Person: Kasper, Ekkehard
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Kasper
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Ekkehard
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Kasper, Ekkehard
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Publication Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1(2017) Krishnan, Vaishnav; Stoppel, David C.; Nong, Yi; Johnson, Mark; Nadler, Monica; Ozkaynak, Ekim; Teng, Brian L.; Nagakura, Ikue; Mohammad, Fahim; Silva, Michael; Peterson, Sally; Cruz, Tristan J.; Kasper, Ekkehard; Arnaout, Ramy; Anderson, MatthewSummary Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant autism linked to increased gene dosages of UBE3A, which both possesses ubiquitin-ligase and transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus down-regulates glutamatergic synapse organizer cerebellin-1 (Cbln1) that is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases of UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA) where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activations of, or Cbln1 restorations in VTA glutamatergic neurons rescues sociability deficits induced by Ube3a and/or seizures. Our results suggest a gene × seizure interaction in VTA glutamatergic neurons that impairs sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.Publication Stereotactic radiosurgery for brain metastasis from gynecological malignancies(D.A. Spandidos, 2017) Kasper, Ekkehard; Ippen, Franziska; Wong, Eric; Uhlmann, Eric; Floyd, Scott; Mahadevan, AnandBrain metastases are relatively uncommon in gynecological malignancies, and there is limited available data on their management. The present study reports the outcomes of patients with brain metastasis from gynecological malignancies who were treated with stereotactic radiosurgery (SRS). Patients with brain metastasis from a gynecological primary site were treated with SRS using the Cyberknife™ frameless SRS system. Primary lesions were treated with a single fraction of 16–22 Gy. A total of 3 resection cavities were treated with 8 Gy 3 times, meaning a total of 24 Gy, and 1 recurrent lesion was re-irradiated with 5 Gy 5 times, meaning a total of 25 Gy. All patients were followed up with regular magnetic resonance imaging and clinical examinations 1 month after treatment and every 2 months thereafter. A total of 20 lesions in 8 patients were included in this study; 1 patient presented with metastatic endometrial cancer and the remaining 7 presented with metastatic ovarian cancer. The median age was 61 years (range, 48–78 years). All patients had received systemic therapy prior to developing brain metastasis. A total of 3 patients underwent surgical resection and 1 patient was administered re-irradiation for recurrence. There were 3 local failures in 2 patients. The actuarial 1-, 2- and 3-year local control rates were 91, 91 and 76%, respectively. The median overall survival time was 29 months. No SRS-associated toxicities or neurological mortalities were observed. In conclusion, brain metastasis from gynecological malignancies is uncommon, however, SRS is a safe and effective treatment modality for local control as a primary or adjuvant treatment in patients with this disease.Publication Chronic Q-Fever (Coxiella burnetii) Causing Abdominal Aortic Aneurysm and Lumbar Osteomyelitis: A Case Report(Oxford University Press, 2015) Leahey, P. Alexander; Tahan, Steven R.; Kasper, Ekkehard; Albrecht, MaryCoxiella burnetii is a rare cause of chronic infection that most frequently presents as endocarditis. We report a case of C burnetii causing an infected abdominal aortic aneurysm with contiguous lumbar osteomyelitis resulting in spinal cord compromise. The diagnosis was established by serologic studies consistent with chronic Q-fever (ratio of C burnetii immunoglobulin [Ig]G phase II titer to IgG phase I titer <1) and was confirmed by positive C burnetii polymerase chain reaction of vertebral tissue in addition to pathology of vertebral bone showing intracellular Gram-negative coccobacillary bacteria. The patient clinically improved after surgical decompression and prolonged treatment with doxycycline and hydroxychloroquine.Publication Stereotactic Radiosurgery for Renal Cancer Brain Metastasis: Prognostic Factors and the Role of Whole-Brain Radiation and Surgical Resection(Hindawi Publishing Corporation, 2015) Ippen, Franziska M.; Mahadevan, Anand; Wong, Eric; Uhlmann, Erik; Sengupta, Soma; Kasper, EkkehardBackground:. Renal cell carcinoma is a frequent source of brain metastasis. We present our consecutive series of patients treated with Stereotactic Radiosurgery (SRS) and analyse prognostic factors and the interplay of WBRT and surgical resection. Methods. This is a retrospective study of 66 patients with 207 lesions treated with the Cyberknife radiosurgery system in our institution. The patients were followed up with imaging and clinical examination 1 month and 2-3 months thereafter for the brain metastasis. Patient, treatment, and outcomes characteristics were analysed. Results. 51 male (77.3%) and 15 female (22.7%) patients, with a mean age of 58.9 years (range of 31–85 years) and a median Karnofsky Performance Status (KPS) of 90 (range of 60–100), were included in the study. The overall survival was 13.9 months, 21.9 months, and 5.9 months for the patients treated with SRS only, additional surgery, and WBRT, respectively. The actuarial 1-year Local Control rates were 84%, 94%, and 88% for SRS only, for surgery and SRS, and for WBRT and additional SRS, respectively. Conclusions. Stereotactic radiosurgery is a safe and effective treatment option in patients with brain metastases from RCC. In case of a limited number of brain metastases, surgery and SRS might be appropriate.Publication Dosimetric analysis of the alopecia preventing effect of hippocampus sparing whole brain radiation therapy(BioMed Central, 2015) Mahadevan, Anand; Sampson, Carrie; LaRosa, Salvatore; Floyd, Scott R.; Wong, Eric; Uhlmann, Erik; Sengupta, Soma; Kasper, EkkehardBackground: Whole brain radiation therapy (WBRT) is widely used for the treatment of brain metastases. Cognitive decline and alopecia are recognized adverse effects of WBRT. Recently hippocampus sparing whole brain radiation therapy (HS-WBRT) has been shown to reduce the incidence of memory loss. In this study, we found that multi-field intensity modulated radiation therapy (IMRT), with strict constraints to the brain parenchyma and to the hippocampus, reduces follicular scalp dose and prevents alopecia. Methods: Suitable patients befitting the inclusion criteria of the RTOG 0933 trial received Hippocampus sparing whole brain radiation. On follow up, they were noticed to have full scalp hair preservation. 5 mm thickness of follicle bearing scalp in the radiation field was outlined in the planning CT scans. Conventional opposed lateral WBRT radiation fields were applied to these patient-specific image sets and planned with the same nominal dose of 30 Gy in 10 fractions. The mean and maximum dose to follicle bearing skin and Dose Volume Histogram (DVH) data were analyzed for conventional and HS-WBRT. Paired t-test was used to compare the means. Results: All six patients had fully preserved scalp hair and remained clinically cognitively intact 1–3 months after HS-WBRT. Compared to conventional WBRT, in addition to the intended sparing of the Hippocampus, HS-WBRT delivered significantly lower mean dose (22.42 cGy vs. 16.33 cGy, p < 0.0001), V24 (9 cc vs. 44 cc, p < 0.0000) and V30 (9 cc vs. 0.096 cc, p = 0.0106) to follicle hair bearing scalp and prevented alopecia. There were no recurrences in the Hippocampus area. Conclusions: HS-WBRT, with an 11-field set up as described, while attempting to conserve hippocampus radiation and maintain radiation dose to brain inadvertently spares follicle-bearing scalp and prevents alopecia.Publication Preoperative Embolization of Extra-axial Hypervascular Tumors with Onyx(Korean Society of Cerebrovascular Surgeons; Society of Korean Endovascular Neurosurgeons, 2016) Fusco, Matthew R.; Salem, Mohamed M.; Gross, Bradley A.; Reddy, Arra S.; Ogilvy, Christopher; Kasper, Ekkehard; Thomas, AjithObjective: Preoperative endovascular embolization of intracranial tumors is performed to mitigate anticipated intraoperative blood loss. Although the usage of a wide array of embolic agents, particularly polyvinyl alcohol (PVA), has been described for a variety of tumors, literature detailing the efficacy, safety and complication rates for the usage of Onyx is relatively sparse. Materials and Methods We reviewed our single institutional experience with pre-surgical Onyx embolization of extra-axial tumors to evaluate its efficacy and safety and highlight nuances of individualized cases. Results: Five patients underwent pre-surgical Onyx embolization of large or giant extra-axial tumors within 24 hours of surgical resection. Four patients harbored falcine or convexity meningiomas (grade I in 2 patients, grade II in 1 patient and grade III in one patient), and one patient had a grade II hemangiopericytoma. Embolization proceeded uneventfully in all cases and there were no complications. Conclusion: This series augments the expanding literature confirming the safety and efficacy of Onyx in the preoperative embolization of extra-axial tumors, underscoring its advantage of being able to attain extensive devascularization via only one supplying pedicle.Publication Complex single step skull reconstruction in Gorham’s disease - a technical report and review of the literature(BioMed Central, 2015) Ohla, Victoria; Bayoumi, Ahmed B; Hefty, Markus; Anderson, Matthew; Kasper, EkkehardBackground: Gorham’s disease is a rare osteolytic disorder characterized by progressive resorption of bone and replacement of osseous matrix by a proliferative non-neoplastic vascular or lymphatic tissue. A standardized treatment protocol has not yet been defined due to the unpredictable natural history of the disease and variable clinical presentations. No single treatment has proven to be superior in arresting the course of the disease. Trials have included surgery, radiation and medical therapies using drugs such as calcium salts, vitamin D supplements and hormones. We report on our advantageous experience in the management of this osteolyic disorder in a case when it affected only the skull vault. A brief review of pertinent literature about Gorham’s disease with skull involvement is provided. Case presentation: A 25-year-old Caucasian male presented with a skull depression over the left fronto-temporal region. He noticed progressive enlargement of the skull defect associated with local pain and mild headache. Physical examination revealed a tender palpable depression of the fronto-temporal convexity. Conventional X-ray of the skull showed widespread loss of bone substance. Subsequent CT scans showed features of patchy erosions indicative of an underlying osteolysis. MRI also revealed marginal enhancement at the site of the defect. The patient was in need of a pathological diagnosis as well as complex reconstruction of the afflicted area. A density graded CT scan was done to determine the variable degrees of osteolysis and a custom made allograft was designed for cranioplasty preoperatively to allow for a single step excisional craniectomy with synchronous skull repair. Gorham’s disease was diagnosed based on histopathological examination. No neurological deficit or wound complications were reported postoperatively. Over a two-year follow up period, the patient had no evidence of local recurrence or other systemic involvement. Conclusions: A single step excisional craniectomy and cranioplasty can be an effective treatment for patients with Gorham’s disease affecting the skull vault only. Preoperative planning by a density graded CT aids to design a synthetic bone flap and is beneficial in skull reconstruction. Systemic involvement is variable in this patient’s population.Publication Primary epidural lymphocyte-depleted Hodgkin’s lymphoma of the thoracic spine – presentation of a rare disease variant(BioMed Central, 2012) Kasper, Ekkehard; Lam, Fred C; Luedi, Markus M; Zinn, Pascal O; Pihan, GermanBackground: Lymphocyte-depleted Hodgkin’s lymphoma is the rarest form of classical Hodgkin’s lymphoma, accounting for < 1% of all cases. Patients often have advanced-stage disease at the time of presentation with an aggressive clinical course. Even more uncommon is primary extranodal disease and rarely it will be presenting with spinal cord compression. Case presentation: An 88-year-old Caucasian female presented with a history of upper back pain for several months and new onset bilateral leg numbness and weakness. MRI of the spine showed a dorsal epidural lesion with cord compression at T1-T4 with involvement of the paraspinal muscles. The patient received urgent surgical decompression, with final histopathology showing a lymphocyte-depleted Hodgkin’s lymphoma. Systemic work-up did not show evidence of nodal disease. Following surgery, she received a course of radiotherapy with good outcome. Conclusion: To the best of our knowledge, this is the first reported case of primary lymphocyte-depleted Hodgkin lymphoma presenting as epidural spinal cord compression. Our report, in conjunction with a review of the literature, suggests that surgical intervention is clearly indicated in de novo disease followed by radiotherapy.Publication Hypofractionated Radiotherapy and Stereotactic Boost with Concurrent and Adjuvant Temozolamide for Glioblastoma in Good Performance Status Elderly Patients – Early Results of a Phase II Trial(Frontiers Media S.A., 2012) Floyd, Scott R.; Kasper, Ekkehard; Uhlmann, Erik; Fonkem, Ekokobe; Wong, Eric; Mahadevan, AnandGlioblastoma Multiforme (GBM) is an aggressive primary brain neoplasm with dismal prognosis. Based on successful phase III trials, 60 Gy involved-field radiotherapy in 30 fractions over 6 weeks [Standard radiation therapy (RT)] with concurrent and adjuvant temozolomide is currently the standard of care. In this disease, age and Karnofsky Performance Status (KPS) are the most important prognostic factors. For elderly patients, clinical trials comparing standard RT with radiotherapy abbreviated to 40 Gy in 15 fractions over 3 weeks demonstrated similar outcomes, indicating shortened radiotherapy may be an appropriate option for elderly patients. However, these trials did not include temozolomide chemotherapy, and included patients with poor KPS, possibly obscuring benefits of more aggressive treatment for some elderly patients. We conducted a prospective Phase II trial to examine the efficacy of a hypofractionated radiation course followed by a stereotactic boost with concurrent and adjuvant temozolomide chemotherapy in elderly patients with good performance status. In this study, patients 65 years and older with a KPS > 70 and histologically confirmed GBM received 40 Gy in 15 fractions with 3D conformal technique followed by a 1–3 fraction stereotactic boost to the enhancing tumor. All patients also received concurrent and adjuvant temozolomide. Patients were evaluated 1 month post-treatment and every 2 months thereafter. Between 2007 and 2010, 20 patients (9 males and 11 females) were enrolled in this study. The median age was 75.4 years (range 65–87 years). At a median follow-up of 11 months (range 7–32 months), 12 patients progressed and 5 are alive. The median progression free survival was 11 months and the median overall survival was 13 months. There was no additional toxicity. These results indicate that elderly patients with good KPS can achieve outcomes comparable to the current standard of care using an abbreviated radiotherapy course, radiosurgery boost, and temozolomide.Publication Cranio-Spinal Migration of a Metallic Clip Placed During Arteriovenous Malformation Resection - A Case Report, Review of the Literature, and Management Strategies(BioMed Central, 2010) Chen, Clark Chin-Chung; Zinn, Pascal Olivier; Kasper, Ekkehard; Ogilvy, ChristopherBackground: Microclip placement during AVM resection is generally accepted to be a safe practice in neurosurgery. Here, we describe an unusual complication involving cranio-spinal clip migration discovered five years after the initial AVM surgery. Case Presentation: A 53-year-old man underwent resection of a superior vermian AVM that required the placement of two microclips during the procedure. Five years after surgery, the patient suffered from descending sensory radiculopathy that resolved spontaneously. The workup revealed cranio-spinal migration of one of the previously placed microclips. Conclusions: AVM clip migration is a rare phenomenon; however, the diagnosis should be entertained in patients with posterior fossa instrumentation who suffer from unusual neurologic symptoms.