Manuela Caroli

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial

IMPORTANCEnGlioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly.nnnOBJECTIVEnTo evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma.nnnDESIGN, SETTING, AND PARTICIPANTSnAfter completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (nu2009=u2009466) or temozolomide alone (nu2009=u2009229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis.nnnINTERVENTIONSnTreatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle.nnnMAIN OUTCOMES AND MEASURESnThe primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (nu2009=u2009280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up.nnnRESULTSnThe interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; Pu2009=u2009.001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (nu2009=u2009196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (nu2009=u200984) (HR, 0.64 [99.4% CI, 0.42-0.98]; Pu2009=u2009.004).nnnCONCLUSIONS AND RELEVANCEnIn this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00916409.

Management of head-injured patients in the emergency department: A practical protocol

BACKGROUNDnThe management of head-injured patients admitted to emergency departments is not standardized.nnnMETHODSnThe authors performed a retrospective analysis of 10,000 head-injured patients admitted to the Emergency Department of our hospital in a 21-month period and, on the basis of a statistical correlation between each clinical parameter (symptoms and signs upon arrival at the hospital or risk factors) and the presence of intracranial lesions, they propose a practical protocol in an attempt to avoid the overuse or radiologic examinations and yet identify patients with possible life-threatening complications.nnnRESULTSnOn the basis of this correlation the patients have been divided into four groups. In the first group (called group alpha) are patients with: no history of loss of consciousness, no vomiting or amnesia, a normal neurologic examination, and minimal if any subgaleal swelling. They can be released into the care of relatives who are given a special instruction sheet (X rays unnecessary). No patient in group alpha had complications of any kind. The second group (group beta) is made up of patients with at least one of the following features: transient loss of consciousness, post-traumatic amnesia, a single episode of vomiting or significant subgaleal swelling. They undergo a computed tomography (CT) scan and if this is normal, only a short period of observation is needed. If CT scan is not available, the skull is X rayed and, if this X ray is negative, the patient is sent home with the warning sheet after an observation period. If a fracture is found, CT scan should be performed promptly. No patient in group beta with normal skull X rays developed intracranial lesions. The third group (group gamma) contains patients with at least one of the following symptoms: impaired consciousness, repeated episodes of vomiting, neurologic deficits, otorrhagia, otorrhea, rhinorrea, signs of basal skull fracture, seizures, penetrating or perforating wounds, lack of cooperation for varying reasons, patients who have undergone previous intracranial operations or been affected by coagulopathy or submitted to anticoagulant therapy, and finally, epileptic or alcoholic patients. They receive a CT scan immediately and, if necessary, again prior to discharge. Six patients in group gamma with GCS = 15 upon admission were operated on for intracranial hematoma. The fourth group (group delta) is composed of comatose patients. Immediately following resuscitation maneuvers and prior to any surgical intervention, they undergo a CT scan. A linear association between the severity groups and the presence of intracranial lesions has been demonstrated.nnnCONCLUSIONSnThe present protocol stresses the importance of the patients clinical and anamnestic evaluation upon arrival in the Emergency Department, especially in minor head injuries.

Multiple intracranial lesions in head injury: clinical considerations, prognostic factors, management, and results in 95 patients.

BACKGROUNDnThe goal of this study was to identify clinical and radiological predictors of prognosis in patients with multiple post-traumatic intracranial lesions.nnnMETHODSnWe reviewed 95 patients (75 male and 20 female) between the ages of 18 and 70 (average 38) admitted between 1993 and 2000 with multiple post-traumatic intracranial lesions. Intracranial pressure (ICP) monitoring was carried out in 67 patients (70%); 77 received intensive care unit (ICU) treatment. Since in all cases it was possible to identify a clearly predominant lesion, 3 groups of patients emerged from the data: the first with extradural hematoma (EDH), the second with a combination of homolateral subdural (SDH) and intracerebral hematoma (ICH), and the third with pure focal intracerebral hematoma (ICH).nnnRESULTSnTwenty-seven patients were treated conservatively, 2 of whom died (7.4%); both had bilateral ICH and compression of the basal cisterns. Sixty-eight patients underwent one or more surgeries; 8 died (11.7%). In the group with EDH-predominant lesions (27 cases) all patients were operated (16 for multiple lesions); no one died. In the group with SDH+ICH-predominant lesions, 26 of 32 patients were operated (10 had multiple procedures); 6 died (18.7%), 3 were vegetative. In the group with ICH-predominant lesion, 15 of 36 patients were operated (7 bilaterally); 4 died (11%). Decompressive craniectomy proved to be a useful means to control ICP. Bilateral lobectomy is not recommended because of poor results. Immediate postoperative computed tomography (CT) scan proved to be mandatory to detect additional surgically treatable lesions (16 cases). Statistical analysis was performed by means of chi(2) analysis and multiple linear regression model. The multiple linear regression model was used to ascertain risk factors independently associated with the outcome. The type of lesion (presence of SDH+ICH predominant lesion), the worst recorded Glasgow Coma Scale (GCS) score, the presence of prolonged increased ICP, and the absence of pupillary reflexes were all statistically significant predictors of a bad outcome (dead or vegetative state).nnnCONCLUSIONSnMultiple lesions have the same prognosis as the corresponding single lesions; therefore, their management should be guided by the predominant pathology.

Intracranial meningiomas in patients over 70 years old. Follow-up in operated and unoperated cases

Forty-six cases of intracranial meningioma in patients above 70 years of age form the basis of this study; 34 underwent surgery while 12 did not. The decision to operate was based on the general condition of the patient, evaluated according to the Karnofsky index, neurological conditions, the site and dimensions of the tumor, and the presence of peritumoral edema. The post-surgical mortality rate was 11.5% at 30 days, and 20% at 3 months. Long-term follow-up in both patient groups ranged from 1 to 5 years, and quality of life was evaluated by the Karnofsky index. Five operated patients died during follow-up (only 1 from intracranial pathology); the 22 survivors showed further improvement in their grading level compared to scores immediately following surgery. Among the unoperated patients, 6 died within two years of diagnosis, all from causes related to intracranial pathology; among the survivors, the Karnofsky index was unchanged in 2, and diminished in the other 4 cases. (Aging Clin. Exp. Res. 4: 29–33, 1992)

Multicentre prospective collection of newly diagnosed glioblastoma patients: update on the Lombardia experience

A prospective collection of newly diagnosed cases of grade IV glioma in Lombardia, Italy, was started in 2003. In the present report, data are shown on 349 adult patients recruited up to 2005. The clinical features, pattern of care and outcome are discussed, together with the main prognostic factors. Males were affected more frequently than women; median age at onset was 60. Overall, gross total tumour resection was performed in roughly 50% of the patients, and partial resection and biopsy in 25% each; only 5 patients did not undergo histology. Adjuvant radiotherapy was delivered to 89% and chemotherapy to 82% of patients. Median survival was of 54 weeks. Most patients received protracted therapy with antiepileptic drugs, despite absence of seizures; over the course of the study, the practice pattern tended to change, shifting to the use of non-enzyme-inducing anti-epileptic drugs.

Mass spectrometry-based assay for the molecular diagnosis of glioma: concomitant detection of chromosome 1p/19q codeletion, and IDH1 , IDH2 , and TERT mutation status

The World Health Organization recently revised the diagnosis of glioma, to integrate molecular parameters, including IDH mutations and codeletion (loss of heterozygosity; LOH) of chromosome arms 1p/19q, into the definitions of adult glioma histological subtypes. Mutations in the TERT promoter may also be useful for glioma diagnosis and prognosis. The integration of molecular markers into routine diagnosis requires their rapid and reliable assessment. We propose a MassARRAY (MS)-based test that can identify 1p/19q codeletion using quantitative SNP genotyping and, simultaneously, characterize hotspot mutations in the IDH1, IDH2, and TERT genes in tumor DNA. We determined the reliability of the MS approach testing 50 gliomas and comparing the MS results with those obtained by standard methods, such as short tandem repeat genotyping, array comparative genomic hybridization (array-CGH) and Fluorescence In Situ Hybridization (FISH) for 1p/19q codeletion and Sanger sequencing for hotspots mutations. The results indicate that MS is suitable for the accurate, rapid, and cost-effective evaluation of chromosome deletions combined with hotspot mutation detection. This MS approach could be similarly exploited in evaluation of LOH in other situations of clinical and/or research importance.

P17.77PRELIMINARY DATA ON THE PATTERN OF CARE IN GRADE III GLIOMA PATIENTS IN 6 LOMBARDIA HOSPITALS, 2012-2013

The standard of care in grade III gliomas is still controversial; concerning anaplastic astrocytoma, the addition of chemotherapy to post-surgery radiation therapy is being assessed in the CATNON EORTC trial, whereas long-term follow-up data on grade III gliomas with oligodendroglial component suggest a strong impact of chemotherapy on survival, especially in patients positive for 1p/19q LOH. We have collected data on the pattern of care in grade III glioma patients prospectively treated in 6 Hospitals in Lombardia over the last 2 years. 78 patients were diagnosed (42 M, 36 F), with a median age of 50 (range 17-79). Histological diagnosis was AA in 49, AOD in 10, AOA in 19. The disease onset was characterized by seizures in 35 patients, intracranial hypertension in 7 and by focal non-epileptic neurological signs in 27. Surgery was total/subtotal resection in 43, partial resection in 18, biopsy in 17. Molecular biology data were available in 23/49 of the AA group (10 with methylated MGMT, 8 unmethylated MGMT, 1 with LOH 1p/10q) and in 16/29 of AOD/AOA group (12 with LOH for 1p/19q). Data about post-surgical treatment were available in 71 ot the 78 patients (42 AA and 29 AOD/AOA). Concerning AA, 3 patients died within 3 months from surgery (1 for encephalitis, 1 for early progression, 1 for perioperative complications). In the reamining 39, 37 were treated with both RT and CT (of whom 27 with the Stupp schedule and 10 with adjuvant temozolomide), 2 were treated with RT only. Toxicities included one fatal herpetic encephalitis, one Herpes Zoster, 4 grade 3-4 platelet toxicity, one case of pancytopenia. In AOD and AOA patients, 27 out of 29 were treated with radiotherapy and only 2 with upfront chemotherapy aiming to differe RT. 4 of the 27 received only radiotherapy, while 23 were treated by both RT and CT (of whom 5 with the Stupp schedule and 18 with adjuvant CT). 2 patients had to interrupt CT due to piastrinopenia. Overall, the results stress the need to implement molecular biology analyses and confirm the heterogeneity in the clinical approach to newly diagnosed grade III gliomas. In AA, both the Stupp schedule and adjuvant CT after RT are used, whereas in gliomas with oligodendroglial component a low number of patients start being treated with upfront chemoterapy if they present favourable prognostic factors.