Sachiko Kimura

p73: Structure and function

Alteration of the p53 tumor suppressor gene is a common, if not general, observation in human malignant tumors. p73 Is a novel member of the p53 family at chromosome 1p36.3, at which locus frequent defects are seen in many tumors including neuroblastoma. Besides structural similarities, the fact that p73 functions in the regulation of the cell cycle and apoptosis promotes the expansion of the research field concerning p53‐associated tumor progression. In this paper, we review the structure and function of p73 as well as the mutational status in various human tumors. In addition, possibilities for new therapeutic applications with p73 for cancer cell control are discussed.

Growth of hepatic angiomyolipoma indicating malignant potential.

To the Editor, Hepatic angiomyolipoma (HAML) has been considered a benign rare tumor since Ishak first described it in 1976. There have been a number of reports of HAML that investigated its clinical and pathological features. Although the progression of radiological imaging techniques has resulted in a high detection rate and diagnostic accuracy of the liver tumor, definitive diagnosis of HAML still requires histological confirmation. Reactivity of HMB-45 confirms the definitive diagnosis of HAML and once it is determined, surgical treatment has been avoided. Unlike renal angimyolipomas, well known to possess malignant potential, little information about malignant HAML has been available since Dalle et al. first described its existence in 2000. Subsequently, awareness of malignant HAML with a metastatic character has increased. Although all of these reports supported the existence of malignant HMAL, growth activity of HAML has never been reported. A 49-year-old woman was found to have a liver tumor in the right lobe on a medical examination. Computed tomography (CT) images with contrast medium revealed double hypervascular liver tumors (Fig. 1a,b) and a fine needle biopsy resulted in a definite diagnosis

The Reproducibility of a Binary Tumor Grading System for Uterine Endometrial Endometrioid Carcinoma, Compared with FIGO System and Nuclear Grading

Objective: A binary grading system has been proposed to assess the amount of solid growth, the pattern of invasion, and the presence of necrosis, and thereby divide endometrial endometrioid carcinomas into low- and high-grade tumors. We analyzed this system for predicting the prognosis, with respect to inter- and intraobserver reproducibility and treatment modalities. Methods: A total of 200 endometrial carcinomas, based on hysterectomy specimens, were graded according to the binary grading system, for comparison against The International Federation of Gynecology and Obstetrics (FIGO) system and nuclear grading. Results: Both inter- and intraobserver agreement using the binary grading system (ĸ = 0.57; percent agreement: 82% and ĸ = 0.62; 84%) were superior compared with the FIGO system (0.50; 60% and 0.62; 73%) and the nuclear grading (0.23; 49% and 0.43; 65%). Patients with early-stage low-grade tumors had a 98% rate for 5-year survival (5YS). Patients with early-stage high-grade tumors, and those with advanced-stage low-grade tumors, had respectively 86% to 87% rates for 5YS. But patients with advanced-stage high-grade tumors had a 49% rate for 5YS. In binary low-grade early-stage tumors, the patient outcome was better with no adjuvant therapy and chemotherapy, compared with other therapies. Conclusion: A binary grading system was superior to others in permitting greater reproducibility and predicting the prognosis of endometrial cancer patients.

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.

Bob1 limits cellular frequency of T‐follicular helper cells

T follicular helper (Tfh) cells are involved in specific humoral immunity at initial and recall phases. The fact that the transcription repressors B‐cell lymphoma‐6 and Blimp‐1 determine lineages of Tfh cells and other types of effector CD4+ T cells, respectively, suggests that there are unique mechanisms to establish Tfh‐cell identity. In this study, we found that Tfh cells preferentially express the transcriptional coactivator Bob1. Bob1 of Tfh cells was dispensable for the expression of B‐cell lymphoma‐6 and the functional property of the cells for B cell help. However, upon initial immunization of foreign antigens, the percentages of Tfh cells in Bob1−/− mice were much higher than those in wild‐type (WT) mice. In addition, expansion of Tfh cells within Bob1−/−CD4+ T cells transferred into WT mice revealed that the high frequency of Tfh cells was caused by a T‐cell‐intrinsic mechanism. These findings were further supported by the results of in vitro studies demonstrating that Bob1−/− Tfh cells had greater proliferative activity in response to stimuli by CD3/CD28 monoclonal antibody and were also refractory to CD3‐induced cell death in comparison to WT Tfh cells. These results suggest that Tfh cells harbor a Bob1‐related mechanism to restrict numerical frequency against stimulation of TCRs.

A Case of Castleman's Disease with Myasthenia Gravis

A rare case of Castlemans disease with myasthenia gravis is reported. A 55-year-old woman with bilateral ptosis, speech impairment, and severe dyspnea had been previously diagnosed with myasthenia gravis. Computed tomography showed a 5 cm × 3 cm paratracheal mass in the mediastinum, thought to be an ectopic thymoma. Two days after surgical resection, the patient suddenly developed dyspnea. Postoperative myasthenic crisis was diagnosed, and plasmapheresis was performed. Her general condition improved, and her subsequent course was uneventful. The final pathological diagnosis was mediastinal solitary Castlemans disease, hyaline vascular type. Castlemans disease with myasthenia gravis is especially rare. One of the serious complications is postoperative myasthenic crisis. For patients with myasthenia gravis, the rate of postoperative myasthenic crisis seems significantly higher in Castlemans disease patients than in patients with thymic epithelial tumors. Castlemans disease with myasthenia gravis is discussed along with a review of the literature.

Anemia associated with increased hepcidin in two children with Castleman disease

Castleman disease (CD) is a rare lymphoproliferative disorder that can be classified into two clinical subgroups: localized and multicentric. In children localized CD often has varying symptoms, making diagnosis difficult. We report the cases of two children with localized CD who presented with anemia and other symptoms. Written informed consent was obtained from the patients’ parents for publication of the two case reports and all accompanying images. A 6-year-old boy was referred to Sapporo Medical University Hospital for investigation of a chronic inflammatory state with anemia. On admission, laboratory data indicated microcytic hypochromic anemia (hemoglobin [Hb], 78 g/L; mean corpuscular volume [MCV], 58.8 9 10 15 L; mean corpuscular Hb [MCH] concentration, 28.3 g/dL). Serum iron was 0.1 g/L, and C-reactive protein (CRP) was increased to 118.8 mg/L. Bone marrow aspiration showed no malignancy. Thoracic and abdominal computed tomography (CT) and gallium scintigraphy were performed. Abdominal CT showed a tumor 3 9 10 m in diameter in the root of the mesentery. Ga scintigram also showed accumulation in exactly the same location (Fig. 1a). Given that CD was under consideration, serum interleukin (IL)-6 and hepcidin-25 were measured, and found to be elevated at 28.0 ng/L (normal range, <2.41 ng/L) and 25.6 lg/L (normal range, 0.8–14.8 lg/L), respectively. These data supported the possibility of CD. Laparotomy was done for diagnosis and treatment. After complete resection of the tumor, pathology supported a diagnosis of localized hyaline vascular (HV)-type CD (Fig. 1b). After the operation, CRP decreased rapidly, and the anemia was improved (Hb, 124 g/L; MCV, 69.0 9 10 L; serum iron, 0.4 g/L). IL-6 and hepcidin were in the normal range. An 8-year-old boy was admitted to a general hospital with a 1 week history of fever. Laboratory examination indicated elevated CRP (170.5 mg/L), with increased erythrocyte sedimentation rate (116 mm/h). White cell count was 14 600 9 10 cells/L. Cerebrospinal fluid was normal. Ceftriaxone was given i.v., but the high temperature persisted. All imaging, including whole body CT, abdominal ultrasonography, and Ga scintigraphy were normal. Bone marrow aspiration showed no malignancy. He was referred to Sapporo Medical University Hospital for evaluation of fever of unknown origin. Laboratory data indicated microcytic hypochromic anemia (Hb, 10 g/L; MCV, 70.8 9 10 L; MCH, 23.0 g/dL) and no other abnormality of blood cells. Serum iron was 0.17 g/L, and CRP was still elevated to 50.5 mg/L. The remainder of the blood tests were in the normal range. Thereafter, on F-fluorodeoxyglucose (F-FDG) positron emission tomography, high-level FDG accumulation was noted in the abdominal para-aortic lymph nodes (Fig. 1c). Serum IL6 and hepcidin-25 were also found to be elevated, at 23.7 ng/ L and 16.1 lg/L, respectively. Laparotomy was done for diagnosis and treatment. The tumor was located in the caudal region of the left renal vein, between inferior vena cava and aorta in the region expected from the images. On laparotomy, histology indicated a diagnosis of localized HV-type CD (Fig. 1d). All symptoms and laboratory abnormalities improved after surgery. Localized HV-type CD is, especially in adults, asymptomatic with few abnormal laboratory parameters, whereas the majority of multicentric CD cases can involve a variety of constitutional symptoms and laboratory abnormalities. Localized CD in children is therefore more similar to adult multicentric CD. The symptoms and laboratory abnormalities are caused by overproduction of IL-6. Microcytic hypochromic anemia often occurs in childhood CD. The regulation of hepcidin synthesis by IL-6 has been found to be an important component in the pathogenesis of anemia in chronic disease. Hepcidin-25, the bioactive form of hepcidin, secreted by hepatocytes, is a significant regulator of iron homeostasis, and is usually elevated in CD. In the present two cases, serum hepcidin-25 was elevated, and decreased after resection of the tumor. Although there are a number ofreports of childhood CD with microcytic hypochromic anemia, they do not mention elevated serum hepcidin. The Correspondence: Yuko Yoto, MD, PhD, Department of Pediatrics, Sapporo Medical University School of Medicine, S-1 W-16 Chuoku, Sapporo, Hokkaido 060-8543, Japan. Email: yoto@sapmed.ac.jp Received 7 June 2017; revised 5 February 2018; accepted 3 April 2018. doi: 10.1111/ped.13631

Adrenocortical carcinoma characterized by gynecomastia: A case report

Abstract. We present a 4-yr-old boy with adrenocortical carcinoma (ACC), diagnosed due to the appearance of gynecomastia as the presenting symptom. Six months prior to admission, an acute growth spurt along with the development of bilateral breast swelling was observed. He did not present any features of virilization, including enlargement of the testes, increase in testis volume, and penis size. Laboratory investigations showed gonadotropin-independent hypergonadism, with low LH/ FSH levels and elevated estradiol/testosterone levels. Abdominal computed tomography revealed a large heterogeneous mass adjacent to the right kidney and below the liver. Pathological investigations of the biopsy specimen demonstrated that the tumor was an ACC. Pre- and post-operative combination chemotherapy with mitotane was administered and surgical resection was carried out. Post-surgery, the elevated estradiol/testosterone concentrations reverted to within the reference range. Urinary steroid profile and tissue concentration analysis of estradiol and testosterone indicated the presence of estrogen in the ACC tissue. An investigation for TP53 gene aberrations revealed the presence of a germline point mutation in exon 4 (c.215C>G (p.Pro72Arg)). In ACC, the most common symptom is virilization, and feminization, characterized by gynecomastia, is very rare. However, a diagnostic possibility of ACC should be considered when we encounter patients who have developed gynecomastia without the influence of causative factors such as obesity or puberty, and do not present with the typical signs of virilization.

Subcortical heterotopia appearing as huge midline mass in the newborn brain.

IntroductionWe report the case of a 2-year-old boy who showed a huge midline mass in the brain at prenatal assessment.Case reportAfter birth, magnetic resonance imaging (MRI) revealed a conglomerate mass with an infolded microgyrus at the midline, which was suspected as a midline brain-in-brain malformation. MRI also showed incomplete cleavage of his frontal cortex and thalamus, consistent with lobar holoprosencephaly. The patient underwent an incisional biopsy of the mass on the second day of life. The mass consisted of normal central nervous tissue with gray and white matter, representing a heterotopic brain. The malformation was considered to be a subcortical heterotopia. With maturity, focal signal changes and decreased cerebral perfusion became clear on brain imaging, suggesting secondary glial degeneration. Coincident with these MRI abnormalities, the child developed psychomotor retardation and severe epilepsy focused on the side of the intracranial mass.