Advanced instrumentation concepts for environmental control subsystems

Design, evaluation and demonstration of advanced instrumentation concepts for improving performance of manned spacecraft environmental control and life support systems were successfully completed. Concepts to aid maintenance following fault detection and isolation were defined. A computer-guided fault correction instruction program was developed and demonstrated in a packaged unit which also contains the operator/system interface

The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases – A multicenter cohort study

Purpose: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. Methods: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. Results: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4e12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. Conclusion: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.Carl-Jacob Holmberg ... Brendon Coventry ... Hidde Kroon ... et al

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Paracrine interactions between primary human macrophages and human fibroblasts enhance murine mammary gland humanization in vivo

Abstract Introduction Macrophages comprise an essential component of the mammary microenvironment necessary for normal gland development. However, there is no viable in vivo model to study their role in normal human breast function. We hypothesized that adding primary human macrophages to the murine mammary gland would enhance and provide a novel approach to examine immune-stromal cell interactions during the humanization process. Methods Primary human macrophages, in the presence or absence of ectopic estrogen stimulation, were used to humanize mouse mammary glands. Mechanisms of enhanced humanization were identified by cytokine/chemokine ELISAs, zymography, western analysis, invasion and proliferation assays; results were confirmed with immunohistological analysis. Results The combined treatment of macrophages and estrogen stimulation significantly enhanced the percentage of the total gland humanized and the engraftment/outgrowth success rate. Timecourse analysis revealed the disappearance of the human macrophages by two weeks post-injection, suggesting that the improved overall growth and invasiveness of the fibroblasts provided a larger stromal bed for epithelial cell proliferation and structure formation. Confirming their promotion of fibroblasts humanization, estrogen-stimulated macrophages significantly enhanced fibroblast proliferation and invasion in vitro, as well as significantly increased proliferating cell nuclear antigen (PCNA) positive cells in humanized glands. Cytokine/chemokine ELISAs, zymography and western analyses identified TNFα and MMP9 as potential mechanisms by which estrogen-stimulated macrophages enhanced humanization. Specific inhibitors to TNFα and MMP9 validated the effects of these molecules on fibroblast behavior in vitro, as well as by immunohistochemical analysis of humanized glands for human-specific MMP9 expression. Lastly, glands humanized with macrophages had enhanced engraftment and tumor growth compared to glands humanized with fibroblasts alone. Conclusions Herein, we demonstrate intricate immune and stromal cell paracrine interactions in a humanized in vivo model system. We confirmed our in vivo results with in vitro analyses, highlighting the value of this model to interchangeably substantiate in vitro and in vivo results. It is critical to understand the signaling networks that drive paracrine cell interactions, for tumor cells exploit these signaling mechanisms to support their growth and invasive properties. This report presents a dynamic in vivo model to study primary human immune/fibroblast/epithelial interactions and to advance our knowledge of the stromal-derived signals that promote tumorigenesis

Macrophage biology in development, homeostasis and disease

Macrophages the most plastic cells of the hematopoietic system are found in all tissues and exhibit great functional diversity. They have roles in development, homeostasis, tissue repair, and immunity. While anatomically distinct, resident tissue macrophages exhibit different transcriptional profiles, and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this review, we discuss how macrophages regulate normal physiology and development and provide several examples of their pathophysiologic roles in disease. We define the “hallmarks” of macrophages performing particular functions, taking into account novel insights into the diversity of their lineages, identity, and regulation. This diversity is essential to understand because macrophages have emerged as important therapeutic targets in many important human diseases

3-YEAR RESULTS OF THE PHASE 2 RANDOMIZED TRIAL FOR TALIMOGENE LAHERPAREPVEC (T-VEC) NEOADJUVANT TREATMENT PLUS SURGERY VS SURGERY IN PATIENTS WITH RESECTABLE STAGE IIIB-IVM1A MELANOMA

Background Neoadjuvant immunotherapies and targeted therapies for advanced melanoma are an active area of investigation. This is the first clinical trial of an approved oncolytic viral immunotherapy as a neoadjuvant treatment in advanced melanoma and the largest randomized controlled neoadjuvant trial including all types of resectable regional metastases to date. Previously published 2-year primary analysis results reported improved recurrence-free survival (RFS, HR 0.66, P=0.038) and overall survival (OS, HR 0.49, P=0.050) for neoadjuvant T-VEC plus surgery vs immediate surgery in resectable stage IIIB-IVM1a melanoma patients.1 Here, we report the 3-year interim analysis results. Methods Patients with resectable stage IIIB-IVM1a melanoma and ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions were randomized 1:1 to receive 6 doses/12 weeks of neoadjuvant T-VEC then surgery (Arm 1) vs immediate surgical resection (Arm 2). T-VEC was administered until surgery, no remaining injectable tumors, or intolerance. RFS was defined as time from randomization to the first of local, regional, or distant recurrence, or death, where patients who did not receive surgery were imputed as events at baseline. Key secondary and exploratory endpoints include safety, an RFS sensitivity analysis that censored events at the start of subsequent anticancer therapy, OS, and event-free survival (EFS), defined as time from randomization to disease progression that precludes surgery, or local, regional or distant recurrence post-surgery, or death from any cause, whichever occurs first. All P values are descriptive. NCT02211131. Results As of April 30, 2020, median follow-up for all patients was 41.3 months. For Arm 1 vs. Arm 2, the 3-year KM estimates of RFS were 46.5% vs. 31.0% (HR 0.67, P=0.043). In the RFS sensitivity analysis that removed the potential effect of subsequent anticancer therapy on RFS, the 3-year Kaplan-Meier (KM) estimates of RFS were 49.1% for Arm 1 and 22.9% for Arm 2 (HR 0.60, P=0.022). The 3-year KM estimates of EFS were 50.3% for Arm 1 and 32.7% for Arm 2 (HR 0.58, P=0.015). For OS, the 3-year KM estimates were 83.2% for Arm 1 and 71.6% for Arm 2 (HR 0.54, P=0.061). No new safety signals were detected. Conclusions At 3-year follow up, we continued to observe improved RFS and OS and observed improved EFS with neoadjuvant T-VEC plus surgery compared with surgery alone. These results build upon the prior 2-year results to support the treatment effect of neoadjuvant T-VEC on advanced resectable melanoma. The final analysis will occur at 5 years. Acknowledgements • The authors thank the investigators, patients, and study staff who are contributing to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.). Trial Registration NCT02211131 Ethics Approval The study was approved by all institutional ethics boards. Reference Dummer R, Gyorki DE, Hyngstrom J, et al. Primary 2-year (yr) results of a phase II, multicenter, randomized, open-label trial of efficacy and safety for talimogene laherparepvec (T-VEC) neoadjuvant (neo) treatment (tx) plus surgery (surg) vs surg in patients (pts) with resectable stage IIIB-IVM1a melanoma. Ann Oncol 2019;30;V903

Incidence and location of positive nonsentinel lymph nodes in head and neck melanoma

BACKGROUND: The complex lymphatic drainage in the head and neck makes sentinel lymph node biopsy (SLNB) for melanomas in this region challenging. This study describes the incidence, and location of additional positive nonsentinel lymph nodes (NSLN) in patients with cutaneous head and neck melanoma following a positive SLNB. METHODS: A retrospective review was performed using a single institution prospective database. Patients with a primary melanoma in the head or neck with a positive cervical SLNB were identified. The lymphadenectomy specimen was divided intraoperatively into lymph node levels I-V, and NSLN status determined for each level. RESULTS: Of 387 patients with melanoma of the head and neck who underwent cervical SLNB, 54 had a positive SLN identified (14%). Thirty six patients (67%) underwent immediate completion lymph node dissection (CLND) of whom eight patients (22%) had a positive NSLN. The remaining 18 patients (33%) did not undergo CLND and were observed. Half of positive NSLNs (50%) were in the same lymph node level as the SLN and 33% were in an immediately adjacent level; only two patients were found to have NSLNs in non-adjacent levels. The only factor predictive of NSLN involvement was the size of the tumor deposit in the SLN\u3e0.2 mm (p = 0.05). Superficial parotidectomy at CLND revealed metastatic melanoma only in patients with a positive parotid SLN. CONCLUSIONS: A positive NLSN was identified in 22% of patients undergoing CLND after a positive SLNB. The majority of positive NSLNs are found within or immediately adjacent to the nodal level containing the SLN