The Diagnostic Utility of IDH2 R172 Immunohistochemistry in Tall Cell Carcinoma With Reversed Polarity of the Breast.

Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic type of low-grade breast cancer, consisting of tall columnar cells with reversed nuclear polarity and characterized by frequent IDH2 mutations. We herein report 3 cases of TCCRP with sequencing analyses of the IDH2 gene and immunohistochemical examination using monoclonal antibodies (11C8B1) against IDH2 R172. IDH2 R172 mutations were detected in all 3 resected tumors (R172S in 2 tumors and R172T in 1 tumor), and the presence of these mutations was confirmed by IDH2 R172 immunohistochemistry. Tumor cells of TCCRP showed strong and diffuse staining for the antibody against IDH2 R172. In 1 case, tumor tissue from 2 core needle biopsy samples collected on different days were also immunohistochemically positive for IDH2 R172. These results indicate that IDH2 R172 immunohistochemistry is suitable for the detection of TCCRP in both resection and biopsy samples. In addition, a literature review revealed that R172S and R172T account for 76% of IDH2 mutations in TCCRP, suggesting that 11C8B1, which reacts with R172S and R172T, was likely most sensitive for IDH2 -mutated TCCRP among many available antibodies for IDH2 R172. Furthermore, the combination of 2 or more antibodies against IDH2 R172 could be more effective for detecting TCCRP mutation. However, it is important to note that IDH2 R172 immunohistochemistry is not absolute, because IDH2 wild type is found in a small proportion (10%) of cases, and a few cases of IDH2 -mutated TCCRP may harbor rare subtypes of R172 that are not covered by available antibodies.

[Tubulointerstitial nephritis with IgM-positive plasma cells in an elderly woman diagnosed by a renal biopsy and treated with corticosteroid therapy].

An 81-year-old female was referred to our department 1 year ago due to a worsening renal function. Her manifestations met the criteria of Sjögren syndrome, suggesting renal failure likely resulting from tubulointerstitial nephritis (TIN) due to Sjögren syndrome. However, at her request, she was followed up with no further investigation or treatment. The following July, since her renal function deteriorated again, a renal biopsy was performed. Using IgM-CD138 dual staining, the renal pathology showed the infiltration of accumulated IgM-positive plasma cells within the renal insterstitium, so she was diagnosed with tubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN).IgMPC-TIN, proposed by Takahashi et al. in 2017, as a type of TIN, is characterized by the pathological infiltrations of IgM-positive plasma cells within the renal insterstitium and is effectively treated with corticosteroid therapy. Despite her old age, corticosteroid therapy was performed, resulting in the improvement in her renal function according to blood and urine tests and an improved pulmonary involvement, although renal dysfunction remained.Elderly patients often have multiple underlying medical conditions and take numerous medications, so differentiating renal disorders is challenging. However, a renal biopsy, even in an elderly patient, can aid in identifying the cause of renal disorders and predicting the prognosis. IgMPC-TIN is a condition in which renal function can be expected to improve if treated. It is thus important to make a diagnosis of IgMPC-TIN without overlooking and to consider proper treatment.

Evidence of both foetal inflammation and hypoxia-ischaemia is associated with meconium aspiration syndrome.

Foetal hypoxia-ischaemia is a key trigger of meconium aspiration syndrome (MAS). However, many neonates develop MAS without evidence of hypoxia-ischaemia, suggesting the presence of covert but important risk variables. We evaluated the association of MAS with clinical variables, placental histopathologic findings, and inflammatory biomarkers at birth. Of 1336 symptomatic and asymptomatic term singleton neonates with meconium-stained amniotic fluid, 88 neonates (6.6%) developed MAS. Univariate analysis showed that MAS development was associated with low 1- and 5-min Apgar scores, low cord blood pH, funisitis, higher α1-acid glycoprotein levels, and higher haptoglobin levels (all p < 0.001 except for p = 0.001 for haptoglobin). Associations of MAS with caesarean delivery (p = 0.004), premature rupture of the membranes (p = 0.006), chorioamnionitis (p = 0.007), and higher C-reactive protein levels (p = 0.008) were lost when adjusted for multiple comparisons. The final multivariate model to explain MAS development comprised lower cord blood pH (odds ratio [OR] 0.58; 95% confidence interval [CI] 0.47-0.73; p < 0.001), funisitis (OR 2.45; 95% Cl 1.41-4.26; p = 0.002), and higher α1-acid glycoprotein levels (OR 1.02; 95% Cl 1.01-1.03; p = 0.001). Our data from a large cohort of neonates suggested that intrauterine inflammation is one of the key independent variables of MAS development, together with foetal hypoxia-ischaemia.

Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature.

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is a life-long, autoinflammatory disease associated with a gain-of-function mutation in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3 (NLRP3) gene, which result in uncontrolled production of IL-1ß and chronic inflammation. Chronic infantile neurologic cutaneous and articular (CINCA) syndrome/neonatal-Onset multisystem inflammatory disease (NOMID) is the most severe form of CAPS. Although the first symptoms may be presented at birth, there are few reports on the involvement of the placenta and umbilical cord in the disease. Therefore, we present herein a preterm case of CINCA/NOMID syndrome and confirms intrauterine-onset inflammation with conclusive evidence by using fetal and placental histopathological examination. CASE PRESENTATION: The female patient was born at 33weeks of gestation by emergency caesarean section and weighted at 1,514 g. The most common manifestations of CINCA/NOMID syndrome including recurrent fever, urticarial rash, and ventriculomegaly due to aseptic meningitis were presented. She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis. The genetic analysis of NLRP3 revealed a heterozygous c.1698 C > G (p.Phe566Leu) mutation, and she was diagnosed with CINCA/NOMID syndrome. Further, a histopathological examination revealed necrotizing funisitis, mainly inflammation of the umbilical artery, along with focal neutrophilic and lymphocytic villitis. CONCLUSIONS: The necrotizing funisitis, which only involved the artery, was an unusual observation for chorioamnionitis. These evidences suggest that foetal inflammation, probably due to overproduction of IL-1ß, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID.

Epithelioid variant of gastrointestinal stromal tumor harboring PDGFRA mutation and MLH1 gene alteration: A case report.

Gastrointestinal stromal tumors (GISTs) are the most important and common mesenchymal tumors of the gastrointestinal tract, especially in the stomach. GISTs are usually driven by activating mutations in either KIT or PDGFRA genes. It is known that activating gene mutations predicts, to a certain extent, not only the morphology of the tumor cells but also a response to treatment with tyrosine kinase inhibitors. Here, we present a case of an epithelioid variant of GIST harboring PDGFRA and MLH1 gene alterations in the stomach of a 55-year-old Japanese woman. The tumor of 98 mm with multiple cysts showed exophytic growth from the gastric fundus. Histopathologically, it consisted of scattered medium-sized epithelioid tumor cells in a loose myxoid background. Based on c-kit and DOG-1 immunoreactivity and a PDGFRA mutation (p.Trp559_Arg560del), the tumor was diagnosed as an epithelioid variant GIST. Interestingly, it had a gene alteration (p.Met524Ile) in the MLH1 gene of unknown pathogenicity. It was assigned to Group 3a (low risk for malignant behavior). After surgery, the patient has been on imatinib therapy and disease-free for 10 months.

Pioglitazone, a Peroxisome Proliferator-Activated Receptor γ Agonist, Suppresses Rat Prostate Carcinogenesis.

Pioglitazone (PGZ), a peroxisome proliferator-activated receptor γ agonist, which is known as a type 2 diabetes drug, inhibits cell proliferation in various cancer cell lines, including prostate carcinomas. This study focused on the effect of PGZ on prostate carcinogenesis using a transgenic rat for an adenocarcinoma of prostate (TRAP) model. Adenocarcinoma lesions as a percentage of overall lesions in the ventral prostate were significantly reduced by PGZ treatment in a dose-dependent manner. The number of adenocarcinomas per given area in the ventral prostate was also significantly reduced by PGZ treatment. The Ki67 labeling index in the ventral prostate was also significantly reduced by PGZ. Decreased cyclin D1 expression in addition to the inactivation of both p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)κB were detected in PGZ-treated TRAP rat groups. In LNCaP, a human androgen-dependent prostate cancer cell line, PGZ also inhibited cyclin D1 expression and the activation of both p38 MAPK and NFκB. The suppression of cultured cell growth was mainly regulated by the NFκB pathway as detected using specific inhibitors in both LNCaP and PC3, a human androgen-independent prostate cancer cell line. These data suggest that PGZ possesses a chemopreventive potential for prostate cancer.

[Nutritional treatment for bronchopleural fistula-promising effect of arginine as a pharmaconutrient].

Pharmaconutrition, which is a supportive nutritional care of surgical patients, has been proven to shorten hospital stay, decrease the incidence of infection, and reduce hospital costs in selected groups of patients. Arginine, one of the most essential pharmaconutrients, has also been proven to enhance would healing process. In severely malnourished patients like bronchopleural fistula with resultant empyema, aggressive nutritional approach should be mandatory. And management of the fistula is also important in stabilizing the ongoing infection. Our hypothesis was that basic nutritional support enhanced with arginine would be effective in not only improving the general condition including nutritional status but also in healing the fistula. We report a case of major bronchopleural fistula in which arginine-supplemented diet as well as aggressive nutritional support could accelerate the postoperative recovery after open thoracic window, ultimately leading to the healing of the fistula.

[Perioperative nutritional support with immune-enhancing diet for surgical closure of open thoracic window].

Immunonutrition, which is a therapeutic approach to modulate acute surgical or medical conditions, has been proven to decrease surgical site complications in patients undergoing major elective surgery for upper gastrointestinal and esophageal malignancy. For immunonutrition to be carried out effectively, specific nutrients called pharmaconutrients are quite important. In our case, to enhance the perioperative nutritional status of the patient, special formulas supplemented with specific pharmaconutrients, which are arginine and omega-3 fatty acids, were orally administered. The open thoracic window for chronic empyema caused by postoperative bronchopleural fistula was successfully closed. Perioperative immunonutrition is likely to have beneficial effect in decreasing postoperative infectious complications in high-risk malnourished thoracic surgical patients.

Clinical usefulness of a prognostic score in histological analysis of renal biopsy in patients with lupus nephritis.

OBJECTIVE: To evaluate active and chronic lesions in association with renal outcome according to the International Society of Nephrology/Renal Pathology Society classification in patients with lupus nephritis. METHODS: A retrospective analysis of 99 biopsy-proven subjects with lupus nephritis from 1990 to 2006 was performed in our center using the new classification. Each histological lesion was evaluated by multivariate survival analysis as predictive factor for renal insufficiency in patients with lupus nephritis, and independent predictors were graded to develop the prognostic score based on the regression coefficient. A receiver operating-characteristic curve based on the prognostic score was plotted to determine the most appropriate cutoff point. RESULTS: In class IV, the IV-G group tended to exhibit a worse renal outcome compared with the IV-S group, but the difference was not significant (log-rank test, p = 0.4330). Independent histological predictors of poor renal outcome were extracapillary proliferation, glomerular sclerosis, and fibrous crescents analyzed by Cox proportional hazards model, while predictors of favorable renal outcome were hyaline thrombi and fibrous adhesions. By the prognostic score, renal outcome was significantly worse in the group with the higher score (> or = 0.25) than in the group with the lower score (< 0.25) in class IV patients (log-rank test, p < 0.001). CONCLUSION: These results demonstrate the advantage of our prognostic score compared to subclasses in predicting the renal outcome of class IV patients [University Hospital Medical Information Network (UMIN) clinical trials registry, number UMIN 000001943].

Telmisartan inhibits both oxidative stress and renal fibrosis after unilateral ureteral obstruction in acatalasemic mice.

BACKGROUND: Reactive oxygen species are involved in many of the angiotensin II signalling pathways. We have thus investigated whether the angiotensin II type 1 (AT1) receptor antagonist, telmisartan, can inhibit the accelerated renal fibrosis and excess oxidative stress, which occurs after unilateral ureteral obstruction (UUO) in acatalasemic mice. METHODS: The effect of daily intraperitoneal injection of telmisartan (0.1-0.3 mg/kg body weight) on the renal tubulointerstitial injury induced by UUO has been studied in homozygous acatalasemic mutant mice (C3H/AnLCs b Cs b) and wild-type mice (C3H/AnLCs a Cs a). We evaluated the systemic blood pressure of the mice on the seventh day. In addition, the tubulointerstitial expression of collagens type I and type IV, the p22-, p47- and p67-phox subunits of NADPH oxidase, 4-hydroxy-2-nonenal, and 4-hydroxy-2-hexenal lipid peroxidation products were assessed by immunohistochemistry. The level of apoptosis was determined by terminal deoxynucleotidyl transferase nick end-labelling analysis, while the mRNA level of the p22-, p47- and p67-phox subunits was quantified by real-time PCR. The renal content of each of the antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase was determined by specific assay. RESULTS: Obstructed kidneys from acatalasemic mice exhibited increased tubulointerstitial deposition in dilated tubules of collagens type I and IV, lipid peroxidation products, and the p22/p47/p67-phox subunits of NADPH oxidase. The level of the p22/p47/p67-phox subunit mRNA, and of apoptosis in tubular epithelial cells, was also increased compared with those from wild-type kidneys. Treatment with telmisartan attenuated all of the changes and prevented renal fibrosis in a dose-dependent manner; despite the low dose (0.1 mg/kg). The treatment did not lower the systemic blood pressure. The catalase activity remained low in acatalasemic obstructed kidneys without compensatory upregulation of glutathione peroxidase or superoxide dismutase activity; the level of neither anti-oxidant enzymes in obstructed kidneys was affected by telmisartan. CONCLUSIONS: The AT1 receptor antagonist telmisartan ameliorated renal fibrosis after UUO by inhibition of oxidative stress, even under acatalasemic conditions.

Catalase deficiency renders remnant kidneys more susceptible to oxidant tissue injury and renal fibrosis in mice.

BACKGROUND: Catalase is one of the important antioxidant enzymes regulating the levels of intracellular hydrogen peroxide and hydroxyl radical. The effect of catalase deficiency on progressive renal fibrosis has not been fully elucidated. METHODS: Homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) and control wild-type mice (C3H/AnLCs(a)Cs(a)) were subjected to 5/6 nephrectomy. The functional and morphological alterations of the remnant kidneys, including tubulointerstitial fibrosis, epithelial to mesenchymal transition (EMT), peroxidation, antioxidant enzyme activity, and gene expression of EMT-related molecules were compared between the two groups at 6, 12, and 18 weeks after 5/6 nephrectomy. RESULTS: The 5/6 nephrectomy resulted in albuminuria, decreased renal function, and tubulointerstitial fibrosis with accumulation of type I and type IV collagens in the remnant kidneys of both mouse groups. However, the degree of these changes was significantly higher in acatalasemic mice after 5/6 nephrectomy as compared with wild-type mice until week 18. EMT, a crucial phenotypic alteration of tubular epithelial cells, was observed in acatalasemic mice by electron microscopy and was associated with upregulation of EMT-related alpha-smooth muscle actin (alpha-SMA), transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), and fibroblast specific protein-1 (FSP-1) gene expression. Significant increases in the tubulointerstitial deposition of lipid peroxidation products, including 4-hydroxy-2-nonenal and urinary excretion of 8-hydroxy-2'- deoxyguanosine were observed in the acatalasemic mice after 5/6 nephrectomy as compared with the wild-type mice. Glomerular sclerosis developed after tubulointerstitial injury in acatalasemic mice. The level of catalase activity remained low in the remnant kidneys of acatalasemic mice until week 18 without compensatory up-regulation of glutathione peroxidase or superoxide dismutase (SOD) activity. Finally, supplementation of a SOD mimetic tempol did not prevent peroxidation and tubulointerstitial fibrosis in the acatalasemic remnant kidneys. CONCLUSION: These findings indicate that acatalasemia exacerbates renal oxidant tissue injury and sensitizes remnant kidneys to EMT and progressive renal fibrosis. This study suggests a central role for catalase in the defense against oxidant-mediated renal fibrosis.

Mesangial cell Fas ligand: upregulation in human lupus nephritis and NF-kappaB-mediated expression in cultured human mesangial cells.

BACKGROUND: Fas ligand (FasL) is a well-known death factor; however, the role of FasL in the regulation of human glomerulonephritis remains unclear. METHODS: We investigated the renal expression and localization of FasL in various forms of human glomerulonephritis by immunohistochemistry, utilizing confocal laser scanning microscopy. We further evaluated cytokine-induced FasL expression via nuclear factor (NF)kappaB in cultured human mesangial cells (HMC). The level of soluble FasL was measured by a specific enzyme-linked immunosorbent assay (ELISA). RESULTS: The frequency of glomerular FasL-positive cases was higher in lupus nephritis (37.9%) as compared with other forms of glomerulonephritis (8.7%). The glomerular FasL score in proliferative lupus nephritis was significantly higher than that in nonproliferative forms. Patients with a high apoptosis score, severe microhematuria, proteinuria, or decreased renal function had a high FasL score. Double immunolabelling demonstrated that the most prevalent phenotypes of FasL-positive cells were mesangial cells. In cultured HMC, interleukin (IL)1beta, lipopolysaccharide (LPS), or gamma interferon (IFN) upregulated membrane-bound FasL. IL1beta significantly, and LPS or gammaIFN weakly activated NFkappaB, but none of these agents activated NFkappaB/Rel-related nuclear factor of activated T cells (NFATc) or IFN regulatory factor-1. IL1beta-mediated NFkappaB was completely inhibited in the presence of lactacystin, a potent inhibitor of NFkappaB. Lactacystin-mediated inhibition of NFkappaB reduced FasL protein levels. Matrix metalloproteinase (MMP)-7, but not other MMPs (1, 2, 3, 8, or 9), significantly sensitized HMC to release soluble FasL after IL1beta stimulation. CONCLUSIONS: The results suggest that: (1) upregulation of mesangial FasL may contribute to the glomerular inflammation in proliferative lupus nephritis in vivo; (2) proinflammatory cytokines, in particular IL1beta, produced in nephritis can upregulate FasL via the transcription factor NFkappaB in HMC; and (3) MMP-7-mediated release of soluble FasL could control the mesangial inflammation.

Acatalasemia sensitizes renal tubular epithelial cells to apoptosis and exacerbates renal fibrosis after unilateral ureteral obstruction.

Tissue homeostasis is determined by the balance between oxidants and antioxidants. Catalase is an important antioxidant enzyme regulating the level of intracellular hydrogen peroxide and hydroxyl radicals. The effect of catalase deficiency on renal tubulointerstitial injury induced by unilateral ureteral obstruction (UUO) has been studied in homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) compared with wild-type mice (C3H/AnLCs(a)Cs(a)). Complete UUO caused interstitial cell infiltration, tubular dilation and atrophy, and interstitial fibrosis with accumulation of type IV collagen in obstructed kidneys (OBK) of both mouse groups. However, the degree of injury showed a significant increase in OBK of acatalasemic mice compared with that of wild-type mice until day 7. The deposition of lipid peroxidation products including 4-hydroxy-2-hexenal, malondialdehyde, and 4-hydroxy-2-nonenal was severer in dilated tubules of acatalasemic OBK. Apoptosis in tubular epithelial cells significantly increased in acatalasemic OBK at day 4. Expression of caspase-9, a marker of mitochondrial pathway-derived apoptosis, increased in dilated tubules of acatalasemic mice. The level of catalase activity remained low in acatalasemic OBK until day 7 without compensatory upregulation of glutathione peroxidase activity. The data indicate that acatalasemia exacerbated oxidation of renal tissue and sensitized tubular epithelial cells to apoptosis in OBK of UUO. This study demonstrates that catalase deficiency enhanced tubulointerstitial injury and fibrosis in a murine model of UUO and thus supports the protective role of catalase in this model.

[A case of minimal change nephrotic syndrome manifesting acute renal failure in the course of systemic lupus erythematosus].

A 51-year-old woman with systematic lupus erythematosus(SLE) associated with minimal change nephrotic syndrome(MCNS) is described. The patient was diagnosed as SLE at 33 years of age. After steroid therapy for two years, the patient's course was uneventful without therapy until June 2000, when facial erythema and facial, pretibial edema developed. On admission, proteinuria and renal dysfunction were detected. Subsequently, oliguric acute renal failure developed and hemodialysis was started. Laboratory examination showed no significant change in complements and anti ds-DNA antibody levels. Renal biopsy revealed minor glomerular abnormalities without the deposition of immune complexes. Electron microscopic examination showed foot process fusion and a vacuolar change in glomerular epithelial cells. The diagnosis of MCNS was made and administration of steroid(40 mg/day) was started. Urine volume and renal function improved after 2 weeks, and nephrotic syndrome remitted completely after 5 weeks. Although the association of SLE and MCNS is rare, the findings suggest that in the course of SLE manifesting acute ranal failure, not only lupus nephritis, but also the complication of MCNS should be considered.