Kosaku Amano

Prospective Study of High-Dose Cabergoline Treatment of Prolactinomas in 150 Patients

CONTEXT Cabergoline fails to normalize hyperprolactinemia in a considerable proportion of prolactinomas, especially macroadenomas. OBJECTIVE We examined the effect of individualized high-dose cabergoline treatment on hyperprolactinemia in prolactinomas. PATIENTS The study included 122 women and 28 men (93 microadenomas and 57 macroadenomas). Forty-seven had undergone transsphenoidal surgery. According to the preceding medical treatment, the participants were separated into untreated (group U; n = 60), intolerant (group I; n = 64), and resistant (group R; n = 26) groups. INTERVENTIONS We promptly increased cabergoline dose on the basis of individual prolactin levels. Length of treatment was 1 yr. RESULTS Cabergoline normalized hyperprolactinemia in all patients except one. The proportion of prolactin normalization in both groups U and I was 83% at 3 months and 95% at 6 months. By contrast, that in group R was 35% at 3 months and 58% at 6 months. Mean cabergoline dose in milligrams per week at the time of prolactin normalization was 2.0 +/- 0.3 in group U, 0.9 +/- 0.1 in group I, and 5.2 +/- 0.6 in group R. Prolactin normalization rate at the 3 mg/wk dose was 84% overall but only 35% in group R. Serum progesterone or testosterone levels, diminished in 122 women or 16 men, respectively, were recovered in all except one resistant and four postmenopausal or panhypopituitary patients. CONCLUSION Individualized high-dose cabergoline treatment can normalize hyperprolactinemia and hypogonadism in nearly all prolactinomas irrespective of tumor size or preceding treatments. Hyperprolactinemia could be controlled in poor responders within 1 yr with doses higher than 3 mg/wk.

Clinical and radiological features related to the growth potential of meningioma

Clinical and radiological features that help predict the growth potential of meningioma would be beneficial. The purpose of this study is to clarify the characteristics related to proliferating potential using the MIB-1 staining index. We analyzed the relationship of MIB-1 staining indices to characteristics of 342 consecutive patients with meningioma surgically removed between 1995 and 2004 by logistic regression analysis. One hundred and forty-nine of the patients with meningioma were ≥60 in age; 89 male; 48 recurrent; 203 symptomatic; 157 at the skull base; 124 over 20 cm3; 24 multiple; 136 with edema; 117 with calcification. The MIB-1 staining index in 56 of 296 grade I meningiomas in WHO classification was ≥ 3.0; in 27 of 28 grade II; and in 17 of 18 grade III, respectively. Logistic regression analysis demonstrated that male (odds ratio [OR], 2.374, p=0.003), recurrence (OR, 7.574, p=0.0001), skull base (OR, 0.540, p=0.035), calcification (OR, 0.498, p=0.019) were independent risk factors for a high MIB-1 staining index (≥3.0); age, symptomatic, volume, multiple, edema were not. Male, recurrence, non-skull base, absence of calcification are independent risk factors for a high proliferative potential. These should be taken into consideration when managing meningiomas.

Individualized High-Dose Cabergoline Therapy for Hyperprolactinemic Infertility in Women with Micro- and Macroprolactinomas

CONTEXT Cabergoline is effective for hyperprolactinemic hypogonadism. However, the rate of cabergoline-induced pregnancy in women with prolactinoma remains unknown. Also unknown is whether cabergoline can control tumor growth and thereby achieve successful pregnancy in patients with macroprolactinomas. METHODS Eighty-five women with macroprolactinomas (n = 29) or microprolactinomas (n = 56) received prospective, high-dose cabergoline therapy for infertility based on individual prolactin suppression and/or tumor shrinkage. The patients included 31 bromocriptine-resistant, 32 bromocriptine-intolerant, and 22 previously untreated women. Conception was withheld until three regular cycles returned in women with microadenoma and until tumors shrank below 1.0 cm in height in women with macroadenoma. Cabergoline was withdrawn at the fourth gestational week. RESULTS Cabergoline normalized hyperprolactinemia and recovered the ovulatory cycle in all patients. All adenomas contracted, and 11 macroadenomas and 29 microadenomas disappeared. Eighty patients (94%) conceived 95 pregnancies, two of which were cabergoline-free second pregnancies. The dose of cabergoline at the first pregnancy was 0.25-9 mg/wk overall and 2-9 mg/wk in the resistant patients. Of the 93 pregnancies achieved on cabergoline, 86 resulted in 83 single live births, one stillbirth, and two abortions; the remaining seven were ongoing. All babies were born healthy, without any malformations. No mothers experienced impaired vision or headache suggestive of abnormal tumor reexpansion throughout pregnancy. CONCLUSION Cabergoline achieved a high pregnancy rate with uneventful outcomes in infertile women with prolactinoma, independent of tumor size and bromocriptine resistance or intolerance. Cabergoline monotherapy could substitute for the conventional combination therapy of pregestational surgery or irradiation plus bromocriptine in macroprolactinomas.

DNA Mismatch Repair Protein (MSH6) Correlated With the Responses of Atypical Pituitary Adenomas and Pituitary Carcinomas to Temozolomide: The National Cooperative Study by the Japan Society for Hypothalamic and Pituitary Tumors

CONTEXT Temozolomide (TMZ) is an alkylating agent and was a first-line chemotherapeutic agent for malignant gliomas. Recently, TMZ has been documented to be effective against atypical pituitary adenomas (APAs) and pituitary carcinomas (PCs). OBJECTIVE The clinical and pathological characteristics of APAs and PCs treated with TMZ in Japan were surveyed and analyzed retrospectively. DESIGN Members of the Japan Society of Hypothalamic and Pituitary Tumors were surveyed regarding the clinical characteristics of APAs and PCs treated with TMZ. Stored tumor samples were gathered from the responders and were assessed by the immunohistochemistry of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, p53, MSH6, and anterior pituitary hormones. Responses to TMZ treatment were defined as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 2.0. SUBJECTS Three samples from 3 subjects with APA and 11 samples from 10 subjects with PC were available. RESULTS The 13 subjects had APAs and PCs consisting of 5 prolactin-producing tumors, 5 ACTH-producing tumors, and 3 null cell adenomas. The clinical response to TMZ treatment was as follows: 4 cases of CR and PR (31%), 2 cases of SD (15%), 6 cases of recurrence after CR and PR (46%), and 1 case of PD (8%). However, considerable subjects had recurrent disease after a response to TMZ. The immunohistochemical findings of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, and p53 did not show any significant correlation with the efficacy of TMZ. However, the immunopositivity of MSH6 was positively correlated with TMZ response (P = .015, Fishers exact test). CONCLUSIONS This study showed that preserving MSH6 function was contributory to the effectiveness of TMZ in malignant pituitary neoplasms. It is necessary to survey more cases and evaluate multifactor analyses.

Anterior interhemispheric approach for 100 tumors in and around the anterior third ventricle.

OBJECTIVE We report our experience with anterior interhemispheric approach for tumors in and around the anterior third ventricle, including surgical technique, instrumentation, pre- and postoperative hormonal disturbances, and resection rate. METHODS One hundred patients with 46 craniopharyngiomas, 12 hypothalamic gliomas, 12 meningiomas, 6 hypothalamic hamartomas, and 24 other lesions were operated on using an anterior interhemispheric approach with or without opening of the lamina terminalis. This surgical approach involves no frontal sinus opening; a narrow (approximately 15–20 mm in width) access between the bridging veins, which is sufficient to remove the tumor totally; and sparing of the anterior communicating artery. Specially designed long bipolar forceps and scissors are necessary for this approach, and concomitant use of angled instruments (endoscope, aspirator, and microforceps) is required frequently. The postsurgical follow-up period varied from 4 months to 18 years. RESULTS Total removal of the neoplasm was accomplished in 37 of 46 patients with craniopharyngiomas (80.4%), whereas subtotal resection was performed in hypothalamic gliomas. No significant differences in pre- and postoperative hormonal disturbances were observed in 37 craniopharyngiomas and 10 hypothalamic gliomas. There was no operative mortality. Visual acuity was preserved or improved in 68 of 75 patients assessed. The Karnofsky Performance Scale score did not deteriorate in 72 of 75 patients tested. CONCLUSION The minimally invasive anterior interhemispheric approach, with or without opening of the lamina terminalis, is useful for removal of tumors in and around the anterior third ventricle, such as craniopharyngiomas and hypothalamic gliomas.

A highly sensitive and specific chemiluminescent enzyme immunoassay for placental alkaline phosphatase in the cerebrospinal fluid of patients with intracranial germinomas.

Background: Placental alkaline phosphatase (PLAP) in cerebrospinal fluid (CSF) has been proposed as a tumor marker for intracranial germinomas. The purpose of the present study was to develop a sensitive assay for measuring CSF PLAP and to evaluate the clinical significance of PLAP in patients with germinomas. Methods: A chemiluminescent enzyme assay for PLAP was developed using an anti-human-PLAP monoclonal antibody. PLAP concentrations were determined in 37 controls, 36 germinomas, 3 nongerminomatous germ cell tumors, 21 gliomas and 12 other brain tumors. Results: The assay detection limit was 5 pg/ml. The median PLAP concentration in the control group was below the detection limit. Significantly higher PLAP levels were detected in all 36 germinoma patients, with values ranging from 16 to 3,700 pg/ml. The high PLAP concentrations of 17 germinoma patients decreased to below the detection limit after complete remission had been achieved with radiochemotherapy. The sensitivity and specificity of PLAP for germinomas were 94 and 97%, respectively, with a cutoff value of 30 pg/ml. Conclusions: The results of this study suggest that the determination of CSF PLAP by the chemiluminescent method described here provides a clinically useful tumor marker for the diagnosis and monitoring of intracranial germinomas.

Novel flexible forceps for endoscopic transsphenoidal resection of pituitary tumors: technical report

The endoscope has become an essential tool for transsphenoidal pituitary surgeries because of the panoramic view and the ability to visualize structures beyond the direct line of vision. However, the regular dedicated instruments for these surgeries sometimes do not reach the areas visualized by an angled endoscope, and instrument maneuverability is limited. To overcome or minimize these problems, we constructed a new flexible tumor forceps that can be manipulated to change shape after placing into the surgical fields via the endonasal or sublabial route, to reach any desirable location for tumor dissection and excision. We applied this newly developed instrument in endonasal endoscopic resection complementing microsurgical procedure in 20 cases of pituitary tumors. The flexible forceps was able to access sites where regular dedicated instruments for transsphenoidal pituitary surgeries could not readily reach despite endoscopic visualization. No complication was observed in the present series, confirming the safety of the newly designed flexible forceps. Our newly developed flexible forceps improves the instrument maneuverability of endoscopic transsphenoidal resection of pituitary tumors, especially those located laterally at the cavernous sinuses or with frontal extension. The use of this instrument makes the best use of endoscopic panoramic visualization for tumor removal.

Pulsed Laser-induced Liquid Jet System for Treatment of Sellar and Parasellar Tumors: Safety Evaluation.

OBJECTIVE The pulsed laser-induced liquid jet (LILJ) system is an emerging surgical instrument intended to assist both maximal removal of the lesion and functional maintenance through preservation of fine vessels and minimal damage to the surrounding tissue. The system ejects the minimum required amount of pulsed water through a handy bayonet-shaped catheter. We have already shown a significant increase in removal rate, in addition to a noteworthy reduction of intraoperative blood loss and procedure time in the treatment of large pituitary and skull base tumors in a single-institution series. The present study evaluated the safety of the system in multiple institutions. METHODS The study included 46 patients, 29 men and 17 women (mean age: 59.1 years) who underwent microsurgical/endoscopic resection of lesions in or in the vicinity of the pituitary fossa through the transsphenoidal approach between October 2011 and June 2012 at six institutions. The histologic diagnoses were pituitary adenoma (31 cases), meningioma (4), craniopharyngioma (3), cavernous angioma (2), and Rathke cyst cleft (1). Lesion volume ranged from 2.0 to 30.4 cm³ (mean: 3.7 cm³). Cavernous sinus invasion was observed in 11 cases and suprasellar extension in 29 cases. RESULTS Preservation of intralesional arteries (diameter: 150 µm) was achieved in all situations in > 80% of cases. Intended surgical steps were achieved except for some restrictions in motion due to the use of an optical quartz fiber. No complications occurred directly related to the use of the device. CONCLUSIONS The LILJ system can be used for safe removal of lesions in or in the vicinity of the pituitary fossa.

The role of 4D CT angiography for preoperative screening in patients with intracranial tumors

Introduction Four-dimensional computed tomography angiography (4D CTA) is now becoming an often used diagnostic imaging modality for the assessment of patients with intracranial tumors. The purpose of this study was to demonstrate the utility of 4D CTA for preoperative screening in patients with intracranial tumors as well as to examine the correlation between perfusion data and grading of gliomas. Methods We performed preoperative screening using 320-row detector CT scanner in 186 patients with intracranial tumors, and 115 patients were finally included in the study. Time-resolved subtracted maximum intensity projection images and volume-rendered images were reconstructed to evaluate vascular structures, tumor staining and incidental lesions. We also evaluated the perfusion functional map for gliomas to find correlations between their vascularity and tumor grading. Results We evaluated gliomas in 70 patients, meningiomas in 29, and other tumors in 16. Patients with gliomas of a pathologically higher grade showed high cerebral blood volume (p < 0.05). Tumor staining was observed on MIP images for 12 meningiomas, 4 gliomas, and 3 other tumors. Fifty patients showed a mass effect on vascular structures, seven had cerebral venous sinus obstruction, and two had aneurysms. No iatrogenic accidents with the CT procedure were reported. Conclusions The 4D CTA technique is effective and safe for depicting vascular structures such as arteries, veins, tumor-related vessels, and direct and indirect anatomical complications such as vascular obstruction or vascular compression. This information is useful for preoperative screening. Although 4D CTA also provides perfusion data correlating with the tumor vascularity and grading of gliomas, its clinical value remains limited.

A Rare Case of Malignant Craniopharyngioma Reactive to Adjunctive Stereotactic Radiotherapy and Chemotherapy: Case Report and Literature Review

BACKGROUND Malignant craniopharyngioma or anaplastic craniopharyngioma was first reported in 1987 by Akachi and colleagues. It has malignant clinical and histological features, remarkably rapid progression, atypical pathology like squamous cell carcinoma, and a poor prognosis. To date, 17 cases of malignant craniopharyngioma have been reported, most of which were secondary malignant tumors. In classic benign craniopharyngioma, adjunctive treatment after gross total removal is not necessary, but in cases of malignant tumors, adjunctive treatment is important. CASE DESCRIPTION Here we report the first case of malignant craniopharyngioma treated with adjunctive gamma knife stereotactic radiosurgery and chemotherapy (carboplatin and etoposide, as well as temozolomide chemotherapy). Treatment effectively controlled progression of the tumor temporarily. CONCLUSIONS Adjunctive gamma knife stereotactic radiosurgery and chemotherapy for malignant craniopharyngioma affects follow-up strategies, we propose the need for a revision to the World Health Organization classification regarding the evaluation of malignant craniopharyngioma.