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Both anti-angiogenesis and immunotherapy are well-established therapeutic options in solid tumors. Here, we review the rationale as well as clinical evidence of combining these two approaches. There is strong rationale and substantial preclinical and clinical evidence that anti-angiogenesis plays a pivotal role in overcoming immunotherapy resistance. The combination of an anti-angiogenic agent and a checkpoint inhibitor offers a more robust treatment option in many clinical trials in a wide variety of solid tumor types. Combination of anti-angiogenesis and immunotherapy has emerged as a standard of care in some tumor types and the indication is expected to expand to more tumor types in the years to come.

In June 2019, a meeting was held in Paris in which experts from different countries (Israel, Spain, Belgium, Italy, USA, and France) met to discuss a selection of topics in integrative oncology (IO). The objectives were to draw on the delegates’ experience and expertise to begin an international collaboration, sharing details of differing existing models and discussing future perspectives to help define and guide practice in IO and define unmet needs. This report presents a summary of the meeting’s main presentations, and also reports on the experts’ responses to a questionnaire examining different aspects of IO service delivery, infrastructure, and utilization.

Background: Fetal autopsy has been an indispensable tool in evaluating the cause of death. The most common cause for fetal deaths is associated with respiratory disorders accounting for around 60%. This study was undertaken to evaluate the gross and microscopic features of lungs in fetal autopsies and estimate the incidence of deaths attributable to pulmonary causes. Materials and Methods: All fetuses received for autopsy at our institute were included in the study with prior consent. Gross and microscopic findings along with relevant clinical data were recorded. Results: A total of 426 autopsies were conducted from January 2011 to August 2016. Of those, 184 had abnormal pulmonary findings constituting 43.19%. Aspiration pneumonia was the most common finding with 67 cases (36.4%), followed by atelectasis 54 cases (29.3%), congenital cystic adenomatoid malformation in 13 cases (7.1%), lung hypoplasia 12 cases (6.5%), pulmonary hemorrhage 21 (11.4%), 15 cases (8.15%) of hyaline membrane disease, one case (0.5%) of heterotaxy, and one case of extralobar pulmonary sequestration (0.5%). Congenital malformations of lungs were seen in 27 (14.67%) cases and 38 cases (20.65%) had other associated anomalies. Conclusion: Pulmonary pathology is the most common finding in fetal deaths with aspiration pneumonitis being the most common avoidable cause. Accurate fetal autopsy along with clinical data are important in evaluating fetal deaths and can help in reduction of unexplained stillbirths.

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan to kynurenine, suppressing T cell effector activity and increasing T regulatory cell activity. IDO1 expression is induced in some cancer cells and has been associated with suppression of effector T cell responses toward tumors. In nonclinical studies, IDO1 inhibition combined with other clinically established immune modulating agents (eg, anti-CTLA-4 or anti-PD-1 antibodies) showed a significant improvement in tumor growth suppression. KHK2455 is a long acting and selective IDO1 inhibitor under development as a new approach to enhance anti-tumor immunity. KHK2455 is being combined with different anti-cancer therapies to explore its ability to enhance anti-tumor immunity and overcome tumor immune evasion. Avelumab is a PD-L1 checkpoint inhibitor approved for treatment of urothelial carcinoma. This study represents an opportunity to assess the complementary action of KHK2455 IDO1 inhibition and avelumab checkpoint inhibition in the treatment of urothelial carcinoma. Methods: Study 2455-002 is a two-part, multicenter, open-label Phase 1 study of KHK2455 in combination with avelumab in adult subjects with locally advanced or metastatic urothelial carcinoma (including bladder, urethra, ureters, and renal pelvis), who are checkpoint inhibitor naїve and previously treated with platinum-based therapy. Part 1 (dose-escalation) has a 3+3 design to evaluate safety and tolerability and identify the maximum tolerated dose (MTD). Dose de-escalation based on dose limiting toxicities is permitted. Part 2 (cohort expansion) further explores the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity for the combination regimen at the MTD or highest tested dose. All subjects will receive oral KHK2455 at their assigned dose and avelumab IV. The primary study endpoints are safety and tolerability, and the secondary endpoints are efficacy (based on RECIST v1.1 criteria), pharmacokinetics, and immunogenicity. Exploratory endpoints include examination of pre and post treatment biopsies for intratumoral suppression of IDO1 activity to correlate peripheral and intratumoral suppression, along with pre and post treatment serum markers including, but not limited to, immune mediators and related cytokines. Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for continuous variables and frequency distributions and percentages for discrete variables will be utilized. Approximately 44 subjects are planned for enrollment (12 subjects in Part 1 and 32 subjects in Part 2). Clinical trial information: NCT03915405 (sponsor: Kyowa Kirin Pharmaceutical Development, Inc.) Citation Format: Pratibha Desai, Santosh Rao, Yuta Ikawa, Barbara Kapelan, Sergey Efuni, Robert Latek, Takashi Sato, Denis Healy, Yousef Zakharia. An open-label, phase 1 study of IDO inhibitor KHK2455 in combination with avelumab in adult subjects with locally advanced or metastatic urothelial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT238.

BACKGROUND The aim of this study was to evaluate the feasibility and efficacy of the injection of a nonabsorbable substance into the base of the left ventricle (LV) to treat functional mitral regurgitation (MR). METHODS Tyramine-based hyaluronan hydrogel was injected into the base of the LV of the beating heart in a canine model of rapid ventricular pacing-induced functional MR (n = 4). The severity of MR was evaluated by epicardial echocardiography before and after hydrogel injection. RESULTS The injection improved MR grade from 3.4 +/- 0.8 to 1.3 +/- 0.5 (P = .006) without inducing hemodynamic instability or any evidence of myocardial ischemia. We noted significant decreases in the septal-lateral dimension at the mitral annulus (3.4 +/- 0.4 cm to 2.9 +/- 0.3 cm; P = .039) and MR volume (20.6 +/- 7.3 mm3 to 5.2 +/- 2.2 mm3; P = .044). CONCLUSIONS A novel treatment consisting of hydrogel injection into the base of the LV between the 2 papillary muscles was found to be feasible and effective for reducing functional MR in a canine model.

Objective The purpose of this study was to evaluate the implantability of a novel epicardial mitral annuloplasty device and its ability to reduce the septal-lateral (S-L) dimension of the mitral annulus. Methods The devices were implanted on the beating heart in 2 healthy dogs (the 24-mm long device in dog A and the 27-mm and 24-mm standard devices in dog B) by sliding the anterior arm onto the floor of the transverse sinus and positioning the posterior arm just apical to the atrioventricular groove on the left ventricular posterolateral wall. The devices were secured with titanium helical tacks driven through the device into the ventricular wall. Two-dimensional epicardial echocardiograms were performed before and after device implantation to evaluate the degree of mitral regurgitation (MR) and the S-L dimension. Results Device implantation was uneventful, taking only ~30 seconds to deploy. MR (1 +) in both dogs at baseline was reduced to zero after implant. The reductions in S-L dimension in systole for the 24-mm device were 7.5% in dog A and 30.5% in dog B. For the 27-mm device in dog B, S-L reduction in systole was 29.9%. The leaflet coaptation length was increased in both cases. Conclusions The new device was effective in reducing S-L dimension and 1 + MR without requiring the use of cardiopulmonary bypass. We are currently evaluating this device for the treatment of MR in a rapid-pacing canine heart failure model.

Emerging evidence suggests that short sleep is associated with an increased risk of cancer; however, little has been done to study the role of sleep on tumor characteristics. In this study, we evaluated the relationship between sleep duration and tumor phenotype in 972 breast cancer patients. Sleep duration was inversely associated with tumor grade (univariateP=0.032), particularly in postmenopausal women (univariateP=0.018). This association did not reach statistical significance after adjustments for age, race, body mass index, hormone replacement therapy use, alcohol consumption, smoking, and physical activity in the entire study sample (P=0.052), but it remained statistically significant (P=0.049) among post-menopausal patients. We did not observe a statistically significant association between sleep duration and stage at diagnosis, ER, or HER2 receptor status. These results present a modest association between short duration of sleep and higher grade breast cancer in post-menopausal women. Further work needs to be done to validate these findings.

Right ventricular failure (RVF) following left ventricular assist device (LVAD) implantation is associated with morbidity and mortality. Our purpose is to validate the right ventricular failure risk score (RVFRS) proposed by University of Michigan in a large cohort of patients supported with an LVAD

The clinical use of left ventricular assist devices (LVADs) is becoming more widely accepted, due in large part to the introduction of continuous-flow blood pumps.1-6 These newer devices show significant improvements in size, simplicity, reliability, durability, and clinical results. However, 20-50% of patients undergoing LVAD implantation also have significant right ventricular failure, which limits the utility of implantable LVAD therapy.7-11 Existing total artificial hearts (TAHs) are either a temporary pneumatic system (CardioWest™, SynCardia, Tucson, AZ) with an externalized pneumatic driver or a permanent pulsatile implantable system (AbioCor™, Abiomed®, Danvers, MA). To date, they have demonstrated significant limitations in initial clinical trials because of their large size, limited durability, and incidence of thrombus formation and embolization.12 The inherent design characteristics of these pulsatile systems prevent significant reductions in size. The feasibility of native heart replacement with two separate continuous-flow pumps has recently been demonstrated at the Texas Heart Institute (Houston, TX)13 and Tohoku University (Sendai, Japan).14 These systems require duplication of pump components, increasing the potential for component failure and necessitating the development of complex algorithms to appropriately coordinate the outputs of the two pumps. We are developing a continuous-flow TAH (CFTAH) that is extremely innovative, exploring radical new concepts in TAH design. The proposed concept involves the use of a valveless, sensorless, continuous-flow pump and automatic control system. This double-pump concept comprises a single, continuously rotating, brushless DC motor and a pump assembly with a centrifugal pump on both ends. Pump speed will be modulated to create pulsatile flow and pressure. This report details the CFTAH design concept and our initial in vitro data in a mock circulatory loop.

Results: A total of 199 (47.3%) had RV failure following LVAD implantation. The area under the curve (AUC) for the RVFRS was 0.675 (0.623, 0.726). Post-operative RVF was present in 26 (49%) of patients with a continuous low pump and 173 (47%) in patients supported with a pulsatile device (p=0.9). Conclusions: The RVFRS may be used to estimate the risk of RVF following LVAD implantation. There was no difference in post-operative RVF in patients supported with a continuous low vs. pulsatile low LVAD. These indings may have important implications on patient selection regarding mechanical circulatory support for end-stage heart failure patients. RVFRS N (%) RVF, N(%) No RVF, N(%) OR(95%CI) vs. ≤ 3.0 OR(95%CI) vs. 4.0-5.0 Sensitivity (%) Speciicity (%) ≤3.0 248(59) 91(37) 157(63) 54 71