Anomalous Origin of The Coronary Arteries-Review Article.

Anomalous origin of the coronary arteries is rare in clinical practice. Different anomalies have different clinical or symptomatic manifestations depending on the patient’s age. However, the majority of coronary artery origin anomalies are silent and are only discovered incidentally during Left Heart Catheterization (LHC). Acute Myocardial Infarction (MI) or even sudden death may occur in patients with an anomalous origin of the Left Main (LM) coronary artery from the right coronary cusp with a subsequent course between the aorta and the pulmonary artery. Therefore, recognition of anomalous origin of the coronary arteries is essential for clinical practice to further classify and properly manage patients with increased risk of Acute Coronary Syndrome (ACS). Furthermore, patients found to have an anomaly may be eligible for surgical correction

Anomalous Origin of The Coronary Arteries-Review Article.

Anomalous origin of the coronary arteries is rare in clinical practice. Different anomalies have different clinical or symptomatic manifestations depending on the patient’s age. However, the majority of coronary artery origin anomalies are silent and are only discovered incidentally during Left Heart Catheterization (LHC). Acute Myocardial Infarction (MI) or even sudden death may occur in patients with an anomalous origin of the Left Main (LM) coronary artery from the right coronary cusp with a subsequent course between the aorta and the pulmonary artery. Therefore, recognition of anomalous origin of the coronary arteries is essential for clinical practice to further classify and properly manage patients with increased risk of Acute Coronary Syndrome (ACS). Furthermore, patients found to have an anomaly may be eligible for surgical correction

Haploinsufficiency for BRCA1 is associated with normal levels of DNA nucleotide excision repair in breast tissue and blood lymphocytes

BACKGROUND: Screening mammography has had a positive impact on breast cancer mortality but cannot detect all breast tumors. In a small study, we confirmed that low power magnetic resonance imaging (MRI) could identify mammographically undetectable tumors by applying it to a high risk population. Tumors detected by this new technology could have unique etiologies and/or presentations, and may represent an increasing proportion of clinical practice as new screening methods are validated and applied A very important aspect of this etiology is genomic instability, which is associated with the loss of activity of the breast cancer-predisposing genes BRCA1 and BRCA2. In sporadic breast cancer, however, there is evidence for the involvement of a different pathway of DNA repair, nucleotide excision repair (NER), which remediates lesions that cause a distortion of the DNA helix, including DNA cross-links. CASE PRESENTATION: We describe a breast cancer patient with a mammographically undetectable stage I tumor identified in our MRI screening study. She was originally considered to be at high risk due to the familial occurrence of breast and other types of cancer, and after diagnosis was confirmed as a carrier of a Q1200X mutation in the BRCA1 gene. In vitro analysis of her normal breast tissue showed no differences in growth rate or differentiation potential from disease-free controls. Analysis of cultured blood lymphocyte and breast epithelial cell samples with the unscheduled DNA synthesis assay (UDS) revealed no deficiency in nucleotide excision repair (NER). CONCLUSION: As new breast cancer screening methods become available and cost effective, patients such as this one will constitute an increasing proportion of the incident population, so it is important to determine whether they differ from current patients in any clinically important ways. Despite her status as a BRCA1 mutation carrier, and her mammographically dense breast tissue, we did not find increased cell proliferation or deficient differentiation potential in her breast epithelial cells, which might have contributed to her cancer susceptibility. Although NER deficiency has been demonstrated repeatedly in blood samples from sporadic breast cancer patients, analysis of blood cultured lymphocytes and breast epithelial cells for this patient proves definitively that heterozygosity for inactivation of BRCA1 does not intrinsically confer this type of genetic instability. These data suggest that the mechanism of genomic instability driving the carcinogenic process may be fundamentally different in hereditary and sporadic breast cancer, resulting in different genotoxic susceptibilities, oncogene mutations, and a different molecular pathogenesis

Tuberculoid Leprosy with External Jugular Vein Thrombosis: A Case Report and Literature Review

Thrombotic disease represents a rare manifestation of leprosy. In this study, we report the case of an external jugular vein thrombosis associated with tuberculoid leprosy in a 23-year-old male patient. The patient presented with a 3-month history of painful cord-like swelling on the left side of the neck and a nearly 3-week history of skin lesions on the left cheek and right leg. Physical examination revealed cord-like, tender swelling on the left lateral aspect of the neck overlying the sternocleidomastoid muscle, and a hypopigmented, hypoaesthetic 6×7 cm lesion with an irregular margin on the left cheek. A Doppler ultrasound examination of the jugular vein showed thrombosis of the left external jugular vein. Three-dimensional reconstruction of the computed tomography scan showed the enlarged and enhanced left external jugular vein, as well as 1 of its tributaries, and the thickened skin patch. A skin punch biopsy from the left cheek lesion revealed granulomatous inflammation with occasional peri-adnexal granulomas, consistent with the clinical impression of tuberculoid leprosy. A diagnosis of leprosy with external jugular vein thrombosis was established. Anticoagulation therapy was initiated, and the patient was referred to an infectious disease clinic for treatment with anti-leprosy medications

Trans-radial coronary intervention (TCI) using 5-Fr versus 6-Fr guiding catheters in the setting of acute coronary syndrome (ACS)

Background: As in any vascular access the size of guiding catheter is an operator preference. Although multiple studies showed the use of 5-Fr versus 6-Fr guiding catheters for Transradial coronary intervention (TCI) have similar vascular safety profile and can be performed safely and successfully with both of them, the data comparing the 5-Fr vs 6-Fr guiding catheters for TCI in terms of fluoroscopy time, procedure time and contrast amount in the setting of ACS is limited. We conducted this study to compare the use of 5-Fr versus 6-Fr guiding catheters for TCI in the settings of ACS. Method: Our study is a single center, retrospective cohort study designed to compare the use of 5-Fr versus 6-Fr guiding catheters for TCI in the setting of ACS. In the period between July 2014 and July 2015, all patients who had previously undergone PCI with at least one stent being placed, utilizing a radial access, and using a 5Fr or 6Fr guiding catheter were included. No exclusion criteria were applied. The study was approved by Marshall University’s institutional review board. Results: There was a significant reduction in the volume of contrast medium used with the 5 Fr group compared to the 6 Fr group (130.66 +/- 3.46 ml vs. 166.25 +/- 10.05 ml in the 5 and 6 Fr groups, respectively; p < 0.001), fluoroscopy time (12.62 +/- 0.50 min vs. 16.61 +/- 1.28 min in the 5 and 6 Fr groups, respectively; p = 0.005) and there was also significant reduction in the procedure time in the 5 Fr group (38.74 +/- 1.27 min vs. 46.03 +/- 2.86 min in the 5 and 6 Fr groups, respectively; p = 0.023). Conclusion: TCI in the settings of ACS is safe and feasible, whether using 5 Fr or 6 Fr catheters. Our study concluded that using 5 Fr catheters for TCI could be preferred for patients presenting with ACS due to lower amount of contrast medium used and less fluoroscopy and procedure time. However, this is a single center retrospective study, so we suggest that large randomized controlled studies are needed

Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients

Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes of NSCLC patients with better overall survival. However, 15-40% of the patients still fail to respond to ICIs therapy. Identification of biomarkers associated with responses are mandated in order to increase the efficacy of such therapy. In this study we evaluated 27 serum-derived exosomal immuno-oncological proteins and 44 cytokines/chemokines before and after ICIs therapy in 17 NSCLC patients to identify surrogate biomarkers for treatment/monitoring patient stratification for maximum therapeutic benefit. We first confirmed the identity of the isolated exosomes to have their specific markers (CD63, CD81, HSP70 and CD91). We have demonstrated that baseline concentration of exosomal-PD-L1 (p<0.0001), exosomal-PD-L2 (p=0.0413) and exosomal-PD-1 (p=0.0131) from NSCLC patients were significantly higher than their soluble-free forms. Furthermore, the exosomal-PD-L1 was present in all the patients (100%), while only 71% of patients expressed tissue PD-L1. This indicates that exosomal-PD-L1 is a more reliable diagnostic biomarker. Interestingly, exosomal-PD-L2 expression was significantly higher (p=0.0193) in tissue PD-L1-negative patients compared to tissue PD-L1-positive patients. We have also shown that immuno-oncological proteins isolated from pre-ICIs treated patients were significantly higher in exosomes compared to their soluble-free counterparts (CD152, p=0.0008; CD80, p=0.0182; IDO, p=0.0443; Arginase, p<0.0001; Nectin-2, p<0.0001; NT5E, p<0.0001; Siglec-7, p<0.0001; Siglec-9, p=0.0335; CD28, p=0.0092; GITR, p<0.0001; MICA, p<0.0001). Finally, the changes in the expression levels of exosomal immuno-oncological proteins/cytokines and their correlation with tumor response to ICIs treatment were assessed. There was a significant downregulation of exosomal PD-L1 (p=0.0156), E-Cadherin (p=0.0312), ULBP1 (p=0.0156), ULBP3 (p=0.0391), MICA (p=0.0391), MICB (p=0.0469), Siglec7 (p=0.0078) and significant upregulation of exosomal PD-1 (p=0.0156) and IFN- γ (p=0.0156) in responding patients. Non-responding patients showed a significant increase in exosomal-PD-L1 (p=0.0078). Furthermore, responding-patients without liver-metastasis showed significant-upregulation of PD-1 (p=0.0070), and downregulation of ULBP1 (p=0.0137) and Siglec-7 (p=0.0037). Non-responding patients had significant-downregulation of ULBP3 (p=0.0317) in patient without brain-metastasis and significant-upregulation/downregulation of PD-L1 and ULBP3 (p=0.0262/0.0286) in patients with pulmonary-metastasis. We demonstrated for the first time that exosomal immuno-oncological proteins/cytokines are potential biomarkers to monitor response to ICIs therapy and can predict the clinical outcomes in NSCLC patients.This research was funded by Academic Health System, Medical Research Center, Hamad Medical Corporation, Doha, Qatar, grant number MRC-01-20-507 and the Article Processing Charges was funded by Academic Health System, Medical Research Center, Hamad Medical Corporation, Doha, Qatar

Serum immune mediators as novel predictors of response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients with high tissue-PD-L1 expression

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes with better overall survival, but only 15-40% of the patients respond to ICIs therapy. The search for predictive biomarkers of responses is warranted for better clinical outcomes. We aim here to identify pre-treatment soluble immune molecules as surrogate biomarkers for tissue PD-L1 (TPD-L1) status and as predictors of response to anti-PD-1/PD-L1 therapy in NSCLC patients. Sera from 31 metastatic NSCLC patients, eligible for anti-PD-1/PD-L1 or combined chemoimmunotherapy, were collected prior to treatment. Analysis of soluble biomarkers with TPD-L1 status showed significant up/down regulation of the immune inhibitory checkpoint markers (sSiglec7, sSiglec9, sULBP4 and sPD-L2) in patients with higher TPD-L1 (TPD-L1 >50%) expression. Moreover, correlation analysis showed significant positive linear correlation of soluble PD-L1 (sPD-L1) with higher TPD-L1 expression. Interestingly, only responders in the TPD-L1 >50% group showed significant down regulation of the immune inhibitory markers (sPD-L2, sTIMD4, sNectin2 and CEA). When responders vs. non-responders were compared, significant down regulation of other immune inhibitory biomarkers (sCD80, sTIMD4 and CEA) was recorded only in responding patients. In this, the optimal cut-off values of CD80 <91.7 pg/ml and CEA <1614 pg/ml were found to be significantly associated with better progression free survival (PFS). Indeed, multivariate analysis identified the cutoff-value of CEA <1614 pg/ml as an independent predictor of response in our patients. We identified here novel immune inhibitory/stimulatory soluble mediators as potential surrogate/predictive biomarkers for TPD-L1 status, treatment response and PFS in NSCLC patients treated with anti-PD-1/PD-L1 therapy.This research was funded by Academic Health System, Medical Research Center, Hamad Medical Corporation, Doha, Qatar, grant number MRC-01-20-507 and the Article Processing Charges was funded by Academic Health System, Medical Research Center, Hamad Medical Corporation, Doha, Qatar. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. AcknowledgmentsScopu

Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients

Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes of NSCLC patients with better overall survival. However, 15-40% of the patients still fail to respond to ICIs therapy. Identification of biomarkers associated with responses are mandated in order to increase the efficacy of such therapy. In this study we evaluated 27 serum-derived exosomal immuno-oncological proteins and 44 cytokines/chemokines before and after ICIs therapy in 17 NSCLC patients to identify surrogate biomarkers for treatment/monitoring patient stratification for maximum therapeutic benefit. We first confirmed the identity of the isolated exosomes to have their specific markers (CD63, CD81, HSP70 and CD91). We have demonstrated that baseline concentration of exosomal-PD-L1 (p&lt;0.0001), exosomal-PD-L2 (p=0.0413) and exosomal-PD-1 (p=0.0131) from NSCLC patients were significantly higher than their soluble-free forms. Furthermore, the exosomal-PD-L1 was present in all the patients (100%), while only 71% of patients expressed tissue PD-L1. This indicates that exosomal-PD-L1 is a more reliable diagnostic biomarker. Interestingly, exosomal-PD-L2 expression was significantly higher (p=0.0193) in tissue PD-L1-negative patients compared to tissue PD-L1-positive patients. We have also shown that immuno-oncological proteins isolated from pre-ICIs treated patients were significantly higher in exosomes compared to their soluble-free counterparts (CD152, p=0.0008; CD80, p=0.0182; IDO, p=0.0443; Arginase, p&lt;0.0001; Nectin-2, p&lt;0.0001; NT5E, p&lt;0.0001; Siglec-7, p&lt;0.0001; Siglec-9, p=0.0335; CD28, p=0.0092; GITR, p&lt;0.0001; MICA, p&lt;0.0001). Finally, the changes in the expression levels of exosomal immuno-oncological proteins/cytokines and their correlation with tumor response to ICIs treatment were assessed. There was a significant downregulation of exosomal PD-L1 (p=0.0156), E-Cadherin (p=0.0312), ULBP1 (p=0.0156), ULBP3 (p=0.0391), MICA (p=0.0391), MICB (p=0.0469), Siglec7 (p=0.0078) and significant upregulation of exosomal PD-1 (p=0.0156) and IFN- γ (p=0.0156) in responding patients. Non-responding patients showed a significant increase in exosomal-PD-L1 (p=0.0078). Furthermore, responding-patients without liver-metastasis showed significant-upregulation of PD-1 (p=0.0070), and downregulation of ULBP1 (p=0.0137) and Siglec-7 (p=0.0037). Non-responding patients had significant-downregulation of ULBP3 (p=0.0317) in patient without brain-metastasis and significant-upregulation/downregulation of PD-L1 and ULBP3 (p=0.0262/0.0286) in patients with pulmonary-metastasis. We demonstrated for the first time that exosomal immuno-oncological proteins/cytokines are potential biomarkers to monitor response to ICIs therapy and can predict the clinical outcomes in NSCLC patients