Cranial and intra-axial metastasis originating from a primary ovarian Dysgerminoma.

Dysgerminomas are aggressive germ cell tumors that typically have a favorable prognosis, especially in patients diagnosed with early stage disease. We recount the history of a 23-year-old woman who was treated for a stage IA ovarian dysgerminoma in November 2017. Postoperatively, the patient was noncompliant insofar as obtaining routine lab evaluations; ten months later, she was diagnosed with a cranial metastasis that extended into the meninges. The patient subsequently underwent a posterior fossa craniotomy and adjuvant etoposide, bleomycin and cisplatin chemotherapy to which she initially responded; however, during cycle 4, she developed pancytopenia whereupon the chemotherapy was summarily discontinued. Thereafter, the patient was surveilled and currently, she remains in clinical remission. Early stage ovarian dysgerminoma, albeit rarely, has the capacity to metastasize to the cranium or brain, further underscoring the significance of employing active follow-up with these patients

LV reverse remodeling imparted by aortic valve replacement for severe aortic stenosis; is it durable? A cardiovascular MRI study sponsored by the American Heart Association

<p>Abstract</p> <p>Background</p> <p>In patients with severe aortic stenosis (AS), long-term data tracking surgically induced effects of afterload reduction on reverse LV remodeling are not available. Echocardiographic data is available short term, but in limited fashion beyond one year. Cardiovascular MRI (CMR) offers the ability to serially track changes in LV metrics with small numbers due to its inherent high spatial resolution and low variability.</p> <p>Hypothesis</p> <p>We hypothesize that changes in LV structure and function following aortic valve replacement (AVR) are detectable by CMR and once triggered by AVR, continue for an extended period.</p> <p>Methods</p> <p>Tweny-four patients of which ten (67 ± 12 years, 6 female) with severe, but compensated AS underwent CMR pre-AVR, 6 months, 1 year and up to 4 years post-AVR. 3D LV mass index, volumetrics, LV geometry, and EF were measured.</p> <p>Results</p> <p>All patients survived AVR and underwent CMR 4 serial CMR's. LVMI markedly decreased by 6 months (157 ± 42 to 134 ± 32 g/m^<b>2</b>, p < 0.005) and continued trending downwards through 4 years (127 ± 32 g/m^<b>2</b>). Similarly, EF increased pre to post-AVR (55 ± 22 to 65 ± 11%,(p < 0.05)) and continued trending upwards, remaining stable through years 1-4 (66 ± 11 vs. 65 ± 9%). LVEDVI, initially high pre-AVR, decreased post-AVR (83 ± 30 to 68 ± 11 ml/m2, p < 0.05) trending even lower by year 4 (66 ± 10 ml/m^<b>2</b>). LV stroke volume increased rapidly from pre to post-AVR (40 ± 11 to 44 ± 7 ml, p < 0.05) continuing to increase non-significantly through 4 years (49 ± 14 ml) with these LV metrics paralleling improvements in NYHA. However, LVmass/volume, a 3D measure of LV geometry, remained unchanged over 4 years.</p> <p>Conclusion</p> <p>After initial beneficial effects imparted by AVR in severe AS patients, there are, as expected, marked improvements in LV reverse remodeling. Via CMR, surgically induced benefits to LV structure and function are durable and, unexpectedly express continued, albeit markedly incomplete improvement through 4 years post-AVR concordant with sustained improved clinical status. This supports down-regulation of both mRNA and MMP activity acutely with robust suppression long term.</p

Genetic analysis of scattered populations of the Indian eri silkworm, Samia cynthia ricini Donovan: Differentiation of subpopulations

Deforestation and exploitation has led to the fragmentation of habitats and scattering of populations of the economically important eri silkworm, Samia cynthia ricini, in north-east India. Genetic analysis of 15 eri populations, using ISSR markers, showed 98% inter-population, and 23% to 58% intra-population polymorphism. Nei’s genetic distance between populations increased significantly with altitude (R2 = 0.71) and geographic distance (R2 = 0.78). On the dendrogram, the lower and upper Assam populations were clustered separately, with intermediate grouping of those from Barpathar and Chuchuyimlang, consistent with geographical distribution. The Nei’s gene diversity index was 0.350 in total populations and 0.121 in subpopulations. The genetic differentiation estimate (Gst) was 0.276 among scattered populations. Neutrality tests showed deviation of 118 loci from Hardy-Weinberg equilibrium. The number of loci that deviated from neutrality increased with altitude (R2 = 0.63). Test of linkage disequilibrium showed greater contribution of variance among eri subpopulations to total variance. D’2IS exceeded D’2ST, showed significant contribution of random genetic drift to the increase in variance of disequilibrium in subpopulations. In the Lakhimpur population, the peripheral part was separated from the core by a genetic distance of 0.260. Patchy habitats promoted low genetic variability, high linkage disequilibrium and colonization by new subpopulations. Increased gene flow and habitat-area expansion are required to maintain higher genetic variability and conservation of the original S. c. ricini gene pool

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Background For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. Trial registration ClinicalTrials.gov NCT03505723. Registered on 23 April 2018

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Target site specificity and in vivo complexity of the mammalian arginylome

Protein arginylation mediated by arginyltransferase ATE1 is a key regulatory process essential for mammalian embryogenesis, cell migration, and protein regulation. Despite decades of studies, very little is known about the specificity of ATE1-mediated target site recognition. Here, we used in vitro assays and computational analysis to dissect target site specificity of mouse arginyltransferases and gain insights into the complexity of the mammalian arginylome. We found that the four ATE1 isoforms have different, only partially overlapping target site specificity that includes more variability in the target residues than previously believed. Based on all the available data, we generated an algorithm for identifying potential arginylation consensus motif and used this algorithm for global prediction of proteins arginylated in vivo on the N-terminal D and E. Our analysis reveals multiple proteins with potential ATE1 target sites and expand our understanding of the biological complexity of the intracellular arginylome