SUMMARY The angiographic, clinical, and genetic characteristics of fibromuscular dysplasia (FMD) are reviewed in 37 patients (mean age 48 years) selected from a pool of 4000 angiograms of carotid or vertebral arteries. FMD was a neglected pathogenic factor in 28 patients with hemorrhagic or ischemic cerebral lesions. The aneurysms found in 19 patients had conventional appearance and were mainly located in the internal carotid or middle cerebral arteries and on the same side as the most affected cervical artery, which suggests that aneurysms and FMD are pathogenically related. A clinical syndrome is presented where headache, ECGabnormalities, hypertension, mental distress, tinnitus, vertigo, arrhythmia, TIA, and syncope are frequent components. Hemicrania, sometimes combined with ipsilateral Horner's Syndrome, was found in patients with advanced lesions in the carotid artery of the same side. An associated occurrence of stroke in pedigrees, especially among young and middle aged females, indicates that FMD in the majority of cases is inherited as an autosomal dominant trait with reduced penetrance in males.Stroke, Vol 13, No 1,1982 EARLIER reports of fibromuscular dysplasia (FMD), to be reviewed in part two, have essentially contributed the same picture of FMD: an angiopathy often associated with hypertension, most often discovered in middle aged females, characterized by dysplastic vessel wall deformations multifocally spread within branches of the aorta, and a high frequency of intracranial aneurysms. The association of FMD with aneurysmal arterial disease, recognized early 1 as well as with an abundance of congenital abnormalities and an increasing number of reports of familial occurrence, raises the suggestion that FMD is a congenital mesenchymal disorder.In a recent ultrastructural study, Bragin and Chercaso 1979 2 suggest that FMD is based on a uniform morphogenetic process in which the leading role is played by fibroblast-like transformation of smooth muscle cells. Each one of the three major structures of the vessel wall (tunica intima, media, and adventitia) might be deformed by dysplastic lesions. Unfortunately, histological verification of aortocranial lesions is available only in a minority of cases. Thus, the clinical diagnosis in most cases has to be made with angiography. However, the characteristic macroscopic appearance and topography of the lesions are considered pathognomonic in the cervical as well as in the renal arteries.In this study, 37 patients from Karolinska Hospital are reviewed with special regard to the angiographic, clinical, and genetic features. We have found it important to discuss our results in the light of 1100 cases of FMD, with various locations, reported in the literature (part two). Patients and MethodsThirty females and 7 males with FMD (mean age 48 years, range 24-70) were found by scrutinizing 4000Departments of Neurology, Neuroradiology and Clinical Physiology, Karolinska Institute, Stockholm, Sweden.All correspondence should be directed to: Dr. K.L. Mettinger, Depa...

SUMMARY Eleven hundred cases from the literature of fibromuscular dysplasia (FMD) are reviewed including 300 cases with aortocranial lesions. The male-female ratio is 1:2, and the prevalence seems increased among Caucasians. The clinical diagnosis of FMD is made by angiography, ten years earlier in patients with hypertension (mean age 39 years) than in those with cerebrovascular symptoms (mean age 50 years). Segmental dysplastic lesions are found mainly in primary aortic branches. All age groups may be affected and follow-up studies give evidence for stationary as well as slowly progressive lesions. A multifactorial hypothesis of etiology is presented: congenital minor lesions of tunica media might predispose to aneurysms and to an abnormal fibroproliferative response to mechanical or circulatory stimuli. The association of FMD and intracranial aneurysmal disease in females is discussed. Inheritance as a dominant trait with reduced penetrance in males is suspected. Current aspects on morphology, symptomatology and clinical management are presented.

Summary Background Reolysin® is reovirus serotype 3-Dearing strain, a double-stranded replication-competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activated ras pathway due to inhibition of the dsRNA-activated protein kinase. Methods This was a single center dose escalation trial of Reolysin administered intravenously every 4 weeks in doses ranging from 1×108 to 3×1010 tissue culture infective dose (TCID)50. Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. Results Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a ras G12A mutation. Biopsy from her chest wall mass showed evidence of necrosis and viral replication by electron microscopy. Overall clinical benefit (1 PR + 7 stable disease) rate was 45%, and appeared higher in patients with viral shedding (67%) than those without (33%). Conclusion Reolysin administered monthly as a one-hour infusion is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies.

Purpose Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. Experimental Design Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 109, 1 × 1010, and 3 × 1010 TCID50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 1010 TCID50 dose characterized the response rate in patients with head and neck cancer. Results Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. Conclusions The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.