Patrick François

Temozolomide Treatment in Aggressive Pituitary Tumors and Pituitary Carcinomas: A French Multicenter Experience

CONTEXT To date only 18 patients with aggressive pituitary tumors or carcinomas treated with temozolomide have been reported. Increased expression of O6-methylguanine-DNA-methyltranferase (MGMT) has been suggested to predict resistance to temozolomide. OBJECTIVES The objective of the study was to describe the antitumoral efficacy and toxicity of temozolomide in patients with aggressive pituitary tumors or carcinomas and evaluate the possible prognostic value of MGMT promoter methylation and protein expression. PATIENTS Eight patients, five with pituitary carcinomas (three prolactin (PRL) and two ACTH) and three with aggressive pituitary tumors (one PRL and two ACTH), all treated with temozolomide administered orally for four to 24 cycles, were included in our French multicenter study. DESIGN MGMT expression was assessed by immunohistochemistry and MGMT promoter methylation by pyrosequencing. RESULTS Three of the eight patients (two ACTH adenomas and one PRL carcinoma) responded to temozolomide as demonstrated by significant tumor shrinkage and reduced hormone secretion. Three cycles of temozolomide were sufficient to identify treatment-responsive patients. Additional cycles did not improve treatment efficacy in those not responding, even when associated with carboplatin and vepeside. MGMT expression did not predict tumoral response to temozolomide because it was positive in one responder and negative in two nonresponders. Similarly, MGMT promoter methylation (three of seven tumors) did not predict clinical response. Toxicity remained mild in all patients. CONCLUSION Temozolomide treatment may be an effective option for some aggressive pituitary tumors or carcinomas. Response to a trial of three cycles of treatment seems sufficient to identify responders and more reliable than patient MGMT status.

Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of malignant glioma: a randomized phase II trial.

OBJECTIVE:This study was a randomized, multicenter Phase II trial comparing the effect of perioperative implantation of 5-fluorouracil-releasing microspheres followed by early radiotherapy (Arm A) and early radiotherapy alone (Arm B) in patients with gross total resection of high-grade glioma. METHODS:Patients were randomized on clinical and radiological assumption of supratentorial high-grade glioma. All patients underwent surgery, and after resection and histological confirmation, patients randomized to Arm A received multiple injections of microsphere suspension (130 mg of 5-fluorouracil). Conventional fractionated radiotherapy (59.4 Gy) was initiated between the second and the seventh day after surgery for both arms. RESULTS:A total of 95 patients were randomized. Seventy-seven patients were treated and analyzed in intention to treat for efficacy and safety. Overall survival was 15.2 months in Arm A and 13.5 months in Arm B. In the subpopulation of patients with complete resection, overall survival was 15.2 months in Arm A versus 12.3 months in Arm B. However, these differences were not significant. Safety was acceptable with prophylactic high doses of corticosteroids. CONCLUSION:It may be hypothesized that the implantation of 5-fluorouracil-loaded microspheres in the wall of the cavity resection did increase the overall survival, but the present study was not designed and sufficiently powered to demonstrate this.

Expression of somatostatin receptors, SSTR2A and SSTR5, in 108 endocrine pituitary tumors using immunohistochemical detection with new specific monoclonal antibodies

Medical treatment of endocrine pituitary tumors with somatostatin analogs depends on tumor type and somatostatin receptor (SSTR) expression. Immunohistochemical detection of these receptors using polyclonal antibodies has given conflicting results. We studied the expression of SSTR(2A) and SSTR(5) with new procedures in 108 pituitary tumors. Using 2 new, specific monoclonal antibodies (clone UMB-1 and UMB-4), 2 fixatives (Bouin-Hollande and zinc-formalin) and 2 technical procedures (manual and automated), SSTR(2A) and SSTR(5) expression was studied in 60 GH (growth hormone), 15 ACTH (adrenocorticotropic hormone), 23 FSH/LH (follicle-stimulating hormone/luteinizing hormone), 7 PRL (prolactin), and 3 TSH (thyroid-stimulating hormone) tumors. Only membrane staining was taken into account, and the SSTR expression was considered positive when more than 5% of the cells were immunoreactive. GH tumors were classified as GH or GH/PRL, densely or sparsely granulated, and into 3 groups according to the percentage of SSTR-immunoreactive cells (group 1: <25%; group 2: 25%-75%; group 3: >75%). Almost all GH tumors expressed SSTR(2A) (93%) and SSTR(5) (83%) at high levels (group 3: >75%) in 52% and 37%, respectively. SSTR(2A) expression was significantly higher in densely than in sparsely granulated tumors. Moreover, SSTR(2A) was also expressed in the 3 TSH tumors and weakly expressed in 26% of the FSH/LH tumors, although not in ACTH or PRL tumors. SSTR(5) expression was noted in 2 of the 3 TSH tumors, in only 20% of ACTH tumors, and was absent from FSH/LH and PRL tumors. The immunohistochemical detection of SSTR is a reproducible and specific method that could help direct the choice of postoperative medical treatment.

Prognostic factors in central neurocytomas: a multicenter study of 71 cases.

Central neurocytoma (CN) is a rare intraventricular tumor presenting a benign histologic appearance and favorable prognosis after surgery. In contrast, “atypical” CN is defined by a high MIB1 proliferation index and/or histologic features of malignancy, which are associated with a poorer outcome. This variant of CN remains somewhat controversial. To better characterize CN and its “atypical” variant, a retrospective multicenter study was conducted on 71 patients presenting with CN. A statistical analysis of clinical, radiologic, and histologic data was conducted to validate prognostic factors. The immunohistochemical phenotype of CNs, analyzed by tissue microarrays, and the MIB1 index were evaluated for 45 cases. Tissue microarrays validated the expression of neuronal markers synaptophysin and NeuN, but not that of glial markers glial fibrillary acidic protein and oligodendrocyte transcription factor 2. In the univariate analysis, a tumor volume ≥30 cm3 (P=0.025), incomplete surgery (P=0.033), and a mitotic count ≥3 per 10 high-power fields (P=0.009) were predictors of a higher risk of recurrence, unlike the other usual histologic features of malignancy and the high MIB1 index. Partial surgery was the only criterion associated with a poorer outcome in the multivariate model. Our results, based on a large multicenter series, show the striking homogeneity of CNs and do not support the use of histologic criteria as reliable markers to define an “atypical” group of CNs. Our study suggests that the extent of surgery is the main factor to be considered in the prognostic assessment of patients with CN.

The interperiosteo-dural concept applied to the perisellar compartment: a microanatomical and electron microscopic study

OBJECT The dura mater has 2 dural layers: the endosteal layer (outer layer), which is firmly attached to the bone, and the meningeal layer (inner layer), which directly covers the brain. These 2 dural layers join together in the middle temporal fossa or the convexity and separate into the orbital, lateral sellar compartment (LSC), or spinal epidural space to form the extradural neural axis compartment (EDNAC). The aim of this work was to anatomically verify the concept of the EDNAC by using electron microscopy. METHODS The authors studied the cadaveric heads obtained from 13 adults. Ten of the specimens (or 20 perisellar areas) were injected with colored latex and fixed in formalin. They carefully removed each brain to allow a superior approach to the perisellar area. The 3 other specimens were studied by microscopic and ultrastructural methods to describe the EDNAC in the perisellar area. Special attention was paid to the dural layers surrounding the perisellar area. The authors studied the anatomy of the meningeal architecture of the LSC, the petroclival venous confluence, the orbit, and the trigeminal cave. After dissection, the authors took photographs of the dural layers with the aid of optical magnification. The 3 remaining heads, obtained from fresh cadavers, were prepared for electron microscopic study. RESULTS The EDNAC is limited by the endosteal layer and the meningeal layer and contains fat and/or venous blood. The endosteal layer and meningeal layer were not identical on electron microscopy; this finding can be readily related to the histology of the meninges. CONCLUSIONS In this study, the authors demonstrated the existence of the EDNAC concept in the perisellar area by using dissected cadaveric heads and verified the reality of the concept of the meningeal layer with electron microscopy. These findings clearly demonstrated the existence of the EDNAC, a notion that has generally been accepted but never demonstrated microscopically.

Natural history of supratentorial hemangioblastomas in von Hippel-Lindau disease.

BACKGROUNDSupratentorial hemangioblastomas are rare lesions, occurring either sporadically or in von Hippel-Lindau disease. OBJECTIVEFollowing recent advances in our understanding of the natural history of von Hippel-Lindau–associated cerebellar and spinal hemangioblastomas, we conducted a study of the natural history of supratentorial hemangioblastomas in von Hippel-Lindau disease. METHODSWe reviewed a series of 18 supratentorial hemangioblastomas in 13 patients with von Hippel-Lindau disease. Clinical, genetic, and serial imaging data and operative records were analyzed. RESULTSHemangioblastomas were most commonly seen in the temporal lobe. Only 6 tumors had a cyst at diagnosis or during follow-up, and only 6 patients had associated symptoms at presentation or during follow-up. The most frequent clinical presentations were intracranial hypertension and visual loss. Of 14 tumors with documented serial imaging, 13 demonstrated tumor growth. Rates and patterns of tumor growth were unique to each patient. The mechanism of cyst formation described in other locations was also demonstrated in the supratentorial region. Patterns of peritumoral edema and rate of cyst formation seemed to be influenced by the presence of anatomic barriers. Germline VHL mutation was identified in all patients, but no specific genotype-phenotype correlation was found, although a familial predisposition is suggested. CONCLUSIONThis series illustrates the wide variation in tumor locations, patterns of growth, and edema progression seen in supratentorial hemangioblastomas and adds to our knowledge of the natural history of hemangioblastomas.

Changes in the management and comorbidities of acromegaly over three decades. The French Acromegaly Registry.

CONTEXT Acromegaly is a rare disease associated with chronic multisystem complications. National registries have been created in several countries. DESIGN The French Registry contains data on acromegaly epidemiology, management and comorbidities recorded over more than three decades, retrospectively until 1999 and prospectively from 1999 to 2012. RESULTS Data could be analyzed for 999 of the 1034 patients included in the registry (46% males). Disease control, defined as IGF-I normalization (adjusted for age and sex), was achieved in 75% of patients at the last follow-up visit. Half the patients with uncontrolled disease had IGF-I levels below 1.5 times the upper limit of normal (ULN). The proportion of patients with surgically cured disease did not change markedly over time, whereas the proportion of patients with uncontrolled disease fell and the proportion of patients with medically controlled disease rose. Cardiovascular, metabolic, respiratory and rheumatologic comorbidities and their outcomes were recorded for most patients, and no noteworthy overall deterioration was noted over time. Cancer occurred in 10% of patients, for a standardized incidence ratio of 1.34 (95% CI: 0.94-1.87) in men and 1.24 (0.77-1.73) in women. Forty-one patients died during follow-up, for a standardized mortality ratio of 1.05 (0.70-1.42). Most deaths were due to cancer. CONCLUSIONS The majority of patients with acromegaly now have successful disease control thanks to the multistep management. The incidence of comorbidities following diagnosis of acromegaly is very low. Life expectancy is now close to that of the general population, probably owing to better management of the GH/IGF-I excess and comorbidities.

Lateral sellar angiolipoma: a tumor illustrative of the extradural compartment of the neural axis

Angiolipomas are rare tumors of the CNS that most frequently develop in the orbit, the cavernous space, and the epidural space of the spine. The authors report the case of a patient who presented with an angiolipoma of the cavernous space. Using data from the published literature and an experimental anatomical approach, they demonstrate that the cavernous space contains adipose tissue. Consequently, they suggest that angiolipomas constitute a characteristic tumor illustrating the interperiosteo-dural concept. The authors report the clinical, radiological, and histological data of a patient who presented with a tumor of the cavernous space. In addition, they prepared 2 encephalic extremities (4 cavernous spaces) using a special anatomical preparation consisting of an injection of colored neoprene latex followed by a 6-month immersion in a formaldehyde solution enriched with hydrogen peroxide to soften the bone structures (coronal sections) while leaving the fat in the cavernous space intact. This case report corroborates previously published clinical data and shows that the tumor was a hamartoma comprising mature fat cells associated with vascular proliferation. The tumor developed in the cavernous space, which is an interperiosteo-dural space extending from the sphenoid periosteum (osteoperiosteal layer) to the superior and lateral walls of the cavernous space (encephalic layer). This space represents an anatomical continuum extending from the coccyx to the orbit: the interperiosteo-dural concept. It contains fat tissue that is abundant at the level of the orbit and the epidural spinal space and sparser at the level of the cavernous spaces, as was shown in our anatomical study. The authors suggest that angiolipomas represent a characteristic tumor that illustrates the interperiosteo-dural concept because they essentially develop in the fat tissue contained in these spaces.

A deletion causing NF2 exon 9 skipping is associated with familial autosomal dominant intramedullary ependymoma.

BACKGROUND Intramedullary ependymomas are rare and benign tumors in the adult. Little is known about their physiopathology, but the implication of the NF2 gene is suspected because of their presence in a third of patients with type 2 neurofibromatosis (NF2), a disorder caused by mutation of the NF2 gene. METHODS We conducted a clinical and genetic study of a family in which 5 of 9 members suffered from intramedullary ependymoma. Karyotyping and CGH array analysis were performed on DNA from peripheral blood lymphocytes from affected participants. The NF2 gene sequences were then determined in DNA from 3 nonaffected and all 5 affected members of the family. RESULTS Karyotype and CGH array findings were normal. Sequencing of NF2 revealed a heterozygous deletion, c.811-39_841del69bp, at the intron 8/exon 9 junction, in all affected members that was absent from all nonaffected members. RT-PCR analysis and sequencing revealed a novel NF2 transcript characterized by a skipping of exon 9 (75 bp). This deletion is predicted to result in a 25-amino acid deletion in the N-terminal FERM domain of neurofibromin 2. Modeling of this mutant domain suggests possible disorganization of the subdomain C. CONCLUSION We report the first family with an NF2 mutation associated with intramedullary ependymomas without other features of NF2 syndrome. This mutation, which has not been described previously, may particularly affect the function of neurofibromin 2 in ependymocytes leading to the development of intramedullary WHO grade II ependymomas. We propose that sporadic intramedullary ependymomas should also be analyzed for this region of NF2 gene.

Vestibular Schwannoma: Dissection of the Tumor and Arachnoidal Duplication

Introduction: In vestibular schwannoma (VS) surgery, the arachnoidal duplication, based on an epiarachnoidal origin of the tumor, is reputedly induced by medial growth of tumor and helpful in atraumatic dissection. This study was intended to verify the epiarachnoidal origin of VS. Materials and Methods: We studied 49 human temporal bones (TBs) specimens. Twenty-two TBs from 18 patients with VS were selected. An additional series of 27 TBs without any tumor within the internal auditory meatus were also included. We identified the location of the meninges and the position of the transition zone inside the meatus and described the lateral extension of the subarachnoid spaces. Results: In VS specimens, psammoma bodies were seen at the fundus along the arachnoidal layer. No connective tissue or protrusion of a psammoma body was observed between the nerves and the VS. High magnification failed to demonstrate any meningeal cleavage plane between the facial or cochlear nerve and the tumor. The subarachnoid space was visible within the internal auditory meatus and extended from the porus to the fundus. In every case, the transition zone, the vestibular ganglion, or the VS was located in the subarachnoid fluid space. Conclusion: We were not able to identify any layer between tumor and the intrameatal contents and did not observe any conjunctive-tissue capsule surrounding the intrameatal VS, as an epiarachnoidal tumor origin would suggest. These observations are in contradiction with the descriptions concerning the epiarachnoidal origin of VS.