Modern Multidisciplinary Management of Soft Tissue Sarcoma of the Extremity and Trunk.

Soft tissue sarcomas (STS) of the extremity and trunk are heterogeneous and rare tumors that require coordinated multidisciplinary management. Surgical resection remains the backbone of treatment for localized tumors, with the addition of radiotherapy to surgery to achieve high rates of local control. Despite this, overall survival is limited because of significant distant metastatic risk and a lack of efficacious systemic therapies. Clinical trials have produced conflicting results on the impact of systemic therapy in the neoadjuvant and adjuvant settings for patients with localized disease, leaving systemic treatment decisions largely guided by shared decision making and prognostic prediction tools such as nomograms. This article will review the foundational data as well as latest developments in surgical, radiotherapy, and systemic management supporting current practice guidelines for localized STS of the extremity and trunk.

Pediatric versus Adult Medulloblastoma: Towards a Definition That Goes beyond Age.

Medulloblastoma is a rare malignant brain tumor that predominantly affects children but also occurs in adults. The incidence declines significantly after age 15, and distinct tumor molecular features are seen across the age spectrum. Standard of care treatment consists of maximal safe surgical resection followed by adjuvant radiation and/or chemotherapy. Adjuvant treatment decisions are based on individual patient risk factors and have been informed by decades of prospective clinical trials. These trials have historically relied on arbitrary age cutoffs for inclusion (age 16, 18, or 21, for example), while trials that include adult patients or stratify patients by molecular features of disease have been rare. The aim of this literature review is to review the history of clinical trials in medulloblastoma, with an emphasis on selection criteria, and argue in favor of rational and inclusive trials based on molecular features of disease as opposed to chronological age. We performed a scoping literature review for medulloblastoma and clinical trials and include a summary of those results. We also discuss some of the significant advances made in understanding the molecular biology of medulloblastoma within the past decade, most notably the identification of four distinct subgroups based on gene expression profiling. We will also cite the recent experiences of childhood leukemia and the emergence of tissue-agnostic therapies as examples of successes of rationally designed, inclusive trials translating to improved clinical outcomes for patients across the age spectrum. Despite the prior trial history and recent molecular advances outcomes remain poor for ~30% of medulloblastoma patients. We believe that defining patients by the specific molecular alterations their tumors harbor is the best way to ensure they can access potentially efficacious therapies on clinical trials.

Management options of non-syndromic sagittal craniosynostosis.

There have been various effective surgical procedures for the treatment of non-syndromic sagittal craniosynostosis, but no definitive guidelines for management have been established. We conducted a study to elucidate the current state of practice and establish a warranted standard of care. An Internet-based study was sent to 180 pediatric neurosurgeons across the country and 102 craniofacial plastic surgeons in fourteen different countries, to collect data for primary indication for surgical management, preference for timing and choice of surgery, and pre-, peri-, and post-operative management options. The overall response rate from both groups was 32% (n=90/284). Skull deformity was the primary indication for surgical treatment in patients without signs of hydrocephalus for both neurosurgeons and craniofacial surgeons (80% and 63%, respectively). Open surgical management was most commonly performed at six months of age by neurosurgeons (46%) and also by craniofacial surgeons (35%). Open surgical approach was favored for patients younger than four months of age by neurosurgeons (50%), but endoscopic approach was favored by craniofacial surgeons (35%). When performing an open surgical intervention, most neurosurgeons preferred pi or reversed pi procedure (27%), whereas total cranial vault remodeling was the most commonly performed procedure by craniofacial surgeons (37%). The data demonstrated a discrepancy in the treatment options for non-syndromic sagittal craniosynostosis. By conducting/comparing a wide survey to collect consolidative data from both groups of pediatric neurosurgeons and craniofacial plastic surgeons, we can attempt to facilitate the establishment of standard of care.

The extracellular matrix proteoglycan perlecan facilitates transmembrane semaphorin-mediated repulsive guidance.

The Drosophila transmembrane semaphorin-1a (Sema-1a) is a repulsive guidance cue that uses the Plexin A (PlexA) receptor during neural development. Sema-1a is required in axons to facilitate motor axon defasciculation at guidance choice points. We found that mutations in the trol gene strongly suppress Sema-1a-mediated repulsive axon guidance. trol encodes the phylogenetically conserved secreted heparan sulfate proteoglycan (HSPG) perlecan, a component of the extracellular matrix. Motor axon guidance defects in perlecan mutants resemble those observed in Sema-1a- and PlexA-null mutant embryos, and perlecan mutants genetically interact with PlexA and Sema-1a. Perlecan protein is found in both the CNS and the periphery, with higher expression levels in close proximity to motor axon trajectories and pathway choice points. Restoring perlecan to mutant motor neurons rescues perlecan axon guidance defects. Perlecan augments the reduction in phospho-focal adhesion kinase (phospho-FAK) levels that result from treating insect cells in vitro with Sema-1a, and genetic interactions among integrin, Sema-1a, and FAK in vivo support an antagonistic relationship between Sema-1a and integrin signaling. Therefore, perlecan is required for Sema-1a-PlexA-mediated repulsive guidance, revealing roles for extracellular matrix proteoglycans in modulating transmembrane guidance cue signaling during neural development.