Primary degeneration of oculomotor, motor, and somatosensory systems and auditory and visual pathways in spinocerebellar ataxia type 7: A clinicopathological study in a Japanese autopsy case.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia associated with retinal degeneration. The disease is rare in Japan, and this is the first full description of clinicopathological findings in a Japanese autopsy case of genetically confirmed SCA7 having 49 cytosine-adenine-guanine (CAG) trinucleotide repeats in the ataxin 7 gene. A 34-year-old Japanese man with no family history of clinically apparent neurodegenerative diseases presented with gait disturbance, gradually followed by truncal instability with progressive visual loss by the age of 42 years. He became wheelchair-dependent by 51 years old, neurologically exhibiting cerebellar ataxia, slow eye movement, slurred and scanning speech, lower limb spasticity, hyperreflexia, action-related slowly torsional dystonic movements in the trunk and limbs, diminished vibratory sensation in the lower limbs, auditory impairment, and macular degeneration. Brain magnetic resonance imaging revealed atrophy of the brainstem and cerebellum. He died of pneumonia at age 60 with a 26-year clinical duration of disease. Postmortem neuropathological examination revealed pronounced atrophy of the spinal cord, brainstem, cerebellum, external globus pallidus (GP), and subthalamic nucleus, microscopically showing neuronal cell loss and fibrillary astrogliosis with polyglutamine-immunoreactive neuronal nuclei and/or neuronal nuclear inclusions (NNIs). Degeneration was also accentuated in the oculomotor system, auditory and visual pathways, upper and lower motor neurons, and somatosensory system, including the spinal dorsal root ganglia. There was a weak negative correlation between the frequency of nuclear polyglutamine-positive neurons and the extent of neuronal cell loss. Clinicopathological features in the present case suggest that neurological symptoms, such as oculomotor, auditory, visual, and sensory impairments, are attributable to degeneration in their respective projection systems affected by SCA7 pathomechanisms and that dystonic movement is related to more significant degeneration in the external than internal GP.

[Coexistence of Lung Adenocarcinoma and Non-caseous Epithelioid Granuloma Possibly due to Systemic Sarcoidosis in the Same Lesion].

A lung cancer coexists with non-caseous epithelioid granulomas (NEG) in the same lesion is uncommon. A 62-year-old female was referred to our hospital for examination of a right lung S3 nodule which was recently increasing in its size. Positron emission tomography-computed tomography (PET-CT) examination revealed positive signals at the S3 nodule as well as mediastinal lymph nodes, apex of heart and right pleura. Pathological examination revealed the S3 nodule coexisting with both adenocarcinoma and NEG. The differential diagnosis between the systemic sarcoidosis and sarcoid reaction is usually important in such a case. Since the pleura and mediastinal lymph nodes contained many NEGs, the adenocarcinoma arising based on the systemic sarcoidosis was possibly suggested in the present case.

[Primary breast diffuse large B-cell lymphoma in an elderly man maintaining long-term complete response].

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin's lymphoma that mostly affects women. Here, we report a case of primary breast DLBCL that affected an older man without any autoimmune disease or drug-related female hormones. The patient was a 65-year-old man whose chief complaints were gradually-increasing lump in the right chest and swelling of the right axillary lymph nodes. He was diagnosed with malignant lymphoma through a needle biopsy on suspicion of right breast cancer with right axillary lymph node metastasis. Since the histological type could not be confirmed, right breast mass resection was performed. The patient was referred to our department for treatment because of the diagnoses of primary breast DLBCL, germinal center B-cell type (Hans classification), and clinical stage IIA. In addition to the six courses of R-CHOP therapy, intrathecal injections were used in combination to prevent CNS infiltration. He has been in complete remission for 5 years. Although rare, breast lymphoma can also occur in men; therefore, early histological diagnosis and response to CNS recurrence prevention are important.

Two autopsy cases of desmoplastic small round cell tumor.

Desmoplastic small round cell tumor (DSRCT) is a rare aggressive malignant tumor. It is a refractory tumor and the median overall survival is very short. We report two autopsy cases of DSRCT, both of which were already advanced and metastasized at the first medical examination. Both cases showed typical DSRCT findings in terms of localization of the lesions, histopathology and genetics, but the rate of disease progression was quite different. Survival after initial symptoms in Case 1 was only 12 months. On the other hand, survival after primary hospitalization in Case 2 was 42 months. The Case 2 patient initially received chemotherapy for advanced pancreatic carcinoma, because a nodule of the pancreatic tail was found on computed tomography (CT) scan. After chemotherapy, tumor regression was observed on CT scan. It is thus implied that adoption of the regimen for pancreatic carcinoma might have been one of reasons of the long survival in Case 2.

Sonographic findings in two cases of lymphangioma of the mesocolon in adults.

Lymphangioma of the mesocolon is very rare. We report two cases of surgically resected and histologically proven mesocolic lymphangioma in adults. In both cases, ultrasound revealed a large cystic mass with multiple thin septa in the lower abdomen. A peculiar finding was the large craniocaudal sliding movement of the mass synchronized with the patient's respiration, which was a clue to the diagnosis of mesenteric lymphangioma. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:78-81, 2018.

[Antineutrophil Cytoplasmic Antibody (ANCA) Negative Limited-form Granulomatosis with Polyangiitis of the Lung Diagnosed by the Thoracoscopic Lung Biopsy].

Antineutrophil cytoplasmic antibody (ANCA) negative pulmonary limited-form granulomatous with polyangiitis (GPA) is a rare type of GPA. A 53-year-old female had been followed as the possible pulmonary infarction of bilateral lungs for 4 years without any therapy. Chest computed tomography(CT) examination of the patient showed newly appeared nodular lesions in the lungs, which were suspected as malignancy by positron emission tomography (PET) -CT. Thoracoscopic lung biopsy of the lesions was performed and histopathological diagnosis was GPA showing multiple granulomas with vasculitis. Since both C and P-ANCA were negative and no evidence of kidney involvement, we finally diagnosed the lung lesions as ANCA negative limited-form GPA.

Contributions of hepatocytes and bile ductular cells in ductular reactions and remodeling of the biliary system after chronic liver injury.

Mature hepatocytes are suggested to possess a capacity for bile ductular transdifferentiation, but whether and how hepatocytes contribute to ductular reaction in chronic liver diseases has not been elucidated. We examined whether mouse hepatocytes can transdifferentiate into bile ductular cells in vitro, using a three-dimensional collagen gel culture method, and in vivo, using a liver repopulation model in which ß-galactosidase-positive hepatocytes from Alb-Cre × ROSA26R mice were transplanted into the liver of wild-type mice. We further examined the relative contribution of intrinsic hepatocytes in ductular reaction in a hepatocyte lineage-tracing model using Mx1-Cre × ROSA26R mice treated with polyinosinic-polycytidylic acid. Within collagen gels, hepatocytes exhibited branching morphogenesis associated with the emergence of bile duct-like phenotype. In the liver repopulation model, many ß-galactosidase-positive, hepatocyte-derived bile ductular structures were identified; these markedly increased after liver injury. In Mx1-Cre × ROSA26R mice, relatively minor but significant contributions of hepatocyte-derived bile ductules were observed in both periportal and centrilobular ductular reaction. As the centrilobular ductular reaction progressed, the portal ducts or ductules migrated toward the injured area and joined with hepatocyte-derived ductules, leaving the portal tract without biliary structures. We conclude that hepatocytes and bile ducts or ductules are important sources of ductular reaction and that the intrahepatic biliary system undergoes remarkable remodeling in response to chronic liver injury.

Hypercalcemic Crisis Due to Parathyroid Adenoma Improved by Continuous Hemodialysis with a Common Calcium Concentration Dialysate: Discussion of Therapeutic Management.

A hypercalcemic crisis due to primary hyperparathyroidism is a life-threatening condition. We herein report a 71-years-old man with hypercalcemic crisis due to primary hyperparathyroidism with parathyroid adenoma. Generally, hemodialysis or continuous hemodiafiltration using calcium-free or low-calcium dialysate is performed early for hypercalcemic crisis. In this case, continuous hemodialysis with a common calcium concentration dialysate improved the hypercalcemic crisis, and parathyroidectomy was performed. The patient recovered sufficiently. Prediction of hypercalcemia crisis, appropriate introduction and methods of blood purification therapy, and timing decisions for parathyroidectomy are required for therapeutic management of hypercalcemic crisis with parathyroid adenoma.

Tumor necrosis factor-α promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro.

We previously showed that mature hepatocytes could transdifferentiate into bile ductular cells when placed in a collagen-rich microenvironment. To explore the mechanism of transdifferentiation, we examined whether inflammatory cytokines affected the phenotype of hepatocytes in a three-dimensional culture system. Spheroidal aggregates of rat hepatocytes were embedded within a type I collagen gel matrix and cultured in the presence of various cytokines. In the control, hepatocytes gradually lost expression of albumin, tyrosine aminotransferase, and hepatocyte nuclear factor (HNF)-4α, while aberrantly expressed bile ductular markers, including cytokeratin 19 (CK 19) and spermatogenic immunoglobulin superfamily (SgIGSF). Among the cytokines examined, tumor necrosis factor (TNF)-α inhibited expression of albumin and HNF-4α, both at mRNA and protein levels. After culturing for 2 weeks with TNF-α, hepatocytic spheroids were transformed into extensively branching tubular structures composed of CK 19- and SgIGSF-positive small cuboidal cells. These cells responded to secretin with an increase in secretion and expressed functional bile duct markers. TNF-α also induced the phosphorylation of Jun N-terminal kinase (JNK) and c-Jun, and the morphogenesis was inhibited by SP600125, a specific JNK inhibitor. Furthermore, in chronic rat liver injury induced by CCl(4) , ductular reaction in the centrilobular area demonstrated strong nuclear staining of phosphorylated c-Jun. Our results demonstrate that TNF-α promotes the ductular transdifferentiation of hepatocytes and suggest a role of TNF-α in the pathogenesis of ductular reaction.

Recovery of mature hepatocytic phenotype following bile ductular transdifferentiation of rat hepatocytes in vitro.

We previously demonstrated that mature rat hepatocytes transdifferentiate to bile ductular cells when cultured in a three-dimensional collagen-rich matrix. Here, we show that the phenotype of transdifferentiated hepatocytes can be reversed by modulating culture conditions. Spheroidal aggregates of hepatocytes were cultured within a collagen gel matrix in the presence of serum and tumor necrosis factor-α. Spheroids transformed into ductular structures composed of small cuboidal cells, lost the expression of hepatocytic markers, whereas aberrantly expressed bile ductular markers. The transdifferentiated cells were then retrieved from the gels, plated on surfaces coated with a basement membrane-like material, and cultured in serum-free media. Cells spontaneously formed spheroidal aggregates and recovered hepatocytic phenotype. Dexamethasone (Dex), which suppressed the phosphorylation of ERK and Jun N-terminal kinase, facilitated the recovery, and the combination with interleukin-6 or oncostatin M resulted in the recovery of hepatocyte nuclear factor 4 α protein expression and the typical hepatocytic morphology, and a decrease in the expression of bile ductular markers. A cDNA microarray analysis revealed that the hepatocyte-specific mRNA expression profile was recovered in these cells. Our results demonstrate that hepatocytes are able to recover their phenotypes following bile ductular transdifferentiation, suggesting that hepatocytic and bile ductular phenotypes may be mutually reversible.

Ovarian Follicular Lymphoma Diagnosed Due to Hydronephrosis.

A 74-year-old woman presented with left lateral abdominal pain. Abdominal echography revealed left hydronephrosis and a pelvic mass. The patient underwent left adnexal resection of a suspected left ovarian tumor and was diagnosed with follicular lymphoma (FL) of clinical stage IIIA, grade 2. The patient was treated with rituximab-combined chemotherapy and achieved complete remission. The most common histological types of ovarian lymphoma are diffuse large B-cell lymphoma and Burkitt lymphoma, with FL being an extremely rare variant. We herein report a case of ovarian FL diagnosed as hydronephrosis.

Phosphorylated Syk expression is enhanced in Nasu-Hakola disease brains.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by a loss-of-function mutation of DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 and DAP12 constitute a receptor/adaptor complex on myeloid cells. The post-receptor signals are transmitted via rapid phosphorylation of the immunoreceptor tyrosine-based activating motif (ITAM) of DAP12, mediated by Src protein tyrosine kinases, followed by binding of phosphorylated ITAM to Src homology 2 (SH2) domains of spleen tyrosine kinase (Syk), resulting in autophosphorylation of the activation loop of Syk. To elucidate the molecular mechanism underlying the pathogenesis of NHD, we investigated Syk expression and activation in the frontal cortex and the hippocampus of three NHD and eight control brains by immunohistochemistry. In NHD brains, the majority of neurons expressed intense immunoreactivities for Syk and Y525/Y526-phosphorylated Syk (pSyk) chiefly located in the cytoplasm, while more limited populations of neurons expressed Src. The levels of pSyk expression were elevated significantly in NHD brains compared with control brains. In both NHD and control brains, substantial populations of microglia and macrophages expressed pSyk, while the great majority of reactive astrocytes and myelinating oligodendrocytes did not express pSyk, Syk or Src. These observations indicate that neuronal expression of pSyk was greatly enhanced in the cerebral cortex and the hippocampus of NHD brains, possibly via non-TREM2/DAP12 signaling pathways involved in Syk activation.

Cytoplasmic accumulation of connexin32 expands cancer stem cell population in human HuH7 hepatoma cells by enhancing its self-renewal.

Although the connexin32 (Cx32)-mediated gap junction is abolished in hepatocellular carcinoma (HCC), the expression of cytoplasmic Cx32 tends to increase in correspondence with the grade of malignancy. Establishing a Tet-off expression system in human nonmetastatic HuH7 HCC cells where cytoplasmic Cx32 was overexpressed by doxycycline (Dox) withdrawal, we previously demonstrated that overexpression of cytoplasmic Cx32 made HuH7 cells metastatic in mice. In our study, hypothesizing that the cytoplasmic Cx32-induced metastasis may involve expansion of the cancer stem cell (CSC) population, we examined whether cytoplasmic Cx32 controlled the size of the side population (SP) in HuH7 Tet-off Cx32 cells. Fluorescence-activated cell sorting revealed that SP was expanded in a Dox-free medium compared with a Dox-supplemented one. Although cytoplasmic Cx32 did not block maturation from SP to non-SP, purified SP reconstituted a larger SP fraction in the Dox-free medium than in the Dox-supplemented one. Furthermore, although SP from HuH7 Tet-off mock cells formed a similar number of CSC spheres of a similar size whether with or without Dox, SP from HuH7 Tet-off Cx32 cells developed a greater number of larger CSC spheres in the Dox-free medium than in the Dox-supplemented one. Taken together, these results suggest that accumulation of cytoplasmic Cx32 should enhance self-renewal of CSC to expand the CSC population in HCC.

Fatal hemorrhagic pneumonia caused by Stenotrophomanas maltophilia in a patient with non-Hodgkin lymphoma.

Stenotrophomonas maltophilia is increasingly emerging as a multiresistant pathogen in the hospital environment. In immunosuppressed patients, this bacterium may cause severe infections associated with sepsis and multiple organ dysfunction. We report on a 57-year-old woman treated with intensive chemotherapy for non-Hodgkin lymphoma who developed severe neutropenia, hemorrhagic pneumonia, and acute respiratory failure, which led to her death within 36 h of onset of pneumonia. Postmortem examination revealed bilateral extensive intraalveolar hemorrhage associated with severe infection by the gram-negative bacterium Stenotrophomonas maltophilia. In vitro susceptibility testing showed resistance to carbapenem, cephalosporines and aminoglycosides, but sensitivity to minocycline, ciprofloxacin, levofloxacin, and trimethoprim/sulfamethoxazole (cotrimoxazole). Early diagnosis and adequate antibiotic treatment were difficult, as the clinical course was rapid and fulminant, and this bacterium is resistant to multiple antibiotics. To improve prognosis in such cases, it will be necessary to develop an effective prophylactic strategy for high-risk patients.

Immunohistochemical characterization of microglia in Nasu-Hakola disease brains.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 and DAP12 constitute a receptor/adapter signaling complex expressed on osteoclasts, dendritic cells (DC), macrophages and microglia. Previous studies using knockout mice and mouse brain cell cultures suggest that a loss-of-function of DAP12/TREM2 in microglia plays a central role in the neuropathological manifestation of NHD. However, there exist no immunohistochemical studies that focus attention on microglia in NHD brains. To elucidate a role of microglia in the pathogenesis of NHD, we searched NHD-specific biomarkers and characterized their expression on microglia in NHD brains. Here, we identified allograft inflammatory factor 1 (AIF1, Iba1) and sialic acid binding Ig-like lectin 1 (SIGLEC1) as putative NHD-specific biomarkers by bioinformatics analysis of microarray data of NHD DC. We studied three NHD and eight control brains by immunohistochemistry with a panel of 16 antibodies, including those against Iba1 and SIGLEC1. We verified the absence of DAP12 expression in NHD brains and the expression of DAP12 immunoreactivity on ramified microglia in control brains. Unexpectedly, TREM2 was not expressed on microglia but expressed on a small subset of intravascular monocytes/macrophages in control and NHD brains. In the cortex of NHD brains, we identified accumulation of numerous Iba1-positive microglia to an extent similar to control brains, while SIGLEC1 was undetectable on microglia in all the brains examined. These observations indicate that human microglia in brain tissues do not express TREM2 and DAP12-deficient microglia are preserved in NHD brains, suggesting that the loss of DAP2/TREM2 function in microglia might not be primarily responsible for the neuropathological phenotype of NHD.

Severe Abdominal Recurrence of Low-grade Endometrial Stromal Sarcoma After Hysteroscopic Surgery.

BACKGROUND: Low-grade endometrial stromal sarcoma (LG-ESS) is an indolent tumor harboring gene fusion involving polycomb family genes. While early LG-ESS has a good clinical course, some tumors have pelvic recurrence. The etiology and genetic alterations involved in the process remain unknown. CASE REPORT: A 44-year-old nulliparous woman underwent hysteroscopic surgery for a 2.5 cm submucosal uterine tumor with negative endometrial cytology. Pathological evaluation revealed LG-ESS. On the 31st day, total laparoscopic hysterectomy was indicated. She was diagnosed with stage IA (pT1aNXM0) LG-ESS without lymphovascular invasion. At 4 years, positron-emission tomography showed multiple pelvic masses. Secondary debulking surgery was performed, which revealed severe intra-abdominal recurrence of LG-ESS with JAZF1-SUZ12 fusion. CONCLUSION: Hysteroscopic surgery is a convenient tool for benign uterine submucosal diseases. However, intrauterine morcellation with fluid can lead to unexpected recurrence of occult LG-ESS. It is important when seeking consent for surgery to inform patients about the possible risk of dissemination of uterine mesenchymal tumors.

Basal cell carcinoma with signet ring cell morphology accumulating the ubiquitinated cytokeratin 5/6.

Basal cell carcinoma (BCC) showing signet ring (SR) cell morphology is a very rare variant of BCC. Here, we report BCC with SR cell morphology developed in the right cheek skin of a 79-year-old man. Histopathologic examination showed irregularly shaped islands of basaloid cells with characteristic peripheral palisading. Inside of the cancer islands, many tumour cells showed an enlarged fine granular cytoplasm with the peripherally compressed nuclei, being similar to the SR cell. Immunohistochemical examination revealed dense accumulation of cytokeratin (CK) 5/6 and a faint signal of 34ßE12 in SR cells. The reported myoepithelial markers were not detected. Interestingly, ubiquitin, a component of the ubiquitin-proteasome protein degradation system, was co-localised in the SR cells. These suggest, for the first time, that accumulation of the undegraded CK5/6 with ubiquitination results in the SR cell morphology. Our report showed that the aberrant keratin turnover is associated with the SR cell BCC.

Significance of integrin αvß5 and erbB3 in enhanced cell migration and liver metastasis of colon carcinomas stimulated by hepatocyte-derived heregulin.

To study the mechanisms of the highly liver-metastatic character of colon carcinoma cells, we studied the expression pattern of surface integrins on LS-LM6 (a highly liver-metastatic human colon cancer cell line) and the effects of hepatocyte-derived soluble factors on cell migration. LS-LM6 showed significantly higher expression of integrin αvß5, a ligand for vitronectin (VN), as compared with its parental cell line (LS174T). A conditioned medium of cultured mouse hepatocytes enhanced VN-mediated cell migration of LS-LM6, which was blocked by neutralizing antibody against integrin αvß5, while the medium did not affect cell adhesion to VN-coated plastic surfaces. The conditioned medium induced phosphorylation of erbB3 and its heterodimeric partner, erbB2. Heregulin (HRG), a ligand for erbB3, exerted similar effects on VN-mediated cell migration and phosphorylation of erbB3 and erbB2. The conditioned medium contained HRG, and depletion of HRG from the medium by pre-absorption with HRG antibody abolished its effects on cell migration. Heregulin (HRG) was expressed in some hepatocytes in the liver with carcinoma cell metastasis. Furthermore, knockdown of integrin αv and erbB3 by small-interfering RNAs significantly inhibited cell migration induced by HRG as well as liver metastasis in vivo. Finally, we found that HRG-induced cell migration was associated with marked phosphorylation of Akt and that cell migration was suppressed by treatment with specific inhibitors of phosphatidylinositol 3-kinase. Our study suggests that hepatocyte-derived HRG might participate in a highly liver-metastatic phenotype of LS-LM6 through enhancement of integrin αvß5-mediated cell migration and erbB3/erbB2 signaling.

Suppressive effect of orthovanadate on hepatic stellate cell activation and liver fibrosis in rats.

Orthovanadate (OV), an inhibitor of protein tyrosine phosphatases, affects various biological processes in a cell-type-specific manner. In this study, we investigated the effect of OV on hepatic stellate cells (HSCs). When primary rat HSCs were cultured in the presence of 10% serum, they spontaneously lost characteristic stellate morphology, proliferated, and were transformed into an activated state with the formation of abundant stress fibers and increased expression of both alpha-smooth muscle actin and collagen type I mRNA. OV treatment inhibited proliferation and activation of HSCs and partially reversed the phenotype of activated HSCs. Among the signaling molecules investigated, phosphorylation of the Src protein at tyrosine 416 was the most striking in OV-treated HSCs. Treatment of cells with Src family inhibitors partially abrogated the effects of OV. Furthermore, transfection of v-Src into activated HSCs induced a stellate morphology similar to that in the quiescent state. We then examined whether OV could effectively suppress HSC activation in vivo after liver injury induced by either carbon tetrachloride or dimethylnitrosamine. OV significantly reduced the appearance of alpha-smooth muscle actin-positive cells and decreased collagen deposition, concomitant with an improvement in liver function. Our study showed for the first time that OV was able to suppress the activation of HSCs, possibly through the modulation of Src activity, and attenuated fibrosis after chronic liver injury.