New insights in radiation-induced leukoencephalopathy: a prospective cross-sectional study.

BACKGROUND: Radiation-induced leukoencephalopathy (RIL) is the most threatening delayed complication of cerebral radiotherapy (RT) and remains roughly defined by cognitive dysfunction associated with diffuse FLAIR MRI white matter hyperintensities after brain irradiation. We documented clinical, neuropsychological, and radiological aspects of RI in order to refine diagnostic criteria. METHODS: Patients referred to our center for deterioration in cognitive complaint at least 6 months after completing a focal or whole brain RT underwent a systematic cross-sectional assessment including clinical examination, neuropsychological tests, and a standardized MRI protocol. Patients with progressive tumor were excluded. RESULTS: Forty patients were prospectively enrolled. Of these, 26 had received a focal RT, median dose of 53 Gy (range 50 to 60), and 14 had received a whole brain RT, median dose of 30 Gy. Cognitive complaints, gait apraxia, and urinary troubles were reported in 100, 67, and 38% of cases, respectively. On neuropsychological examination, patients displayed a global and severe cognitive decline through a subcortical frontal mode. The cognitive changes observed were not hippocampic, but related to executive dysfunction. On MRI, 68% of the patients had extensive FLAIR hyperintensities with anterior predominance, 87% had brain atrophy, and 21% had intraparenchymal cysts. T2*-weighted MRI showed small asignal areas in 53% of the patients. These abnormalities are evocative of cerebral small vessel disease. Fractional anisotropy in the corpus callosum correlated with the cognitive evaluation. No differentiation in terms of cognitive and MRI features could be made between patients treated with focal brain RT (glioma) and patients treated with WBRT (for brain metastases or PCNSL). CONCLUSIONS: RIL can be defined by clinical symptoms (subcortical frontal decline, gait apraxia, urinary incontinence) and MRI criteria (cortico-subcortical atrophy, spread FLAIR HI, T2* asignals). This condition mimics a diffuse progressive cerebral small vessel disease triggered by RT, independent of RT protocol.

[Single center experience with bevacizumab in a cohort of patients treated for a relapsing glioblastoma]. / Expérience monocentrique d'un traitement par bévacizumab dans la prise en charge des glioblastomes récidivant.

PURPOSE: Although there is no standard treatment for recurrent glioblastoma, prospective data in selected patients have suggested the usefulness of bevacizumab. We report our single center experience with bevacizumab in a cohort of patients treated for a relapsing glioblastoma. METHODS: We performed a retrospective analysis of consecutive patients treated with bevacizumab for a relapsed glioblastoma, between 2008 and 2013. Tumor responses, toxicities, time to progression and overall survival rates were analyzed. RESULTS: Thirty-five consecutive patients were identified. They were treated with bevacizumab 10mg/kg biweekly, associated with irinotecan (n=29; 84%), temozolomide (n=3; 9%) or as single agent (n=3; 9%) for a glioblastoma relapsing after chemoradiation (n=29) or after first line temozolomide only because of a poor general health status or because of multifocal tumor. Two (6%), 28 (80%) and five (14%) patients presented with Recursive Partitioning Analysis (RPA) III, IV and V-VI, respectively. After 2-3 months of treatment, median dose of prednisolone per patient was decreased three times. Clinical improvements or stability were reported in eight (23%) and 17 patients (49%). The best tumor response was partial response in 14 patients (40%), stable disease in nine patients (26%) and tumor progression in 11 patients (31%). Toxicities requiring treatment disruption were reported in five patients (14%). Median survival was 18.4 months (5-41 months). Median time interval between bevacizumab initiation and its disruption because of clinical/radiological progression and/or toxicity was 5.0 months (0.6-21.4 months). Median survival from bevacizumab initiation was 8.1 months (1.4-34 months). CONCLUSION: This single center retrospective experience suggests that bevacizumab is active for recurrent glioblastoma, in a series of poorly selected patients. Median survival times were in the range of those reported in therapeutic trials. This study questions the validity of usual predictive factors in the era of bevacizumab.

Contrast enhancement in 1p/19q-codeleted anaplastic oligodendrogliomas is associated with 9p loss, genomic instability, and angiogenic gene expression.

BACKGROUND: The aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs). METHODS: The MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays. RESULTS: Most of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2. CONCLUSION: In AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.

Incidence of pulmonary cement embolism after real-time CT fluoroscopy-guided vertebroplasty.

PURPOSE: To prospectively evaluate the incidence of pulmonary cement embolism (PCE) after vertebroplasty in procedures performed under real-time computed tomographic (CT) fluoroscopy guidance. MATERIALS AND METHODS: A total of 85 vertebroplasties were performed in 51 consecutive patients (31 women, 20 men; mean age, 71.9 y; range, 48-92 y) in 51 sessions. The needle was inserted with guidance from intermittent single-shot CT scans, and intermittent CT fluoroscopy was used during cement injection only. To reduce the risk of extravertebral or extraosseous leakage, several procedures (cement injection stopping/slowing, needle position changes) were employed. The chest and treated bone were scanned immediately after vertebroplasty. These CT images included the entire thorax as well as the treated vertebrae. RESULTS: No cement emboli were observed on CT after vertebroplasty. After 85 vertebroplasty procedures, 44 extravertebral leaks were detected. Epidural leaks were observed on CT in six treated vertebrae (7%), in 12 cases in the anterior external venous plexus (14.1%), in five in the azygos vein (5.8%), in 19 in the disc space (22%), and in two in the foraminal space (2.3%). On a per-patient basis, the odds of leaks increased with the number of vertebroplasties (P = .05) and the volume of cement used (P = .0412). There was also a higher probability of leak (P < .05) for osteoporotic vertebral compression fractures (67.9%; 95% confidence interval, 47.7%-84.1%) than osteolytic spinal metastases (34.8%; 16.4%-57.3%). CONCLUSIONS: PCE did not occur after vertebroplasty under CT fluoroscopy guidance. Further larger prospective vertebroplasty studies are needed to compare the rates of PCE for CT versus conventional fluoroscopic guidance.

Peripherally inserted central catheter placement in cancer patients with profound thrombocytopaenia: a prospective analysis.

OBJECTIVE: No studies have specifically evaluated the safety of peripherally inserted central catheter (PICC) placement in patients with profound thrombocytopaenia. We prospectively determined the frequency of haemorrhagic complications of PICC placement in cancer patients with uncorrected profound thrombocytopaenia. METHODS: Profound thrombocytopaenia was defined as a platelet count <50 × 10(9)/l. No patients received transfusions before or after the procedure. Three types of adverse effects were analysed: minor oozing, mild haematoma and major haemorrhage. RESULTS: One hundred and forty-three PICC implantations in 101 cancer patients were prospectively included in the study: seven patients (7 %) had a solid tumour and 94 (93 %) a haematological malignancy. Among these 143 procedures in thrombocytopaenic patients, 93 (65 %) were performed with a platelet count 20-50 × 10(9)/l and 50 (35 %) had lower than 20 × 10(9)/l. No major haemorrhage was observed. Minor oozing was observed in six implantations (4 %) and mild haematoma in two (1.5 %), for a total of eight minor haemorrhagic adverse events (5.5 %). In patients with a platelet count <20 × 10(9)/l, 1/50 (2 %) had minor oozing and none had minor haematoma. CONCLUSIONS: In cancer patients with uncorrected profound thrombocytopaenia, the incidence of adverse events after PICC implantation was low, and was limited to minor haemorrhagic adverse events. KEY POINTS: • PICC placement has high technical success in profound thrombocytopaenic cancer patients. • Few adverse events are encountered after PICC placement, limited to minor haemorrhage. • PICC placement does not routinely require platelet transfusion in patients with thrombocytopaenia. • Such PICC placement still seems safe when the platelet count is <20 × 10 (9) /l.

Evaluation of quantitative criteria for glioma grading with static and dynamic 18F-FDopa PET/CT.

PURPOSE: The aim of this study was to compare various acquisition and processing protocols for noninvasive glioma grading using either static or dynamic (18)F-FDopa PET. METHODS: Dynamic studies were performed in 33 patients. Based on histopathological analysis, 18 patients had a high-grade (HG) tumor and 15 patients had a low-grade (LG) tumor. For static imaging, SUV(mean) and SUV(max) were calculated for different acquisition time ranges after injection. For dynamic imaging, the transport rate constant k1 was calculated according to a compartmental kinetic analysis using an image-derived input function. RESULTS: With the use of a 5-minute static imaging protocol starting at 38 minutes after injection, newly diagnosed HG tumors could be distinguished from LG tumors with a sensitivity of 70% and a specificity of 90% with a threshold of SUV(mean) of 2.5. In recurrent tumors, a sensitivity of 100% and a specificity of 80% for identifying HG tumors were obtained with a threshold set to 1.8. Dynamic imaging only slightly, but nonsignificantly, improved differential diagnosis. CONCLUSIONS: Static and dynamic imaging without blood sampling can discriminate between LG and HG for both newly diagnosed and recurrent gliomas. In dynamic imaging, excellent discrimination was obtained by considering the transport rate constant k1 of tumors. In static imaging, the best discrimination based on SUV was obtained for SUV(mean) calculated from a 5-minute acquisition started at 38 minutes after injection.

Primary brain tumours in adults.

Important advances have been made in the understanding and management of adult gliomas and primary CNS lymphomas--the two most common primary brain tumours. Progress in imaging has led to a better analysis of the nature and grade of these tumours. Findings from large phase 3 studies have yielded some standard treatments for gliomas, and have confirmed the prognostic value of specific molecular alterations. High-throughput methods that enable genome-wide analysis of tumours have improved the knowledge of tumour biology, which should lead to a better classification of gliomas and pave the way for so-called targeted therapy trials. Primary CNS lymphomas are a group of rare non-Hodgkin lymphomas. High-dose methotrexate-based regimens increase survival, but the standards of care and the place of whole-brain radiotherapy remain unclear, and are likely to depend on the age of the patient. The focus now is on the development of new polychemotherapy regimens to reduce or defer whole-brain radiotherapy and its delayed complications.

Response assessment in recurrent glioblastoma treated with irinotecan-bevacizumab: comparative analysis of the Macdonald, RECIST, RANO, and RECIST + F criteria.

Traditionally, the most widely used criteria for response assessment in glioblastoma have been Macdonald and the Response Evaluation Criteria In Solid Tumors (RECIST). Recently, new criteria addressing contrast enhancement and fluid-attenuated inversion recovery (FLAIR)/T2 hyperintensity have been defined (the Response Assessment in Neuro-Oncology criteria) to better evaluate the effect of antiangiogenic therapy. Whether FLAIR/T2 imaging could also be helpful to refine RECIST criteria remains unresolved. This study proposed the RECIST + F criteria and compared the 4 methods (Macdonald, RECIST, RANO, and RECIST + F) to determine their agreement in identifying response and progression of recurrent glioblastomas to irinotecan-bevacizumab. Patients with recurrent glioblastoma treated with second-line irinotecan-bevacizumab were eligible. Clinical status, corticosteroid dose, and 1-dimensional and 2-dimensional measurements of tumor contrast enhancement and FLAIR hyperintensity were retrospectively assessed. Response and progression were determined according to each set of criteria. Seventy-eight patients were included. Response rates ranged from 34.2% with RECIST + F to 44.7% with Macdonald criteria. Agreement among the 4 methods in determining response and type of progression was high (kappa statistic > 0.75). One-third of patients exhibited nonenhancing progression with stable or improved contrast enhancement. Median progression-free survival was predicted by RECIST, at 13.6 weeks; RECIST + F, 12.3; Macdonald, 12.7; and RANO, 11.7 (P = .840). Intra- and interobserver correlations were high for both contrast enhancement and FLAIR hyperintensity measurements. There was a strong concordance among the different methods in determining response and progression to irinotecan-bevacizumab. Criteria integrating FLAIR hyperintensity tended, however, to reduce response rates and progression-free survival compared with criteria considering only contrast enhancement. The 1-dimensional approach appeared to be as valid as the 2-dimensional approach.

Severe meningo-radiculo-neuritis associated with ipilimumab.

PURPOSE: Ipilimumab is a T-cell-potentiating monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) to promote antitumoural immunity. In phase III trials, ipilimumab was shown to be the first agent to improve survival in advanced melanoma patients, regardless of previous treatment. We report a case of severe neurologic disease after ipilimumab treatment. PATIENT AND METHODS: Neurologic symptoms including facial diplegia, tetraplegia, areflexia progressed with time a few days after the fourth monthly ipilimumab infusion. Analysis of the cerebro-spinal fluid showed elevated proteinorachy and lymphocytic meningitis. Despite high doses of steroids and symptomatic treatment, the symptoms worsened. RESULTS: Veinoglobulins were then infused and the patient began to improve and recovered almost normal activity two years later. CONCLUSION: The adverse event profile associated with ipilimumab was primarily immune-related. This is the first case in which such a severe event has been reported.

Place of modern imaging modalities for solitary plasmacytoma: toward improved primary staging and treatment monitoring.

Radiation therapy (RT) is the mainstay of treatment of solitary plasmacytoma. In most cases, doses ranging from 40 to 50 Gy yield in a local control more than 80%. However, the prognosis of patients with SP is marked by a high rate of transformation to multiple myeloma (MM), and there is no demonstrated benefit of adjuvant chemotherapy for decreasing this probability. However, clinical benefits could be reached from improving screening for other primary sites of plasmacytoma and earlier discovering signs suggestive of MM. Since such strategy could provide significant information regarding both prognosis and therapy, it has become first importance to improve initial staging of tumor widespread. Although conventional skeletal X-ray survey remains standard, usual sensitivity of radiographies does not permit diagnosing early myeloma lesions and a significant number of patients with supposed SP might be understaged and do not receive the appropriate treatment. The development of more sensitive and specific imaging modalities will make it feasible to earlier detect subclinical lesions, thus leading lead to new approaches in the treatment strategies. Here, we discuss the benefits and limitations of magnetic resonance imaging and positron emission tomography for primary staging of patients with solitary plasmacytoma. Both imaging modalities could also improve target volume delineation and assessment of tumor response after RT.