Why We Should Still Treat by Neurosurgery Patients With Cushing Disease and a Normal or Inconclusive Pituitary MRI.

CONTEXT: In patients with Cushing disease (CD) and a typical image of adenoma at MRI, transsphenoidal surgery is consensual. However, when MRI is inconclusive or normal, some authors now advocate medical treatment instead. The implicit assumption is that modern MRI should miss only very small microadenomas that are too difficult to visualize at surgery. OBJECTIVE: To analyze the evolution with time of the performances of MRI and the outcomes of surgery in patients with CD with a typical image of adenoma vs an inconclusive or normal MRI. DESIGN AND PATIENTS: Retrospective single center study of 195 patients with CD treated by transsphenoidal surgery between 1992 and 2018, using first a translabial microscopic and then a transnasal endoscopic approach. Patients with inconclusive or normal MRI were explored by bilateral inferior petrosal sinus sampling. Four MRI groups were defined: microadenomas (n = 89), macroadenomas (n = 18), or MRI either inconclusive (n = 44) or normal (n = 44). RESULTS: The proportion of inconclusive/normal MRI decreased with time, from 60% (21/35) in 1992 to 1996 to 27% (14/51) in 2012 to 2018 (P = 0.037). In the four MRI groups, the per-operatory adenoma visualization rate was only slightly lower when MRI was normal (95%, 100%, 86%, 79%; P = 0.012) and postoperative remission rates were not different (85%, 94%, 73%, 75%; P = 0.11). CONCLUSION: The diagnostic performances of MRI have improved but remain inferior to the eye of an expert neurosurgeon, best assisted by endoscopy. We propose that patients with CD and an inconclusive/normal MRI be addressed by an expert neurosurgeon for transsphenoidal surgery rather than being treated medically.

Late sequelae of symptomatic epidural compression in children with localized neuroblastoma.

BACKGROUND: To describe late sequelae and their correlation with presenting clinical features and tumor treatment in children with symptomatic epidural compression (EC) secondary to localized neuroblastoma. PROCEDURES: A total of 98 evaluable children diagnosed with neuroblastoma and EC, who survived a minimum of 2 years were identified in two Italian and French neuroblastoma series. RESULTS: Symptoms of EC at diagnosis included motor deficit in 94 cases and sphincter deficits in 33. Initial treatment was chemotherapy in 66 cases, neurosurgical decompression in 29 and radiotherapy in 3. Chemotherapy was chosen more frequently for younger children and for those with stage 3 disease. Overall treatment consisted of chemotherapy alone in 44 cases, neurosurgery and chemotherapy in 38, radiotherapy and chemotherapy, with or without neurosurgery, in 16. After a median follow-up of 7.3 years, 57 children (58.2%) had one or more sequelae. Motor sequelae involved 50/57 of these children and correlated with age and severity of motor deficit at diagnosis and neurosurgical treatment. Spine deformities involved 27/57 children and were more frequent in those with severe motor deficit at diagnosis, or who were treated by neurosurgery or radiotherapy. Sphincter dysfunctions involved 31/57 children and were more frequent among children who presented with sphincter symptoms and severe motor deficit. CONCLUSIONS: Fifty-eight percent of the children with localized neuroblastoma and symptomatic EC registered in this study developed late sequelae. The severity of motor deficit at diagnosis was the main risk factor.

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.

A combined dexamethasone desmopressin test as an early marker of postsurgical recurrence in Cushing's disease.

CONTEXT: Recurrence of Cushing's disease (CD) after transsphenoidal surgery (TSS) occurs in about 25% of cases. Twenty percent of patients with immediate postsurgical corticotroph deficiency will present late recurrence. OBJECTIVE: The aim of the study was to evaluate a coupled dexamethasone desmopressin test (CDDT) as a predictor of recurrence of CD. DESIGN: We conducted a prospective bicenter study (Marseille and Grenoble, France). PATIENTS: We studied 38 patients treated by TSS for CD with a mean follow-up of 60 months. INTERVENTION(S): We evaluated 24-h urinary free cortisol, ACTH, and cortisol plasmatic levels and performed low-dose dexamethasone suppression test and CDDT 3 to 6 months after surgery and then yearly. MAIN OUTCOME MEASURES: After CDDT, ACTH ratio (ACTHr) was defined as (PeakACTH - BaseACTH)/BaseACTH. Cortisol ratio (Cortisolr) was defined as (PeakCortisol - BaseCortisol)/BaseCortisol. Basal values were observed after low-dose dexamethasone suppression test. Receiver operator characteristics curve defined ACTHr and Cortisolr giving the best sensitivity and specificity associated with recurrence. RESULTS: Ten patients presented recurrence. ACTHr and Cortisolr were superior or equal to 0.5 in all patients with recurrence and in three of 28 patients in remission (100% sensitivity, 89% specificity). The test became positive in eight of 10 patients with recurrence 6-60 months before classical markers of hypercortisolism. Six patients with immediate postsurgical corticotroph deficiency presented recurrence. All of them presented CDDT positivity during the 3 yr after surgery, and recurrence 6 to 60 months after CDDT positivity. CONCLUSIONS: CDDT is an early predictor of recurrence of CD and could be of particular interest in the first 3 yr after surgery, by selecting patients at high risk of recurrence despite falsely reassuring classical hormonal markers.

Mineralocorticoid deficiency in post-operative cerebral salt wasting.

Acute hyponatremia, following neurosurgery, results from inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting (CSW). CSW is due to abnormally high atrial or brain natriuretic peptides (ANP, BNP), which block all stimulators of zona glomerulosa steroidogenesis, resulting in mineralocorticoid deficiency. A 3 year-old girl presented CSW at day 4, after resection of craniopharyngioma and hypophysectomy. Hyponatremia, hyperkalemia and high natriuresis occurred on day 8, with low renin and aldosterone and elevated BNP 120.3 ng/ml (undetectable before surgery). Fludrocortisone 100 microg/day controlled natriuresis and restored electrolytes within 24 hours. A 5 year-old boy presented CSW at day 6 after partial resection of optic glioma. Fludocortisone 100 microg/day restored electrolytes within 8 hours. ANP was elevated, 60.6 ng/l, aldosterone and renin were low. Fludrocortisone supplementation should be considered in CSW, as excessive natriuresis is controlled, and electrolytes are easily restored, avoiding life-threatening complications of this complex disorder.

Intraoperative and postoperative gamma detection of somatostatin receptors in bone-invasive en plaque meningiomas.

OBJECTIVE: Scintigraphy with a radiolabeled somatostatin analog ((111)In-diethylenetriaminepenta-acetic acid octreotide) detects the somatostatin receptors that are found in vitro in all meningiomas. Previous studies have proved the benefit of radioimmunoguided surgery, with a hand-held gamma probe, for the assessment and removal of neuroendocrine tumors. We conducted a study to determine whether intraoperative radiodetection of somatostatin receptors is feasible and could increase the probability of complete meningioma resection, especially for bone-invasive en plaque meningiomas, which are difficult to control surgically. METHODS: Eighteen patients with en plaque sphenoid wing and cranial convexity meningiomas were studied by preoperative and postoperative somatostatin receptor scintigraphy. In 10 of them, intraoperative radiodetection with a hand-held gamma probe was performed 24 hours after the intravenous administration of (111)In-diethylenetriaminepenta-acetic acid octreotide. This procedure was combined with a computer-aided navigation system. RESULTS: All preoperative scintigrams were positive. Intraoperative gamma probe detection was achieved for the invaded bone, dura, and periorbit of sphenoid wing meningiomas. The average tumor/nontumor count ratio was 2:1, with a maximum of 12:1, thus allowing precise detection capable of defining the tumor margins. In three cases of sphenoid wing meningiomas, postoperative scintigrams were helpful for the determination of recurrences that magnetic resonance imaging failed to detect. CONCLUSION: These preliminary data show that intraoperative radiodetection of somatostatin receptors with a hand-held gamma probe is feasible and may be helpful to guide the surgical removal of bone-invasive en plaque meningiomas. Preoperative and postoperative scintigraphy may be useful for the management and follow-up of patients with these tumors.

Accuracy of bilateral inferior petrosal or cavernous sinuses sampling in predicting the lateralization of Cushing's disease pituitary microadenoma: influence of catheter position and anatomy of venous drainage.

Bilateral inferior petrosal sinus sampling (BIPSS) is the most reliable procedure for distinguishing Cushing's disease from ectopic ACTH secretion. However, it is less reliable at predicting the lateralization of the pituitary corticotroph microadenoma. We sought to determine whether this could be improved by taking into account the pattern of venous drainage and the precise location of the catheters. We retrospectively studied data from 86 patients who underwent BIPSS. Cushing's disease was predicted in 74 patients, of whom 69 underwent transsphenoidal surgery. Surgical cure was obtained in 65 patients, with identification of a corticotroph microadenoma in 58 cases. In 49 patients the location of the microadenoma predicted by the intersinus ACTH gradient could be compared with the pathologist's data. BIPSS accurately predicted the lateralization of the microadenoma in only 57% of these patients. Prediction was improved to 71% when both venograms and catheters were symmetric (35 patients). In this subgroup accuracy was 86% in patients with both catheters in the inferior petrosal sinuses compared with 50% in patients with both catheters in the cavernous sinuses (CS). Two transient sixth nerve palsies occurred during CS catheterization. Our data suggest that BIPSS results are much improved when venous drainage is symmetric. Catheterization of CS did not improve the results and was less safe.