Fatal fulminant hepatitis induced by combined ipilimumab and nivolumab therapy despite favorable histologic response and confirmed by autopsy in a patient with clear cell renal cell carcinoma.

Effective management of immune-related adverse events in patients receiving immunotherapy for cancer is problematic. In this report, we present the case of a 58-year-old man with advanced clear cell renal cell carcinoma who responded well to a combination of ipilimumab and nivolumab. However, after two courses of treatment, he developed fulminant hepatitis and died. An autopsy confirmed that the primary lesion in the left kidney was more than 99% necrotic with only six small residual tumor lesions. These lesions were infiltrated by large numbers of CD8-positive/TIA-1-positive lymphocytes. However, a metastatic lesion in the right kidney harbored few lymphocytes. Furthermore, the tumor cells in the metastatic lesion and one of the residual lesions showed decreased expression of HLA class I molecules, which are a prerequisite for cytotoxic T-lymphocyte-mediated immunotherapy in tumor cells. In this patient, more than 80% of hepatocytes were destroyed and the parenchyma was infiltrated with CD8-positive/TIA-1-positive lymphocytes. The patient had polyuria, which was attributed to neurohypophysitis caused by the infiltration of CD8-positive/TIA-1-positive lymphocytes. We believe that this is an instructive case for immuno-oncologists.

Detection of the KIAA1549-BRAF fusion gene in cells forming microvascular proliferations in pilocytic astrocytoma.

Microvascular proliferation (MVP), an aberrant vascular structure containing multilayered mitotically active endothelial- and smooth-muscle cells/pericytes, is a histopathological hallmark of glioblastoma multiforme (GBM). Although MVP tends to be associated with high-grade glioma, it has also been detected in WHO grade I pilocytic astrocytoma (PA). However, little is known about the mechanism underlying its formation. Using TP53 point mutations as a marker for tumor-derived cells, we earlier reported that MVP was partially converted from tumor cells via mesenchymal transition. In the current study we used the KIAA1549-BRAF fusion gene as a marker to assess whether MVPs in PA contained tumor-derived cells and/or phenotypically distinct tumor cells expressing vascular markers. cDNA synthesized from frozen tissue of six PA patients operated at our institute was analyzed to detect the KIAA1549-BRAF fusion gene by reverse transcription polymerase chain reaction (RT-PCR) assay. The breakpoint in the fusion gene was identified by long and accurate PCR (LA-PCR) and Sanger sequencing of genomic DNA. Distinct tumor cells and cellular components of MVP were obtained by laser microdissection. For the qualitative and quantitative detection of the KIAA1549-BRAF fusion gene we performed genomic and digital PCR assays. Fluorescence in situ hybridization (FISH) was used to assess gene fusion in cellular components of MVP. Samples from three PA patients harbored the KIAA1549 exon 15, BRAF exon 9 fusion gene. In two patient samples with abundant MVP, RT-PCR assay detected strong bands arising from the KIAA1549-BRAF fusion gene in both tumor cells and cellular components of MVP. Digital PCR showed that vis-à-vis tumor tissue, its relative expression in cellular components of MVP was 42% in one- and 76% in another sample. FISH revealed amplified signals in both tumor cells and cellular components of MVP indicative of tandem duplication. Our findings suggest that in patients with PA, some cellular components of MVP contained tumor derived cell and/or phenotypically distinct tumor cells expressing vascular markers.

Eosinophilic meningitis triggered by implanted Gliadel wafers: case report.

Although carmustine (Gliadel) wafers improve local tumor control and extend the overall survival in patients with malignant glioma, adverse effects have been documented. The authors report the first case of eosinophilic meningitis triggered by the placement of Gliadel wafers. A 61-year-old man with a history of alimentary allergy and glioblastoma in the right frontal lobe underwent resection followed by the implantation of Gliadel wafers. Three weeks later he suffered the sudden onset of headache, vomiting, and progressive consciousness disturbance. Computed tomography revealed enlargement of the ventricular system and subdural space on the side of the tumor. His CSF leukocyte count increased up to 3990 cells/mm3; 95% of the cells were eosinophilic granulocytes (EGs), suggesting eosinophilic meningitis. Laboratory examination showed the patient to have various elevated allergy indicators. The administration of corticosteroids failed to improve his condition. Despite the insertion of a lumbar drain his symptoms failed to improve. He underwent a second surgical intervention to remove the Gliadel wafers. Histologically, EGs had assembled around the wafers. Eosinophilic infiltrate was present in the brain parenchyma around small vessels. After ventriculoperitoneal shunting his course was favorable. A drug lymphocyte stimulation test against the Gliadel wafers failed to demonstrate a positive reaction; polifeprosan, the wafer matrix without 1,3-bis(2-chloroethyl)-1-nitrosourea, yielded a positive reaction. These findings strongly suggest that although extremely rare, polifeprosan (the wafer matrix) can elicit an allergic reaction. When eosinophilic meningitis is suspected after the implantation of Gliadel wafers, their immediate removal should be considered.

Rapidly Enlarging Pediatric Cortical Ependymoma.

We report a 10-year-old boy with supratentorial cortical ependymoma that rapidly grew in the course of 3 years. He suffered generalized seizures when he was 5 years old; MRI showed a small cortical lesion in the right postcentral gyrus. MRI performed 2 years later revealed no changes. For the next 3 years he was free of seizures. However, at the age of 10 he again suffered generalized seizures and MRI disclosed a large parietal tumor. It was resected totally and he remains free of neurological deficits. The histopathological diagnosis was ependymoma. Pediatric supratentorial cortical ependymomas are extremely rare. We recommend including cortical ependymoma as a differential diagnosis in pediatric patients with cortical mass lesions presenting with seizures and careful follow-up even in the absence of symptoms because these tumors may progress.

Agenesis of the Left Internal Carotid Artery in the Right Aortic Arch with Isolation of the Left Innominate Artery Associated with Ruptured Cerebral Aneurysm: Case Report.

As we occasionally encounter congenital blood vessel abnormalities, their variety, embryology, and associated clinical problems must be understood. We report a case of a 50-year-old man with subarachnoid hemorrhage due to a ruptured cerebral aneurysm at the internal carotid-anterior choroidal artery bifurcation who manifested extremely rare congenital anomalies, i.e., a right aortic arch, isolated left innominate artery, agenesis of the left internal carotid artery, and dysplasia of the basilar artery to the posterior cerebral arteries. This complex anomaly, to the best of our knowledge, has not been previously reported.

Detection of p53 mutations in proliferating vascular cells in glioblastoma multiforme.

OBJECT: Glioblastoma multiforme (GBM), one of the most aggressive tumors in humans, is highly angiogenic. However, treatment with the angiogenesis inhibitor bevacizumab has not significantly prolonged overall patient survival times. GBM resistance to angiogenesis inhibitors is attributed to multiple interacting mechanisms. Although mesenchymal transition via glioma stem-like cells has attracted attention, it is considered a poor biomarker. There is no simple method for differentiating tumor-derived and reactive vascular cells from normal cells. The authors attempted to detect the mesenchymal transition of tumor cells by means of p53 and isocitrate dehydrogenase 1 (IDH1) immunohistochemistry. METHODS: Using antibody against p53 and IDH1 R132H, the authors immunohistochemically analyzed GBM tissue from patients who had undergone surgery at the University of Miyazaki Hospital during August 2005-December 2011. They focused on microvascular proliferation with a p53-positive ratio exceeding 50%. They compared TP53 mutations in original tumor tissues and in p53-positive and p53-negative microvascular proliferation cells collected by laser microdissection. RESULTS: Among 61 enrolled GBM patients, the first screening step (immunostaining) identified 46 GBMs as p53 positive, 3 of which manifested areas of prominent p53-positive microvascular proliferation (>50%). Histologically, areas of p53-positive microvascular proliferation tended to be clustered, and they coexisted with areas of p53-negative microvascular proliferation. Both types of microvascular proliferation cells were clearly separated from original tumor cells by glial fibrillary acidic protein, epidermal growth factor receptor, and low-/high-molecular-weight cytokeratin. DNA sequencing analysis disclosed that p53-positive microvascular proliferation cells exhibited TP53 mutations identical to those observed in the original tumor; p53-negative microvascular proliferation cells contained a normal allele. Although immunostaining indicated that 3 (2 primary and 1 secondary) of the 61 GBMs were positive for IDH1, no tumors contained microvascular proliferation cells positive for IDH1 R132H. CONCLUSIONS: Some microvascular proliferation clusters in GBM result from mesenchymal transition. The identification of useful markers might reveal this phenomenon as an infrequent event in GBMs.

Case of primary diffuse leptomeningeal gliomatosis.

Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare and fatal disease characterized by diffuse infiltration of the leptomeninges by neoplastic glial cells without evidence of tumor in the brain parenchyma or spinal cord. We report a 60-year-old man with PDLG. He suffered transient right hemiparesis and generalized seizures. MRI showed diffuse leptomeningeal thickening and enhancement throughout the brain and spinal cord without any intraaxial involvement. Biopsy resulted in a diagnosis of glioblastoma with methylated MGMT promoter and wild-type IDH1. He underwent craniospinal radiotherapy and temozolomide treatment but despite concomitant adjuvant therapy he died 8 months after initial presentation.

Urinary bladder pyogenic granuloma: a case report.

INTRODUCTION: Although more than 100 cases of hemangioma of the urinary bladder have been reported, capillary-type hemangiomas of the bladder are rare. Pyogenic granulomas, which are common tumor-like vascular lesions of the skin and oral mucous membranes, reveal histopathological findings similar to capillary-type hemangiomas and are differentiated from ordinary hemangiomas by clinical features and etiologic factors. Little is known regarding the occurrence of pyogenic granulomas in the urinary bladder. CASE PRESENTATION: We present the case of a 78-year-old Japanese man who had developed a hemangiomatous lesion in his bladder which led to acute clot retention. He had a recent history of chemotherapy for pancreatic cancer. A solitary pedunculated mass measuring 1.2 cm was observed in the bladder. Histopathological analysis of the resected mass revealed marked lobular capillary proliferation with surface erosions. CONCLUSION: Cystoscopic and pathologic findings in addition to possible predisposing factors supported a diagnosis of pyogenic granuloma of the urinary bladder.

Granulomatous amoebic encephalitis caused by Balamuthia mandrillaris.

A 51-year-old immunocompetent Japanese woman presented with a rare case of granulomatous amoebic encephalitis (GAE) caused by Balamuthia mandrillaris. She was brought to our hospital with epilepsy. Magnetic resonance imaging of the brain revealed a homogeneously enhanced solitary mass in the left frontal lobe. Histological diagnosis was made by a biopsy, which suggested lymphomatoid granulomatosis. After that, her neurological condition got worse. New masses were found and had spread across the whole brain. She died 2 months later of cerebral hernia. Autopsy revealed that the patient had GAE caused by Balamuthia mandrillaris. GAE is usually fatal, and is difficult to diagnose except at autopsy. Therefore, awareness of this disease is important, and earlier diagnosis and the development of a better therapeutic strategy will improve clinical outcome.