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Eric C. Raps, David H. Gutmann, James R. Brorson, Michael O'Connor and Howard I. Hurtig

✓ Central nervous system infections with Listeria monocytogenes result in varied clinical syndromes ranging from meningitis to rhomboencephalitis. A case of Listeria meningitis complicated by symptomatic communicating hydrocephalus and hydrostatic cervical cord compression is presented which clinically and radiographically improved with aggressive ventricular drainage.

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Russell Payne, Oliver D. Mrowczynski, Becky Slagle-Webb, Alexandre Bourcier, Christine Mau, Dawit Aregawi, Achuthamangalam B. Madhankumar, Sang Y. Lee, Kimberly Harbaugh, James Connor and Elias B. Rizk

OBJECTIVE

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15% to 60%. MPNSTs are currently treated with resection (sometimes requiring limb amputation) in combination with chemoradiation, both of which demonstrate limited effectiveness. The authors present the results of immunohistochemical, in vitro, and in vivo analyses of MLN8237 for the treatment of MPNSTs in an orthoxenograft murine model.

METHODS

Immunohistochemistry was performed on tumor sections to confirm the increased expression of aurora kinase A. Cytotoxicity analysis was then performed on an MPNST cell line (STS26T) to assess the efficacy of MLN8237 in vitro. A murine orthoxenograft MPNST model transfected to express luciferase was then developed to assess the efficacy of aurora kinase A inhibition in the treatment of MPNSTs in vivo. Mice with confirmed tumor on in vivo imaging were divided into 3 groups: 1) controls, 2) mice treated with MLN8237, and 3) mice treated with doxorubicin/ifosfamide. Treatment was carried out for 32 days, with imaging performed at weekly intervals until postinjection day 42. Average bioluminescence among groups was compared at weekly intervals using 1-way ANOVA. A survival analysis was performed using Kaplan-Meier curves.

RESULTS

Immunohistochemical analysis showed robust expression of aurora kinase A in tumor cells. Cytotoxicity analysis revealed STS26T susceptibility to MLN8237 in vitro. The group receiving treatment with MLN8237 showed a statistically significant difference in tumor size compared with the control group starting at postinjection day 21 and persisting until the end of the study. The MLN8237 group also showed decreased tumor size compared with the doxorubicin/ifosfamide group at the conclusion of the study (p = 0.036). Survival analysis revealed a significantly increased median survival in the MLN8237 group (83 days) compared with both the control (64 days) and doxorubicin/ifosfamide (67 days) groups. A hazard ratio comparing the 2 treatment groups showed a decreased hazard rate in the MLN8237 group compared with the doxorubicin/ifosfamide group (HR 2.945; p = 0.0134).

CONCLUSIONS

The results of this study demonstrate that MLN8237 is superior to combination treatment with doxorubicin/ifosfamide in a preclinical orthoxenograft murine model. These data have major implications for the future of MPNST research by providing a robust murine model as well as providing evidence that MLN8237 may be an effective treatment for MPNSTs.

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Mark D. Meadowcroft, Timothy K. Cooper, Sebastian Rupprecht, Thaddeus C. Wright, Elizabeth E. Neely, Michele Ferenci, Weimin Kang, Qing X. Yang, Robert E. Harbaugh, James R. Connor and James McInerney

OBJECTIVE

Intracranial aneurysms are vascular abnormalities associated with neurological morbidity and mortality due to risk of rupture. In addition, many aneurysm treatments have associated risk profiles that can preclude the prophylactic treatment of asymptomatic lesions. Gamma Knife radiosurgery (GKRS) is a standard treatment for trigeminal neuralgia, tumors, and arteriovenous malformations. Aneurysms associated with arteriovenous malformations have been noted to resolve after treatment of the malformation. The aim of this study was to determine the efficacy of GKRS treatment in a saccular aneurysm animal model.

METHODS

Aneurysms were surgically produced using an elastase-induced aneurysm model in the right common carotid artery of 10 New Zealand white rabbits. Following initial observation for 4 years, each rabbit aneurysm was treated with a conformal GKRS isodose of 25 Gy to the 50% margin. Longitudinal MRI studies obtained over 2 years and terminal measures obtained at multiple time points were used to track aneurysm size and shape index modifications.

RESULTS

Aneurysms did not rupture or involute during the observation period. Whole aneurysm and blood volume averages decreased with a linear trend, at rates of 1.7% and 1.6% per month, respectively, over 24 months. Aneurysm wall percent volume increased linearly at a rate of 0.3% per month, indicating a relative thickening of the aneurysm wall during occlusion. Nonsphericity of the average volume, aspect ratio, and isoperimetric ratio of whole aneurysm volume all remained constant. Histopathological samples demonstrated progressive reduction in aneurysm size and wall thickening, with subintimal fibrosis. Consistent shape indices demonstrate stable aneurysm patency and maintenance of minimal rupture risk following treatment.

CONCLUSIONS

The data indicate that GKRS targeted to saccular aneurysms is associated with histopathological changes and linear reduction of aneurysm size over time. The results suggest that GKRS may be a viable, minimally invasive treatment option for intracranial aneurysm obliteration.

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Abhaya V. Kulkarni, James M. Drake, John R. W. Kestle, Conor L. Mallucci, Spyros Sgouros and Shlomi Constantini

Object

The authors recently developed and internally validated the ETV Success Score (ETVSS)—a simplified means of predicting the 6-month success rate of endoscopic third ventriculostomy (ETV) for a child with hydrocephalus, based on age, etiology of hydrocephalus, and presence of a previous shunt. A high ETVSS predicts a high chance of early ETV success. In this paper, they assess the clinical utility of the ETVSS by determining whether long-term survival outcomes for ETV versus shunt insertion are different within strata of ETVSS (low, moderate, and high scores).

Methods

A multicenter, international cohort of children (≤ 19 years old) with newly diagnosed hydrocephalus treated with either ETV (489 patients) or shunt insertion (720 patients) was analyzed. The ETVSS was calculated for all patients. Survival analyses with time-dependent modeling of the hazard ratios were performed.

Results

For the High-ETVSS Group (255 ETV-treated patients, 117 shunt-treated patients), ETV appeared to have a lower risk of failure right from the early postoperative phase and became more favorable with time. For the Moderate-ETVSS Group (172 ETV-treated patients, 245 shunt-treated patients), ETV appeared to have a higher initial failure rate, but after about 3 months the instantaneous risk of ETV failure became slightly lower than shunt failure (that is, the hazard ratio became < 1). For the Low-ETVSS Group (62 ETV-treated patients, 358 shunt-treated patients), the early risk of ETV failure was much higher than the risk of shunt failure, but the instantaneous risk of ETV failure became lower than the risk of shunt failure at about 6 months following surgery (the hazard ratio became < 1).

Conclusions

Across all ETVSS strata, the risk of ETV failure becomes progressively lower compared with the risk of shunt failure with increasing time from the surgery. In the best ETV candidates (ETVSS ≥ 80), however, the risk of ETV failure is lower than the risk of shunt failure very soon after surgery, while for less-than-ideal ETV candidates (ETVSS ≤ 70), the risk of ETV failure is initially higher than the risk of shunt failure and only becomes lower after 3–6 months from surgery. These results need to be confirmed by larger, prospective, and preferably randomized studies.

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Editorial

Prediction, with restriction

Alan R. Cohen

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Oliver D. Mrowczynski, Russell A. Payne, Alexandre J. Bourcier, Christine Y. Mau, Becky Slagle-Webb, Ganesh Shenoy, Achuthamangalam B. Madhankumar, Stephan B. Abramson, Darren Wolfe, Kimberly S. Harbaugh, Elias B. Rizk and James R. Connor

OBJECTIVE

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that harbor a high potential for metastasis and have a devastating prognosis. Combination chemoradiation aids in tumor control and decreases tumor recurrence but causes deleterious side effects and does not extend long-term survival. An effective treatment with limited toxicity and enhanced efficacy is critical for patients suffering from MPNSTs.

METHODS

The authors recently identified that interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed on MPNSTs and could serve as a precision-based target for delivery of chemotherapeutic agents. In the work reported here, a recombinant fusion molecule consisting of a mutant human IL-13 targeting moiety and a point mutant variant of Pseudomonas exotoxin A (IL-13.E13 K-PE4E) was utilized to treat MPNST in vitro in cell culture and in an in vivo murine model.

RESULTS

IL-13.E13 K-PE4E had a potent cytotoxic effect on MPNST cells in vitro. Furthermore, intratumoral administration of IL-13.E13 K-PE4E to orthotopically implanted MPNSTs decreased tumor burden 6-fold and 11-fold in late-stage and early-stage MPNST models, respectively. IL-13.E13 K-PE4E treatment also increased survival by 23 days in the early-stage MPNST model.

CONCLUSIONS

The current MPNST treatment paradigm consists of 3 prongs: surgery, chemotherapy, and radiation, none of which, either singly or in combination, are curative or extend survival to a clinically meaningful degree. The results presented here provide the possibility of intratumoral therapy with a potent and highly tumor-specific cytotoxin as a fourth treatment prong with the potential to yield improved outcomes in patients with MPNSTs.