Pietro Amistà

Recurrence Pattern After Temozolomide Concomitant With and Adjuvant to Radiotherapy in Newly Diagnosed Patients With Glioblastoma: Correlation With MGMT Promoter Methylation Status

PURPOSE The aim of the present study was to evaluate factors predicting the recurrence pattern after the administration of temozolomide (TMZ), initially concurrent with radiotherapy (RT) and subsequently as maintenance therapy, which has become standard treatment for patients with newly diagnosed glioblastoma (GBM). PATIENTS AND METHODS Ninety-five patients with newly diagnosed GBM were treated with RT plus TMZ (75 mg/m(2)/d) followed by maintenance TMZ cycles (150 to 200 mg/m(2) for 5 days every 28 days). Assessable MGMT methylation status and magnetic resonance imaging follow-up were mandatory in all cases. RESULTS After a median follow-up of 18.9 months (range, 6.6 to 44.8 months), 79 patients (83%) had recurrence: inside the RT field in 57 patients (72.2%), outside in 17 patients (21.5%), and at RT margin in five patients (6.3%). MGMT status was correlated with the site of recurrence, which occurred inside, or at the margin of, the RT field in 51 patients (85%) with MGMT unmethylated status and in 11 patients (57.9%) with MGMT methylated status (P = .01). Recurrences outside the RT field occurred after a longer time interval than those inside the RT field (14.9 v 9.2 months, P = .02). CONCLUSION After the administration of TMZ concomitant with and adjuvant to RT in patients with GBM, the pattern of, and time to, recurrence are strictly correlated with MGMT methylation status.

Second-Line Chemotherapy With Irinotecan Plus Carmustine in Glioblastoma Recurrent or Progressive After First-Line Temozolomide Chemotherapy: A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

PURPOSE Glioblastoma multiforme (GBM), the most frequent brain tumor in adults, is not considered chemosensitive. Nevertheless, there is widespread use of first-line chemotherapy, often with temozolomide, as a therapeutic option in patients with progressive disease after surgery and radiotherapy. However, at the time of second recurrence and/or progression, active and noncross-resistant chemotherapy regimens are required. The aim of the present multicenter phase II trial, therefore, was to ascertain the efficacy of second-line carmustine (BCNU) and irinotecan chemotherapy. PATIENTS AND METHODS Patients with histologically confirmed GBM, recurring or progressing after surgery, standard radiotherapy and a first-line temozolomide-based chemotherapy, were considered eligible. The primary end-point was progression-free survival at 6 months (PFS-6), and secondary end-points included response rate, toxicity, and survival. All patients were on enzyme-inducing antiepileptic prophylaxis. Chemotherapy consisted of BCNU (100 mg/m2 on day 1) plus irinotecan (175 mg/m2/weekly for 4 weeks), every 6 weeks, for a maximum of eight cycles. In the absence of grade 2 toxicity, the irinotecan dose was increased to 200 mg/m2. RESULTS A total of 42 patients (median age, 53.4 years; median Karnofsky performance status, 80; range, 60 to 90) were included in the study. PFS-6 was 30.3% (95% CI, 18.5% to 49.7%). Median time to progression was 17 weeks (95% CI, 11.9 to 23.9). Nine partial responses (21.4%; 95% CI, 9% to 34%) were obtained. Toxicity was manageable. CONCLUSION The BCNU plus irinotecan regimen seems active and non-cross-resistant in patients with GBM with recurrence after temozolomide-based chemotherapy.

Temozolomide in Patients with Glioblastoma at Second Relapse after First Line Nitrosourea-Procarbazine Failure: A Phase II Study

Objectives: To investigate the efficacy of temozolomide (TMZ) in relationship to progression free survival at 6 months (PFS-6), median time to progression (TTP), response rate and toxicity, a phase II study was conducted in patients with recurrent glioblastoma multiforme (GBM) following surgery plus radiotherapy and a first-line regimen based on nitrosourea, procarbazine and vincristine. Methods: Forty-two patients with GBM were administered TMZ at the dose of 150 mg/m2/daily for 5 days every 4 weeks. Results: The PFS-6 and at 12 months (PFS-12) was 24% (95% Confidence Interval [CI] = 14–42%) and 8% (CI = 2–27%), respectively, with a median TTP of 11.7 weeks (CI = 9–22 weeks). The response was assessed in all 42 patients; we observed 2 complete responses (CR) (4.7%), 6 partial responses (PR) (14.3%), and 9 stable disease (SD) (21.4%), with CR+PR = 19% (CI = 7–31%). Conclusion: TMZ as a second line regimen is a valid option in patients with heavily pretreated GBM.

Phase II trial with BCNU plus α-interferon in patients with recurrent high-grade gliomas

Malignant gliomas are primary CNS tumors with a poor prognosis which has not improved recently.

Synchronous carotid endarterectomy and retrograde endovascular treatment of brachiocephalic or common carotid artery stenosis.

OBJECTIVES To retrospectively evaluate the safety and the long-term results of retrograde brachiocephalic and common carotid angioplasty and stenting (AS) performed for >70% stenosis synchronously with the carotid endarterectomy (CEA). PATIENTS Sixteen patients operated between April 1999 and March 2002. RESULTS 14/16 procedures were successful. There was no neurological morbidity or mortality. Per-operative angiography showed the optimal stent positioning and patency of both proximal and distal arteries in all patients. In the follow-up, all patients showed patency of the treated vessels without restenosis and the absence of any cerebrovascular symptoms. CONCLUSION Intra-operative retrograde AS combined with CEA is an effective, safe and durable alternative to conventional surgery when a tandem significant proximal lesion is identified in a patient with an high grade carotid stenosis.

Paraganglioma syndrome: SDHB, SDHC, and SDHD mutations in head and neck paragangliomas.

Abstract:  Paraganglioma syndrome includes head and neck paraganglioma and pheochromocytoma, and is classified according to the three susceptibility genes involved, SDHB, SDHC, and SDHD. This study assessed the prevalence of germline mutations in SDHB, SDHC, and SDHD genes in a consecutive population admitted to Padova Hospital consisting of 20 patients with head and neck paraganglioma (HNP). Mutations were identified in the three genes in four affected individuals, three sporadic cases and one with family history of HNP. The novel SDHB p.R242C mutation was identified in a sporadic monolateral carotid body tumor. The SDHC p.Q147X mutation, the first to be described in Italy, was detected in a sporadic monolateral jugulotympanic paraganglioma. The SDHD p.Y114C mutation was identified in two unrelated patients, one familial case of bilateral carotid body tumor and one multiple paraganglioma. SDHB, SDHC, and SDHD molecular screening is important in all HNPs, with or without primary indicators of paraganglioma syndrome, to orient mutation‐driven clinical screening for additional HNPs and pheochromocytoma.

Early chemotherapy and concurrent radio-chemotherapy in high grade glioma.

SummaryPurpose: The poor results from treatment of high grade glioma prompted us to explore new protocols involving concurrent radio-chemotherapy. Our primary objective was to evaluate the feasibility of very early postoperative chemotherapy with BCNU, concurrent radio-chemotherapy with carboplatin and teniposide, and post-radiotherapy BCNU. Our secondary objectives were to evaluate time to progression, and overall survival. Patients and methods: We treated 24 newly diagnosed patients (pts) with BCNU 150 mg/m2 seven days after surgery. Thirty days later, we started radiotherapy, 1.8 to 2 Gy/day for 5 days a week on limited fields up to 60 Gy, and concurrent chemotherapy with carboplatin 250 mg/m2 on days 1, 22, and 43, and teniposide 50 mg/m2 on days 1, 2, 3, 22, 23, 24, 43, 44 and 45. Two cycles of 150 mg/m2 BCNU were then given at 30 and 70 days, respectively, after the end of the radio-chemotherapy course. Therapy was then suspended, but if disease progression was evident, treatment was resumed with drugs that had not been previously employed. Surgical reintervention was not routinely considered. Results: Following radio-chemotherapy treatment in the 24 pts evauble for response, we observed partial remissions in 8 cases (33%) and stable disease in 12 (50%). Actuarial estimates of progression free survival (PFS) were 33 weeks, with 56 wks for anaplastic astrocytoma and 31 weeks for glioblastoma. Median survival time (MST) of all pts was 58 weeks; 51 weeks for glioblastoma and was not reached for anaplastic astrocytoma. This regimen was feasible. Of 144 planned cycles, 139 were delivered, and among these only in 13 and 9 cycles the doses were reduced by 75 and 50%, respectively. We did not observe any gastrointestinal toxicity. Grade 2 hematological toxicity occurred in 25% of pts, grade 3 in 4% and neurological toxicity in 3% of the pts during BCNU delivery, probably due to a sharp increase in intracranial pressure. Conclusion: Early chemotherapy, concurrent chemo-radiotherapy and brief post-radio-therapy chemotherapy are feasible and well tolerated. The objective response and disease stabilization rates appear similar to previous experiences.

Reduced right posterior hippocampal volume in women with recurrent familial pure depressive disorder

Volumetric changes in mood-relevant distributed limbic/paralimbic structures have been reported in the recent literature on the course of mood disorders. Patients with unipolar and bipolar disorders have been found to have smaller hippocampal and anterior cingulate volumes. We examined hippocampal, amygdalar and anterior cingulate cortex (ACC) volumes in female patients with recurrent familial pure depressive disorder (rFPDD). We used semi-automated software for magnetic resonance imaging (MRI) to measure the volumes of the hippocampus, amygdala, ACC and subgenual prefrontal cortex (SGPFC) in 15 female patients with familial recurrent major depression (MD) and 15 healthy female subjects. Analysis of covariance, with whole brain volume as covariate, was used to compare volumetric measurements in the two groups. Volumes of the right hippocampal body and tail were significantly smaller in female patients with familial depressive disorder than in healthy subjects. Our data provide evidence of structural lateralized hippocampal body and tail abnormalities in women with familial history and recurrent episodes of depression. Although global reduction of hippocampal volume has been widely reported, data on lateralized regional reductions in familial recurrent depression had not been previously reported. Reduced volume of the right posterior hippocampus could be a structural endophenotype for recurrent depressive disorders in women.

Ultrarapid high-dose course of prophylactic cranial irradiation in small-cell lung cancer : Evaluation of late neurologic morbidity in 16 long-term survivors

Despite the reduction in the incidence of brain metastases following prophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC), the use of this modality is still controversial due to the lack of improvement in survival and the appearance of neurotoxicity in long-term survivors. Moreover, the optimum dose, fraction size, and timing are not known. From 1980 to 1988, 70 patients with limited stage SCLC underwent PCI after or during multimodality treatment of their primary tumor. Most of these patients (75.7%) received an unconventional ultrarapid high-dose course of 17 Gy in two fractions over 3 days. Long-term (range 60-138 months) survivors (n = 16) were invited to have a complete neurological evaluation including computed cranial tomography (CCT), 99mTc-HMPAO single photon emission computerized tomography (SPECT) scan, electroencephalography (EEG), magnetic resonance imaging (MRI), and neuropsychometry. Delayed neurologic complications or psychometric impairment was observed in 46% of patients. One or more abnormalities were detected by CCT in all patients, and the presence of neurologic complications seemed to correlate with periventricular and subcortical white matter changes. A strong correlation was found between CCT and SPECT periventricular white matter changes. Although the incidence of late neurologic toxicity following this rapid course of irradiation was high, clinical findings were less severe than expected, and all the patients were capable of self-care.

Hippocampal remodelling after MDMA neurotoxicity: A single case study

Acute ingestion of MDMA (ecstasy) causes a transient marked increase in serotonin and dopamine at central synapses. Recent studies demonstrated that MDMA induces damage of serotonergic nerve terminals and alters hippocampal processing. Pronounced cognitive deficits in MDMA users affect learning and memory abilities. This pattern of predominant and long-lasting memory dysfunction suggests that the functioning of the hippocampus might be affected by the neurotoxic effects of MDMA. We present the case of a 16-year-old girl who developed an acute organic and psychotic syndrome caused by occasional use of low to moderate dose of MDMA. Serial neuroimaging (18F-FDG-PET and brain MRI) were correlated with her neurocognitive performance and clinical evolution. The structural and metabolic changes correlated with a severe cognitive impairment. After 16 months of intensive neuropsychological rehabilitation she showed significant improvement in hippocampal-related memory cognitive functions, which correlated with normalization of her 18F-FDG-PET and remarkable hippocampal remodelling. This case report indicates that even non-chronic MDMA use may cause subacute toxic encephalopathy in which the clinical evolution is paralleled by neuroimaging changes in specific cerebral areas. The most relevant aspect is the reversibility of the volumetric changes, which may be the structural correlate of an ongoing hippocampal remodelling.