Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial.

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.

Modeling human tumor-immune environments in vivo for the preclinical assessment of immunotherapies.

Despite the significant contributions of immunocompetent mouse models to the development and assessment of cancer immunotherapies, they inadequately represent the genetic and biological complexity of corresponding human cancers. Immunocompromised mice reconstituted with a human immune system (HIS) and engrafted with patient-derived tumor xenografts are a promising novel preclinical model for the study of human tumor-immune interactions. Whilst overcoming limitations of immunocompetent models, HIS-tumor models often rely on reconstitution with allogeneic immune cells, making it difficult to distinguish between anti-tumor and alloantigen responses. Models that comprise of autologous human tumor and human immune cells provide a platform that is more representative of the patient immune-tumor interaction. However, limited access to autologous tissues, short experimental windows, and poor retention of tumor microenvironment and tumor infiltrating lymphocyte components are major challenges affecting the establishment and application of autologous models. This review outlines existing preclinical murine models for the study of immuno-oncology, and highlights innovations that can be applied to improve the feasibility and efficacy of autologous models.

Use of human splenocytes in an innovative humanised mouse model for prediction of immunotherapy-induced cytokine release syndrome.

OBJECTIVES: Humanised mice have emerged as valuable models for pre-clinical testing of the safety and efficacy of immunotherapies. Given the variety of models available, selection of the most appropriate humanised mouse model is critical in study design. Here, we aimed to develop a model for predicting cytokine release syndrome (CRS) while minimising graft-versus-host disease (GvHD). METHODS: To overcome donor-induced variation, we directly compared the in vitro and in vivo immune phenotype of immunodeficient NSG mice reconstituted with human bone marrow (BM) CD34+ haematopoietic stem cells (HSCs), peripheral blood mononuclear cells (PBMCs) or spleen mononuclear cells (SPMCs) from the same human donors. SPMC engraftment in NSG-dKO mice, which lack MHC class I and II, was also evaluated as a strategy to limit GvHD. Another group of mice was engrafted with umbilical cord blood (UCB) CD34+ HSCs. Induction of CRS in vivo was investigated upon administration of the anti-CD3 monoclonal antibody OKT3. RESULTS: PBMC- and SPMC-reconstituted NSG mice showed short-term survival, with engrafted human T cells exhibiting mostly an effector memory phenotype. Survival in SPMC-reconstituted NSG-dKO mice was significantly longer. Conversely, both BM and UCB-HSC models showed longer survival, without demonstrable GvHD and a more naïve T-cell phenotype. PBMC- and SPMC-reconstituted mice, but not BM-HSC or UCB-HSC mice, experienced severe clinical signs of CRS upon administration of OKT3. CONCLUSION: PBMC- and SPMC-reconstituted NSG mice better predict OKT3-mediated CRS. The SPMC model allows generation of large experimental groups, and the use of NSG-dKO mice mitigates the limitation of early GvHD.

The Impact of Pre-existing Comorbidities and Therapeutic Interventions on COVID-19.

Evidence from the global outbreak of SARS-CoV-2 has clearly demonstrated that individuals with pre-existing comorbidities are at a much greater risk of dying from COVID-19. This is of great concern for individuals living with these conditions, and a major challenge for global healthcare systems and biomedical research. Not all comorbidities confer the same risk, however, many affect the function of the immune system, which in turn directly impacts the response to COVID-19. Furthermore, the myriad of drugs prescribed for these comorbidities can also influence the progression of COVID-19 and limit additional treatment options available for COVID-19. Here, we review immune dysfunction in response to SARS-CoV-2 infection and the impact of pre-existing comorbidities on the development of COVID-19. We explore how underlying disease etiologies and common therapies used to treat these conditions exacerbate COVID-19 progression. Moreover, we discuss the long-term challenges associated with the use of both novel and repurposed therapies for the treatment of COVID-19 in patients with pre-existing comorbidities.

The benefits of physical exercise for the health of the pancreatic ß-cell: a review of the evidence.

NEW FINDINGS: What is the topic of this review? This review discusses the evidence of the benefits of exercise training for ß-cell health through improvements in function, proliferation and survival which may have implications in the treatment of diabetes. What advances does it highlight? This review highlights how exercise may modulate ß-cell health in the context of diabetes and highlights the need for further exploration of whether ß-cell preserving effects of exercise translates to T1D. ABSTRACT: Physical exercise is a core therapy for type 1 and type 2 diabetes. Whilst the benefits of exercise for different physiological systems are recognised, the effect of exercise specifically on the pancreatic ß-cell is not well described. Here we review the effects of physical exercise on ß-cell health. We show that exercise improves ß-cell mass and function. The improved function manifests primarily through the increased insulin content of the ß-cell and its increased ability to secrete insulin in response to a glucose stimulus. We review the evidence relating to glucose sensing, insulin signalling, ß-cell proliferation and ß-cell apoptosis in humans and animal models with acute exercise and following exercise training programmes. Some of the mechanisms through which these benefits manifest are discussed.

Effects of music in exercise and sport: A meta-analytic review.

Regular physical activity has multifarious benefits for physical and mental health, and music has been found to exert positive effects on physical activity. Summative literature reviews and conceptual models have hypothesized potential benefits and salient mechanisms associated with music listening in exercise and sport contexts, although no large-scale objective summary of the literature has been conducted. A multilevel meta-analysis of 139 studies was used to quantify the effects of music listening in exercise and sport domains. In total, 598 effect sizes from four categories of potential benefits (i.e., psychological responses, physiological responses, psychophysical responses, and performance outcomes) were calculated based on 3,599 participants. Music was associated with significant beneficial effects on affective valence (g = 0.48, CI [0.39, 0.56]), physical performance (g = 0.31, CI [0.25, 0.36]), perceived exertion (g = 0.22, CI [0.14, 0.30]), and oxygen consumption (g = 0.15, CI [0.02, 0.27]). No significant benefit of music was found for heart rate (g = 0.07, CI [-0.03, 0.16]). Performance effects were moderated by study domain (exercise > sport) and music tempo (fast > slow-to-medium). Overall, results supported the use of music listening across a range of physical activities to promote more positive affective valence, enhance physical performance (i.e., ergogenic effect), reduce perceived exertion, and improve physiological efficiency. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Recent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology.

Significant advances in immunotherapies have resulted in the increasing need of predictive preclinical models to improve immunotherapeutic drug development, treatment combination, and to prevent or minimize toxicity in clinical trials. Immunodeficient mice reconstituted with human immune system (HIS), termed humanized mice or HIS mice, permit detailed analysis of human immune biology, development, and function. Although this model constitutes a great translational model, some aspects need to be improved as the incomplete engraftment of immune cells, graft versus host disease and the lack of human cytokines and growth factors. In this review, we discuss current HIS platforms, their pathology, and recent advances in their development to improve the quality of human immune cell reconstitution. We also highlight new technologies that can be used to better understand these models and how improved characterization is needed for their application in immuno-oncology safety, efficacy, and new modalities therapy development.

Analysis of the effects of storage temperature and contamination on aerobic bacterial culture results of bronchoalveolar lavage fluid.

BACKGROUND: Storage temperature of bronchoalveolar lavage fluid (BALF) impacts cytological evaluation. The effect of storage temperature before bacterial culture has not been evaluated. OBJECTIVES: To assess whether BALF storage temperature alters aerobic bacterial culture results. ANIMALS: Eight healthy, male, intact, purpose-bred Beagles. METHODS: Prospective, controlled investigation. Samples of BALF were collected sterilely. Half of each sample was reserved for controls, and half was inoculated with 104 colony forming units per milliliter (cfu/mL) Bordetella bronchiseptica and 102 cfu/mL Escherichia coli. Control and inoculated samples each were separated into 4 aliquots (1 plated immediately; 3 stored at 4, 24, or 37°C, respectively, for 24 hours before aerobic bacterial culture). Colony counts were compared across treatments for each organism. RESULTS: In inoculated samples, a statistical difference could not be detected in growth of E. coli or B. bronchiseptica between the baseline culture and BALF stored at 4°C for 24 hours before culture. However, for E. coli, growth in cfu/mL at both 24 and 37°C was higher compared to baseline (P < .05) and compared to 4°C (P < .05). For B. bronchiseptica cfu/mL, growth at 37°C was significantly different (P = .003) compared to both baseline and 4°C. CONCLUSIONS AND CLINICAL IMPORTANCE: Samples of BALF may be stored at 4°C for 24 hours before culture without substantially altering culture results. Inappropriate storage or shipment temperature (room temperature or exposure to heat) can result in overgrowth of E. coli or B. bronchiseptica, which could alter clinical decisions.

Type 1 diabetes impairs the mobilisation of highly-differentiated CD8+T cells during a single bout of acute exercise.

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that targets and destroys insulin-secreting pancreatic beta cells. Beta cell specific T cells are highly differentiated and show evidence of previous antigen exposure. Exerciseinduced mobilisation of highly-differentiated CD8+ T cells facilitates immune surveillance and regulation. We aimed to explore exercise-induced T cell mobilisation in T1D. In this study, we compared the effects of a single bout of vigorous intensity exercise on T cell mobilisation in T1D and control participants. N=12 T1D (mean age 33.2yrs, predicted VO2 max 32.2 mL/(kg·min), BMI 25.3Kg/m2) and N=12 control (mean age 29.4yrs, predicted VO2 max 38.5mL(kg.min), BMI 23.7Kg/m2) male participants completed a 30-minute bout of cycling at 80% predicted VO2 max in a fasted state. Peripheral blood was collected at baseline, immediately post-exercise, and 1 hour post-exercise. Exercise-induced mobilisation was observed for T cells in both T1D and control groups. Total CD8+ T cells mobilised to a similar extent in T1D (42.7%; p=0.016) and controls (39.7%; p=0.001). CD8 effector memory CD45RA+ (EMRA) subset were the only T cell lineage subset to be significantly mobilised in both groups though the percentage increase of CD8+ EMRA was blunted in T1D (T1D (26.5%) p=0.004, control (66.1%) p=0.010). Further phenotyping of these subsets revealed that the blunting was most evident in CD8+ EMRA that expressed adhesion (CD11b: T1D 37.70%, Control 91.48%) and activation markers (CD69: T1D 29.87%, Control 161.43%), and appeared to be the most differentiated (CD27-CD28-: T1D 7.12%, Control 113.76%). CD4+ T cells mobilised during vigorous intensity exercise in controls (p=0.001), but not in T1D. The blunted mobilisation response of particular T cell subsets was not due to CMV serostatus or apparent differences in exertion during the exercise bout as defined by heart rate and RPE. Predicted VO2 max showed a trend to be lower in the T1D group than the control group but is unlikely to contribute to this blunted response. We postulate the reasons for a blunted mobilisation of differentiated CD8+ EMRA cells includes differences in blood glucose, adrenaline receptor density, and sequestration of T cells in the pancreas of T1D participants. In conclusion, mobilisation of CD8+ EMRA and CD4+ subsets T cells is decreased in people with T1D during acute exercise.