Hidenobu Ochiai

Systemic CTLA-4 Blockade Ameliorates Glioma-Induced Changes to the CD4+ T Cell Compartment without Affecting Regulatory T-Cell Function

Purpose: Patients with malignant glioma suffer global compromise of their cellular immunity, characterized by dramatic reductions in CD4+ T cell numbers and function. We have previously shown that increased regulatory T cell (Treg) fractions in these patients explain T-cell functional deficits. Our murine glioma model recapitulates these findings. Here, we investigate the effects of systemic CTLA-4 blockade in this model. Experimental Design: A monoclonal antibody (9H10) to CTLA-4 was employed against well-established glioma. Survival and risks for experimental allergic encephalomyelitis were assessed, as were CD4+ T cell numbers and function in the peripheral blood, spleen, and cervical lymph nodes. The specific capacities for anti-CTLA-4 to modify the functions of regulatory versus CD4+CD25− responder T cells were evaluated. Results: CTLA-4 blockade confers long-term survival in 80% of treated mice, without eliciting experimental allergic encephalomyelitis. Changes to the CD4 compartment were reversed, as anti-CTLA-4 reestablishes normal CD4 counts and abrogates increases in CD4+CD25+Foxp3+GITR+ regulatory T cell fraction observed in tumor-bearing mice. CD4+ T-cell proliferative capacity is restored and the cervical lymph node antitumor response is enhanced. Treatment benefits are bestowed exclusively on the CD4+CD25− T cell population and not Tregs, as CD4+CD25− T cells from treated mice show improved proliferative responses and resistance to Treg-mediated suppression, whereas Tregs from the same mice remain anergic and exhibit no restriction of their suppressive capacity. Conclusions: CTLA-4 blockade is a rational means of reversing glioma-induced changes to the CD4 compartment and enhancing antitumor immunity. These benefits were attained through the conferment of resistance to Treg-mediated suppression, and not through direct effects on Tregs.

Treatment of Intracerebral Neoplasia and Neoplastic Meningitis with Regional Delivery of Oncolytic Recombinant Poliovirus

Purpose: Spread to the central nervous system (CNS) and the leptomeninges is a frequent complication of systemic cancers that is associated with serious morbidity and high mortality. We have evaluated a novel therapeutic approach against CNS complications of breast cancer based on the human neuropathogen poliovirus (PV). Experimental Design: Susceptibility to PV infection and ensuing rapid cell lysis is mediated by the cellular receptor of PV, CD155. We evaluated CD155 expression in several human breast tumor tissue specimens and cultured breast cancer cell lines. In addition, we tested an oncolytic PV recombinant for efficacy in xenotransplantation models of neoplastic meningitis and cerebral metastasis secondary to breast cancer. Results: We observed that breast cancer tissues and cell lines derived thereof express CD155 at levels mediating exquisite sensitivity toward PV-induced oncolysis in the latter. An association with the immunoglobulin superfamily molecule CD155 renders breast cancer a likely target for oncolytic PV recombinants. This assumption was confirmed in xenotransplantation models for neoplastic meningitis or solitary cerebral metastasis, where local virus treatment dramatically improved survival. Conclusions: Our findings suggest oncolytic PV recombinants as a viable treatment option for CNS complications of breast cancer.

Targeted therapy for glioblastoma multiforme neoplastic meningitis with intrathecal delivery of an oncolytic recombinant poliovirus.

PURPOSE: The toxicity and antitumor activity of regional intrathecal delivery of an oncolytic recombinant poliovirus, PVS-RIPO, was evaluated in rodent models of glioblastoma multiforme neoplastic meningitis. EXPERIMENTAL DESIGN: To evaluate for toxicity, PVS-RIPO was administered into the spinal cord of transgenic mice that express the human poliovirus receptor, CD155, and into the intrathecal space of athymic rats without tumor. To evaluate efficacy, two different doses of PVS-RIPO were administered intrathecally 3 days after athymic rats were inoculated intrathecally with an aggressive human glioblastoma multiforme xenograft. RESULTS: No clinical or histologic evidence of toxicity was found. In efficacy studies, median survival was increased by 174.47% from 8.5 days in the group treated with UV light-inactivated virus to 15 days in the rats treated with 1.0 x 10(7) plaque-forming units (pfu) of PVS-RIPO (P < 0.0001). A similar increase in median survival was seen in the group receiving 1.0 x 10(9) pfu PVS-RIPO (P < 0.0001); however, there was no statistically significant dose-response relationship (P = 0.345). In addition, 1 of 10 rats in lower-dose PVS-RIPO-treated group and 3 of 10 rats in higher-dose PVS-RIPO-treated group survived >60 days after tumor cell inoculation and had no evidence of residual tumor at autopsy. CONCLUSION: These results suggest that intrathecal treatment with PVS-RIPO may be useful for treatment of neoplastic meningitis in patients with glioblastoma multiforme and provides a rationale for clinical trials in this area.

Primary leiomyosarcoma of the cervical spine causing spontaneous compression fracture: Report of an autospy case

An extremely rare case of the primary leiomyosarcoma of the cervical spine presenting as a compression fracture is reported. A 69‐year‐old man complained of dysesthesia of both hands. A plain radiograph, computed tomography and magnetic resonance imaging of the cervical spine showed a compression fracture of the vertebral body at C7 without the formation of an obvious mass. From radiological findings, the fracture was considered to be caused by an infiltrative vertebral bone tumor. Biopsy of the tumor revealed a leiomyosarcoma, a metastatic tumor being ruled out by a systemic investigation. The patient died of pleural metastasis 6 months later, and an autopsy confirmed the primary site of the tumor as the cervical spine.

Clinical features of the localized girdle sensation of mid-trunk (false localizing sign) appeared in cervical compressive myelopathy patients

Cervical compressive myelopathy patients sometimes show localized girdle sensation in the mid trunk (so-called false localizing sign). This symptom often confuses physicians, but the clinical features and mechanism of this symptom are still unclear. We investigated the clinical features and possible mechanism. In each of five cases of cervical compressive myelopathy disease with and without mid-truncal girdle sensation, the clinical features, degree and shape of cord compression were analysed. The girdle sensation was expressed as a vague or burning sensation, and was localized with a width of 3 or 4 dermatomes from the T3 to T11 level. There was no correlation between the appearance of the girdle sensation and etiology and level of cervical cord compression. Pyramidal tract signs and disturbance of superficial sensation were observed in all cases. Furthermore, on axial MRI, the midline ventral surface of the cervical cord was remarkably compressed in cases with girdle sensation, as if the compressive lesion entered the anterior medial fissure of the cervical cord. From these findings, this false localizing sign may be caused by severe compression of midline ventral structure of the cervical cord. Ischemia of the thoracic watershed zone of the anterior spinal artery from the compression of the anterior spinal artery at the cervical level might also be considered to be a possible cause.

Factors affecting outcome of intracerebral hemorrhage in patients undergoing chronic hemodialysis.

To date, despite a markedly high incidence of intracerebral hemorrhage (ICH) in patients with end-stage renal disease, only few studies have focused on factors that affect patients prognosis. To elucidate these factors, we retrospectively investigated 22 consecutive patients who had chronic renal failure, were maintained by hemodialysis (HD), had suffered from ICH, and were hospitalized and treated in our institute from 2006 to 2008. Hematoma volume, blood pressure on admission, blood pressure 3 days after ICH onset, and neurological deterioration significantly affected patient mortality. Progression of neurological symptoms during HD was observed often in patients with hematoma of more than 60 mL or in patients with pontine hemorrhages. Age, gender, duration of HD, anti-platelet or anticoagulant therapies, or maximal dose of nicardipine did not affect patients prognosis. Based on this study we conclude that controlling blood pressure on admission and within 3 days after onset of ICH may be the most important factor that would improve patients prognosis. Further, special care might be required for patients with large hematomas (more than 60 mL) or those with brainstem hemorrhages, because progression of neurological symptoms occurs often in such patients.

Developmental abnormalities of corticospinal tract neurons in prenatally irradiated rats: a study using retrograde labeling with Fast blue and intracellular Lucifer yellow staining

The effect of prenatal X-irradiation on the ontogenesis of corticospinal tract (CST) neurons was examined in rats using retrograde labeling with Fast blue and intracellular Lucifer yellow staining. In prenatally irradiated rats, the cortical laminar architecture of the CST neurons was confused and many cells demonstrated migratory disturbances. Migratory-disordered CST neurons at deeper cortical levels resembled pyramidal cells, but their apical dendrites were oriented in various directions and the development of their dendrites was poor. Migratory-disordered CST neurons near the ependymal layer demonstrated round somata and many thin dendrites with spokewise radiation, suggesting a maturation disturbance. These results suggested that prenatal X-irradiation impeded the migration and maturation of CST neurons. These findings may form the basis for analyzing the mechanisms of radiation-induced mental retardation and behavioral changes.

Cerebral phaeohyphomycosis: case report.

Cerebral phaeohyphomycosis is a rare and frequently fatal disease. This disease is often caused by hematogenous spread of pathogens that are inoculated in the skin of the extremities after slight or minor trauma, and its mortality rate is rather high despite aggressive treatment. Our patient presented with headache and pyrexia. She was diagnosed with fungal meningitis and treated by systemic administration of voriconazole (VRCZ). However, after initial improvement, meningitis recurred. MRI of the brain showed multiple small masses in the cerebral hemisphere and she was thus referred to our Department of Neurosurgery. On admission, an examination showed that the masses were deeply located in the brain and were too small to be excised; therefore, treatment with systemic VRCZ and intrathecal amphotericin B was initially selected. However, the intracerebral masses continued to grow; therefore, they were surgically excised. Histological examination of the surgical specimens at that time identified the masses as granuloma caused by infection with Aspergillus niger. After the surgery, her general condition improved; therefore treatment with systemic and intrathecal antifungal agents were continued. However, the intracerebral masses recurred, and despite further aggressive surgical treatment and systemic and intrathecal antifungal administration, she died 43 months after the initial diagnosis. Autopsy examination showed that the cerebral lesions were phaeohyphomycotic granulomas. This paper describes the clinical presentation, histopathological results and treatment for this rare disease.

Clinical Features and Treatment Outcomes of 81 Patients with Aggressive Type Adult T-cell Leukemia-lymphoma at a Single Institution over a 7-year Period (2006-2012)

OBJECTIVE Despite the remarkable advances in chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), adult T-cell leukemia-lymphoma (ATL) is still associated with a high mortality rate. It is therefore essential to elucidate the current features of ATL. METHODS We retrospectively analyzed 81 patients with aggressive type ATL at our institution over a 7-year period based on Shimoyamas diagnostic criteria. RESULTS Eighty-one patients with a median age of 67.5 years were classified as having acute (n=47), lymphoma (n=32), or chronic type (n=2) ATL. They were initially treated by either palliative therapy (n=25) or systemic chemotherapy [n=56; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (n=25)/vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP)-doxorubicin, ranimustine, and prednisone (AMP)-vindesine, etoposide, carboplatin, and prednisone (VECP) therapy (VCAP-AMP-VECP) or CHOP-VMMV therapy (n=31)], and showed median survival durations of 16 and 277 days, respectively. Subsequent to the initial treatment, HSCT (n=6) was performed for certain patients, thus revealing that two-thirds (n=4) relapsed, and one-third (n=2) survived for 131 days and 203 days, respectively. The relapsed ATL patients were treated with conventional salvage therapy (n=29) or anti-CC chemokine receptor 4 antibody (mogamulizumab) (n=3). The patients treated with mogamulizumab demonstrated complete response (2) and partical response (1) with short duration periods of 82 days, 83 days, and 192 days, respectively. Among the five long-term survivors (>5 years) who received chemotherapy, most showed a low and intermediate risk according to the ATL prognostic index. CONCLUSION In our study, the overall survival of ATL remains poor due to the advanced age of the patients at diagnosis, a high proportion of patients receiving palliative therapy, and a small proportion of long-term survivors receiving chemotherapy and undergoing HSCT. This study illustrates the current clinical features, treatment strategies, and outcomes in clinical practice.

Magnetic resonance imaging of a malignant transformation of an intracranial cellular blue nevus. A case report

As a follow-up to a case previously reported, a rare case of malignant transformation of cellular blue nevus (CBN) in the central nervous system preoperatively diagnosed by magnetic resonance imaging (MRI) is reported. On MRI, the malignant portion of the nevus was slightly hyperintense on both T1- and T2-weighted images. In contrast, the benign portion with a great deal of melanin was hyperintense on T1-weighted image and hypointense on T2-weighted image. MRI was useful and indispensable for detecting the malignant transformation of CBN.