Dawit Aregawi

OPTIC NEUROPATHY IN PATIENTS WITH GLIOBLASTOMA RECEIVING BEVACIZUMAB

Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, was recently approved for treatment of glioblastoma. Initial data indicate increased response rates and progression-free survival compared to historical controls. Despite these promising data, we have identified several cases of severe optic neuropathy in patients with glioblastoma treated with bevacizumab. ### Methods. We performed a retrospective record review from 2005 to 2008 to identify adult patients with glioblastoma receiving bevacizumab who developed severe optic neuropathy. Five institutions participated, including the University of Virginia, UCLA, Columbia University, Rush University, and the University of Nebraska. The UCLA patient has already been reported in a larger case series discussing patients with glioblastoma receiving bevacizumab.1 Age at diagnosis, gender, radiation therapy data, chemotherapeutic regimens including the bevacizumab dosing schedule, ophthalmologic records, CSF results, and MRI were assessed. ### Standard protocol approvals, registrations, and patient consents. Each institution provided institutional review board approval. Since data were collected retrospectively without identifiers, institutional review boards did not require patient or surrogate consent. ### Results. Six patients (5 women) were identified. Median age at diagnosis was 61 years (range 37 to 68). Following surgery, all patients received fractionated radiation therapy with concomitant temozolomide. One patient received bevacizumab at initial diagnosis; 5 received it at progression. Tumors received 60 Gy delivered in a mean of 30 fractions. Mean radiation dose to the optic chiasm, left optic nerve, and right optic nerve was 5,602.4 cGy, 3,673 cGy, and …

Neuroleukemiosis: Case report of leukemic nerve infiltration in acute lymphoblastic leukemia

We describe a patient in remission from acute lymphoblastic leukemia who developed a painless common peroneal neuropathy. Magnetic resonance imaging (MRI) revealed nerve thickening and enhancement, while a positron emission tomography (PET) scan demonstrated increased fluorodeoxyglucose uptake in a large segment of the neurovascular bundle, suggesting peripheral nerve infiltration. Both findings resolved following treatment with chemotherapy that crossed the blood–nerve barrier. In selected patients presenting with peripheral neuropathy, MRI and PET scan can be helpful in the diagnosis of peripheral nerve infiltration. Muscle Nerve, 2008

Ramifications of four concurrent thrombophilic mutations and one hypofibrinolytic mutation.

A kindred was examined in which the 48-year-old white female proband with three deep venous thrombosis-pulmonary emboli events had four thrombophilic and one hypofibrinolytic mutations, and in which her 14-year-old asymptomatic daughter had four thrombophilic mutations. The proband was heterozygous for the G1691A factor V Leiden, G20210A prothrombin, and platelet glycoprotein IIIa PL A1/A2 mutations, had high factor VIII (221%), and was homozygous for the 4G4G plasminogen activator inhibitor-1 gene mutation, with high plasminogen activator inhibitor activity (23.7 U/mL). Her 14-year-old daughter was homozygous for the G1691A factor V Leiden and platelet glycoprotein IIb-IIIa PL A2/A2 mutations, compound heterozygous for the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) mutations, and heterozygous for the G20210A prothrombin mutation, a combination with an estimated likelihood of 1.6 × 10-7. In 247 white healthy controls, there was no V Leiden homozygosity and no V Leiden-prothrombin gene compound heterozygosity. Heterozygosity for the V Leiden and prothrombin gene mutations was 3.2% and 4.1%, respectively. Homozygosity for the platelet glycoprotein IIb-IIIa PL A2A2, PAI-1 gene 4G4G, and C677T MTHFR mutations was 3.2%, 22.7%, and 12%, respectively. The proband will receive anticoagulation therapy for life. Beyond aspirin, avoidance of exogenous estrogens, and enoxaparin prophylaxis during pregnancy, it is not known whether the proband’s daughter should have lifelong anticoagulation therapy, or only after her first thrombotic event.

Spinal Metastasis as Complication of Systemic Cancers

This chapter discusses the current natural history and techniques for management of metastatic spine tumors. We highlight the elements of the natural history, the imaging modalities for work-up and staging, and treatment. This treatment includes chemotherapy, radiation, surgery and the combination of each. The surgical options for diagnosis and treatment, current thoughts on extent of resection, as well as non-operative treatment options and the increasingly important role they play are discussed. It is our hope that this chapter gives an overview that can help educate and update healthcare providers of the evolving treatment of this disease. Metastatic tumors to the spine are a significant source of co-morbidity to patients already struggling with metastatic cancer. With thoughtful management both increased length of survival and improved quality of life can be achieved.

MLN8237 treatment in an orthoxenograft murine model for malignant peripheral nerve sheath tumors

OBJECTIVEMalignant 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.METHODSImmunohistochemistry 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.RESULTSImmunohistochemical 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).CONCLUSIONSThe 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.

Case of the month: Leukemic nerve infiltration

CASE OF THE MONTH: LEUKEMIC NERVE INFILTRATION We read with interest the Case of the Month article entitled “Neuroleukemiosis: case report of leukemic nerve infiltration in acute lymphoblastic leukemia.”1 The blood–nerve barrier is a recently described concept that may explain neurological relapse of successfully treated acute leukemias, especially when a peripheral neuropathy secondary to neoplastic infiltration manifests itself months prior to hematological relapse. The use of chemotherapy that penetrates the blood–nerve barrier, as mentioned in this case, is a way of overcoming this obstacle. Another treatment can be the use of radiation therapy, especially in the case of isolated peripheral nerve or plexus involvement. We have encountered a similar case2 where a young patient who was thought to be in remission from acute myelogenous leukemia (AML) type 5 presented with paresthesiae in a right ulnar nerve territory for about 6 months. Her symptoms were followed by progressive weakness of the intrinsic muscles of the right hand. Electromyographic (EMG) and nerve conduction studies (NCS) were consistent with a chronic denervating right ulnar neuropathy at the elbow. The right antebrachial cutaneous nerve of forearm sensory conduction and EMG of the right abductor pollicis brevis (APB) and extensor indicis muscles were normal. The false reassurance provided by evidence of hematological remission at neurological presentation and restriction of electrodiagnostic abnormalities to an ulnar distribution led to a diagnosis an ulnarneuropathy at the elbow (UNE). With further progression of symptoms, repeat electrophysiological showed disappearance of the medial antebrachial sensory response and acute denervation in the APB. Magnetic resonance imaging (MRI) showed infiltration by extra medullary tumors (EMTs) of the right brachial plexus, and ultimately the left brachial plexus and both lumbosacral plexi. By this time, 2 months after the original neurological presentation, the patient had developed an AML blast crisis. EMTs are depositions of blasts outside the blood vessels. They have been described in lymphomas and leukemias. They can compress and/or infiltrate peripheral nerve trunks and brachial or lumbosacral plexi, as in our case. This can result in progressive symptoms, as different fascicles are compressed and infiltrated earlier than others. We would like to know if the patient reported herein had brachial plexus imaging that could have explained the ulnar numbness, since there was no fluoro-deoxyglucose (FDG) uptake tracking along the ulnar nerves.

Focal Neuronal Gigantism: A Rare Complication of Therapeutic Radiation

SUMMARY: Radiation therapy, a mainstay in the treatment of many brain tumors, results in a variety of well-documented acute and chronic complications. Isolated cortical damage following irradiation represents an extremely rare delayed therapeutic complication, described only twice in the medical literature. We report this rare delayed complication in a patient following treatment of a right frontal anaplastic oligodendroglioma.

41 ROSUVASTATIN ACCEPTABILITY, EFFICACY, AND SAFETY IN HYPERCHOLESTEROLEMIC PATIENTS UNABLE TO TOLERATE OTHER STATINS.

Statins as a class are well tolerated. We assessed acceptability, efficacy, and safety of rosuvastatin in 57 euthyroid patients with primary high LDL cholesterol (LDLC) who, serially, could not tolerate most other statins or cholesterol-lowering drugs, primarily because of myocitis. Of the 57 patients, 44 could not tolerate atorvastatin, 27 simvastatin, 15 pravastatin, 7 fluvastatin, 2 lovastatin, 1 Vytorin, 10 WelChol, 5 Zetia, 2 TriCor, and 2 Niaspan. Rosuvastatin (5 mg/day)-diet was given to 24 patients (3 men, 21 women, 21 white, 3 black, 3 type 2 diabetics, mean ± SD age 61 ± 9 years, BMI 31.7 ± 4.2, LDLC 179 ± 32 mg/dL). On rosuvastatin 5 mg-diet for a median of 5 months, weight fell 3.0 ± 7.7 lb (p = .016), LDLC fell 76 ± 35 mg/dL (p < .0001) to 103 ± 31 mg/dL, with median percent change -47%. Adjusted for changes in body weight, decrements in LDLC remained significant, LS mean ± SE -75 ± 8 mg/dL, p < .0001. None of the 24 patients discontinued the 5 mg rosuvastatin, muscle symptoms were minor to absent, and there were no untoward changes in liver function tests (

4 SUCCESS OF METFORMIN-PIOGLITAZONE IN RESOLVING ENDOCRINOPATHY AND INSULIN RESISTANCE-HYPERINSULINEMIA IN 40 WOMEN WITH POLYCYSTIC OVARY SYNDROME NOT OPTIMALLY RESPONSIVE TO METFORMIN ALONE.

3 times the laboratory upper normal limit), or in CPK (

74 METFORMIN-DIET AMELIORATES CORONARY HEART DISEASE RISK FACTORS AND FACILITATES RESUMPTION OF REGULAR MENSES IN ADOLESCENTS WITH POLYCYSTIC OVARY SYNDROME.

10 times the laboratory upper normal limit). Rosuvastatin (10 mg/day) was given to 33 patients, 16 men, 17 women, 31 white, 1 black, 1 other, 9 smokers, 4 type 2 diabetics, mean ± SD age 59 ± 10 years, BMI 31.1 ± 5.2, and LDLC 178 ± 53 mg/dL. On therapy for a median of 11 months, body weight fell 3.1 ± 6.8 lb (p = .014), LDLC fell 80 ± 49 mg/dL (p < .0001) to 96 ± 38 mg/dL, median percent change -48%. Adjusted for body weight change, decrements in LDLC remained significant, LS mean ± SE -82 ± 11 mg/dL, p < .0001. None of the 33 patients discontinued the 10 mg rosuvastatin, muscle symptoms were minor to absent, and there were no untoward changes in liver function tests (