Short-course radiotherapy in elderly patients with glioblastoma: feasibility and efficacy of results from a single centre.

BACKGROUND: The incidence of glioblastoma (GBM) in the elderly population is currently increasing, with a peak seen between 65 and 84 years. The optimal treatment in terms of both efficacy and quality of life still remains a relevant and debated issue today. The purpose of our study was to evaluate the feasibility of short-course hypofractionated accelerated radiotherapy (HART) in GBM patients aged over 70 years and with a good Karnofsky performance score (KPS). METHODS: A review of medical records at the "Istituto Neurologico C. Besta" was undertaken; patients aged ≥ 70 years who had undergone adjuvant HART for GBM between January 2000 and January 2004 were included in the study. HART was administered to a total dose of 45 Gy, 2.5 Gy/fraction, in three daily fractions for three consecutive days/cycle fractions each, delivered in two cycles (split 15 days). RESULTS: A total of 33 patients were evaluable for the current analysis. Median follow-up was 10 months. According to CTCAE (version 3.0) criteria, none of the patients developed radiation-induced neurological status deterioration or necrosis. KPS evaluation after HART was found to be stable in 73 % of patients, improved in 24 %, and worse in 3 %. The median overall survival time of the entire study population was 8 months (range 2-24). CONCLUSIONS: Our findings suggest that a hypofractionated accelerated schedule can be a safe and effective option in the treatment of GBM in the elderly.

Liposomal cytarabine in neoplastic meningitis from primary brain tumors: a single institutional experience.

Neoplastic meningitis (NM) is diagnosed in 1-2 % of patients with primary brain tumors. Standard treatment of NM includes single-agent or combination chemotherapy, with compounds such as methotrexate, thiotepa, and cytarabine (Ara-C) or its injectable, sustained-release formulation Depocyte(®). In this Report, we reported the data of efficacy and tolerability of an intrathecal Depocyte(®) regimen for patients presenting with NM from primary brain tumors. We described 12 patients with NM confirmed at magnetic resonance imaging (MRI) and with a positive cerebrospinal fluid (CSF) cytology. Patients were treated with repeated courses of intrathecal Depocyte(®) (once every 2 weeks for 1 month of induction therapy and as consolidation therapy on a monthly base in responding patients). Twelve patients (10 males and 2 females) were treated by our Institution. The diagnosis of primitive brain tumor was medulloblastoma in six patients, germinoma in two patients, pylocitic astrocytomas with spongioblastic aspects, teratocarcinoma, meningeal melanoma, and ependimoma in the other four patients. The total number of Depocyte(®) cycles ranged from one to nine. In 7/12 patients, there was clinical and/or radiological response after Depocyte(®), and the toxicity was moderate and transient, mainly due to the lumbar puncture procedure. In the two patients with germinoma, we observed a normalization of MRI Imaging and negativization of CSF with disappearance of the tumor cells. OS was 180 days (range 20-300, CI 95 %).

Adult medulloblastoma: multiagent chemotherapy with cisplatinum and etoposide: a single institutional experience.

In 1991, a prospective phase II trial was initiated to evaluate the efficacy of treatment for adults with medulloblastoma (MB). After surgery, patients were staged with a neuroradiologic examination of the brain and neuroaxis and by cerebrospinal fluid cytology. All patients received three cycles of upfront cisplatinum (cisplatinum) and etoposide (VP16) chemotherapy followed by cranio-spinal radiation therapy. The current article reports on the long-term results from that trial. After a median follow-up of 14.9 years, among a total of 28 adults with MB, the overall progression-free survival and overall survival (OS) rates at 5 years were 57.6 and 80%, respectively. The median OS for the whole group of patients was 11.3 years. The observed toxicity was mainly hematological, with leukopenia and thrombocytopenia (16% of grades 3 and 4). In summary, in our small series of patients, the role of combination administration of CDDP + VP16 started before the initiation of radiotherapy in reducing recurrences, particularly distant recurrences, remains unclear. To know whether adding chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.

Infections in neuro-oncology.

Infections represent a serious and frequent complication in neuro-oncology patients. Decreased immune defences, along with poor nutritional status are the main predisposition factors. The combined therapeutic strategies of chemotherapy and radiotherapy may favour bone marrow depression and further increase the risk of developing opportunistic infections in brain tumour patients. The spectrum of infections in neuro-oncology patients is large and includes opportunistic infections by bacteria, viruses, fungi and parasites. Importantly, a high index of suspicion for opportunistic infections in general should be maintained, especially in glioma patients receiving dose-dense schedules of temozolomide. After neurosurgical procedures, infections most commonly present as meningitis, subdural empyema, or cerebral abscess. Infections represent a frequent and possibly serious complication in general immunocompromised oncology population. It should be underlined that infections are not limited to immunocompromised patients, being also present at the early disease stages, especially due to therapeutic strategies (chemo and radiotherapy, surgical procedures). Therefore this issue deserves more attention in neuroncology setting.

Natural history and management of brainstem gliomas in adults. A retrospective Italian study.

Brainstem gliomas in adults are rare tumors, with heterogeneous clinical course; only a few studies in the MRI era describe the features in consistent groups of patients. In this retrospective study, we report clinical features at onset, imaging characteristics and subsequent course in a group of 34 adult patients with either histologically proven or clinico-radiologically diagnosed brainstem gliomas followed at two centers in Northern Italy. Of the patients 18 were male, 14 female, with a median age of 31. In 21 of the patients histology was obtained and in 20 it was informative (2 pilocytic astrocytoma, 9 low-grade astrocytoma, 8 anaplastic astrocytoma and 1 glioblastoma). Contrast enhancement at MRI was present in 14 patients. In all of the 9 patients who were investigated with MR spectroscopy, the Cho/NAA ratio was elevated at diagnosis. In 8 of the patients, an initial watch and wait policy was adopted, while 24 were treated shortly after diagnosis with either radiotherapy alone [4] or radiotherapy and chemotherapy [20] (mostly temozolomide). Only minor radiological responses were observed after treatments; in a significant proportion of patients (9 out of 15) clinical improvement during therapy occurred in the context of radiologically (MRI) stable disease. Grade III or IV myelotoxicity was observed in 6 patients. After a follow-up ranging from 9 to 180 months, all but 2 patients have progressed and 14 have died (12 for disease progression, 2 for pulmonary embolism). Median overall survival time was of 59 months. Investigation of putative prognostically relevant parameters showed that a short time between disease onset and diagnosis was related to a shorter survival. Compared with literature data, our study confirms the clinical and radiological heterogeneity of adult brainstem gliomas and underscores the need for multicenter trials in order to assess the efficacy of treatments in these tumors.

Methotrexate based chemotherapy and deferred radiotherapy for primary central nervous system lymphoma (PCNSL): single institution experience.

In the following study, we present our experience in the treatment of PCNSL patients using a multi-step schedule combining chemotherapy and deferred radiotherapy. Patients were treated with two modified M-BACOD cycles and then differently according to radiological response For PR, SD and PD patients, chemotherapy was interrupted and radiotherapy initiated immediately (45 Gy Whole-brain RT). With CR patients, chemotherapy was continued with a combination of HMTX, VCZ, PCB and HD Ara-C up to a total of nine cycles. In 36 patients suitable for evaluation (2 patients had undergone tumour resection): 69.4% (25 of 36) had a complete response (CR), 19.4% (7 of 36) had a partial response(PR), 8.3% (3 of 36) had stable disease(SD), and 2.7% (one of 36) had progressive disease (PD). The PR, SD and PD patients were immediately treated by radiotherapy. In this cohort of patients, we observed 6 CR, 4 PR and 2 PD, respectively, following radiotherapy. At first relapse, a total of 16 CR patients were treated by radiotherapy for a total dose of 45 Gy. The OS was 42.1 months for the entire group of patients. In CR patients treated at the moment of recurrence by salvage radiotherapy, the TTP (time lasting from histological diagnosis until recurrence of disease before RT) was 28.3 months, with a 43.4% of disease free patients observed at 2 years. The median disease-free time observed after complete response to radiotherapy was 10.5 months. In 16 patients (34%), further progression of disease was observed following radiotherapy. Two patients developed extra-CNS disease in the breast and testis. When taking into account the patients with radiotherapy delayed at recurrence, the OS was 48 months and the survival rates were 70% and 60% at 2 years and 5 years, respectively.

Efficacy of intratumoral delivery of mitoxantrone in recurrent malignant glial tumours.

Ninety-nine patients bearing recurrent malignant glioma sequentially selected according to strict eligibility criteria (72 GBL and 27 AA) entered the study. All patients were previously managed with radiotherapy 60 Gy total dose and chemotherapy with nitrosoureas and platinum compounds. At recurrence they were subdivided in homogeneous groups, all treated with the same systemic chemotherapy protocol: 27 GBL (group A) only systemically treated, 20 GBL (group B) treated also locally by delivering 4mg of mitoxantrone every 20 days through the Ommaya reservoire, and 25 GBL (group C) treated with a second surgery and locally as group B. Of the AA group, 13/27 were treated locally trough the Ommaya reservoir after repeat surgery. A trend to different demographic features among subgroups (with locoregionally treated patients and patients undergoing repeat surgery being younger than the others) was seen in this non-randomized study, but this was not statistically significant. Median overall survival was 27, 26 and 15.5 months respectively for groups c, b and a (log-rank = 0.1). After tumor recurrence median survival was 16.8, 12 and 6.6 months respectively for groups c, b and a (log-rank = 0.001) For the 29 AA, overall survival was 48.5 and 100 months (log-rank = 0.03) if treated locally with second tumor debulking. Our results stress the opinion that a second operation could be indicated only if it is a part of a therapeutic protocol to allow a locoregional treatment. Moreover we can finally assume that local delivery of chemotherapy after tumor recurrence, possibly extends patients survival but certainly improves the number of long-survivors.

Cisplatin and BCNU chemotherapy for anaplastic oligoastrocytomas.

In this study 32 newly diagnosed anaplastic oligoastrocytoma patients were enrolled (median age of 41 years, range 19-63; median Karnofsky performance status of 90, range 70-100). All patients were treated with Cisplatin (109 mg/m2) and BCNU (160 mg/m2). The chemotherapy started in the first week after surgery and it was administered every 6 weeks (5 scheduled cycles) for a total of 127 cycles. After the second cycle of chemotherapy all patients received radiotherapy (56.5 Gy). The median follow-up was 63.2 months (10-91). Nine patients were reoperated-on. The median time to tumor progression (TTP) and median survival time (ST) for the whole group of patients were 54.6 and 70.1 months, respectively. A proportional hazard model was used to look at potential prognostic factors for survival including lower age (< 40 years), extent of surgery (total/subtotal versus partial) and reoperation. When we analyzed the group of patients with total/subtotal surgery or age under 40 years the median ST could not be assessed due to the high number of surviving patients after a follow-up of 52 months. The median ST for the older patients or for patients partially operated-on was 54.1 and 42.2 months. In our study only total/subtotal surgery predicted for longer survival (p < 0.001). This schedule of treatment provides durable response in a selected group of anaplastic oligoastrocytoma patients.

Congenital muscular dystrophy with merosin deficiency: MRI findings in five patients.

We present the MRI findings in five patients with congenital muscular dystrophy (CMD) and merosin (laminin alpha2) deficiency, which was total in one and partial in four. In one patient with partial merosin deficiency, MRI was normal. The other four patients had supratentorial white matter abnormalities. In three, T2-weighted images revealed subcortical, deep lobar and periventricular high signal in white matter, while in the other there were only small peritrigonal areas of increased signal. On T1-weighted images, there was slightly low signal. Cortical abnormalities were absent. None of these changes were accompanied by symptoms or signs of central nervous system involvement. White matter abnormalities in a patient with CMD should prompt investigation of merosin.

[Flow-cytometric study of familial paragangliomas of the carotid body]. / Studio citofluorimetrico di paragangliomi familiari del corpo carotideo.

Paragangliomas of the carotid body with an autosomal dominant genetic transmission have been described in a familial presentation in 7-10% of all the cases observed. In less than 10% malignancy is confirmed by secondary metastatic localization rather than by typical histological features of malignant diseases, such as vascular or perineural invasion, nuclear pleomorphism, mitotic activity. The purpose of the study is to present a familial group of paragangliomas of the carotid boy and a flow cytometric analysis of tumor content DNA and to discuss the prognostic value of the results. The paragangliomas of these related patients (father and daughter) are diploid, without regional lymph node or distant metastases; clinical and cytometric findings support a good prognosis even if an accurate follow up of such neuroendocrine tumors is nonetheless mandatory. Considering data in Literature, the Authors also propose a prognostic classification of paragangliomas as follows: noninvasive (capsulated, without vascular or perineural infiltration, diploid); locally invasive (histological signs such as vascular or perineural infiltration, nuclear pleomorphism, abnormal mitoses etc, diploid); potentially malignant (histological signs, non-diploid, expression of few antigens) and malignant (regional or distant metastases).

Carboplatin combined with carmustine and etoposide in the treatment of glioblastoma.

The aim of this study was to verify the tolerability and efficacy of therapeutic chemotherapy protocols, employing different combinations of cisplatin, carboplatin, etoposide and carmustine in primary glioblastoma patients. The purpose was focused on 2 end points: the response index to treatment, the TTP (tumor progression) and the ST (survival time). Eighty-four out of a group of 99 consecutive glioblastoma patients, entered this study. Patients were divided into 4 disparate treatment groups: (A) BCNU alone; (B) CDDP + VP-16; (C) CBDCA + BCNU; (D) CBDCA + BCNU + VP-16. The effectiveness and the TTP of the protocols differed, but differences were not statistically significant. Data concerning platinum treatment compare favorably with the best literature results. At 18 months more than half the carboplatin-treated patients are alive. Moreover these patients had a significantly longer ST than those treated with BCNU. We conclude that platinum-based chemotherapy has a beneficial effect on glial tumors.

Efficacy of '8-drugs-in-one-day' combination in treatment of recurrent GBM patients.

Thirty-five adult recurrent GBM patients, divided randomly in two groups of 19 and 16 cases, had been treated with two regimens of chemotherapy: a) 'eight-drugs-in-one-day'; b) procarbazine + CCNU + vincristine (PCV) respectively. Chemotherapy was planned at the tumour relapse and delivered as long as tolerated without irreversible sequelae or until the CT scan showed tumor progression. Multiple agents are used simultaneously in the therapeutic approach using 'eight-in-one' to kill as many heterogeneous cells of malignant glial tumor as possible and minimize the emergence of cellular resistance to chemotherapy. Rate response to chemotherapy and the median adjunctive survival time (6.5 and 6 months, respectively) are not significantly different in the two arms of this study. Our experience with such an aggressive multi-drugs combination 'eight-in-one-day' was disappointing if compared with less toxic, better tolerated and easy delivered (PCV) regimen.

Primary glial tumor patients treated by combining cis-platin and etoposide.

Thirty eight patients with malignant gliomas (27 GBM and 11 AA) were treated with up to 7 cycles of CDDP + VP16 every month after surgery. Chemotherapy was planned as two cycles before and 5 cycles after radiation (42 Gy) using a three times daily fractionation schedule. No severe toxicity was observed. The object of our study was to investigate the antitumor effectiveness by combining CDDP plus VP16 against primary malignant glial tumors. The time to tumor progression (TTP) and survival time (ST) of the GBM patients in the present study were 38.5 and 68.5 weeks respectively. The TTP of the AA patients was 73 weeks and the ST was not calculated as most patients are still alive. By the 18th. month after surgery, 38% of GBM and 74% of AA patients treated with (CDDP + VP16) are still alive. This study demonstrates that the combination of CDDP and VP16 is effective in patients with malignant gliomas.

Local immunotherapy (beta-IFN) and systemic chemotherapy in primary glial tumors.

Dosage and schedules for the treatment of malignant glial tumors using IFN (interferon) are still uncertain and controversial. In this study we give the preliminary results of treatment in 28 patients with glioblastoma multiforme (GBM). 6 patients were treated with local injection of beta-IFN through an Ommaya reservoir; 4 patients with beta-IFN followed by systemic chemotherapy (Cisplatin + Etoposide), and 18 patients with chemotherapy only. Two end points were evaluated: 1) Whether or not the patients responded to treatment. 2) Length of Time to Tumor Progression (TTP) after surgery. We found that IFN alone was ineffective. Results were improved when local immunotherapy was associated with systemic chemotherapy. New drugs and investigation of possible pharmacological synergism are needed.

Cisplatin and etoposide combination therapy for primary glial tumors: preliminary results.

In this preliminary trial we studied 29 patients with primary malignant glial tumors to investigate the effectiveness of cisplatin combined with etoposide on these tumors. Hyperfractionated radiation therapy was given in the course of chemotherapy. The time to tumor progression in these glioblastoma multiforme (GBM) patients encouraged us to continue this treatment in a phase III study.

[Direct video-laryngoscopy]. / La videolaringoscopia diretta.

The combination of modern bivalved operative laryngoscopes, laryngeal telescopes and videotaping techniques has given us a new tool in the objective evaluation of organic laryngeal lesions. The purpose of the present study has been to describe a new method for direct video-laryngoscopy, an alternative to the classical Kleinsasser microlaryngoscopy technique, in diagnosis, clinical documentation and endolaryngeal microsurgery under video control without using an operating microscope. The direct video-laryngoscopy system consists of: a Weerda distending operating laryngoscope, Hopkins rod lens and Lumina telescopes (0 degrees, 25 degrees, 70 degrees or Mueller subglottoscope), an original telescope holder for a distending laryngoscope, a lightweight medical videocamera, a VHS videorecorder, laryngoscope holder and chest support. From November 1987 to May 1989, 370 patients with laryngeal lesions were examined and recorded. Only in 3 cases was the microlaryngoscopy technique used as it proved difficult to introduce the telescope into its holder because of patient anatomy: one short-necked, obese patient, and two with a prominent tongue base and limited ability to open the mouth. In 367 cases direct video-laryngoscopy made careful diagnosis possible leaving a permanent record of the size and extent of the lesion. Such information could be used in accurate staging and follow-up. 320 patients were also treated by endolaryngeal microsurgery under video control without an operating microscope. Thanks to the width of the bivalved scope, the space for microsurgical instruments would be appreciably extended laterally, making it possible to better control the instruments on the monitor. The telescope lies on the superior spatula of the laryngoscope without interfering with the surgical procedures. The video material obtained was of high quality and of great value for diagnosis, pre- and post-operative evaluation, follow-up and documentation of various laryngeal disorders.

Preliminary data by cis-platin and etoposide using in primary glioblastoma.

In this preliminary study twenty-nine malignant glioma patients after surgery were treated using Cis-platin (CDDP) combined with etoposide (VP16). Superfractionated radiation therapy comes into chemotherapy. The time to tumor progression in GBM patients is encouraging result to continue in this treatment.

Intratumoral beta interferon and systemic chemotherapy. Preliminary data in GBM patients.

Doses and schedules for treatment of malignant glial tumors, using IFN are still uncertain and controversial. In this study preliminary results of treatment of 10 glioblastoma multiforme patients are shown. Six patients were treated with local injection of beta-IFN through an Ommaya reservoir: 4 with beta-IFN followed by systemic chemotherapy (CDDP-VP16); we found that IFN alone was ineffective. Results were improved when local immunotherapy was associated with systemic chemotherapy. New drugs and investigation of possible pharmacological synergism are needed.

Pharmacologic evaluation of cardiovascular reflex responses in migraine patients: lack of central sympathetic modulation?

To characterize autonomic imbalance in migraine, we compared the cardiovascular reflex responses of 10 migraineurs and 10 healthy subjects after pharmacological noradrenergic stimulation or inhibition. A battery of 5 autonomic tests was administered on basal conditions as well as after pretreatment with drugs acting at different levels on the noradrenergic pathway: pseudoephedrine, clonidine, guanethidine, indenolol, prazosin. Our data confirm a predominantly sympathetic hypofunction in migraine and provide evidence for an impairment of the central autonomic control.