Shingo Fujio

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.

Relationship between cytokeratin staining patterns and clinico-pathological features in somatotropinomae

OBJECTIVE Somatotropinomae are classified as densely and sparsely granulated adenomae, which typically exhibit a perinuclear pattern (PP) and a dot pattern (DP) in cytokeratin (CK) immunostaining respectively. Some exhibit a mixed pattern (MP). We studied the relationship between these somatotropinoma subtypes and their clinico-pathological features. METHODS The study population consisted of 141 Japanese acromegalic patients. We evaluated their clinical presentation and their response to provocation tests with TRH and LHRH and to suppression (octreotide) test. Tumour tissues were subjected to immunostaining for CAM-5.2, MIB-1, CD34, E-cadherin (CDH1) and p53 (TP53). In 43 cases (30 non-DP and 13 DP), we analysed gsp mutations (constitutively activating mutations of the G(s)α protein that is encoded by GNAS gene). RESULTS The 141 adenomae were categorised into three subtypes based on their CK staining patterns; 30 (21.3%) exhibited DP, 83 (58.9%) exhibited PP, and 28 (19.9%) exhibited MP. Compared with the other subtypes, DP adenomae were significantly larger, and their E-cadherin expression and response to TRH, LHRH and octreotide challenge were lower. The postoperative cure rate tended to be lower in DP adenomae. gsp mutations were detected in 25 of 43 cases examined (58.1%); 20 of the 30 non-DP (66.7%) and 5 of the 13 DP tumours (38.5%) were affected by the mutation. CONCLUSION DP somatotropinomae exhibit characteristic features. Compared with the non-DP subtypes, DP adenomae manifested a larger tumour size, a lower incidence of abnormal responses to TRH and LHRH challenge, a poor response to octreotide test and a lower expression of E-cadherin. gsp mutation was not exclusive for non-DP somatotropinomae.

Immunoreactivity of Wnt5a, Fzd2, Fzd6, and Ryk in glioblastoma: evaluative methodology for DAB chromogenic immunostaining

The aim of this study was to determine the influence of Wnt5a and its receptors on the survival of glioblastoma patients and to determine reliable evaluation methods for immunohistochemistry. Diagnostic specimens from 41 histopathologically confirmed primary glioblastoma patients whose Gd-enhanced tumors had been totally removed were immunohistochemically stained for Wnt5a, Fzd2, Fzd6, and Ryk. The immunoreactivity was evaluated using the following methods: (A) grayscale optical density after color deconvolution, (B) percentage of stained cells, (C) density of stained cells, (D) staining amount (multiplication product of B and C), and (E) staining rank. The data sets of A to E were statistically evaluated by correlation matrix analysis and regression analysis. The influence of the expression of the markers on survival was analyzed using a proportional hazard model. The results of color deconvolution (A) were well correlated with the results of the staining rank (E). In the semiquantitative results (B, C, and D), the staining amount (D) tended to show a better correlation with results of color deconvolution (A). Among all data sets, color deconvolution (A) demonstrated the most preferable fit in a proportional hazard model, and the expression of Fzd2 and Fzd6 was associated with poor prognosis in glioblastoma patients.

TLR4, IL-6, IL-18, MyD88 and HMGB1 are highly expressed in intracranial inflammatory lesions and the IgG4/IgG ratio correlates with TLR4 and IL-6.

We determined distribution of plasma cells and IgG4/IgG index and factors associated with the index in intracranial inflammatory lesions. Specimens of nine patients were analyzed immunohistochemically using antibodies against CD45, CD68, CD3, CD4, CD8, CD20, CD138, lambda chain, kappa chain, IgG, IgG4, IL‐1α, IL‐6, IL‐18, toll‐like receptor (TLR) 2, TLR4, high‐mobility group box 1 (HMGB1), tumor necrosis factor‐alpha (TNF‐α), myeloid differentiation factor 88 (MyD88), and anaplastic lymphoma kinase (ALK). The relationship between all the factors was assessed using Spearmans rank correlation coefficient (ρ). Negative ALK staining was observed in all the patients. Plasma cells were detected in eight patients with varying degrees. The highest number of neutrophils, but no plasma cells, was observed in a patient with the shortest history of inflammation. IgG4/IgG index was independent of the number of plasma cells. The index was relatively highly correlated with IL‐6 (ρ = 0.7271) and TLR4 expression (ρ = 0.7246). IL‐6 expression was highly correlated with TLR4 expression (ρ = 0.8042). IL‐18 was maximally expressed in all the patients. TLR4 expression was strong, but TRL2 expression was weak. Positive HMGB1 staining was observed in all the patients, predominantly in the nuclei, but also in the cytoplasm in four patients. The cytoplasmic expression strongly correlated with IL‐1α expression (ρ = 0.9583). The cytoplasmic colocalization of HMGB1 and IL‐1α was histologically confirmed in cells with collapsing nuclei by the double‐staining method. The IgG4/IgG indexes varied case by case. IL‐6 and TLR4 expressions may influence IgG4/IgG index. The nuclei of cells with both IL‐1α and HMGB1 expressions in the cytoplasm collapse in the cell death stage. The cooperative high expression of TLR4, IL‐6, IL‐18, MyD88 and HMGB1 suggest their critical roles in the inflammation circuit.

Improvement in treatment results of glioblastoma over the last three decades and beneficial factors

Abstract Background. The purpose of this study is to elucidate the trend of glioblastoma outcome and scrutinize the factors contributing to better outcome over three decades. Methods. Survival time and the influencing factors were retrospectively analyzed in 223 newly diagnosed primary glioblastoma patients during 1980–2010. Appraised factors included age, sex, tumor site, year of surgery, extent of resections, use of surgery supporting system, Karnofsky Performance Status (KPS), chemotherapy, conventional external beam radiotherapy (EBRT), and CyberKnife stereotactic radiotherapy (CK-SRT) use. Results. The median survival time (MST) in all patients was 13.6 months. The MSTs for 4 periods were 9.8 (1980–1990), 13.7 (1991–2000), 12.9 (2001–2005), and 15.8 months (2006–2010), respectively (p = 0.0047). Total resection, subtotal resection, partial resection, and biopsy had MSTs of 31.8, 13.9, 11.4, and 7.0 months, respectively (p < 0.0001). Regarding chemotherapy, MSTs of the temozolomide base group and nimustine hydrochloride (ACNU) base group were 16.9 and 14.6 months, respectively, whereas the MST of patients without chemotherapy was only 9.8 months (p < 0.0001). The MSTs for 40-Gy EBRT plus CK-SRT and 60-Gy EBRT were 19.1 and 10.7 months, respectively (p < 0.0001). But in sub-selected patients, treated during 2001–2010, whose resection rate was total resection or subtotal resection, EBRT was completed and postoperative KPS was greater than or equal to 70, the MST with and without CK-SRT was 26.6 and 18.3 months, respectively (p = 0.1529). According to the Cox proportional hazards model, degree of resection, KPS, ACNU use, temozolomide use, bevacizumab use, EBRT dose, and CK-SRT use were good prognostic factors. Use of neuronavigation and use of intraoperative magnetic resonance imaging were related to higher resection rate, but not determined as prognostic factors. Conclusions. We observed a gradual improvement in glioblastoma outcome, presumably because of improvements in therapeutic modalities for surgery, anticancer agents, and radiation, but the efficacy of CK-SRT remains unclear.

A Novel Bilateral Approach for Suprasellar Arachnoid Cysts: A Case Report

The endoscopic method is used to treat suprasellar arachnoid cysts (SACs) but it is sometimes difficult to make sufficiently sized fenestrations. Creating a larger fenestration on the cyst wall is preferable to prevent closure of the stoma. In this paper, we report a novel endoscopic approach for SAC treatment in which we use bilateral burr holes to achieve a more extensive cyst fenestration. A 7-year-old girl was referred to our hospital because of incidentally detected hydrocephalus by computed tomography scans. Physical examination did not show any signs of intracranial hypertension, but a digital impression of her skull on X-ray implied chronic intracranial hypertension. Magnetic resonance imaging (MRI) revealed enlargement of both lateral ventricles and a cystic mass occupying the third ventricle. We performed cyst wall fenestration using a bilateral approach in which we created two burr holes to introduce a flexible endoscope and a rigid endoscope. The cyst wall was held by forceps with the flexible endoscope, and resection of the cyst wall was achieved by using a pair of scissors with the rigid endoscope. There were no postoperative complications, and MRI performed 1 year after treatment showed disappearance of the superior part of the cyst wall.

Treatable glomerular hyperfiltration in patients with active acromegaly

OBJECTIVE The glomerular filtration rate (GFR) is increased in patients with active acromegaly. The aim of this study is to elucidate whether renal function deteriorates in patients with acromegaly and whether this deterioration is reversible after surgical remission. DESIGN/METHODS A case-control study of 48 acromegalic patients who were surgically cured (cases) and 48 patients with nonfunctioning pituitary adenomas (NFomas, controls) was conducted. We performed clinical and biochemical examinations before surgery and 3months post-surgery. The GFR of each patient was estimated (estimated GFR, eGFR) using their serum creatinine, age, sex, and body surface area, and postoperative changes in the eGFR were assessed. RESULTS The preoperative eGFR was significantly higher in patients with acromegaly than in those with NFoma (99.8 vs 75.1mL/min respectively, P<0.01). In acromegalic patients, surgical remission was accompanied by a significant decline in the eGFR (from 99.8 to 86.2mL/min, P<0.01). Conversely, in patients with NFoma, the postoperative eGFR did not change significantly (from 75.1 to 81.9mL/min, P=0.12). Among the acromegalic patients, the postoperative decreases in the eGFR were more prominent in patients with a preoperatively high or normal vs low eGFR. CONCLUSIONS Our data demonstrated a significant post-surgical eGFR decrease in patients with acromegaly, but not in patients with NFomas. This change in the eGFR was reversible in acromegalic patients with a high/normal preoperative eGFR, but not in those with a low preoperative eGFR. This suggests that the reversible pathophysiological change in some patients is functional but not organic.

Postoperative Changes in Metabolic Parameters of Patients with Surgically Controlled Acromegaly: Assessment of New Stringent Cure Criteria

The criteria for surgical cure of acromegaly have become more stringent during the past decades and a change from Cortina to new consensus criteria has recently been proposed. However, the superiority of the new consensus over Cortina criteria with respect to postoperative metabolic parameters remains to be ascertained. We retrospectively assessed metabolic parameters, the body habitus, and other health-related parameters of 48 patients with surgically controlled acromegaly who met the Cortina criteria [normalized insulin-like growth factor-1 (IGF-1) level and nadir growth hormone (GH) level <1.0 ng/ml during postoperative oral glucose tolerance test]. The 48 patients were divided into two groups. Group A (n = 33) met the new consensus criteria (normalized IGF-1 and nadir GH level <0.4 ng/ml). Group B (n = 15) met Cortina criteria, but their nadir GH ranged from 0.4 to 1.0 ng/ml. In both groups, the level of triglyceride and homeostasis model assessment-insulin resistance (HOMA-IR) was significantly decreased 1 year after the operation (P < 0.05). High-density lipoprotein cholesterol showed a significant increase only in group B (P = 0.02). However, the two groups did not differ with respect to the postoperative improvement rate of these parameters and the other health-related parameters including body mass index, blood pressure, anterior pituitary function, and self-estimated quality of life scale. In conclusion, our findings show that with respect to changes in metabolic parameters and the body habitus assessed 1 year after surgery, the stricter consensus criteria seemed not to be superior to Cortina criteria.

Preoperative and Postoperative Pituitary Function in Patients with Tuberculum Sellae Meningioma -Based on Pituitary Provocation Tests-

Given the anatomical proximity of tuberculum sellae meningioma (TSM) to the hypothalamo-pituitary system, pituitary function impairments are of great concern. We retrospectively investigated pituitary function changes following surgery in patients with TSM using pituitary provocation tests (PPTs). Thirty-one patients (27 females and 4 males) with TSM underwent initial transcranial surgery (29 patients) or transsphenoidal surgery (two patients); surgeries were performed carefully to avoid injuring the pituitary stalk. In 24 patients, the PPTs were performed via a triple bolus injection with regular insulin, thyrotropin-releasing hormone (TRH), and luteinizing hormone releasing hormone (LH-RH). Seven patients underwent a quadruple test (growth-hormone-releasing factor, corticotrophin-releasing hormone, TRH, and LH-RH). The preoperative and postoperative target hormone levels of the anterior pituitary were normal in 93.5% and 96.8% of patients, respectively. At least one hormonal axis demonstrated impaired PPT responses in two patients (6.5%) preoperatively and in one patient (3.2%) postoperatively. The growth hormone (GH) response was also well preserved. A compromised GH peak level was only observed in one patient (3.2%) preoperatively. Postoperatively, transient diabetes insipidus and transient hyponatremia were observed in four (12.9%) and eight (25.8%) patients, respectively. No patients needed permanent postoperative hormone replacement. The preoperative pituitary function was well preserved in most patients, including those with large tumors pushing against the pituitary stalk considerably or embedded in it. After careful surgery to avoid damaging the pituitary stalk, pituitary function was preserved. However, transient postoperative hyponatremia occurred in 25.8% of patients; thus, surgeons should pay careful attention to this issue.

Choroid Plexus Tumors: Experience of 10 Cases with Special References to Adult Cases

Choroid plexus tumors (CPTs) are rare intraventricular neoplasms accounting for about 0.3–0.6% of all intracranial tumors. This retrospective study on CPTs presents clinico-pathological features and management strategies based on a 20-year single-institutional experience. This series included 10 consecutive patients with pathologically proven CPTs; 5 choroid plexus papillomas (CPPs), 3 atypical CPPs (ACPPs), and 2 choroid plexus carcinomas (CPCs). Their clinical, radiological, and histopathological features as well as management including follow-up studies were reviewed. The patients included five males and five females, aging from 0 years to 61 years with median of 28 years. The affected site was lateral ventricle in two adults and fourth ventricle in eight patients; four children and four adults. The most common symptoms were gait disturbance and memory disturbance. All the patients underwent craniotomy with total, subtotal, and partial removals achieved in 50%, 40%, and 10% of the patients, respectively. The occurrence of the high grade subtypes was 50% in both the adult and pediatric groups. The Ki-67/MIB-1 index increased across the three histological subtypes, from CPP to ACPP and then to CPC. Adjuvant therapy was administered in three patients. The two patients (one adult and one child) with CPC died of whole central nervous system dissemination. At a median of 62-month follow-up, the other eight patients were alive, with only one patient having recurrence and reoperation. The results demonstrate that gross total resection is usually curative for CPP and ACPP, and adjuvant chemoradiotherapy would be required for CPC and incompletely resected ACPP.