Ryan T. Mott

Cooperation between Dmp1 loss and cyclin D1 overexpression in breast cancer.

Cyclin D1 is a component of the core cell-cycle machinery and is frequently overexpressed in breast cancer. It physically interacts with the tumor suppressor Dmp1 that attenuates the oncogenic signals from Ras and HER2 by inducing Arf/p53-dependent cell-cycle arrest. Currently, the biological significance of Dmp1-cyclin D1 interplay in breast cancer has not been determined. Here, we show that cyclin D1 bound to Dmp1 to activate both Arf and Ink4a promoters and, consequently, induced apoptosis or G2/M cell-cycle delay in normal cells to protect them from neoplastic transformation. The cyclin D1-induced Ink4a/Arf gene expression was dependent on Dmp1 because the induction was not detected in Dmp1-deficient or DMP1-depleted cells. Arf/Ink4a expression was increased in pre-malignant mammary glands from Dmp1(+/+);MMTV-cyclin D1 and Dmp1(+/+);MMTV-D1T286A mice but significantly down-regulated in those from Dmp1-deficient mice. Selective Dmp1 deletion was found in 21% of the MMTV-D1 and D1T286A mammary carcinomas, and the Dmp1 heterozygous status significantly accelerated mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Overall, our study reveals a pivotal role of combined Dmp1 loss and cyclin D1 overexpression in breast cancer.

Comprehensive Genomic Profiling of 282 Pediatric Low‐ and High‐Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures

This study highlights the value of comprehensive genomic profiling in the largest known cohort of pediatric glioma patients and explores the most common alterations across diagnosis and anatomic location. Tumor mutational burden and associated genetic factors that may predispose patients to developing a hypermutator phenotype are also discussed.

Reduced ratio of afferent to total vascular density in mesial temporal sclerosis.

Mesial temporal sclerosis (MTS) is the most common cause of drug-resistant temporal lobe epilepsy in adults. Despite nearly 2 centuries since the first reports of MTS, relatively little is known about its etiology and pathogenesis. Increasing attention has been directed toward the potential role of vascular abnormalities in MTS. We evaluated the hippocampal microvasculature in 9 MTS cases and 3 non-MTS controls using celloidin tissue sections and markers for total (collagen type IV) and afferent (enzymatic alkaline phosphatase) vessels. Tissue sections were assessed by light microscopy and quantified by threshold analysis of digital images and stereological analysis using the Space Balls probe. Although consistent alterations in the total microvascular density were not found, there was a significant reduction in the density of afferent vessels using both methodologies; these reductions were in areas CA2 and CA3 by image threshold analysis and in area CA3 using stereological measures of the ratio of afferent to total vessels. Increased numbers of string vessels (i.e. remnants of regressing vasculature) were also observed in Ammons horn, suggesting vascular degeneration in the MTS hippocampus. These findings may help further our understanding of the pathophysiology of MTS.

Ultrasonographic Tinel sign

High‐resolution ultrasound has become increasingly useful in the evaluation of peripheral nerves. As we have gained experience, clinically helpful ultrasonographic signs have been detected. One of these is the ultrasonographic Tinel sign, in which paresthesias are produced when the transducer compresses a nerve lesion. This sign has not been previously described. We present a case in which the ultrasonographic Tinel sign helped accurately guide a nerve biopsy in a woman with mononeuritis multiplex. Muscle Nerve, 2009

A unique case of a giant congenital pulmonary hemangioma in a newborn

Congenital pulmonary hemangiomas are extremely rare lesions. We present a unique case of a giant congenital pulmonary hemangioma in an otherwise healthy newborn who presented with respiratory distress at birth. This was managed with resection after an unsuccessful trial of nonoperative management. The clinical, radiographic, and pathologic features of this unique case are discussed in the context of a review of the literature.

Early or late radiotherapy following gross or subtotal resection for atypical meningiomas: Clinical outcomes and local control

We report a single institution series of surgery followed by either early adjuvant or late radiotherapy for atypical meningiomas (AM). AM patients, by WHO 2007 definition, underwent subtotal resection (STR) or gross total resection (GTR). Sixty-three of a total 115 patients then received fractionated or stereotactic radiation treatment, early adjuvant radiotherapy (≤4months after surgery) or late radiotherapy (at the time of recurrence). Kaplan Meier method was used for survival analysis with competing risk analysis used to assess local failure. Overall survival (OS) at 1, 2, and 5years for all patients was 87%, 85%, 66%, respectively. Progression free survival (PFS) at 1, 2, and 5years for all patients was 65%, 30%, and 18%, respectively. OS at 1, 2, and 5years was 75%, 72%, 55% for surgery alone, and 97%, 95%, 75% for surgery+radiotherapy (log-rank p-value=0.0026). PFS at 1, 2, and 5years for patients undergoing surgery without early adjuvant radiotherapy was 64%, 49%, and 27% versus 81%, 73%, and 59% for surgery+early adjuvant radiotherapy (log-rank p-value=0.0026). The cumulative incidence of local failure at 1, 2, and 5years for patients undergoing surgery without early External Beam Radiation Therapy (EBRT) was 18.7%, 35.0%, and 52.9%, respectively, versus 4.2%, 13.3%, and 20.0% for surgery and early EBRT (p-value=0.02). Adjuvant radiotherapy improves OS in patients with AM. Early adjuvant radiotherapy improves PFS, likely due to the improvement in local control seen with early adjuvant EBRT.

Relapsing intracranial plasma cell granuloma: A case report

Plasma cell granuloma is a pathological entity reported in nearly every organ system; however, intracranial cases remain rare. In the current case report, we present a case of intracranial plasma cell granuloma with the longest known follow-up period in the literature. Medical follow-up over 14 years, detailing four recurrences following the patient’s initial presentation and management, is presented. The patient’s treatment course consisted of three craniotomies, 3,600-cGy fractionated radiation and two courses of glucocorticoid therapy. In addition to disease surveillance using clinical examination and imaging, this case represents the first description of the clinical utility of analyzing changes in an inflammatory blood marker, the erythrocyte sedimentation rate, which coincided with recurrence and response to therapy.

Radiation-induced adult medulloblastoma: a two-case report and review of the literature

Radiation-induced medulloblastoma is an exceedingly rare phenomenon for which treatment standards have not been established. The literature suggests that these tumors are high grade with aggressive behavior. We report two cases of radiation-induced medulloblastoma which have been treated with full dose re-irradiation with curative intent. In both cases, treatment toxicity and tumor progression proved to be insurmountable obstacles. Further reports are necessary in order to fully characterize this clinical entity so that more effective therapies may be sought.

Angiofollicular lymph node hyperplasia resembling a spinal nerve sheath tumor: a rare case of Castleman's disease

BACKGROUND CONTEXT Angiofollicular lymph node hyperplasia (Castlemans disease) is a lymphoproliferative disorder of unknown etiology. Although uncommon, the localized form of this disease can manifest in the central nervous system, typically as a meningeal-based intracranial lesion. Castlemans disease involving the spine is exceedingly rare. This represents only the second reported case of a patient with Castlemans disease whose presentation mimicked that of a spinal nerve sheath tumor. PURPOSE We report a rare case of angiofollicular lymph node hyperplasia that mimicked a spinal nerve sheath tumor and was treated with gross total resection. STUDY DESIGN Case report. PATIENT SAMPLE A 31-year-old female with angiofollicular lymph node hyperplasia presenting with a paraspinal mass. OUTCOME MEASURES The patients outcome was based on clinical history, physical and radiographic examinations. METHODS A 31-year-old woman with a mediastinal mass previously diagnosed as sarcoid via biopsy presented with the new onset of radicular pain and radiographic enlargement of her mass. Magnetic resonance imaging demonstrated a 4.3x5.7x6.0 cm homogenously enhancing soft-tissue lesion that emanated from and widened the T3/T4 neural foramen on the left. The differential diagnosis based on the location of the lesion and imaging characteristics included schwannoma, neurofibroma, paraganglioma, sarcoid, and lymphoma. Gross total resection was performed via thoracotomy. Histological examination identified angiofollicular lymph node hyperplasia (Castlemans disease) of the hyaline-vascular subtype. The patient did not receive adjuvant chemotherapy or radiation therapy. RESULTS The patient had resolution of her symptoms without any clinical or radiographic evidence of recurrence at 1-year follow-up using magnetic resonance imaging with and without contrast. CONCLUSIONS Castlemans disease is a rare pathologic entity that should be considered in the differential diagnosis of a patient with a paraspinal mass. Spine surgeons should be aware of this diagnosis as it has treatment and follow-up implications that differ from the neoplasms it can mimic. Complete surgical excision is an effective treatment for solitary lesions. Screening for concurrent and future malignancies in these patients is prudent.

Evisceration with Injectable Hydrogel Implant in a Rabbit Model.

PURPOSE To determine the safety, durability, and biocompatibility of 2.5% polyacrylamide hydrogel (Aquamid, Specialty European Pharma, Ltd., London, UK) as an injectable viscoelastic implant following evisceration in a rabbit model. METHODS The protocol was reviewed and approved by the Wake Forest Institutional Animal Care and Use Committee. Adult New Zealand rabbits underwent cornea-sparing evisceration of the right eye with injection of 2.5% polyacrylamide hydrogel implant. The rabbits were sacrificed after 2 weeks (n = 1), 5 weeks (n = 2), 12 weeks (n = 3), 25 weeks (n = 3), and 1 year (n = 3) to evaluate the implant volume and host reaction to the implant. Both eyes were enucleated and their diameters were measured. The eviscerated eyes were fixed in formalin and processed using routine histopathologic methods to assess inflammatory reaction and vascularization. RESULTS The implant material was well tolerated with a moderate giant cell reaction seen at 6 weeks that improved over time. Extensive vascularization of the implant was noted starting at 6 weeks. There was excellent maintenance of globe volume that did not diminish over time. The relative diameters of the eviscerated eyes compared with control were 89 ± 6% (mean% ± SD) at 12 weeks (n = 3), 94 ± 2% at 25 weeks (n = 3), and 93 ± 4% at 1 year (n = 3). CONCLUSION With further study, injectable 2.5% polyacrylamide hydrogel may provide an excellent alternative to solid orbital implants. The implant material was universally well tolerated and maintained appropriate volume in the orbit for the study period of 1 year. Extensive vascularization of the implant was noted indicating biointegration.