Segmental spinal dysgenesis: insights from three consecutive cases and a review of the literature.

OBJECTIVE: Segmental spinal dysgenesis (SSD) is a rare congenital spinal abnormality affecting the thoracic and lumbar region of the spine, as well as the spinal cord of neonates and infants. The purpose of the study was to analyze our institution's surgical case series to provide insights into our best practices to contribute to SSD management principles, while conducting a comprehensive literature review. METHODS: Following institutional review board approval, a retrospective review of SSD surgical cases was examined to observe clinical findings, radiographic findings, management, surgical intervention, and outcomes. Keywords in the comprehensive literature review included SSD, congenital spinal dysgenesis, congenital spinal stenosis, spinal aplasia, and surgery. RESULTS: Three cases underwent successful surgical management with either improvement or maintenance of neurological baseline. Patients were diagnosed at an average age of 2.7 months, while surgical intervention averaged at 40.3 months with fecal incontinence, neurogenic bladders, spinal cord compression, clubfoot, and concerns for worsening spinal deformity as surgical indicators. The average time for follow-up was 33.7 months and no complications were reported. CONCLUSIONS: Operative management for SSD is a clinically complex decision that requires multidisciplinary input and care. Patients should be observed at neurological baseline and receive intervention at the appropriate time to allow sufficient growth for functioning without permitting drastic disease progression. Consideration of patient size and spinal instrumentation are significant towards surgical success.

Implementation of Minimally Invasive Brain Tumor Resection in Rodents for High Viability Tissue Collection.

The present protocol describes a standardized paradigm for rodent brain tumor resection and tissue preservation. In clinical practice, maximal tumor resection is the standard-of-care treatment for most brain tumors. However, most currently available preclinical brain tumor models either do not include resection, or utilize surgical resection models that are time-consuming and lead to significant postoperative morbidity, mortality, or experimental variability. In addition, performing resection in rodents can be daunting for several reasons, including a lack of clinically comparable surgical tools or protocols and the absence of an established platform for standardized tissue collection. This protocol highlights the use of a multi-functional, non-ablative resection device and an integrated tissue preservation system adapted from the clinical version of the device. The device applied in the present study combines tunable suction and a cylindrical blade at the aperture to precisely probe, cut, and suction tissue. The minimally invasive resection device performs its functions via the same burr hole used for the initial tumor implantation. This approach minimizes alterations to regional anatomy during biopsy or resection surgeries and reduces the risk of significant blood loss. These factors significantly reduced the operative time (<2 min/animal), improved postoperative animal survival, lower variability in experimental groups, and result in high viability of resected tissues and cells for future analyses. This process is facilitated by a blade speed of ~1,400 cycles/min, which allows the harvesting of tissues into a sterile closed system that can be filled with a physiologic solution of choice. Given the emerging importance of studying and accurately modeling the impact of surgery, preservation and rigorous comparative analysis of regionalized tumor resection specimens, and intra-cavity-delivered therapeutics, this unique protocol will expand opportunities to explore unanswered questions about perioperative management and therapeutic discovery for brain tumor patients.

Buprenorphine implants: a model for expedited development and approval of new drugs.

Regulations for new drug approvals require stringent safety testing and efficacy trial programs. The approval process for generic drugs, however, is significantly streamlined. Bioavailability data can substitute for new rounds of efficacy trials, thereby both decreasing time to approval and reducing the costs required for new studies. This regulatory choice has not been available when generic drugs are offered in a controlled release format such as a subcutaneous depot, transdermal patch or implant. The purpose of this review is to suggest that the approval of generic drugs in inert controlled release envelopes should be eligible for similar regulatory relief. Proof for this concept is provided by the example of the numerous controlled release buprenorphine products. Buprenorphine is a generic opioid used since the 1980s in tablet form to treat pain and to treat opioid addiction. Long-acting, inert delivery vehicles for the drug have become available for the same indications. Safety and bioavailability profiles of the long-acting products are the same or improved over the parent product. A review of the long-acting drugs provides compelling evidence to recommend that generic drug-controlled release products may be eligible for alternative regulatory programs.

Surgical Management of Chronic Subdural Hematoma in Older Adults: A Systematic Review.

BACKGROUND: Chronic subdural hematoma (cSDH) is a form of intracranial hemorrhage common in older adults. Optimal treatment remains controversial. We conducted a systematic review to identify surgical thresholds, characterize outcomes, and delineate critical considerations in the surgical management of older adults in order to summarize the evidence supporting the best contemporary management of cSDH. METHODS: A systematic review exploring surgical management of cSDH among individuals aged 65 years and older was conducting by searching the PubMed, Embase, and Scopus databases for articles in English. Abstracts from articles were read and selected for full-text review according to a priori criteria. Relevant full-text articles were analyzed for bibliographic data, aim, study design, population, interventions, and outcomes. RESULTS: Of 1473 resultant articles, 21 were included. Surgery rationale was case-by-case for symptomatic patients with cSDH. Surgery was superior to conservative management and promoted equivalent neurologic outcomes and rates of complications. Recurrence and reoperation rates in older adults were similar to younger individuals. Some studies reported higher mortality rates for older adults, while others reported no difference. Anticoagulation or antiplatelet agent use did not seem to be associated with poorer outcomes in older adults. CONCLUSIONS: Surgery for cSDH in older adults leads to favorable neurologic outcomes without increased risk of overall complications, recurrence, or reoperation compared to younger patients. However, older adults may be at increased risk for mortality after surgery. It is important to determine use of anticoagulant or antiplatelet agents in older adults to optimally manage patients with cSDH.

High-Intensity Focused Ultrasound: A Review of Mechanisms and Clinical Applications.

High Intensity Focused Ultrasound (HIFU) is an emerging and increasingly useful modality in the treatment of cancer and other diseases. Although traditional use of ultrasound at lower frequencies has primarily been for diagnostic imaging purposes, the development of HIFU has allowed this particular modality to expand into therapeutic use. This non-invasive and acoustic method involves the use of a piezoelectric transducer to deliver high-energy pulses in a spatially coordinated manner, while minimizing damage to tissue outside the target area. This review describes the history of the development of diagnostic and therapeutic ultrasound and explores the biomedical applications utilizing HIFU technology including thermally ablative treatment, therapeutic delivery mechanisms, and neuromodulatory phenomena. The application of HIFU across various tumor types in multiple organ systems is explored in depth, with particular attention to successful models of HIFU in the treatment of various medical conditions. Basic mechanisms, preclinical models, previous clinical use, and ongoing clinical trials are comparatively discussed. Recent advances in HIFU across multiple medical fields reveal the growing importance of this biomedical technology for the care of patients and for the development of possible pathways for the future use of HIFU as a commonplace treatment modality.

Drug Repurposing for Glioblastoma and Current Advances in Drug Delivery-A Comprehensive Review of the Literature.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood-brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM.

Novel therapeutics for brain tumors: current practice and future prospects.

Introduction: Malignant gliomas are the most common and aggressive primary brain tumor with current available therapies increasing median survival to a modest 20 months. Multiple preclinical research efforts aim to further this improvement through advances in therapeutic options for these patients.Areas covered: The unique obstacles that must be managed in developing and delivering safe and efficacious therapeutics into the central nervous system are reviewed. We describe the successes and challenges in local drug delivery in the field of neuro-oncology and explore convection enhanced delivery and high frequency ultrasound as tools for safe and effective delivery. Drug delivery systems are described in addition to combination therapies that are being tested both preclinically, as well as ones currently in clinical trials. The field of immunotherapy is also discussed along with specific considerations as it relates to the brain's microenvironment.Expert opinion: While there have been incremental advances in brain cancer therapeutics over the last few years, novel therapeutics are expanding with multiple opportunities in neuro-oncology. Overcoming the brain's unique challenges might allow for breakthroughs and discoveries in the future.

Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show in vitro that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models in vivo Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both in vitro and in vivo Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium.

Cold Atmospheric Plasma as an Adjunct to Immunotherapy for Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer in adults. GBM carries a dismal prognosis because of its proliferative, invasive, and angiogenic capabilities and because of its ability to downregulate the immune system. Immune-based therapies under investigation for GBM have been unsuccessful in vivo because of this downregulation. Cold atmospheric plasma (CAP) is a high-energy state of matter that can be applied directly or indirectly to tumor tissue to serve as an adjunct to immunotherapy in the treatment of GBM because it upregulates the immune system by the induction of reactive oxygen species. CAP has the potential to improve the efficacy of existing and investigative immunotherapies for GBM.