Akiko Tonooka

A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma.

Differential diagnosis of small round cell sarcomas (SRCSs) grouped under the Ewing sarcoma family of tumors (ESFT) can be a challenging situation for pathologists. Recent studies have revealed that some groups of Ewing-like sarcoma show typical ESFT morphology but lack any EWSR1-ETS gene fusions. Here we identified a novel gene fusion, CIC-FOXO4, in a case of Ewing-like sarcoma with a t(X;19)(q13;q13.3) translocation. The patient was a 63-year-old man who had an asymptomatic, 30-mm, well-demarcated, intramuscular mass in his right posterior neck, and imaging findings suggested a diagnosis of high-grade sarcoma. He was treated with complete resection and subsequent radiotherapy and chemotherapy. He was alive without local recurrence or distant metastasis 6 months after the operation. Histologic examination revealed SRCS with abundant desmoplastic fibrous stroma suggesting a desmoplastic small round cell tumor. Immunohistochemical analysis showed weak to moderate and partial staining for MIC2 (CD99) and WT1, respectively. High-throughput transcriptome sequencing revealed a gene fusion, and the genomic rearrangement between the CIC and FOXO4 genes was identified by fluorescence in situ hybridization. Aside from the desmoplastic stroma, the CIC-FOXO4 fusion sarcoma showed morphologic and immunohistochemical similarity to ESFT and Ewing-like sarcomas, including the recently described CIC-DUX4 fusion sarcoma. Although clinicopathologic analysis with additional cases is necessary, we conclude that CIC-FOXO4 fusion sarcoma is a new type of Ewing-like sarcoma that has a specific genetic signature. These findings have important implications for the differential diagnosis of SRCS.

Glioblastoma simultaneously present with adjacent meningioma: case report and review of the literature

The simultaneous occurrence of multiple primary intracranial tumors has been reported previously. However, most of these tumors arise after cranial radiotherapy or in association with familial tumor syndromes. Double tumors of different histologies that are unrelated to radiotherapy or genetic disorders are very rare. We present a case of two primary intracranial tumors occurring simultaneously at adjacent sites. Preoperative gadolinium-enhanced magnetic resonance imaging of these tumors revealed a single continuous lesion. Postoperative histological examination revealed the presence of two distinct tumors, meningioma and glioblastoma multiforme. To elucidate the mechanism of synchronous tumor formation, we performed immunohistochemical analysis of the proteins involved in the receptor tyrosine kinase, Wnt, and Notch signaling pathways. These analyses showed that platelet-derived growth factor (PDGF) receptors-α and β were overexpressed in both tumors, thereby indicating the oncogenic effects of activated signaling of these receptors. The PDGF-mediated paracrine system may induce one tumor from another.

Arachidonate 5-Lipoxygenase Establishes Adaptive Humoral Immunity by Controlling Primary B Cells and Their Cognate T-Cell Help

In this study, we report the unique role of arachidonate 5-lipoxygenase (Alox5) in the regulation of specific humoral immune responses. We previously reported an L22 monoclonal antibody with which human primary resting B cells in the mantle zones of lymphoid follicles are well-defined. Proteomics analyses enabled identification of an L22 antigen as Alox5, which was highly expressed by naive and memory B cells surrounding germinal centers. Cellular growth of mantle cell lymphoma cells also seemed to depend on Alox5. Alox5(-/-) mice exhibited weak antibody responses specific to foreign antigens at the initial and recall phases. This was probably attributable to the low number of follicular and memory B cells and the functional loss of interleukin-21-mediated responses of follicular B cells. Moreover, Alox5(-/-) mice could not fully foster the development of follicular B helper T (Tfh) cells even after immunization with foreign antigens. Further experiments indicated that Alox5 affected mortality in experimentally induced enterocolitis in germ-prone circumstances, indicating that Alox5 would endow immunologic milieu. Our results illustrate the novel role of Alox5 in adaptive humoral immunity by managing primary B cells and Tfh cells in vivo.

Diffuse in-stent restenosis of CYPHER® stent due to hypersensitivity reaction confirmed by pathohistological findings

The use of drug-eluting stents (DES) reduces the risk of repeat revascularization without increase of death and myocardial infarction compared to standard bare metal stents. However, in-stent restenosis (ISR) after DES implantation still occurs. Here, we report a rare case with a diffuse ISR after CYPHER® stent implantation because of chronic inflammation and hypersensitivity reactions, confirmed by pathohistological findings.

Tonsillar crypt epithelium of palmoplantar pustulosis secretes interleukin-6 to support B-cell development via p63/p73 transcription factors†

Palmoplantar pustulosis (PPP) is an autoimmune disease characterized by psoriasis‐like erythematous lesions on palms and/or soles due to an abnormal humoral immune response. Tonsillectomy is effectively employed for the treatment of PPP; however, how tonsils are involved in the aetiology of PPP remains unclear. Here we analysed surgically resected palatine tonsils from 36 cases of PPP as well as usual recurrent tonsillitis (RT) as a control. Histological examination revealed that a unique lesion, with lymphoid follicles surrounded by reticular crypt epithelial cells, was more frequently observed in tonsils of patients with PPP than in those with RT (p < 0.0001; PPP vs RT). Interestingly, crypt epithelial cells in primary cultures derived from PPP tonsils showed marked production of interleukin‐6 (IL‐6). Moreover, these epithelial cells from PPP tonsils expressed p53‐related transcription factors in their nuclei that were found to contribute to the up‐regulation of IL‐6 gene expression. These findings suggest that, at least in part, the specialized lymphoepithelial symbiosis of PPP tonsils, under the control of p53‐related factors, may be relevant to the generation of the impaired micro‐environment underlying the aberrant production of autoantibodies. Copyright

Evaluation of long-term outcome for patients with renal cell carcinoma after surgery: analysis of cancer deaths occurring more than 10 years after initial treatment

ObjectiveWe evaluated the outcome of renal cell carcinoma (RCC) after surgery in a long-term follow-up study to elucidate the specific biological behaviors of RCC, such as late recurrence and late cancer-specific death.Materials and methodsWe retrospectively reviewed the clinical and pathological features of 625 patients who were diagnosed as having renal cell carcinoma at our institution from 1975 to 2006. We analyzed the parameters and outcomes for the patients who had received radical or partial nephrectomy. Pathological staging was reviewed again by two pathologists.ResultsThe median age of the patients was 61xa0years (range 16–87). The median follow-up was 7.0xa0years (range 0.1–30.3). Of the 516 patients with localized or locally advanced RCC, 124 (24.0xa0%) had recurrence after surgery. Lung metastasis was observed most frequently. The 10-year cancer-specific survival rates were 92.4, 91.0, 64.1 and 11.8xa0% for stages I, II, III and IV, respectively. The late recurrence rates in patients with localized and locally advanced RCC 5 and 10xa0years after initial surgery were 8.5 and 3.7xa0%, respectively. Cancer death more than 10xa0years after initial treatment of the disease occurred in 16 patients. Of the 16 patients, 9 had localized disease at the time of the initial surgery. Specific findings that characterized them were not identified in these patients.ConclusionsLate recurrence of RCC is not rare. Cancer-specific death more than 10xa0years after the initial treatment was observed in 16 patients with localized or advanced disease. No specific findings were identified to characterize these patients with late cancer death.

Wild-type AIRE cooperates with p63 in HLA class II expression of medullary thymic stromal cells

During T cell development in the thymus, autoreactive T cells are deleted through a mechanism that is actively supported by medullary epithelial cells. These epithelial cells possess particular transcription factors including autoimmune regulator (AIRE), which is responsible for regulating expression of self-antigens, as well as p63, a p53-like molecule. Here we present evidence suggesting interaction of AIRE with p63 through a SAND domain and a transactivation domain, respectively. Interestingly an AIRE molecule with a mutated SAND domain of G228W, whose genetic alteration is inherited in an autosomal dominant manner, could not establish a complex with p63 as indicated by immunoprecipitation and molecular modeling analyses. Further in vitro study indicated that the G228W mutation led to downregulation of the transcription levels of CIITA and, accordingly, the cell surface expression of HLA class II molecules in thymic epithelial cells with p63. This indicates novel involvement of AIRE and p63 in the regulation of HLA class II, and suggests that defects in the AIRE-p63 interaction may lead to malfunction of HLA-based selection of self-reactive helper CD4(+) T cells in the thymus.

Long‐term outcome of small, organ‐confined renal cell carcinoma (RCC) is not always favourable

Small, organ‐confined renal cell carcinoma (RCC) generally has favourable pathological characteristics and a good prognosis. However, late recurrence is a known characteristic of the biological behaviour of RCC and no consensus has been established for surveillance protocols from 5 years after radical or partial nephrectomy. In the present study with long‐term follow‐up of patients with small RCCs, 18 of 172 patients (10.5%) with pT1a RCC developed recurrence and eight of these (4.7%) died from cancer. Patients with microvascular invasion had a higher risk for cancer death than those without (P < 0.001, Log‐rank test). Therefore long‐term follow‐up is required after surgery, particularly when the disease has microvascular invasion.

Clinicopathological characteristics of Xp11.2 translocation renal cell carcinoma in adolescents and adults: Diagnosis using immunostaining of transcription factor E3 and fluorescence in situ hybridization analysis

To determine the rate and clinicopathological features of Xp11.2 translocation carcinoma using immunostaining of transcription factor E3 and fluorescence in situ hybridization analysis.

p63 induces CD4+ T-cell chemoattractant TARC/CCL17 in human epithelial cells.

To preserve immunosurveillance, epithelial cells support T-cell trafficking toward inflammatory foci. However, how epithelial cells are enrolled in recruiting T cells has not been fully elucidated. In this study we investigated the function of p63, a p53 family member, in the regulation of the expression of various types of chemokine ligands by focusing on the property of p63 as an epitheliotropic transcription factor. As assessed by experiments using three different human epithelial cell lines with small-interfering RNAs or plasmids of p63, certain CC chemokine ligands were found to be under the control of p63. In these CC chemokine ligands, p63 had the common capacity to upregulate TARC/CCL17 in the different cell lines, whose receptor CCR4 was preferentially presented on CD4(+) T cells such as memory, regulatory, IL-17-producing and type II helper T cells. More interestingly, when cells were stimulated with transforming growth factor-beta (TGF-beta) or epidermal growth factor (EGF) as observed during tissue repair process, the expression of p63 and TARC/CCL17 was concomitantly suppressed. This implies that, in local inflammatory regions with general epithelial tissue remodeling, the p63-TARC/CCL17 axis may participate in the engagement of efficient immune reactions by specified T-cell subsets.