Yudo Ishii

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.

A case of IgG4-related hypophysitis without pituitary insufficiency.

CONTEXT IgG4-related hypophysitis is a novel clinical disease entity, which is typically complicated by hypopituitarism. OBJECTIVE The objective of the study was to describe a novel case of IgG4-related hypophysitis without pituitary insufficiency and summarize the current relevant literature. PATIENT AND METHODS A 55-year-old Japanese man presented with an enlarged pituitary gland and bitemporal hemianopsia. Endocrine studies revealed normal pituitary function, although his serum IgG4 level was high. The patient underwent a transsphenoidal biopsy of the pituitary gland, and the pathological tissues were consistent with IgG4-related hypophysitis. Oral prednisolone therapy was started, and after 6 months, his serum IgG4 level decreased and visual field improved. CONCLUSION We described the first case of IgG4-related hypophysitis without pituitary insufficiency. However, further case collection is needed to characterize the pathophysiology of IgG4-related hypophysitis.

A case of Cushing's disease caused by pituitary adenoma producing adrenocorticotropic hormone and growth hormone concomitantly: aberrant expression of transcription factors NeuroD1 and Pit-1 as a proposed mechanism.

A 53-year-old Japanese woman was diagnosed with Cushings disease caused by a adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma on the basis of clinical an imaging data. The surgically resected tumor tissue was investigated histopathologically using immunohistochemical analysis of pituitary hormones. Our study revealed that the adenoma expressed not only ACTH but growth hormone (GH) in the tumor cells. Furthermore, immunohistochemical double staining showed that some adenoma cells were positive for both ACTH and GH. In situ hybridization for GH mRNA revealed that the adenoma cells produced GH as opposed to simply storing it. Although many pituitary adenomas produce multiple pituitary hormones, pituitary adenoma producing both ACTH and GH in the same adenoma cells, such as seen in this case, is extremely rare. To elucidate the molecular mechanism involved, we investigated the expression of transcription factors NeuroD1 and Pit-1 and found that both transcription factors were expressed in many tumor cells. This case report describes a very rare case of pituitary adenoma that produced both ACTH and GH. We propose a hitherto undescribed translineage expression of transcription factors as the basic mechanism of this unique functional differentiation.

Subarachnoid Haemorrhage and Vasospasm due to Pituitary Apoplexy After Pituitary Function Tests

Pituitary apoplexy is a clinical syndrome characterized by a sudden onset of headache, signs of meningeal irritation, visual impairment due to acute enlargement of a pituitary adenoma caused by haemorrhage or infarction [1, 2]. Various factors are reported to lead to pituitary apoplexy, including bromocriptine therapy, oestrogen treatment, radiation therapy, head trauma, pregnancy, angiography, lumbar puncture, myelography and increased intracranial pressure [1, 3]. Although the occurrence of pituitary apoplexy after a pituitary function test has been reported [4], the pathogenesis of apoplexy has not been clari®ed. We report a unique case of a 55-year-old man who presented with severe headache after a combined pituitary function test, and computed tomography (C T) evidence of an infarction, with subsequent intratumoural haemorrhage and subrachnoid haemorrhage associated with vasospasm.

Molecular status of pituitary carcinoma and atypical adenoma that contributes the effectiveness of temozolomide

There have been several reports of temozolomide (TMZ) treatment of pituitary carcinomas and atypical adenomas. O6-methyl-guanine-DNA methyltransferase is not the sole molecule determining the sensitivity to TMZ in pituitary carcinomas and atypical adenomas. The Japan Society of Hypothalamic and Pituitary Tumors study suggests that MSH6, one of mismatch repair pathway enzyme, fulfills a contributory role to the efficacy of TMZ treatment for pituitary carcinomas and atypical adenomas. The preserved MSH6 function might be essential for the responsiveness to TMZ treatment in pituitary carcinomas and atypical adenomas.

Clinicopathological and molecular histochemical review of skull base metastasis from differentiated thyroid carcinoma.

Skull base metastasis from differentiated thyroid carcinoma including follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) is a rare clinical entity. Eighteen FTC cases and 10 PTC cases showing skull base metastasis have been reported. The most common symptom of skull base metastasis from FTC and PTC is cranial nerve dysfunction. Bone destruction and local invasion to the surrounding soft tissues are common on radiological imaging. Skull base metastases can be the initial clinical presentation of FTC and PTC in the presence of silent primary sites. The possibility of skull base metastasis from FTC and PTC should be considered in patients with the clinical symptoms of cranial nerve dysfunction and radiological findings of bone destruction. A variety of genetic alterations in thyroid tumors have been identified to have a fundamental role in their tumorigenesis. Molecular histochemical studies are useful for elucidating the histopathological features of thyroid carcinoma. Recent molecular findings may provide novel molecular-based treatment strategies for thyroid carcinoma.

Advanced therapeutic strategy for radiation-induced osteosarcoma in the skull base: a case report and review

A review of patients with skull base osteosarcoma secondary to radiation (radiation-induced osteosarcoma: RIOS) of the pituitary tumor shows the mean survival of approximately 7 months (2 weeks – 16 months). This warning prognosis seems to stem from two factors, 1) the anatomical complexity of the skull base for total resection of the tumor, and 2) standard adjuvant therapies for the tumor yet to be established. Contrary to the general belief, the authors report an unusually long survival of a 75-year-old woman with a history of osteosarcoma that developed in the same sequence 20 years after pituitary tumor radiation. On her recent admission, she complained of frontal headaches and MRI studies showed a tumor in the sphenoid sinus. Endoscopic trans-nasal tumor removal allowed for histological diagnosis of an osteosarcoma. However, further rapid tumor growth necessitated a radical tumor resection followed by a combined chemotherapy with ifosfamide, cisplatin, and etoposide (ICE). Despite temporary suppression of the tumor growth, the chemotherapy was discontinued due to severe pancytopenia that occurred after three courses of treatment. Shortly after the discontinuation of ICE therapy, the tumor size increased again rapidly, requiring a novel radiation therapy, Cyber-knife treatment. Following this radiation, the tumor growth was arrested, and the patient remains healthy without neurological symptoms over 24 months. The outcome of Cyber-knife in this case suggests that this specific therapy must be considered for the unresectable skull base RIOS.

Endoscopic Endonasal Skull Base Surgery: Advantages, Limitations, and Our Techniques to Overcome Cerebrospinal Fluid Leakage: Technical Note

In recent years, resections of midline skull base tumors have been conducted using endoscopic endonasal skull base (EESB) approaches. Nevertheless, many surgeons reported that cerebrospinal fluid (CSF) leakage is still a major complication of these approaches. Here, we report the results of our 42 EESB surgeries and discuss the advantages and limits of this approach for resecting various types of tumors, and also report our technique to overcome CSF leakage. All 42 cases involved midline skull base tumors resected using the EESB technique. Dural incisions were closed using nasoseptal flaps and fascia patch inlay sutures. Total removal of the tumor was accomplished in seven pituitary adenomas (33.3%), five craniopharyngiomas (62.5%), five tuberculum sellae meningiomas (83.3%), three clival chordomas (100%), and one suprasellar ependymoma. Residual regions included the cavernous sinus, the outside of the intracranial part of the internal carotid artery, the lower lateral part of the posterior clivus, and the posterior pituitary stalk. Overall incidence of CSF leakage was 7.1%. Even though the versatility of the approach is limited, EESB surgery has many advantages compared to the transcranial approach for managing mid-line skull base lesions. To avoid CSF leakage, surgeons should have skills and techniques for complete closure, including use of the nasoseptal flap and fascia patch inlay techniques.

Endoscopic Extracapsular Removal of Pituitary Adenoma: The Importance of Pretreatment of an Adjacent Unruptured Internal Carotid Artery Aneurysm

The presence of an intracranial aneurysm together with a pituitary adenoma presents tremendous risk of subarachnoid hemorrhage, during transsphenoidal surgery, particularly when the aneurysm lies near the operative field. A left supraclinoid internal carotid artery aneurysm and a clinically nonfunctioning pituitary adenoma coexisted in a 57-year-old woman. Initially, the aneurysm was treated by endovascular coil placement, and then the patient underwent pseudocapsule-based extracapsular resection of the pituitary tumor via a transnasal transsphenoidal endoscopic approach. Pseudocapsule-based extracapsular total resection was safely performed, because of the extirpated risk of rupture of the coil-treated aneurysm. Recently, transsphenoidal pseudocapsule-based extracapsular resection approach for pituitary adenomas provides a more effective and safe alternative compared to the traditional intracapsular one because of its higher tumor removal and remission rates and lower recurrence rate. Compared with conventional subcapsular removal, pseudocapsule-based extracapsular resection has more risks of aneurysmal rupture that is located adjacent to pituitary adenoma. Thus, in a patient having a cerebral aneurysm with the proximity to the operative field, the cerebral aneurysm should be first treated with endovascular coil placement or direct surgical procedure; subsequently, pseudocapsule-based extracapsular resection of the pituitary tumor via a transnasal transsphenoidal endoscopic approach should be performed.

Easy slip-knot: a new simple tying technique for deep sutures

BackgroundKnot-tying in the deep operative field is very complicated because of the narrow working space during endoscopic transsphenoidal surgery. We present a novel technique for tying deep knots called the “easy slip-knot,” which was developed from a knot used to tie fishing lines.MethodAfter threading the dura, an easy slip-knot is made outside the nostril. One end of the string is pulled, the knot then naturally slips, and should reach the operative field without needing a knot-pusher.FindingsThis method is not complicated, is easily applied to the operative field by slipping the knot into position, and is able to tie sutures securely.ConclusionsThe easy slip-knot should be useful for endoscopic surgery.