Immunological features of a lung cancer patient achieving an objective response with anti-programmed death-1 blockade therapy.

The role of immune checkpoint inhibitors in metastatic lung cancer has been established in recent years and the pretherapeutic profiles of the tumor microenvironment in responders have been increasingly reported. The role of salvage surgery and the immune profiles of the posttherapeutic specimens in patients achieving an objective response have rarely been studied. We report a case of metastatic lung cancer treated by anti-programmed death-1 Ab followed by surgical resection. The immune status of the tumor was assessed, showing germinal center formation, memory B cell infiltration, and a high frequency of interferon gamma -secreting T cells.

Atypical hemolytic uremic syndrome diagnosed four years after ABO-incompatible kidney transplantation.

Atypical hemolytic uremic syndrome (aHUS) in allograft kidney transplantation is caused by various factors including rejection, infection, and immunosuppressive drugs. We present a case of a 32 year old woman with aHUS four years after an ABO-incompatible kidney transplantation from a living relative. The primary cause of end-stage renal disease was unknown; however, IgA nephropathy (IgAN) was suspected from her clinical course. She underwent pre-emptive kidney transplantation from her 60 year old mother. The allograft preserved good renal function [serum creatinine (sCr) level 110-130 µmol/L] until a sudden attack of abdominal pain four years after transplant, with acute renal failure (sCr level, 385.3 µmol/L), decreasing platelet count, and hemolytic anemia with schizocytes. On allograft biopsy, there was thrombotic microangiopathy in the glomeruli, with a cellular crescent formation and mesangial IgA and C3 deposition. Microvascular inflammation, such as glomerulitis, peritubular capillaritis, and arteriole endarteritis were also detected. A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) did not decrease and Shiga toxin was not detected. Donor-specific antibodies or autoantibodies, including anti-neutrophil cytoplasmic antibody and anti-glomerular basement membrane (anti-GBM) antibody, were negative. The patient was diagnosed with aHUS and received three sessions of plasmapheresis and methylprednisolone pulse therapy, followed by oral methylprednisolone (0.25-0.5 mg/kg) instead of tacrolimus. She temporarily required hemodialysis (sCr level, 658.3 µmol/L). Thereafter, her sCr level improved to 284.5 µmol/L without dialysis therapy. This case is clinically considered as aHUS after kidney transplantation, associated with various factors, including rejection, glomerulonephritis, and toxicity from drugs such as tacrolimus.

Central fibrous areas: changes in glomerular vascular pole lesions associated with age and disease.

PURPOSE: Central fibrous areas (CFAs) are small, hyalinotic, monotonous nodular areas observed in glomerular vascular pole lesions. We attempted to clarify the relationship between CFA formation and age in healthy kidneys and in those affected by immunoglobulin A (IgA) nephropathy. METHODS: Zero-hour biopsy specimens from living renal donors (135 cases) and IgA nephropathy biopsy specimens (67 cases) were collected retrospectively. We observed each biopsy specimen and determined the total number of glomeruli, total level of glomerulosclerosis, number of observable glomerular vascular poles, number of glomeruli with CFAs, serum creatinine level, and estimated glomerular filtration rate (eGFR). Additionally, we calculated the glomerular sclerosis rate (GSR), vascular pole appearance rate (PAR), and CFA rate (CFAR) to evaluate the relationship between these factors and patient age. RESULTS: There was a significant negative correlation between patient age and eGFR for both the zero-hour (p < 0.0001 in Spearman, p = 0.0009 in multiple regression, the same hereafter) and IgA (p = 0.0022, p = 0.0001) groups. In the zero-hour group, we observed a significant positive correlation between patient age and GSR (p = 0.0001, p < 0.0001); however, there was no such correlation in the IgA group. In both groups, there was a significant positive correlation between patient age and CFAR (zero-hour group: p = 0.0003, p = 0.0091, IgA group; p < 0.0001, p = 0.0004). The slope of the regression line of the IgA group formula was also significantly higher than that of the zero-hour group formula (p < 0.01). CONCLUSION: These findings indicate that CFA may be a useful indicator of kidney aging, especially in patients with kidney disease caused by IgA nephropathy.

Anaplastic myxopapillary ependymoma: A case report and review of literature.

BACKGROUND: Myxopapillary ependymoma (MPE) is a pathological grade I tumor that arises in the filum terminale. MPE with anaplastic features is extremely rare, and only 5 cases have shown malignancy at the time of recurrence. CASE SUMMARY: The patient (a 46-year-old woman) had undergone a MPE operation 30 years ago. After subtotal resection of the tumor located in L4-S1, it had a solid component that extended to the adjacent subcutaneous region. Histologically, the tumor consisted of a typical MPE with anaplastic features. The anaplastic areas of the tumor showed hypercellularity, a rapid mitotic rate, vascular proliferation, and connective tissue proliferation. Pleomorphic cells and atypical mitotic figures were occasionally observed. The MIB-1 index in this area was 12.3%. The immunohistochemical study showed immunoreactivity for vimentin, glial fibrillary acidic protein and S100. The morphological pattern and immunohistochemical profile were consistent with anaplastic MPE. The patient tolerated surgery well without new neurological deficits. She underwent local irradiation for the residual tumor and rehabilitation. CONCLUSION: Although extremely rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, close monitoring is recommended, given concerns about aggressive biological potential. In the future, further study is needed to determine the WHO classification criteria and genetic indicators of tumor progression. The possibility of malignant transformation of MPE should be taken into account, and patients with MPE should be treated with care and follow-up.

Reduction of renal superoxide dismutase in progressive diabetic nephropathy.

Superoxide excess plays a central role in tissue damage that results from diabetes, but the mechanisms of superoxide overproduction in diabetic nephropathy (DN) are incompletely understood. In the present study, we investigated the enzyme superoxide dismutase (SOD), a major defender against superoxide, in the kidneys during the development of murine DN. We assessed SOD activity and the expression of SOD isoforms in the kidneys of two diabetic mouse models (C57BL/6-Akita and KK/Ta-Akita) that exhibit comparable levels of hyperglycemia but different susceptibility to DN. We observed down-regulation of cytosolic CuZn-SOD (SOD1) and extracellular CuZn-SOD (SOD3), but not mitochondrial Mn-SOD (SOD2), in the kidney of KK/Ta-Akita mice which exhibit progressive DN. In contrast, we did not detect a change in renal SOD expression in DN-resistant C57BL/6-Akita mice. Consistent with these findings, there was a significant reduction in total SOD activity in the kidney of KK/Ta-Akita mice compared with C57BL/6-Akita mice. Finally, treatment of KK/Ta-Akita mice with a SOD mimetic, tempol, ameliorated the nephropathic changes in KK/Ta-Akita mice without altering the level of hyperglycemia. Collectively, these results indicate that down-regulation of renal SOD1 and SOD3 may play a key role in the pathogenesis of DN.

Isolated granulomatous gastritis showing discoloration of lesions after Helicobacter pylori eradication.

We report a case of isolated granulomatous gastritis (IGG) with a submucosal tumor and multiple ulcer scars which showed discoloration after Helicobacter pylori (Hp) eradication. Furthermore, other discolored areas were newly observed after Hp eradication in the present case. Although IGG is extremely rare, the relation between IGG and Hp infection has attracted recent attention, and some case reports of IGG with Hp eradication have appeared in the literature. Discoloration after Hp eradication, however, has never been noted in any case reports and, therefore, this feature made the present case clinically interesting.

Histopathology of castration-resistant prostate cancer confirms changes in bone metastasis during radium-223 treatment: A case report.

Radium-223 is used for treating castration-resistant prostate cancer with bone metastases. Here, we report the case of a 76-year-old man diagnosed with castration-resistant prostate cancer with bone metastases who was started on radium-223. Although the patient ultimately died from causes unrelated to the treatment before starting the third treatment course, we observed that radium-223 was more effective in areas closer to the bone cortex than in deeper tumor regions. Through histopathological analysis, we provide important mechanistic insights on the therapeutic effect of radium-223 in human prostate cancer bone metastases.

A case of bilateral multiple pulmonary chondroma: necessity of follow-up for Carney's triad.

We report a case of pulmonary bilateral multiple chondromas that were possibly an initial clinical presentation of Carney's triad. A 56-year-old Japanese non-smoking asymptomatic woman was admitted to the hospital for further examination of small, multiple, bilateral nodules in the lungs. Although chest radiological findings suggested that the nodules were possibly metastatic pulmonary tumors, the malignant origin was not detected. During diagnostic video-assisted thoracic surgery, wedge resections including the nodules were performed. Since pathological examination showed nodules were surrounded by fibrous and eosinophilic stroma, we diagnose the nodules as chondromas. These chondromas were possibly components of Carney's triad, because each nodule had a thin fibrous pseudocapsule and did not have an entrapped epithelium and fat. Some patients die of Carney's triad because of malignant alteration of lesions. Therefore, the patients with Carney's triad should be taken a medical check periodically. This patient was scheduled to undergo the check-up for several years.

[A metastatic rectal carcinoma originating from the uterine cervix].

A 40-year-old woman underwent radical hysterectomy and postoperative radiotherapy for uterine cervical squamous cell carcinoma (SCC) 6 years previously. She was referred to our department for the treatment of a rectal lesion located in the posterior wall approximately 8 cm from the anal verge. She underwent low anterior resection because the lesion was diagnosed as SCC by preoperative endoscopic biopsy. Pathological examination of the resected lesion demonstrated a 3 × 3-cm solid tumor expanding mainly in the muscularis propria layer and infiltrating the mucosal layer without lymph node involvement. Moreover, it was diagnosed as metastatic SCC from the uterine cervical tumor. No recurrence has been detected over 5 years after resection. The prognosis of SCC of the rectum without lymph node metastasis has been considered similar to that of node-negative adenocarcinoma of the rectum. Thus, if there is no distant metastasis and/or peritoneal dissemination, aggressive surgical resection should be performed to ensure a good prognosis.

Fungal granulomatous interstitial nephritis presenting as acute kidney injury diagnosed by renal histology including PCR assay.

We describe two cases of fungal granulomatous interstitial nephritis (GIN) presenting as acute kidney injury (AKI). Increased serum creatinine was detected in Patient 1 after chemotherapy for pharyngeal cancer and in Patient 2 after steroid pulse therapy for bronchial asthma. Renal histology of both patients revealed GIN. Polymerase chain reaction (PCR)-based detection of fungal DNA sequences from kidney tissue demonstrated Trichosporon laibachii and Candida albicans, respectively. When AKI occurs in an immunocompromised host, differential diagnosis of fungal interstitial nephritis should be considered. Furthermore, PCR-based detection of fungal DNA sequences from renal specimens can be useful for rapid diagnosis.

Characteristic tubulointerstitial nephritis in IgG4-related disease.

Nephropathy associated with IgG4-related disease is characterized by tubulointerstitial nephritis. To better identify its pathology, the present study analyzed clinicopathologic features of IgG4-related tubulointerstitial nephritis cases from across Japan. Sixteen cases were identified as IgG4-related nephropathy using the criterion of high serum IgG4 levels (>135 mg/dL) with abnormal kidney computed tomography or elevated serum creatinine levels. Male predominance (75%) and advanced age (average, 62.0 years) were noted. Eight cases displayed no autoimmune pancreatitis. Renal computed tomography abnormalities were found in 12 of 13 cases examined. Renal dysfunction was found in 15 of 16 cases at biopsy. Distinctive features of tubulointerstitial lesions included (1) well-demarcated borders between involved and uninvolved areas; (2) involvement of the cortex and medulla, often extending beyond the renal capsule and with occasional extension to retroperitoneal fibrosis; (3) interstitial inflammatory cells comprising predominantly plasma cells and lymphocytes, with a high prevalence of IgG4-positive cells often admixed with fibrosis; (4) peculiar features of interstitial fibrosis resembling a "bird's-eye" pattern comprising fibrosis among inter-plasma cell spaces; and (5) deposits visible by light and immunofluorescent microscopy in the tubular basement membrane, Bowman capsule, and interstitium that are restricted to the involved portion, sparing normal parts. Ultrastructural analysis revealed the presence of myofibroblasts with intracellular/pericellular collagen accompanied by plasma cell accumulation from an early stage. Histology could not discriminate between IgG4-related tubulointerstitial nephritis with and without autoimmune pancreatitis. In conclusion, the distinctive histologic features of IgG4-related tubulointerstitial nephritis can facilitate the differential diagnosis of tubulointerstitial nephritis, even without autoimmune pancreatitis or an abnormal computed tomography suggesting a renal tumor.

Multiple Pulmonary Metastases following Total Removal of a Bilateral Parasagittal Meningioma with Complete Occlusion of the Superior Sagittal Sinus: Report of a Case.

Pulmonary metastases of benign meningiomas are extremely rare. The case of a 34-year-old man with bilateral parasagittal meningioma who developed pulmonary metastases is described. The meningioma was an enormous hypervascular tumor with invasion of the superior sagittal sinus. The tumor was resected completely and histologically diagnosed as transitional meningioma. The Ki-67 labeling index was 5%. Four months after operation, the patient subsequently developed bilateral multiple lung lesions later identified as metastases. The lung lesions were partially removed surgically and histologically diagnosed as meningothelial meningioma WHO grade I. The Ki-67 labeling index was 2%. The histological findings demonstrated that the tumor occupied the arterial lumen and the perivascular space, suggesting that pulmonary tumors might metastasize via the vascular route. The histopathological features and mechanisms of metastasizing meningiomas are reviewed and discussed.

Clinical and prognostic value of the presence of irregular giant nuclear cells in pT1 ovarian clear cell carcinoma.

In the early stages of epithelial ovarian cancer, histopathological grading is important. However, the grading of ovarian clear cell carcinoma (OCCC) remains controversial. We aimed to identify irregular giant nuclear cells (IGNCs) by a simple method in clinical practice, and to evaluate the prognostic value of IGNCs in pT1 OCCC. Eighty-seven pT1 OCCC patients who underwent initial surgery at Jikei University Kashiwa Hospital, Chiba, Japan, were retrospectively assessed. Paraffin-embedded tissue sections (PTSs) stained with hematoxylin and eosin were reviewed. Giant nuclear cells (GNCs) were defined as cells with a nuclear length of more than twice the median nuclear length. GNCs with irregular nuclear circumferences were defined as IGNCs. Cases where one or more GNCs existed and where IGNCs accounted for >10% of the GNCs were classified as IGNC-positive. We also attempted to identify IGNCs on touch imprint cytology smears (TICSs). Among the 87 cases, 68 were IGNC-negative and 19 were IGNC-positive. The 5-year disease-free and overall survival rates were 88.9% and 90.3% in the total patients, 98.3% and 100% in the IGNC-negative group, and 59.7% and 62.0% in the IGNC-positive group, respectively. These survival rates were significantly lower in the IGNC-positive group than in the IGNC-negative group (adjusted hazard ratio = 14, 95% confidence interval = 2.7-124 and adjusted hazard ratio = 25, 95% confidence interval = 2.9-768, respectively). Prognostic differences were not identified for other factors. IGNC identification on 28 available TICSs predicted IGNC identification on PTSs (sensitivity = 50.0%, specificity = 100%, P = 0.007). The presence of IGNCs has clinical and prognostic value for pT1 OCCC.

Deficiency of endothelial nitric-oxide synthase confers susceptibility to diabetic nephropathy in nephropathy-resistant inbred mice.

Recent studies have implicated dysfunctional endothelial nitric-oxide synthase (eNOS) as a common pathogenic pathway in diabetic vascular complications. However, functional consequences are still incompletely understood. To determine the role of eNOS-derived nitric oxide (NO) in diabetic nephropathy, we induced diabetes in eNOS knockout (KO) and wild-type (WT) mice on the C57BL6 background, using low-dose streptozotocin injection, and we investigated their glomerular phenotype at up to 20 weeks of diabetes. Although the severity of hyperglycemia in diabetic eNOS KO mice was similar to diabetic WT mice, diabetic eNOS KO mice developed overt albuminuria, hypertension, and glomerular mesangiolysis, whereas diabetic WT and nondiabetic control mice did not. Glomerular hyperfiltration was also significantly reduced in diabetic eNOS KO mice. Electron micrographs from diabetic eNOS KO mice revealed an injured endothelial morphology, thickened glomerular basement membrane, and focal foot process effacement. Furthermore, the anionic sites at glomerular endothelial barrier estimated by cationic ferritin binding were reduced in diabetic eNOS KO mice. In aggregate, these results demonstrate that deficiency of eNOS-derived NO causes glomerular endothelial injury in the setting of diabetes and results in overt albuminuria and glomerular mesangiolysis in nephropathy-resistant inbred mice. The findings indicate a vital role for eNOS-derived NO in the pathogenesis of diabetic nephropathy.

Characterization of diabetic nephropathy in a transgenic model of hypoinsulinemic diabetes.

Genetic mouse models provide a unique opportunity to investigate gene function in the natural course of the disease. Although diabetic nephropathy (DN) in models of type II diabetes has been well characterized, diabetic renal disease in hypoinsulinemic diabetic mice is still incompletely understood. Here, we characterized renal changes in the pdx1(PB)-HNF6 transgenic mouse that exhibits beta-cell dysfunction and nonobese hypoinsulinemic diabetes. Male transgenic mice developed hyperglycemia by the age of 7 wk and survived for over 1 yr without insulin treatment. Diabetes ensued earlier and progressed more severely in the HNF6 males than the females. The HNF6 males exhibited albuminuria as early as 10 wk of age, and the urinary albumin excretion increased with age, exceeding 150 microg/24 h at 11 mo of age. Diabetic males developed renal hypertrophy after 7 wk of age, whereas glomerular hyperfiltration was not observed in the mice. Hypertension and hyperlipidemia were not observed in the diabetic mice. Histological analysis of the HNF6 kidneys displayed diabetic glomerular changes, including glomerular enlargement, diffuse mesangial proliferation and matrix expansion, thickened glomerular basement membrane, and arteriolar hyalinosis. Mesangial matrix accumulation increased with age, resulting in nodular lesions by 44 wk of age. Immunohistochemistry showed accumulation of type IV collagen and TGF-beta1 in the mesangial area. No significant immune complex deposition was observed in the HNF6 glomeruli. Thus the HNF6 mouse exhibits diabetic renal changes that parallel the early phase of human DN. The model should facilitate studies of genetic and environmental factors that may affect DN in hypoinsulinemic diabetes.