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Background. Immunoglobulin (Ig) G4-related diseases (RDs) are systemic diseases in which serum IgG4 levels are frequently elevated. They can cause diffuse or focal tumor formation, organ swelling, and tissue thickening in organs infiltrated by IgG4 + plasma cells. The diagnostic criteria for IgG4-RDs include an IgG4/IgG ratio >40%, but counting IgG+ cells can be difficult because of the weakness of IgG staining density. We hypothesized that an antibody cocktail of mixed IgG1, IgG2, IgG3, and IgG4 (AC-IgG) might give immunohistochemistry results comparable with those of IgG in IgG4-RD. Methods. We compared AC-IgG reactivity with IgG expression in type 1 autoimmune pancreatitis (AIP), a representative IgG4-RD. We compared immunohistochemistry results using AC-IgG and IgG-only in 10 cases of AIP. The coefficient of variation (Cv) was used to analyze differences between AC-IgG and IgG findings in AIP by 13 board-certified pathologists. Results. Although mean values for IgG+ cells did not significantly differ between AC-IgG (34.3; range = 27.4-37.1) and IgG (30.0; range = 23.0-45.6; P = .6254), Cv was lower for AC-IgG (33.4%) than for IgG (51.4%; regression equation; y[IgG] = 0.988 x + 0.982; correlation coefficient = 0.907). The data showed that the results of both methods were largely consistent. Conclusion. AC-IgG could replace IgG to count IgG+ cells because of its lower Cv.

Plasma cell myeloma (PCM) is a haematological malignancy defined by aberrant proliferation of plasma cells in the bone marrow. For the diagnosis of PCM, immunostaining of light chains or surface marker analyses by flow cytometry is needed but sometimes difficult. Aberrant methylation at the carbon-5 position of cytosine results in 5-methylcytosine (5-mC), which is a well-known epigenetic hallmark of cancer in mammals. 5-mC is oxidised to 5-hydroxymethylcytosine (5-hmC), and low 5-hmC levels occur in several cancers and haematopoietic malignancies. We compared the expression of 5-hmC by immunohistochemistry (IHC) in neoplastic plasma cells in 31 PCM cases and in non-neoplastic plasma cells in 14 benign reactive lesions. The mean percentage of 5-hmC-positive cells was 7.8% and 81.5% in PCM and plasma cell hyperplasia, respectively. Thus, the frequency of 5-hmC-positive cells in PCM specimens was significantly lower than that in reactive plasma cell hyperplasia (p0.001 by Student's t-test). IHC of 5-hmC is a useful method for differentiating neoplastic plasma cells from non-neoplastic plasma cells in reactive lesions even in tiny tissue samples unsuitable for flow cytometric analyses or for immunoglobulin light chain IHC.

The relationship between methylation abnormality and autoimmune pancreatitis (AIP)-a representative IgG4-related disease-has not yet been elucidated. We identified SKI might have a significant methylation abnormality in AIP through methylation array analysis using the Illumina Infinium Human Methylation 450K BeadChip array, and investigated the relationship of SKI with AIP clinicopathological features. The methylation rate of SKI was assessed by quantitative SYBR green methylation-specific PCR, and the degree of SKI expression in tissue specimens was assessed by immunohistochemistry in 10 AIP cases, 14 cases of obstructive pancreatitis area in pancreatic ductal adenocarcinoma (PDA) without a history of AIP, and 9 normal pancreas (NP) cases. The SKI methylation ratio was significantly lower in AIP than in PDA and NP. Additionally, the immunohistochemical staining-index (SI) score for SKI was significantly higher in AIP than NP, although there was no significant difference between AIP and PDA. There was a strong negative correlation between SI score and SKI methylation ratio, and between the serum concentrations of IgG4 and the SKI methylation ratio. There was a moderate positive correlation between the serum concentrations of IgG4 and SI. SKI is thought to be an oncogene indicating that SKI hypomethylation and carcinogenesis might be linked to AIP. Furthermore, the correlation between serum concentrations of IgG4 and SKI methylation levels suggest SKI might be involved in the pathogenesis of AIP. However, the role of SKI has not been clearly elucidated. Further studies are needed to understand further the function of SKI.

As the number of long-term cancer survivors is increasing, the incidence of post-irradiation malignant mesothelioma may also increase. We herein present the case of an 85-year-old female patient with a history of several surgeries for solid tumors and radiotherapy to the pelvis, who presented with abdominal pain and diarrhea. The patient's general condition gradually worsened and she succumbed to cardiopulmonary arrest triggered by vomiting ~3 months after the onset of the abdominal symptoms. An autopsy revealed malignant intestinal obstruction caused by peritoneal mesothelioma. Irradiation is a known risk factor for malignant mesothelioma, which may develop ~10-30 years after radiotherapy. To the best of our knowledge, this is the first report of a patient with malignant mesothelioma developing ~50 years after radiotherapy. The aim of the present study was to remind physicians that malignant mesothelioma should be considered in the differential diagnosis of patients with a history of radiotherapy who present with gastrointestinal symptoms.

OBJECTIVE In this study, we assessed the significance of complete dissection of the dorsal lymph node of the obturator nerve during radical prostatectomy. PATIENTS AND METHODS Fifty-six patients undergoing open radical prostatectomy and pelvic lymph node dissection for treatment of prostate cancer were included in this study. Neoadjuvant hormonal therapy and radiation therapy were not performed in any of the patients. First, pelvic lymph node dissection was performed between the external iliac vein and obturator nerve and classified as "ventral lymph node of the obturator nerve". Then, the tissue located in the area between the obturator nerve and the surface of the obturator internus muscle was removed and classified as "dorsal lymph node of the obturator nerve". Both lymph nodes were meticulously examined by identical pathologist. Lymph node yields, lymph node positive rate, and the factors associated with lymph node metastasis were studied. RESULTS Eight of the 56 patients had pelvic lymph node metastases (6 were high risk and 2 were intermediate risk according to the D'Amico's criteria). In the 8 node-positive patients, only 1 patient had positive lymph node in "ventral lymph node of the obturator nerve" exclusively. Four patients had positive lymph node exclusively in "dorsal lymph node of the obturator nerve" and 3 patients had in both "ventral and dorsal lymph nodes of the obturator nerve". The total lymph node yields from "ventral lymph node of the obturator nerve" and "dorsal lymph node of the obturator nerve" were 459 (8.2 per patient) and 117 (2.1 per patient), respectively. The total numbers of positive lymph nodes from "ventral lymph node of the obturator nerve" and "dorsal lymph node of the obturator nerve" were 6 and 12, respectively. Lymph node positive rate was significantly higher in "dorsal lymph node of the obturator nerve" (10%) than "ventral lymph node of the obturator nerve" (1.3%) (P or = 20 ng ml), Gleason score sum at prostate biopsy (> or = 9), and lymph node yield (> or = 16) were associated with lymph node status on univariate analysis. In multivariate analysis, only lymph node yield was associated with lymph node status. CONCLUSIONS Dorsal lymph nodes of the obturator nerve should be dissected completely during radical prostatectomy.

Objective To assess the effect of chemotherapy plus bevacizumab on tumor vessels, as well as the reversibility of this effect, using contrast-enhanced ultrasonography (CEUS) and histology in patients with metastatic liver tumors derived from colorectal cancer. Methods The study included 12 patients who received chemotherapy plus bevacizumab, experienced a reduction in tumor vascularity as demonstrated by CEUS and consequently underwent liver resection. CEUS was performed before and after four courses of chemotherapy and before surgery. The numbers of microvessels highlighted by anti-CD34 antibodies in the viable tumor tissue were counted to quantify the microvessel density (MVD). As a control, 12 surgical specimens from 12 patients who had not received chemotherapy were examined. Results A reversal of tumor vascularity was observed in 10 of 12 patients. In two patients, the vascularity remained reduced. The MVD in the treatment group was significantly lower than that observed in the group without treatment. Conclusion The data suggest that the tumor vessels regenerated substantially, although the effect of chemotherapy plus bevacizumab remained weak for approximately 6 weeks after the cessation of treatment. Therefore, future research must determine whether bevacizumab should be used prior to surgery. J. Surg. Oncol. 2013;107:155–159. © 2012 Wiley Periodicals, Inc.

Granulocyte-colony stimulating factor (G-CSF) is a naturally occurring glycoprotein that stimulates the proliferation and maturation of precursor cells in the bone marrow into fully differentiated neutrophils. Several reports of G-CSF-producing malignant tumors have been published, but scarcely any in the hepatobiliary system, such as in hepatocellular carcinoma (HCC). Here, we encountered a 69-yr-old man with a hepatic tumor who had received right hepatic resection. He showed leukocytosis of 25,450/mL along with elevated serum G-CSF. Histological examination of surgical samples demonstrated immunohistochemical staining for G-CSF, but not for G-CSF receptor. The patient survived without recurrence for four years, but ultimately passed away with multiple bone metastases. In light of the above, clinicians may consider G-CSF-producing HCC when encountering patients with leukocytosis and a hepatic tumor. More cases are needed to clarify the clinical picture of G-CSF-producing HCC., http://jkms.org/ | http://jkms.org/, Article, JOURNAL OF KOREAN MEDICAL SCIENCE. 25(3):476-480 (2010)

Pulmonary-renal syndrome is characterized by pulmonary hemorrhage and rapidly progressive glomerulonephritis in various immunological states. Histopathological analysis of pulmonary-renal syndrome is not yet complete.Wistar-Kyoto (WKY) rats were sensitized using the noncollagenous (NC1) domain of type IV collagen from bovine kidney as an antigen. Histopathology of the kidneys and lungs was investigated with light microscopy, immunohistochemistry and electromicroscopy. Expression levels of cytokine mRNA were determined by real-time RT-PCR using renal tissue of rats.Macrophage-rich granulomatous glomerulonephritis and alveolar capillaritis accompanied with pulmonary hemorrhage were induced by the sensitization. The humoral antibody against NC1 was detected on the glomerular and alveolar capillary walls. Th2 cytokine IL-10 was dominant over Th1 cytokine IFN-gamma in renal tissues of WKY rats.The granulomatous transformation seemed to be induced by macrophage conspicuous capillaritis under dominant cellular immune reactions in WKY rats. In addition to Th1 cytokines, Th2 cytokines may also participate in the formation of granulomatous lesions.

A 33-year-old Japanese man was referred to our hospital after a huge intrapelvic tumor with bilateral hydronephrosis was found following persistent lumbago. Natural killer/T-cell lymphoma was suspected due to positive immunostaining for CD56, but CHOP therapy was ineffective. Re-evaluation of the tumor cells showed that they were positive for CD99, neuron-specific enolase, and synaptophysin and had a t(11; 22) (q 24; q12) translocation, leading to the revised diagnosis of primitive neuroectodermal tumor (PNET). Systemic chemotherapies and radiation therapy were added to surgical resection, and no recurrence has been detected for 3 years. Taken together, PNET may be considered in adult patients with CD56-positive tumors., Article, INTERNAL MEDICINE. 48(15):1267-1272 (2009)

A case of pulmonary artery leiomyosarcoma in a 37 year old Japanese man is reported. The patient complained of chest pain and hemosputum. CT scan and angiography revealed that a tumor arose from the right main branch of the pulmonary artery. The surgical specimen was interpreted as an undifferentiated sarcoma at this time. The tumor recurred 6 months after the resection, and he died of right-sided heart failure. At autopsy, the pulmonary artery truncus was distended by the tumor, which protruded into the lumen. The tumor was composed of pleomorphic cells, giant cells and spindle-shaped cells. Many of the tumor cells were immuno-histochemically positive for alpha-smooth muscle action and vimentin. Electron microscopy revealed microfNaments with dense bodies in the cytoplasm and a discontinuous basement membrane around the cells. Although adenocarcinoma was also observed in the colon, the authors conclude that the present tumor is not a metastasis but a primary leiomyosarcoma arising from the pulmonary artery. Imaging techniques were very useful for differentiating sarcoma from thrombus in this site, and immunohistochemical demonstration for alpha-smooth muscle action was necessary for making a histological diagnosis of leiomyosarcoma.

A 73-year-old Japanese man with a history of partial gastrectomy due to gastric cancer 4 years previously was admitted because of intermittent fever. The patient developed abdominal pain, erythema, and myalgia in addition to the fever during the final clinical course, and died of acute heart failure. Autopsy disclosed atrophy of the left lobe of the liver and acute myocardial infarction. Neither metastasis nor recurrence of the cancer was observed. Small and medium-sized arteries of the visceral organs showed various stages of necrotizing vasculitis with narrowing of the lumina. The vasculitis was most prominent in the left lobe of the liver and in the heart. Narrowing of the portal vein due to portal tract inflammation in addition to vasculitis of the hepatic arteries may have induced ischemia and infarction, which had resulted in atrophy of the left hepatic lobe. Acta Pathol Jpn 42: 662–666, 1992.

Here we report two patients with hematological malignancies associated with complications of fatal cardiac zygomycosis. The first case, a 72-year-old man with myelodysplastic syndrome being treated with low-dose cytarabine, died of sudden cardiac arrest. An autopsy revealed disseminated zygomycosis accompanied with occlusion of the coronary artery by fungal thrombi. The second case, a 52-year-old woman with acute lymphoblastic leukemia, developed febrile neutropenia and skin eruptions with induration on the face and extremities during the first induction chemotherapy. She experienced sudden bradycardia with unstable hemodynamics and died of acute myocardial infarction. Histological examination of a skin biopsy demonstrated zygomycosis. In light of the above, it should be kept in mind that cardiac zygomycosis might occur in hematologically compromised patients presenting with acute myocardial infarction., Article, INTERNAL MEDICINE. 47(9):839-842 (2008)

To identify the role of transformed mesangial cells (MC) during glomerular remodeling, anti-thymocyte-1 (Thy1) nephritis; modified Thy1 nephritis (injections of anti-Thy1 antibody four times, weekly); and Thy1 nephritis treated with signal transduction inhibitor 571 (Thy1 + STI); were analyzed. At week 1 the index of MC proliferation in modified Thy1 nephritis and in mesangiolysis in Thy1 + STI nephritis was highest among the three models. From week 4, the index of alpha-smooth muscle actin (alpha-SMA) was significantly higher in modified Thy1 nephritis than the other two models. Production of the mesangial matrix including type IV collagen was increased in modified Thy1 but inhibited in Thy1 + STI nephritis. In contrast to modified Thy1 nephritis, the capillary numbers in glomeruli recovered to normal at week 4 in Thy1, and at week 8 in Thy1 + STI nephritis. At week 12, both the adhesive and sclerotic index was significantly higher in modified Thy1 than in the other two models. Data suggest that a moderate amount of mesangial matrix results in a complete repair of capillary loops. Overproduction of the mesangial matrix retards capillary remodeling and finally induces glomerulosclerosis. Insufficient mesangial matrix delays the repair of capillary loops. In conclusion, transformed MC may influence glomerular remodeling by changing the amount of mesangial matrix.

To clarify the relationship between macrophages and development of glomerulosclerosis, the authors developed a new experimental nephritis model with macrophages persisting in Thy-1 nephritis. Methyl-cellulose was administered intraperitoneally in addition to the intravenous injection of the anti-Thy-1 antibody to Wistar rats. Foamy macrophages influxed into the lytic mesangium and stayed to form nodular aggregates. Mesangial cells proliferated with the formation of extracellular matrices around these nodular aggregates of macrophages. Immunohistochemical analyses revealed that alpha-smooth muscle actin (alpha-SMA) was expressed in the proliferative area around these nodules of foamy macrophages from day 7. Type I collagen and type IV collagen were also expressed around the foamy macrophages in correspondence with alpha-SMA expression from day 7. The electron microscopic study revealed that collagen fibrils were formed around the transformed mesangial cells. The expression of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), a marker of glomerular vasculature endothelial cells, was not found in the area occupied by the foamy macrophages, suggesting the impairment of glomerular reconstruction. Macrophages may participate in the progression of glomerulosclerosis in Thy-1 nephritis by enhancing the production of the extracellular matrix through transformed mesangial cells and preventing reconstruction of the capillary network.

We present a case of a 30-year-old man who received an ABO-incompatible renal transplant from his mother in 1996 after haemodialysis for 3 years. Although his renal function was stable, a renal biopsy was performed while he was in hospital for treatment of herpes zoster in 1999. Light microscopy provided no evidence of obvious acute or chronic rejection but a double contour pattern was observed in many tubular basement membranes (TBM). Immunofluorescence microscopy revealed deposits of IgG and C3 on the TBM in the absence of glomerular deposition. Massive electron-dense deposits were observed clearly by electron microscopy within TBM, revealing splitting and lamellation. This implies that the deposits resulted from the formation of immune complexes, but not from anti-TBM antibody. Although the role of TBM deposits in tubular injury is controversial, careful observation of patients with such deposits may be required because of their potential ability to induce immune reactions.

SUMMARY: Mesangial cells show phenotypic changes such as that of glomerular differentiation at the fetal stage in various nephropathies, including IgA nephropathy. Such a process seems necessary for reparative or regenerative reactions in post-inflammatory or post-injury glomerular tissues, particularly for the rearrangement of glomerular capillary networks. Glomerular sclerosis may be the end result of failure or maldevelopment of this phenotypic glomerular transformation.

背景:皮膚原発のアポクリン癌はまれで, さまざまな抗体を用いることにより組織学的診断が可能であるが, 細胞所見の報告は少ない.われわれは腋窩部原発アポクリン癌の2例を経験し, その細胞学的特徴を検討した.症例:症例1は49歳男性で5年前に左腋窩部腫瘍摘出術を受けたが, 局所再発をきたした.吸引細胞診ではほとんどが孤立散在性で, 一部に上皮性細胞集塊が含まれていた.腫瘍細胞は細胞質が厚くて広く, 断頭分泌を認めた.組織学的には充実性, 索状および腺管状構造を示し, 腫瘍細胞の細胞質は広く好酸性で, 断頭分泌, ジアスターゼ抵抗性PAS陽性顆粒が認められた.GCDFP-15が陽性であった.症例2は53歳の男性で, 15年前に左腋窩部腫瘤の診断を受け, 摘出術が施行された.リンパ節の擦過細胞診では比較的重積性の少ない上皮性細胞集塊が主体で, 腫瘍細胞は大型で広い細胞質, 円形から卵円形の偏在核と明瞭な核小体を持ち, 断頭分泌が認められた.組織学的には潰瘍を形成し, 腺管形成を伴い皮下脂肪織まで浸潤していた.細胞質は広く好酸性で断頭分泌が認められ, ジアスターゼ抵抗性PAS陽性顆粒を含んでいた.GCDFP-15が陽性であった.結論:腋窩部に発生するアポクリン癌は汗腺あるいは副乳由来のアポクリン癌や転移性腺癌が鑑別となる.皮膚原発アポクリン癌は細胞診でも特徴的な像を保持しており, 詳細な検討によって推定診断が可能であると考えられた.

Article, ACTA DERMATO-VENEREOLOGICA.94(6):737-738(2014)

To elucidate the relationship between histological disease states and clinicopathological features in immunoglobulin A nephropathy (IgAN), 90 needle-biopsy specimens diagnosed as IgAN were analyzed. The specimens were divided into four groups according to histological grade and stage index. Immunohistochemical features of alpha-smooth muscle actin (alpha-SMA), macrophages positive for myeloid/histiocyte antigen (MAC387), and expression of type I, III and IV collagens were all examined. Glomerular expression scores of alpha-SMA and the degree of intraglomerular macrophage infiltration were highest in the active and non-sclerotic groups. Type I and IV collagens were significantly more abundant in the sclerotic groups than in the active groups. Type III collagen was strongly expressed in both the active and sclerotic groups. Double immunolabeling of alpha-SMA and intercellular adhesion molecule (ICAM)-1 revealed that ICAM-1 was expressed around the alpha-SMA-positive mesangial area. In multivariate analysis, the glomerular expression score of alpha-SMA was mostly correlated with histological grading in the 10 clinicopathological parameters. Type IV collagen score was mostly correlated with histological staging. These results suggest that glomerular alpha-SMA expression reflects the histological activity of IgAN. Immunohistological staining of alpha-SMA is valuable to estimate the degree of disease activity in IgAN.

The relationship between mesangial cells (MC) and endothelial cells (EC) in the remodeling of glomerular capillary loops was investigated in a rat model of anti-Thy-1 antibody (Ab)-induced glomerulonephritis. Immunohistochemical analysis showed that cells positive for alpha-smooth muscle actin (alpha-SMA) appeared in the mesangial stalks at day three, and had increased in number at day seven, after injection of Thy-1 Ab. Double staining for alpha-SMA and proliferating cell nuclear antigen (PCNA) showed that some MC expressing PCNA were negative for alpha-SMA at day three, but by day seven almost all PCNA-positive MC expressed alpha-SMA. Western blotting for alpha-SMA from isolated glomeruli was negative at day one after injection of Thy-1 Ab, but positive at day seven. Type III collagen appeared at day seven, followed by an increase of EC in the capillary loops, as determined by double immunofluorescent staining for rat endothelial cell antigen-1 (RECA-1) and type III collagen. RECA-1-positive cells increased rapidly in number after day seven and eventually showed the same distribution pattern as that in control rats. Both type I and type III collagens were expressed in the mesangial and the ballooning area of the glomerulus at day seven. Electron microscopy revealed that immature MC and EC forming small capillary lumina appeared in the enlarged mesangial area at day seven. In accordance with the increase of capillaries and the enlargement of the lumina, the number of MC and the amount of mesangial matrix decreased gradually, and most of the glomeruli returned to a normal structure by week 4. These data show that type I and type III collagen produced by transformed MC may be of benefit to proliferation of EC and remodeling of the capillary in Thy-1-induced nephritis.

Localization of calmodulin, a calcium binding protein, was identified in adult gerbil cochleas using paraffin section immunohistochemistry and immunogold electron microscopy with monoclonal antibody against bovine calmodulin. Immunoreactive calmodulin was abundant in inner hair cells (IHCs), outer hair cells (OHCs) and Boettcher cells of the cochleas. Other cell types containing calmodulin were marginal cells and basal cells of the stria vascularis, fibrocytes in the spiral ligament, spiral ganglion neurons and vascular smooth muscle cells. Immunogold labeling for calmodulin was observed in cuticular plate, stereocilia, and within cytoplasm of IHCs and OHCs. In OHCs the labeling was mostly observed in the region underlying lateral wall corresponding to subsurface cisterna. In IHCs the staining was diffuse in the cytoplasm and denser than that in OHCs. Boettcher cells showed dense staining along the microvillous projections facing to the intercellular spaces between Boettcher cells and Claudius cells and between the neighboring Boettcher cells. These distributions of calmodulin in the hair cells consist with the assumption that IHCs act as a true neurotransducer and OHCs as an active bi-directional mechanotransducer. The rich presence of calmodulin in Boettcher cells suggests that the cells may involve in mediating Ca(2+) regulation and play a distinctive active role in ion transport.

Background —P-selectin plays key roles in mediating inflammation through promoting adherence of leukocytes to activated platelets and endothelium. This process is one of the initial events in atherosclerosis and restenosis after coronary angioplasty. Methods and Results —Using a rat balloon-injury model, we examined the role of P-selectin in vascular inflammatory processes. In the acute phase, immunohistochemistry revealed that P-selectin was intensely expressed on both activated platelets covering the denuded segment and endothelial cells of the inflamed adventitial small vessels. Treatment with an anti–P-selectin monoclonal antibody (MAb) for 8 consecutive days significantly inhibited neointimal formation at day 14 (42% inhibition; P P Conclusions —These results suggest that inhibition of P-selectin–mediated leukocyte recruitment prevents the development of neointimal formation, adventitial inflammation, and vascular shrinking and promotes pseudoendothelialization by luminal smooth muscle cells. This treatment thus beneficially affects vascular remodeling after balloon injury in rats.

食道原発の小細胞癌の1例を報告する. 症例は78歳女性, 嚥下時の胸部違和感を主訴に受診した. 中央に浅い潰瘍を形成する中部食道後壁のポリープ状の隆起性病変を認め, 外科的切除術が行われた. 腫瘍の捺印細胞診では, 細胞相互の結合性は弱く, 胞体の乏しい裸核状の異型細胞が散在性に出現し, 境界不明瞭な重積性のある細胞集塊や一部ではロゼット状構造を示す部位を認めた. 核は円形ないし楕円形で, クロマチンは細顆粒状で著明に増量し, 肺の小細胞癌と同様の所見であった. 組織学的には, 大部分は核の濃染した小型の腫瘍細胞から成り, 免疫染色ではクロモグラニンAが陽性で, 電顕では細胞質内に限界膜を有した高電子密度分泌顆粒を認めた. 腫瘍の一部には, 角化を伴う重層扁平上皮への分化と基質の硝子化を伴った基底細胞への分化を示す領域を認め, 類基底細胞-(扁平上皮) 癌への分化を伴ったまれな小細胞癌の症例であった. 生検標本では挫滅が強くリンパ球との区別が困難であったが, 食道における小細胞癌の存在さえ念頭におけば, 腫瘍の捺印細胞像が組織型の推定に非常に有効と考えられた.

Summary: Serum sickness nephritis was induced in young (3 weeks old) and old (50 weeks old) Fischer rats by immunization with egg albumin, and the age-related clinicopathological differences were analyzed. At least four differences were recognized between the young and old nephritis rats. First, the induced proteinuria was transient in the young group, but persistent in the old group and second, intramembranous electron dense deposits (IMEDD) in the thickened glomerular basement membrane were characteristic in the old group by electron microscopic observation. Third, the peripheral distribution of immune complexes in glomemlus was much more dominant in the young group. Fourth, the accumulation of monocytes was more prominent in the young group. These findings support the following suggestions: (i) in the ageing rats, there may be lowered efficiency of turnover of the extracellular matrix and the decreased ability of the mononuclear phagocyte system function; (ii) these changes may be responsible for the delayed clearance of the immune complexes from the glomerulus, and (iii) the longstanding presence of IMEDD observed in the ageing rats may play a role in persistent proteinuria.

A case that revealed the clinical and histologic features of superantigen-related nephritis and hemolytic uremic syndrome is reported. The patient was admitted with purulent arthritis due toStaphylococcus aureus infection, and showed rapidly progressive glomerulonephritic syndrome Clinical and histologic findings were similar to those of cases of superantigen-related nephritis previously reported, but our case had histologic evidence of various endothelial damage resembling that of hemolytic uremic syndrome. We suggest that such hemolytic uremic syndrome-like lesions may be one of the features of superantigen-related nephritis.

Background The organ of Corti in the mammalian cochlea develops from a simple epithelium into a complex structure consisting of as many as ten highly specialized cell types. The purpose of the present study was to examine the possible role of a cell adhesion specific molecule (A-CAM) in mediating morphogenesis of the organ of Corti. Method The expression of A-CAM was studied in a series of inner ears collected from neonatal gerbils at two days intervals from 0 to twenty days after birth. Immunostaining was performed with a mouse monoclonal antibody raised against A-CAM isolated from chicken cardiac muscle. Results The adhesion molecule appeared just prior to opening of the tunnel of Corti and disappeared after full expansion of tunnel space. A-CAM was detected in the basal turn of the cochlea as early as two days after birth and its expression moved progressively toward the apex of the cochlear spiral. It was observed in all three cochlear turns at eight days after birth but disappeared after postnatal day twelve. Immunostaining for A-CAM was localized only to the region where inner and outer pillar cells separate to form the tunnel of Corti. Conclusions A-CAM apparently plays a role in the formation of the tunnel space by modulating apical adhesion above the separation between inner and outer pillar cells.

To assess the effect of chemotherapy plus bevacizumab on tumor vessels, as well as the reversibility of this effect, using contrast-enhanced ultrasonography (CEUS) and histology in patients with metastatic liver tumors derived from colorectal cancer.The study included 12 patients who received chemotherapy plus bevacizumab, experienced a reduction in tumor vascularity as demonstrated by CEUS and consequently underwent liver resection. CEUS was performed before and after four courses of chemotherapy and before surgery. The numbers of microvessels highlighted by anti-CD34 antibodies in the viable tumor tissue were counted to quantify the microvessel density (MVD). As a control, 12 surgical specimens from 12 patients who had not received chemotherapy were examined.A reversal of tumor vascularity was observed in 10 of 12 patients. In two patients, the vascularity remained reduced. The MVD in the treatment group was significantly lower than that observed in the group without treatment.The data suggest that the tumor vessels regenerated substantially, although the effect of chemotherapy plus bevacizumab remained weak for approximately 6 weeks after the cessation of treatment. Therefore, future research must determine whether bevacizumab should be used prior to surgery.

In murine chronic graft-versus-host reaction (GVHR), the immune complex composed of antoantibodies has been considered to induce human lupus-like nephritis. We prepared the replica membranes and immunoelectron-microscopic specimens of glomeruli of GVHR mice. The immunoelectron-microscopic examination revealed that immune deposits were noted mainly in the mesangial matrices and subepithelial area. The replica membranes showed various sizes of the deposits in the same portions. Moreover, fine fibrils around the deposits were strongly disrupted. Microfilaments were increased in the cytoplasm of podocytes and endothelial cells were slightly detached from glomerular basement membrane. In this model system, the immune deposits might play an important role in keeping the glomerular integrity.

Chronic serum sickness nephritis was induced in rats by sensitization with egg albumin. The glomeruli were then examined by the quick-freezing and deep-etching method with immunohistochemical identification of immune complex deposits on replica membranes. In control rats, the glomerular basement membrane showed a three-layered structure. The middle layer was composed of a compact meshwork of fine fibrils that was connected to adjacent endothelial and epithelial cells by perpendicular fibrils in the inner and outer layers. The mesangial matrix contained a similar but looser meshwork structure. In the nephritic rats, small granular deposits were observed within the meshwork, distorting its fine structure. Larger nodular aggregates extended continuously from the middle layer to the epithelial side. Disruption of the connecting fibrils overlying these larger aggregates was noted. The deposits were stained by antiegg albumin or antirat IgG antibodies. Gold particles immunostaining for the sensitizing antigen were also localized within the deposits. These findings suggest that the deposition of immune complexes occurs in the fibrillary meshworks of the mesangium and lamina densa in this experimental model, with the resultant distortion of their meshwork structures and the formation of nodular aggregates.

Herein, we encountered an 89-year-old woman with pancreatic cancer who presented with fever without infective focus, leukocytosis of 45,860/mu L, and elevation of serum granulocyte-colony stimulating factor (G-CSF). The patient could not receive any curative therapy due to an extremely aggressive clinical course. Specimens taken at necropsy revealed an adenosquamous carcinoma positive for G-CSF by immunohistochemistry; it was only the second reported case to date. She was finally diagnosed with G-CSF-producing pancreatic cancer. In light of the above, clinicians should consider the presence of G-CSF-producing tumors, including pancreatic cancer, when presented with patients showing leukocytosis of unknown origin and fever without infective focus., Article, INTERNAL MEDICINE. 48(9):687-691 (2009)

Alterations in glomerular basement membrane (GBM) anionic sites associated with immune deposits (ID) were observed using polyethyleneimine (PEI) as a cationic probe in serum sickness nephritis induced by egg albumin (EA). The anionic sites were fewer in number than in other GBM segments and were irregular in distribution in most, but not all, of the segments of the GBM with ID on the epithelial side of the lamina densa (LD). The disappearance of anionic sites was obvious in areas where the internal aspects of the lamina rara externa (LRE) of the GBM were occupied by ID, even if the ID were very small. In contrast, the disappearance of anionic sites was not evident, even though no change in anionic sites was found in some areas, where the ID had departed from the internal aspects of the LRE and a pale band was seen between the ID and the LD. Further, PEI aggregates, showing localization of anionic sites, were seen within the low density ID, but no PEI aggregates were seen within the high density ID. The results suggest that: 1) whether or not ID induce the disappearance of anionic sites is independent of the size of the ID, but is dependent on the density of and the place occupied by the ID, and 2) the ID seem to induce the disappearance of anionic sites by masking rather than destroying them.

The three-dimensional ultrastructure of glomerular sclerosis in the chronic phase of Masugi nephritis was investigated using a quick-freezing and deep-etching method. Newly formed mesangial matrix, which was increased in the axial portions, was composed of fine fibrillar networks similar to those in the lamina densa of the basement membrane. These fibrils were 10-20 nm in diameter and directly attached to the cell membranes of mesangial cells, endothelial cells and podocytes by connecting fibrils. Moreover, thicker fibrils with diameters of 20-30 nm were present in the networks and were connected with cross-bridges. A newly formed matrix of fine fibrillar networks was also seen in the areas of mesangial interposition in the glomerular capillary wall. The border between the matrix and lamina densa was unclear. The fibrils organizing the networks of lamina densa of the glomerular loop were thickened, with some decoration. Connecting fibrils were disrupted in the areas of endothelial detachment. It is suggested that prolonged tissue injury with endothelial detachment might induce mesangial sclerosis composed of fine fibrillar networks. The increase in density of the networks seemingly interfere with the contractile function of mesangial cells, which is followed by alteration of mesangial flow.

Cutaneous Epstein-Barr virus (EBV)-associated B-cell lymphoma (EBVBL) in non-immunocompromised patients is very rare. Here, we report a case of cutaneous EBVBL in a 72-year-old Japanese woman without any signs of immunosuppression. She showed repeated high fever and skin eruptions on the face, limbs and palms. Histological diagnosis was diffuse large B-cell lymphoma. EBV infection was detected by in situ hybridization and Southern blotting. Immunostaining for viral proteins showed the patient to be positive for latent membrane protein 1 (LMP-1) and negative for Epstein-Barr virus nuclear antigen-1 (EBNA-2), indicating that a type II latency EBV infection pattern.

We report a case of nonocclusive mesenteric ischemia (NOMI) which occurred in a patient with torsion of gallbladder. A 91-year-old woman was admitted to the hospital and was diagnosed of acute cholecystitis. The next day, she went into shock. Then, we diagnosed her illness as torsion of gallbladder by computed tomography and ultrasonography, and performed an emergency operation. After cholecystectomy, it was recognized that the wide range of the small intestine had become necrotic sporadically. We diagnosed it as NOMI, and performed the wide resection of the small intestine followed by making double stomas. There is no previous report of NOMI associated with torsion of gallbladder. We guess the cause of NOMI in this case would be dehydration because of gallbladder torsion. NOMI has high mortality. Early diagnosis and early treatment are of great importance in NOMI.

We present a case of a 30-year-old man who received an ABO-incompatible renal transplant from his mother in 1996 after haemodialysis for 3 years. Although his renal function was stable, a renal biopsy was performed while he was in hospital for treatment of herpes zoster in 1999. Light microscopy provided no evidence of obvious acute or chronic rejection but a double contour pattern was observed in many tubular basement membranes (TBM). Immunofluorescence microscopy revealed deposits of IgG and C3 on the TBM in the absence of glomerular deposition. Massive electron-dense deposits were observed clearly by electron microscopy within TBM, revealing splitting and lamellation. This implies that the deposits resulted from the formation of immune complexes, but not from anti-TBM antibody. Although the role of TBM deposits in tubular injury is controversial, careful observation of patients with such deposits may be required because of their potential ability to induce immune reactions.

Growing evidence obtained from human genomic analysis and antigen-challenged transgenic mice suggests that interleukin-9 (IL-9) is a candidate factor in immunoglobulin E (IgE) production and thus is thought to be associated with bronchial inflammation and bronchial hyperresponsiveness (BHR). To evaluate the expression of the IL-9 receptor and its effect on the IL-9 human bronchial cell line BEAS-2B cells, reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemical investigation, and chemotaxis assay were performed. The components of the IL-9 receptor, consisting of IL-9 receptor alpha (CD129) and IL-2 receptory ((1)132), were expressed on BEAS-2B cells as determined by RT-PCR and flow cytometry. BEAS-2B cells exposed to IL-9 released neutrophil chemotactic activity (NCA) in a time- and dose-dependent manner, and the presence of granulocyte colony-stimulating factor (G-CSF) was also detected. This factor is primarily involved in NCA for the measurement of cytokines and in the inhibition assay of neutrophil chemotaxis. These findings suggest that bronchial epithelial cells may express IL-9 receptors, and that IL-9 may induce airway inflammation through the release of G-CSF from bronchial epithelial cells.

Background. Hemophagocytic syndrome (HPS) is a serious hematological disorder caused by activated T lymphocytes in immunologically compromised patients. There is no report of HPS in liver transplant recipients. Methods. Among 135 patients who underwent living-related liver transplantation between June 1990 and October 2000, HPS developed in two pediatric patients (1.5%) on the 15th and 134th postoperative day, respectively. The courses of these patients were evaluated. Results. The cause of HPS was unknown in patient 1 and suspected to be Epstein-Barr virus infection in patient 2. The course of patient 2 was also complicated by posttransplant lymphoproliferative disorder. Both patients had high fever, pancytopenia, coagulopathy, and marked elevation of serum-soluble interleukin 2 receptor, serum ferritin, and urine β2-microglobulin levels. The diagnosis was established based on clinical findings, laboratory data, and bone marrow biopsy. Both patients died in an acute course despite intensive care. Conclusions. HPS should be recognized as a severe hematological complication in liver transplant patients. Prompt institution of adequate treatment is necessary to prevent fatality.

A 13-year-old girl developed lupus nephritis and Hashimoto thyroiditis in the chronic phase of juvenile myelomonocytic leukemia (JMML). At age 7 months, she was diagnosed as having JMML based on the hepatosplenomegaly, leukocytosis, thrombocytopenia, increased levels of fetal hemoglobin, and spontaneous in vitro growth of granulocyte-macrophage progenitors. At the onset of JMML, she had hypergammaglobulinemia, antinuclear antibodies, rheumatoid factors and anti-smooth muscle antibody. She had been placed on oral 6-mercaptopurine for about 12 years, with clinical improvement. At age 13 years, she was found to have hematuria and proteinuria. She also developed arthritis and Raynaud's phenomenon as well. She had antinuclear antibodies, rheumatoid factors, LE phenomenon, beta-1C (C3) nephritic factor (C3NeF), antithyroid antibodies, and hypocomplementemia. The renal biopsy specimens revealed a diffuse increase in the mesangial cells and matrix by light microscopy, and intense staining of IgG, Clq and C3 by immunofluorescence microscopy. The hormonal study ultimately showed decreased thyroid functions. So she was diagnosed as lupus nephritis and Hashimoto thyroiditis. The patient is the first example to show close relationship between stem cell abnormalities in JMML and development of overt autoimmune disorders.

An asymptomatic 43-year-old female was admitted to the Hospital because of an abnormal nodule in the left lung field on screening chest X-ray. Chest CT showed a tumor shadow mass (4 x 3 cm) in the left lower lobe. Bronchofiberscopy revealed an endobronchial polypoid mass obstructing the lower lobe bronchus at the orifice of left B10. Lt lower lobectomy was performed. Histopathological examination of the specimen showed the tumor (4.5 x 3.6 x 3.6 cm) developing not only within the tracheal lumen, but also in the lung tissue. Because immunohistochemical staining for desmin and alpha-smooth muscle actin was positive, we diagnosed leiomyoma. As MRI revealed multiple uterine masses after operation, we discussed the diagnostic problems in the relation to metastasizing leiomyoma of the uterus.

A case of membranous nephropathy, preexisting in a donor kidney, will be reported. A 41-year-old man underwent a cadaver renal transplantation. An allograft biopsy specimen obtained during the operation showed spike formation on periodic acid-silver methenamine staining and deposition of IgG along the glomerular capillary loop on immunoperoxidase staining. Immunofluorescence staining for IgG remained in the specimens obtained on day 11 and after 4 weeks, but markedly decreased in the specimen obtained 7 weeks after transplantation. Electron-dense deposits also decreased in amount, but irregular thickening of the glomerular basement membrane with spikes, electron-lucent washout lesions, and small amounts of electron-dense deposits remained 20 months after the transplantation. These findings suggest that membranous nephropathy, as well as IgA nephritis and diabetic nephropathy, resolve after renal transplantation and that deposition of IgG markedly decreases within a few months after transplantation, but that complete histological restoration of the basement membrane needs at least a few years.

A case of sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a cadaver renal transplant recipient is reported in this article. The patient underwent a kidney transplant at the age of 43 and was treated with various immunosuppressive agents after surgery. Twelve months after the transplantation, multiple tumors were found in the liver, and the patient died 8 months later. Pathological examination at autopsy revealed renal cell carcinoma with a sarcomatoid component in the right native kidney and metastases to liver and bones. It is unusual for renal cell carcinoma to undergo sarcomatous transformation and to metastasize to the liver before reaching other organs. We speculate that immunosuppressants may have altered malignant cell proliferation, invasion, and the form of metastasis in this case.

The distribution of actin in the lateral wall of the cochlear duct was investigated in the gerbil, rat, mouse and hamster. A monoclonal antibody specific for muscle alpha and gamma actins, and a polyclonal antiserum reactive with smooth muscle gamma and non-muscle beta actins yielded strong immunostaining of basal cells in the stria vascularis and of smooth muscle cells in lateral wall blood vessels. Both cell types stained in all four genera. Diffuse cytosolic staining was observed along the full-length of the basal cell layer including the blunt cell processes which they extend toward strial marginal cells. Immunoreactive basal cells appeared continuous with morphologically similar cells investing vessels penetrating the stria from the spiral ligament. The basal cells failed to bind antibodies to smooth muscle alpha actin and sarcomeric actin. By electron microscopic immunocytochemistry, gold labeling for actin was observed on dense, fine fibrils in the cytoplasm of the basal cells. In paraffin sections adjacent to those stained for actin, antibody to vimentin stained intermediate and basal cells in the stria vascularis whereas antibody to isoform 1 of the facilitated glucose transporter protein family (GLUT1) labeled only the non-overlapping apical and basal plasmalemma of basal cells. Content of vimentin, GLUT1 and muscle gamma actin supports the derivation of basal cells from mesoderm. The presence of stress fibers containing muscle gamma actin points to a possible contractile activity of basal cells which conceivably could be related to transport of K+ to and within the intrastrial compartment or regulation of blood flow in the stria vascularis.

The transport enzyme Na,K-ATPase has been localized to several different cell types within the inner ear by enzyme cytochemistry, immunohistochemistry, and in situ hybridization. Although these histochemical procedures have provided a fairly consistent pattern of the enzyme's distribution, the precise location of Na,K-ATPase in the cell membrane of some polarized and non-polarized cell types remains uncertain. We addressed this problem in the gerbil cochlea using electron microscopic immunogold cytochemistry. The results confirmed prior ultrastructural localization of Na,K-ATPase along the basolateral plasma membrane of strial marginal and outer sulcus epithelial cells but differed from a previous report in failing to detect the enzyme at the surface of strial intermediate cells. The findings also concurred with and extended previous work in showing immunogold labeling along the entire cell membrane of non-polarized Type II fibrocytes in the inferior portion of the spiral ligament and of subpopulations of fibrocytes in the suprastrial and supralimbal regions. Our observations agreed further with light microscopic immunostaining in displaying uniform gold labeling for Na,K-ATPase in the neurilemma of Type I spiral ganglion neurons, even though these cells are completely ensheathed by myelin. Surprisingly, the enzyme was detectable in the neurilemma of afferent but not that of efferent nerve processes beneath hair cells.

The relationship of selected cytoskeletal elements with the rosette complex of Deiters cells was examined immunocytochemically in the gerbil cochlea. By light microscopy, the staining pattern for actin in the apical portion of Deiters cells corresponded with the location of the rosette complex. At the ultrastructural level, the actin antibodies bound selectively at the periphery of the dense trabeculae in the center of the complex. Comparative staining with a battery of polyclonal and isoform-specific monoclonal antibodies revealed selective presence of the gamma muscle actin isoform in this location. The loose meshwork at the periphery of the rosette complex stained selectively with a monoclonal antibody to vimentin. beta-tubulin was not associated with the rosette complex but occurred in abundance in the microtubule-rich stalk. Actin and vimentin were not detected in the apical compartment of Deiters cells at the extreme base of the cochlea, thus confirming their association with the rosette complex which is not present in regions of the gerbil cochlea tuned to frequencies of 20 kHz or higher (Spicer and Schulte, 1993, 1994). The cytoarchitecture of the rosette complex and its preferential distribution along the place-frequency map promote speculation that Deiters cells may play a role in regulating ion homeostasis and/or micromechanical response properties of the organ of Corti.

The fifth isoform from the family of facilitative glucose transporters (GLUT5) was identified in the gerbil cochlea by light and electron microscopic immunohistochemistry. The immunostaining procedure employed a polyclonal antibody raised against a synthetic peptide representing the carboxy terminus of human GLUT 5. Immunoreactive GLUT 5 was abundant in the basolateral plasma membrane of outer hair cells (OHCs) in the mature gerbil cochlea. No immunostaining was observed in any other site in the cochlea or vestibular system. During postnatal development of the gerbil inner ear, OHCs were first observed to express GLUT 5 in a punctate pattern at 10 days after birth. Immunostaining intensity increased gradually and developed a linear pattern along the entire OHC basolateral plasmalemma between 10 and 16 days after birth when it approached adult levels. The developmental expression of GLUT 5 corresponded with the appearance of glycogen in OHCs and structural maturation of the organ of Corti. This time period also coincided with the onset and rapid maturation of auditory function in the gerbil. GLUT 5 apparently supports OHC function by facilitating uptake of glucose which enables these cells to sustain a high level of metabolic activity in a relatively anaerobic environment.

In order to examine the effect of prolonged sensitization on glomerular injury, serum sickness nephritis was induced in Fischer rats by administration of egg albumin (EA). Animals were divided into A, B and C groups with 4-week, 6-week and 6-week sensitization, respectively. The experimental results were as follows: Both group A (4 weeks) and group B (6 weeks) showed mesangial immune complex deposition with proliferation (mesangiopathic pattern), but in the latter both the size and the amount of the deposits were larger than those in the former; while group C (8 weeks) demonstrated predominant distribution of deposition along the capillary walls (membranopathic pattern). It is suggested that such conversion of deposition from mesangiopathic to membranopathic pattern after prolonged repeated sensitization may be the result of the change of the host immune response to antigen, and for the character of the antibody.

Summary Sclerosing pancreatitis is associated with raised concentrations of lgG4. We treated 22 patients with sclerosing pancreatitis, and identified and followed-up three with concomitant hydronephrosis caused by ureteral mass, later diagnosed as retroperitoneal fibrosis. We histologically examined the ureteral and pancreatic lesions of these patients and noted abundant infiltration of lgG4-bearing plasma cells in both tissues. Treatment with corticosteroids lowered serum concentrations of lgG4. lgG4 might also have a pathological role in a systemic fibrosing process that includes pancreatic and retroperitoneal lesions.