Treatment of glioblastoma with re-purposed renin-angiotensin system modulators: Results of a phase I clinical trial.

Glioblastoma is the most common and most aggressive primary brain cancer in adults. Standard treatment of glioblastoma consisting of maximal safe resection, adjuvant radiotherapy and chemotherapy with temozolomide, results in an overall median survival of 14.6 months. The aggressive nature of glioblastoma has been attributed to the presence of glioblastoma stem cells which express components of the renin-angiotensin system (RAS). This phase I clinical trial investigated the tolerability and efficacy of a treatment targeting the RAS and its converging pathways in patients with glioblastoma. Patients who had relapsed following standard treatment of glioblastoma who met the trial criteria were commenced on dose-escalated oral RAS modulators (propranolol, aliskiren, cilazapril, celecoxib, curcumin with piperine, aspirin, and metformin). Of the 17 patients who were enrolled, ten completed full dose-escalation of the treatment. The overall median survival was 19.9 (95% CI:14.1-25.7) months. Serial FET-PET/CTs showed a reduction in both tumor volume and uptake in one patient, an increase in tumor uptake in nine patients with decreased (n = 1), unchanged (n = 1) and increased (n = 7) tumor volume, in the ten patients who had completed full dose-escalation of the treatment. Two patients experienced mild side effects and all patients had preservation of quality of life and performance status during the treatment. There is a trend towards increased survival by 5.3 months although it was not statistically significant. These encouraging results warrant further clinical trials on this potential novel, well-tolerated and cost-effective therapeutic option for patients with glioblastoma.

Relapse patterns after low-dose-rate prostate brachytherapy.

PURPOSE: When biochemical failure (BF) develops after low-dose-rate prostate brachytherapy, the relapse site is frequently not found. We set out to find whether prostate-specific membrane antigen positron emission tomography -CT (PSMA PET-CT) scanning has improved knowledge of relapse patterns. METHODS AND MATERIALS: A database was analyzed, which contained information and long-term followup on 903 men who had an iodine-125 seed implant as monotherapy for early-stage prostate cancer. There was a total of 68 BFs. RESULT: In 38 men developing BF before PSMA PET-CT scanning was available, the site of relapse was local in six, distant in twelve, and unknown in twenty. In 30 men developing BF more recently who had a PSMA PET-CT scan, the relapse site was demonstrated in all cases, and 19 (63%) men had relapsed at the prostate base. Radiation dosimetry of base relapses and paired controls demonstrated that implants routinely delivered a lower radiation dose to the base than to the rest of the prostate. Eight of seventeen cases found to have prostate relapse only underwent salvage prostatectomy. CONCLUSION: PSMA PET-CT scanning is highly effective in demonstrating the relapse site(s) when BF develops after low-dose-rate prostate brachytherapy. Knowledge of the relapse site increases management options for men developing BF.

Management of Orbital and Periorbital Venous Malformation.

BACKGROUND: To review our management of common venous malformation (VM) affecting the orbit and/or periorbital area. METHODS: Consecutive patients with orbital and/or periorbital VM were identified from our vascular anomalies database. Demographic details of the patients, anatomic site(s) affected, symptoms and signs, presence of a family history of VM, and types of treatment(s) were collected, supplemented by chart review. RESULTS: A total of 24 patients' age 1-68 (mean, 30) years with orbital and/or periorbital VM presented with cosmetic concerns (n = 17, 71%), distensibility (n = 15, 63%), pain (n = 9, 38%), diplopia (n = 4, 17%), and spontaneous thrombosis (n = 1, 8%). The VM caused globe dystopia (n = 13, 54%), enophthalmos (n = 6, 25%), proptosis (n = 3, 12%), exotropia (n = 3, 12%), and pseudoptosis with visual obstruction (n = 3, 13%). A total of 11 (46%) patients were managed conservatively. 13 (54%) patients underwent active treatment. Ethanol sclerotherapy (ES) was performed in six patients with extensive facial VM associated with orbital/periorbital involvement, resulting in symptomatic improvement in five patients, one of whom developed skin necrosis and another patient developed reduced infraorbital nerve sensation. Surgery was performed for localized lesion (n = 3, 23%), for extensive lesions (n = 4, 31%) and as an adjunct to ES (n = 6, 46%) resulting in symptomatic improvement in all patients. One patient required correction of lower lid ectropion. CONCLUSION: Orbital and/or periorbital VMs are heterogeneous, and management needs to be individualized. Surgery is used for localized lesions aiming for complete excision, as a debulking procedure for extensive orbital/periorbital VM when ES was not possible, or following ES for extensive facial VM with orbital and/or periorbital involvement.

Ethanol sclerotherapy for venous malformation.

BACKGROUND: Ethanol sclerotherapy (ES) is the preferred treatment for venous malformation (VM) with surgery playing an adjunctive role. Results of ES, however, are not well documented in the literature. METHODS: VM patients were identified from our vascular anomalies database from 1996 to 2011. After treatment completion, patients completed questionnaires evaluating symptoms and their severity and effect on appearance, function and overall quality of life (QoL), before and >6 months after treatment, using visual analogue scales of 0-10. Patients rated their overall satisfaction with ES using a scale of 0-10. RESULTS: Fifty-four (23.9%) of the 226 VM patients underwent a total of 90 ES sessions (average 1.7 sessions per patient). Complications occurred in 12 (22.2%) patients in 12 (13.3%) ES sessions. Minor complications occurred in nine (16.7%) patients including transient paraesthesia (n = 3), transient weakness of facial nerve branch(es) (n = 3), skin blistering (n = 2) and spontaneously healing ulceration (n = 1). Major complications occurred in three (5.6%) patients in three (3.3%) ES sessions including skin necrosis (n = 1), Horner's syndrome (n = 1) and finger paraesthesia with joint stiffness (n = 1). ES improved the severity of background pain, episodic pain, contour deformity and skin discoloration in 86.0%, 72.4%, 83.0% and 72.2% of patients respectively. It reduced the effect of VM on appearance, function and overall QoL in 69.8%, 73.0% and 64.3% of patients. Mean treatment satisfaction was 7.9 (range, 0-10). CONCLUSION: ES reduces pain, contour deformity and skin discoloration, and improves appearance, function and QoL. Our complication rates are consistent with the literature.

PHACE(S) Syndrome With Absent Intracranial Internal Carotid Artery and Anomalous Circle of Willis.

The authors present a case of PHACE(S) (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies, and sternal cleft or supraumbilical raphe) syndrome with a right-sided segmental infantile hemangioma, and describe in detail, the associated absent ipsilateral intracranial internal carotid artery and anomalous Circle of Willis. Propranolol therapy led to accelerated, complete involution. Nadolol may reduce the theoretical risk of treating PHACE(S) patients with ß-blockers.

Surgical treatment for venous malformation.

Sclerotherapy is generally the preferred treatment for venous malformation (VM) with surgery usually playing an adjunctive role. This study presents our experience with surgical treatment of VMs. Consecutive patients were identified from our vascular anomalies database 1996-2011 and patient demographics, location of the lesion, type of tissue(s) affected and symptoms were analysed. The patients completed a questionnaire to assess the impact of surgery on the severity of symptoms, appearance, function and overall quality of life (QoL), using a visual analogue scale of 0 (no symptom) to 10 (maximal symptom). They also rated their overall satisfaction of treatment using a scale of 0 (complete dissatisfaction) to 10 (complete satisfaction). Fifty patients with VM underwent a total of 58 procedures. Complication occurred in six patients (9.7% of operations), including transient sensory loss (n=3) and permanent frontal branch palsy (n=1), haematoma formation (n=1) and minor wound dehiscence (n=1). At least 50% improvement in symptoms of background pain, acute episodic pain, contour deformity and skin discolouration occurred in 88.9%, 92.3%, 83.3% and 75.0% of patients, respectively. At least 50% improvement in the appearance, function and overall QoL occurred in 54.3%, 71.4% and 70.4% of patients, respectively. The mean overall patient satisfaction with the treatment was 8.9 (range, 1-10). Surgery remains an important treatment modality for selected patients with VM having low complication rates and high patient satisfaction. It improves the appearance, function and overall QoL for the majority of the patients by reducing the severity of pain, contour deformity and skin discolouration.

Surgical management of arteriovenous malformation.

This article presents our experience in managing a series of consecutive patients with arteriovenous malformation (AVM) referred to our Vascular Anomalies Centre over a 14-year period. These patients were culled from our prospective Vascular Anomalies Database 1996-2010. The medical records of these patients were reviewed to supplement the data collected. Out of 1131 patients with vascular anomalies, 53 patients (22 males, 31 females) with AVM were identified. Their mean age was 29 (range: 3-88) years with 14 stage-III, 34 stage-II and five stage-I AVMs, affecting the head and neck area (n=32), lower limb (n=13), upper limb (n=7) and trunk (n=1). Eight patients with eight stage-III and 14 patients with 15 stage-II AVMs underwent definitive surgery following preoperative embolisation in 10 patients. Seventeen patients required reconstruction with free flaps (n=8) or local or regional flaps (n=9), tissue expansion (n=4), tendon recession (n=1), tendon transfer (n=1), osseo-integration (n=1) and skin grafting (n=5). Fourteen patients required a combination of reconstructive techniques. During an average follow-up of 54 (range: 10-135) months, two (8.7%) lesions recurred but were improved following surgery. One patient with life-threatening stage-III AVM underwent 'palliative' surgery following preoperative embolisation and the lesion had improved and remained stable during the 4-year follow-up period. AVM is a challenging clinical problem that requires a multidisciplinary team approach. Complete surgical excision remains the gold-standard treatment and immediate reconstruction is an integral part of definitive surgery for AVM. The heterogeneous nature of AVM requires treatment to be tailored for individual patients and the complex excision defects necessitate expertise in a variety of reconstructive techniques. Our experience shows a recurrence rate of 8.7% following definitive surgery for AVM.

Clinical and angiographic outcome after Guglielmi detachable coil embolization of intracranial aneurysms.

BACKGROUND: Between July 1997 and April 2001, forty patients underwent Guglielmi detachable coil (GDC) embolization of intracranial aneurysms at Wellington Hospital. METHODS: The clinical notes and imaging were reviewed retrospectively. RESULTS: Complete initial occlusion was achieved in 28 patients (70%). Eleven patients (27.5%) had small residual neck (>90% occlusion) and one patient (2.5%) had substantial filling of the aneurysm. Follow up angiographic assessment was obtained in 28 patients (70%) of whom 24 patients (85.7%) had no recurrence or stable residual neck and four patients (14.3%) had recurrence or enlargement of the residual neck. Stable occlusion was achieved in 100% of small and medium sized aneurysms and 50% of large and giant aneurysms. Technical complications occurred in 10% including aneurysms perforated in two patients (5%) and presumed parent artery occlusion in another two (5%). CONCLUSIONS: The findings of the present study demonstrate the safety of GDC embolization. The initial clinical grade at presentation strongly predicted the clinical outcome. Although the number of patients in this study is small, there is evidence that the angiographic outcome is better for small and medium sized aneurysms. Our results are comparable to other published series.