Nationwide Emergency Department Sample and National Inpatient Sample to characterize ED visits and inpatient admissions with DKA and HHS. We used corresponding year cross-sectional survey data from the National Health Interview Survey to estimate the number of adults ≥18 years with diagnosed diabetes to calculate population-based rates for DKA and HHS in both ED and inpatient settings. Linear trends from 2009 to 2015 were assessed using Joinpoint software. RESULTS In 2014, there were a total of 184,255 and 27,532 events for DKA and HHS, respectively. The majority of DKA events occurred in young adults aged 18–44 years (61.7%) and in adults with type 1 diabetes (70.6%), while HHS events were more prominent in middle-aged adults 45–64 years (47.5%) and in adults with type 2 diabetes (88.1%). Approximately 40% of the hyperglycemic events were in lower-income populations. Overall, event rates for DKA significantly increased from 2009 to 2015 in both ED (annual percentage change [APC] 13.5%) and inpatient settings (APC 8.3%). A similar trend was seen for HHS (APC 16.5% in ED and 6.3% in inpatient). The increase was in all age-groups and in both men and women. CONCLUSIONS Causes of increased rates of hyperglycemic events are unknown. More detailed data are needed to investigate the etiology and determine prevention strategies.
The burning building
Authors: Fiona Godlee
Journal: BMJ (2020)

With the covid-19 pandemic, we have entered extraordinary times, when some things are known but many more are not and where decisions must be made nonetheless.

The UK government’s recent actions (doi:10.1136/bmj.m1089) bring the country more in line with its European neighbours. Public health has now been prioritised over the economy. The change of heart seems to have been in response both to international criticism of its earlier laissez faire approach and to a new modelling study suggesting that the NHS would not cope unless more was done to curb the spread of the virus. Publication of this study means that we at last have some of the evidence on …
BPI20-011: Prescriber-Assigned Febrile Neutropenia and Emetic Risks Compared to the NCCN Risk Classification for Cancer Treatment Regimens
Authors: Kimberly Rose Hedstrom, Margaret Rausa, Eric Gratias, Stephen Hamilton
Journal: Journal of the National Comprehensive Cancer Network (2020)

"BPI20-011: Prescriber-Assigned Febrile Neutropenia and Emetic Risks Compared to the NCCN Risk Classification for Cancer Treatment Regimens" published on 20 Mar 2020 by National Comprehensive Cancer Network.
CLINICAL IMPACT OF HEMODIALYSIS ON SHORT-TERM PROGNOSIS IN ACUTE HEART FAILURE: MULTI-CENTER REGISTRY FROM TOKYO CARDIOVASCULAR CARE UNIT NETWORK
Authors: Akito Shindo, Masao Yamasaki, Takahiro Jimba, Hiroki Nakano, Shigeto Tsukamoto, Satoshi Kodera, Junya Matsuda, Makoto Takei, Yasuyuki Shiraishi, Kenichi Matsushita, Kiyoshi Iida, Takamichi Miyamoto, Yoshiya Yamamoto, Yoichi Iwasaki, Tetsuro Miyazaki, Shun Kohsaka, Shinji Koba, Kazunori Takemura, Kazumasa Harada, Ken Nagao, Takeshi Yamamoto, Morimasa Takayama
Journal: Journal of the American College of Cardiology (2020)
Bevacizumab, erlotinib, and imatinib in the treatment of patients with advanced renal cell carcinoma: Update of a multicenter phase II trial
Authors: D. S. Thompson, F. A. Greco, D. R. Spigel, J. A. Sosman, E. Burkett, T. J. O’Rourke, L. Hart, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2006)

4594 Background: Most patients with clear cell RCC have loss of von-Hippel-Lindau (VHL) gene function, ultimately leading to overexpression of VEGF, transforming growth factor (TGF-α), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). In this phase II trial, we evaluate the combination blockade of VEGF, and the EGF and PDGF receptors as treatment for metastatic RCC. Methods: Eligibility: metastatic clear cell RCC; 0–2 previous systemic regimens; ECOG PS 0–1; no previous anti-angiogenesis or EGF receptor inhibitor therapy; no active CNS metastases; adequate organ function; no history of thromboembolic disease; informed consent. All patients received bevacizumab 10 mg/kg IV q 2 wks, erlotinib 150 mg PO daily, and imatinib 400 mg PO daily. Patients were evaluated for response after 8 weeks; treatment continued until tumor progression. Results: 92 patients entered this trial between 6/04 and 4/05. Pertinent clinical characteristics: no previous systemic treatment, 71%; Motzer prognostic category low/intermediate/high 47%/50%/3%. 84 patients (91%) received at least 8 weeks of therapy. Objective responses were seen in 11 patients (12%); an additional 52 patients (57%) had stable disease/minor response at first reevaluation. After a median follow-up of 11 months, projected median and 1-year progression-free survivals are 9 months and 40%, respectively. One-year overall survival is 62%. The addition of imatinib to bevacizumab/erlotinib added substantial toxicity. Grade 3/4 toxicity included: diarrhea, 48%; skin rash, 27%; fatigue, 23%; nausea/vomiting, 20%. 2 patients discontinued treatment as a result of toxicity; all patients who received treatment for &gt; 8 weeks required dose reductions of imatinib and/or erlotinib. Conclusions: The addition of imatinib, a PDGF receptor inhibitor, to bevacizumab/erlotinib does not appear to substantially improve the efficacy of the 2-drug combination. This 3-drug combination produced moderate to severe toxicity in the majority of patients, primarily exacerbations of diarrhea, fatigue, and skin rash. Further development of this 3-drug regimen is not recommended. [Table: see text]
Phage display-identified PD-L1-binding peptides reinvigorate T-cell activity and inhibit tumor progression
Authors: Smriti Gurung, Fatima Khan, Gowri Rangaswamy Gunassekaran, Jae Do Yoo, Sri Murugan Poongkavithai Vadevoo, Uttapol Permpoon, Sang-Hyun Kim, Ha-Jeong Kim, In-San Kim, Hyeonjeong Han, Ji-Ho Park, Soyoun Kim, Byungheon Lee
Journal: Biomaterials (2020)
Characterization of a novel founder rearrangement mutation of <i>BRCA1</i> in high-risk Hispanic families
Authors: J. Ho, J. Herzog, V. Lagos, K. Lowstuter, M. Palomares, K. Blazer, D. MacDonald, N. Feldman, J. Weitzel
Journal: Journal of Clinical Oncology (2006)

10015 Background: Large rearrangements are estimated to account for 5–10% of all mutations in BRCA1 and BRCA2. Prevalent founder rearrangement mutations have been described in European populations. We sought to identify rearrangements in the BRCA genes in a cohort of Hispanic patients. Methods: We identified 34 deleterious BRCA mutations via full sequence analysis among 110 unrelated high-risk Hispanic families enrolled in an IRB approved registry who underwent cancer risk assessment (CEBP 2005;14:1–6). DNA from 67 of 76 patients without an identifiable mutation was subjected to multiplexed quantitative differential PCR (MQDP, per B. Erickson and T. Scholl, Myriad Genetics Laboratory) for detection of large rearrangements. An apparent deletion of BRCA1 exons 9–12, indicated by a 50% loss of signal was identified by MQDP in 3 unrelated families (ASHG, 2005). Long range PCR resulted in the generation of a 2.7kb product in these samples, consistent with a deletion event of 15.1kb. This putative mutation was further characterized by cloning and sequencing the breakpoint in all 3 families. RNA splicing was evaluated by sequencing RT-PCR products from lymphoblastoid cell line RNA for each family. Results: Sequence analysis identified the breakpoint within Alu elements in introns 8 and 12, and all 3 unrelated families shared the same breakpoint. Analysis of cDNA demonstrated direct splicing of exons 8–13 predicting a frameshift mutation and premature truncation of the BRCA1 protein, thus confirming the deleterious nature of this mutation. Conclusion: We identified the same novel large deletion in three unrelated families of Mexican ancestry, suggesting potential founder effect. The frequency was 2.7% of the 110 high-risk Hispanic families screened for BRCA mutations, bringing the overall prevalence of deleterious mutations to 33.6%(37/110) in this cohort. This BRCA1 rearrangement may account for a substantial proportion of high-risk Hispanic families, and should be included in all subsequent studies of this ethnic group. No significant financial relationships to disclose.
Tim-3 expression and function in natural killer cells from advanced melanoma patients.
Authors: Ines Esteves Domingues Pires Da Silva, Sonia Jimenez-Baranda, Anne Gallois, Vijay Kuchroo, Iman Osman, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2012)

8571 Background: The concept of CD8 + T cell exhaustion in the context of metastatic cancer has been reinforced by the recent success of immunotherapies targeting the exhaustion markers CTLA-4 and PD-1 in advanced melanoma. T-cell immunoglobulin 3 (Tim-3), another exhaustion marker, is also expressed in natural killer (NK) cells, however its role is still unknown. Recent reports have shown that NK cells, innate immune cells that eliminate tumors through cytotoxicity and IFN-g production, are functionally impaired in advanced melanoma patients, although no receptor has been linked with that phenotype so far. In this study, we characterize the role of Tim-3 in NK cells, particularly in the presence of its natural ligand, Galectin-9 (Gal-9), that is known to be expressed/secreted by some tumor cells including melanoma. Methods: We compared 20 advanced melanoma donors NK cells with 40 healthy donors NK cells as it relates to Tim-3 expression (by flow cytometry) and function (cytotoxicity, IFN-γ production and proliferation). NK cells cytotoxicity was measured by lamp-1 expression, and two different target cells were used: i) K562 cells (Gal-9 - ) and ii) Gmel Gal-9 + and Gmel Gal-9 - sorted melanoma cells. Proliferation was quantified by CFSE after 6 days in the presence of rhIL-2. Recombinant rhGal9 effect was tested in cytotoxicity and IFN-γ production. Results: Melanoma patients NK cells express higher levels of Tim-3 compared to healthy donors NK cells (p&lt;0.05). Melanoma patients NK cells have a defect in cytotoxicity, proliferation and IFN-γ production. Tim-3 expression by itself (without engagement of specific ligands) does not negatively affect NK cell functions (p&lt;0.05). However, when rhGal9 is added to the system, a decrease in NK cell cytotoxicity and IFN-γ production (p&lt;0.05) was observed. Finally, the expression of Gal-9 by the target cells induces a defect in NK cell cytotoxicity (Gmel Gal-9 + vs Gmel Gal-9 - ). Conclusions: These data suggest that advanced melanoma patients NK cells are exhausted, although it still remains unclear if Tim-3 is involved in this phenotype. In addition,the expression/secretion of Galectin-9, immunosuppressive for NK cells, may be a possible mechanism for tumors to evade immune surveillance.
Ready, steady . . . go?
Authors: Rebecca Coombes
Journal: BMJ (2020)

As the gravity of the covid-19 outbreak unfolds, it’s clear that this crisis requires a balanced approach that tells people what they and the health system can do without causing panic.

This week The BMJ publishes a guide for GPs on managing patients with covid-19, pulling together guidance from Public Health England and Health Protection Scotland (doi:10.1136/bmj.m800). It covers identifying potential new cases, how to correctly isolate patients to prevent onward transmission, and referring severely unwell patients safely to …