A Systematic Review of Recent and Ongoing Clinical Trials in Patients With the Neurofibromatoses.

INTRODUCTION: The neurofibromatoses comprise three different genetic conditions causing considerable morbidity and mortality: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). This review summarizes recent and ongoing clinical trials involving patients with neurofibromatoses to better understand the current state of clinical trial research centered around these conditions and inform areas of need. METHODS: A search was conducted using the Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases. Inclusion and exclusion criteria were designed to identify clinical trials focused on patients with NF1, NF2, or SWN completed in or after 2010 and in process as of December 31, 2021. Information was collected using standardized guidelines. RESULTS: A total of 134 clinical trials were included, with 75 (56%) completed and 59 (44%) in process. For completed trials, 74% (n = 56) involved patients with NF1, and of those based on specific tumors (n = 26, 46%), the majority focused on plexiform neurofibromas (PNs) (n = 12, 46%). For ongoing trials, 79% (n = 47) involve patients with NF1, and of those based on specific tumors (n = 29, 61%), the majority are focused on PNs (n = 13, 45%). CONCLUSION: Both recent and ongoing clinical trials have primarily focused on patients with NF1 and the treatment of PNs. This research has led to the first FDA-approved drug for NF1-PN and has changed management of these tumors, allowing for systemic therapy rather than reliance on only a surgical modality. Trials evaluating comorbid psychiatric conditions and quality of life among patients with any of the neurofibromatoses appear less common. These areas may warrant focus in future studies to improve clinical management.

Plexiform neurofibroma: shedding light on the investigational agents in clinical trials.

INTRODUCTION: Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic condition, which predisposes individuals to the development of plexiform neurofibromas (PN), benign nerve sheath tumors seen in 30-50% of patients with NF1. These tumors may cause significant pain and disfigurement or may compromise organ function. Given the morbidity associated with these tumors, therapeutic options for patients with NF1-related PN are necessary. AREAS COVERED: We searched the www.clinicaltrials.gov database for 'plexiform neurofibroma.' This article summarizes completed and ongoing trials involving systemic therapies for PN. EXPERT OPINION: Surgery is the mainstay treatment; however, complete resection is not possible in many cases. Numerous systemic therapies have been evaluated in patients with NF1, with MEK inhibitors (MEKi) showing the greatest efficacy for volumetric reduction and improvement in functional and patient-reported outcomes. The MEKi selumetinib is now FDA approved for the treatment of inoperable, symptomatic PN in pediatric NF1 patients. Questions remain regarding the use of this drug class in terms of when to initiate therapy, overall duration, reduced dosing schedules, and side effect management. Future studies are needed to fully understand the clinical application of MEKi and to evaluate other potential therapies through appropriate trial designs for this potentially devastating, manifestation in NF1.

Pharmacologic and interventional paradigms of diuretic resistance in congestive heart failure: a narrative review.

Diuretic volume reduction continues to be the mainstay of congestive heart failure (CHF) management globally. However, diuretic resistance is a critical topic that lacks standardized evidence-based management guidelines accounting for mechanisms of diuretic resistance, renal function, and co-morbidities. Major healthcare utilization consequences result from this. The authors herein reconcile the definition of renal functional decline with emphasis on biomarker-driven assessment. Novel goal-directed treatment approaches are reviewed including hypertonic saline, acetazolamide, sodium-glucose transporter inhibition, sequential nephron blockade and Elabela-APJ axis targeting are reviewed, as well as percutaneous visceral splanchnic sympathectomy (converting a volume-focused to a distribution-focused paradigm).

Modification of Extracellular Matrix Enhances Oncolytic Adenovirus Immunotherapy in Glioblastoma.

PURPOSE: Extracellular matrix (ECM) component hyaluronan (HA) facilitates malignant phenotypes of glioblastoma (GBM), however, whether HA impacts response to GBM immunotherapies is not known. Herein, we investigated whether degradation of HA enhances oncolytic virus immunotherapy for GBM. EXPERIMENTAL DESIGN: Presence of HA was examined in patient and murine GBM. Hyaluronidase-expressing oncolytic adenovirus, ICOVIR17, and its parental virus, ICOVIR15, without transgene, were tested to determine if they increased animal survival and modulated the immune tumor microenvironment (TME) in orthotopic GBM. HA regulation of NF-κB signaling was examined in virus-infected murine macrophages. We combined ICOVIR17 with PD-1 checkpoint blockade and assessed efficacy and determined mechanistic contributions of tumor-infiltrating myeloid and T cells. RESULTS: Treatment of murine orthotopic GBM with ICOVIR17 increased tumor-infiltrating CD8+ T cells and macrophages, and upregulated PD-L1 on GBM cells and macrophages, leading to prolonged animal survival, compared with control virus ICOVIR15. High molecular weight HA inhibits adenovirus-induced NF-κB signaling in macrophages in vitro, linking HA degradation to macrophage activation. Combining ICOVIR17 with anti-PD-1 antibody further extended the survival of GBM-bearing mice, achieving long-term remission in some animals. Mechanistically, CD4+ T cells, CD8+ T cells, and macrophages all contributed to the combination therapy that induced tumor-associated proinflammatory macrophages and tumor-specific T-cell cytotoxicity locally and systemically. CONCLUSIONS: Our studies are the first to show that immune modulatory ICOVIR17 has a dual role of mediating degradation of HA within GBM ECM and subsequently modifying the immune landscape of the TME, and offers a mechanistic combination immunotherapy with PD-L1/PD-1 blockade that remodels innate and adaptive immune cells.