Inter-individual variations in circadian misalignment-induced NAFLD pathophysiology in mice.

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of intrinsic behavioral rhythms were found to significantly correlate with CJL-induced gene signatures. Together, our results suggest circadian rhythm robustness of the animals contributes to inter-individual variations in pathogenesis of circadian misalignment-induced diseases and raise the possibility that these physiological indicators may be available for predictive hallmarks of circadian rhythm disorders.

Significance of localized expression of full-length growth differentiation factor-15 in cachexia of advanced non-small cell lung cancer.

PURPOSE: Growth differentiation factor-15 (GDF-15) is one of the key cachexia-inducing factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the objective of this study was to investigate the expression of GDF-15 in advanced lung cancer tissues and to understand its role in cachexia. METHODS: We retrospectively examined the expression level of full-length GDF-15 in advanced non-small cell lung cancer tissues and analyzed the relationship between the staining intensity and clinical data in 53 samples. RESULTS: We found that 52.8% of the total samples were GDF-15 positive, and GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio (p = 0.008). It did not correlate with the existence of cancer cachexia and overall survival (p = 0.43). CONCLUSION: Our findings show that GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio, but not the existence of cancer cachexia in advanced NSCLC patients.

Nephrotic-range proteinuria and membranoproliferative glomerulonephritis-like pattern caused by interferon-ß1b in a patient with multiple sclerosis.

Interferon-beta (IFN-ß) subtypes are widely used as immunomodulatory agents for relapsing-remitting multiple sclerosis (MS). Although generally well tolerated, a growing number of reports have recently shown association of long-term IFN-ß therapy with several types of glomerulonephritis. Here, we present the case of a 42-year-old woman with MS who developed nephrotic-range proteinuria after taking IFN-ß1b for nine years. Initially, due to the presence of histological features consistent with immunoglobulin A (IgA) nephropathy (granular IgA deposits in mesangial lesions), a tonsillectomy plus steroid pulse therapy was performed. However, proteinuria did not significantly decrease after these treatments. Therefore, a second renal biopsy was performed after three years, revealing a membranoproliferative glomerulonephritis-like pattern without immune complex. Further immunofluorescence analysis showed attenuated IgA staining. Consequently, IFN-ß1b was replaced with dimethyl fumarate, resulting in complete remission, with proteinuria decreasing to the level of 0.2 g/day. Although it is a rare adverse effect, physicians should pay careful attention to the symptoms and findings of nephritis during the follow-up of patients under treatment with this agent.

Nephritis-associated plasmin receptor (NAPlr)-positive glomerulonephritis in a case of ANCA-negative small vessel vasculitis.

A 75-year-old man with fever was diagnosed with alveolar hemorrhage. Antineutrophil cytoplasmic antibodies for myeloperoxidase and proteinase 3 were absent. He received corticosteroid therapy, which immediately improved his symptoms and chest radiological findings. After the discontinuation of corticosteroids, fever and general fatigue relapsed, and renal function deteriorated with hematuria and proteinuria. A nerve conduction study revealed mononeuritis multiplex. Renal biopsy demonstrated focal necrotizing crescentic glomerulonephritis with endocapillary proliferative lesions, immunofluorescence C3 deposits, and electron-microscopic subepithelial hump-like deposits. Nephritis-associated plasmin receptor (NAPlr) and plasmin activity, biomarkers of infection-related glomerulonephritis, were positive in glomeruli. Although pathological findings suggested infection-related glomerulonephritis (IRGN), clinical manifestations, such as alveolar hemorrhage and mononeuritis multiplex, suggested systemic small vessel vasculitis. After corticosteroid therapy, systemic symptoms disappeared, and the gradual amelioration of hematuria and proteinuria was observed. Based on the clinical symptoms for which steroid therapy was effective, the patient was considered to have systemic small vessel vasculitis, the etiology of which may have been associated with infection.

Extraglomerular Vascular Involvement of Glomerulopathy with Fibronectin Deposits.

Glomerulopathy with fibronectin deposits (GFND) is a rare hereditary kidney disease with autosomal dominant inheritance. A 21-year-old woman who had been diagnosed with GFND 10 years ago was admitted for investigation of a rapid decline in her renal function, hemolytic anemia, and cardiac dysfunction. A renal biopsy showed GFND accompanied by extraglomerular vascular lesions. Comprehensive treatments against hypertension and anemia improved the renal function. Although there have been few reports of vascular lesions in GFND, we suspect that endothelial hyperpermeability resulting from hypertension caused the fibronectin deposition and narrowing of the extraglomerular vascular lumens, thereby accelerating hypertension and inducing hemolytic anemia.

Advanced G-CSF-producing non-small cell lung cancer-not otherwise specified, with favourable response to pembrolizumab monotherapy.

Advanced granulocyte colony-stimulating factor (G-CSF)-producing lung tumours are generally refractory to platinum-based chemotherapy and are associated with poor prognosis. However, therapeutic strategies for these tumours remain unknown. A 74-year-old man was diagnosed with non-small cell lung cancer-not otherwise specified (NSCLC-NOS); the clinical stage was T4N0M1c stage IVb. Blood testing showed leucocytosis and aberrant G-CSF expression. We chose single-agent pembrolizumab as the initial treatment because PD-L1 was highly expressed in the tumours. A clinically favourable response was achieved from seven courses of pembrolizumab with a total disease-free survival of 10 months. During this period, the blood leucocyte count was concordant with the disease condition. These observations showed that pembrolizumab monotherapy may be an effective treatment for patients with advanced G-CSF-producing NSCLC-NOS and that the monitoring of leucocyte count may be a useful biomarker for predicting the efficacy of pembrolizumab monotherapy.

Clinicopathological analysis of ANCA-associated glomerulonephritis focusing on plasma cell infiltrate.

BACKGROUND: When we encounter glomerulonephritis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides demonstrating many plasma cell infiltrations, histological overlapping of immunoglobulin G4-related disease (IgG4-RD) often comes into the differential diagnosis. No previous study has focused on the degree of plasma cells in the kidney infiltrate in ANCA-associated glomerulonephritis (ANCA-GN), and the significance of massive plasma cell infiltrate has not been investigated. METHODS: To clarify the plasma cell ratio in renal biopsy specimens of ANCA-GN and the histological characteristic of "plasma cell-rich" ANCA-GN, 20 cases of ANCA-GN were reviewed and clinicopathologically analyzed. RESULTS: Plasma cell ratio was widely distributed between 1.4 and 81%, and the median ratio was 10%. Three patients were categorized in "plasma cell-rich" ANCA-GN, defined as over 45% plasma cell ratio. They tended to include many active glomerular lesions compared to chronic lesions and to display severe tubulointerstitial inflammation. It is suggested that plasma cell-rich ANCA-GN may be acute onset of the disease, and the target of early inflammation may also be in the tubulointerstitial region. Two of the three plasma cell-rich ANCA-GN cases demonstrated numerous IgG4+ cells, but no bird's-eye pattern fibrosis or obliterative phlebitis. CONCLUSIONS: Plasma cell-rich ANCA-GN is not rare and demonstrates distinct clinicopathological characteristics. This study also reminds us that the presence of the significant number of plasma cells in ANCA-GN, as such, is not a histological diagnostic basis for overlap ANCA-GN and IgG4-related disease.

[A case of liver Mycobacterium avium complex syndrome, diagnosed by liver biopsy].

A man in his 70s was referred to our hospital for evaluation of low-grade fever, weight loss, and liver dysfunction. Serological tests for viral hepatitis or autoimmune diseases were negative. No significant findings were observed on whole-body computed tomography (CT). Histopathologic examination of a liver biopsy sample revealed a non-caseating granuloma with acid-fast bacillus using the Ziehl-Neelsen stain. Serum Mycobacterium avium complex (MAC) antibody was positive. We started treatment for pulmonary MAC disease. His clinical condition and liver function improved within two months. He was diagnosed with liver MAC disease.

Clinicopathological and immunohistochemical analysis of plasma cell-rich rejection in renal transplantation: Involvement of intratubular Th1/Th2 balance in plasma cell enrichment.

AIM: Plasma cell-rich rejection (PCRR) has been considered a subtype of acute T-cell-mediated rejection (ATCR). However, PCRR is recognized as refractory rejection and different from ATCR in various ways. In order to elucidate the pathogenesis of PCRR, we analysed PCRR clinicopathologically and immunohistochemically by comparing it with ATCR. METHODS: Twelve cases of PCRR (PCRRs) and 22 cases of usual ATCR (ATCRs) diagnosed at our hospital between January 2008 and March 2017 were included. Between PCRRs and ATCRs, we compared clinical data, Banff classification, graft outcome and the total sum number of T-bet- and GATA3-positive lymphocytes infiltrating in tubular epithelium using immunohistochemistry. RESULTS: Plasma cell-rich rejections occurred later than ATCRs (median time after transplantation 1340.5 days vs. 52.5 days). Serum creatinine levels at discharge after treatment were significantly higher in PCRRs than in ATCRs (median 2.38 vs. 1.65 mg/dL). Cumulative rate of graft loss was significantly higher in PCRRs than in ATCRs (1-, 2- and 5-year: 26.7%, 51.1% and 51.1% vs. 0%, 0% and 17.5%). For profiles of Th1 and Th2, we found significantly lower ratio of T-bet/GATA3-positive lymphocytes in PCRRs compared with ATCRs. CONCLUSION: This study suggests that PCRR is more refractory than ATCR and there are significant differences in populations of helper T-cell subsets between them. We consider helper T-cell subset analysis valuable for developing new treatment strategies for PCRR.

A Case of the nephrotic syndrome in bone marrow transplantation recipient, histologically showing overlapped glomerular lesions of thrombotic microangiopathy and membranous nephropathy.

Nephrotic syndrome (NS) rarely occurs in post-hematopoietic stem cell transplantation (HSCT) recipients but represents the renal manifestation of graft-versus-host disease (GVHD). Membranous nephropathy (MN) accounts for almost two thirds of post-HSCT NS and is caused by immune complex deposition. Renal thrombotic microangiopathy (TMA) without fulfillment of clinical criteria for TMA has been underreported because of reduced opportunity for histological examination. However, renal TMA has recently been reported in association with GVHD and humoral immunological reactions. Although both MN and TMA after HSCT are associated with GVHD and immunological abnormalities, these diseases are exceptionally coexistent in renal biopsy specimens. We herein describe a case of post-HSCT NS, histologically showing overlapped lesions of TMA and MN. Renal biopsy specimen after presentation of NS revealed early stage MN and TMA with evidence of chronicity. TMA was thought to have preceded MN, and renal biopsy at the phase of pre-nephrotic proteinuria might reveal earlier histological changes of isolated renal TMA. Detection of subclinical renal TMA earlier by spontaneous renal biopsy can help prevent progression of renal injury or overlapping of other renal pathologies. We also demonstrated Th2 predominant intraglomerular infiltration of lymphocytes by immunohistochemistry.

Evaluation of Intravesical Prostatic Protrusion as a Predictor of Dutasteride-Resistant Lower Urinary Tract Symptoms/Benign Prostatic Enlargement With a High Likelihood of Surgical Intervention.

OBJECTIVE: To investigate factors predicting that combination therapy would be insufficient in terms of efficacy, necessitating conversion to surgical intervention, in patients with lower urinary tract symptoms and/or benign prostatic enlargement. MATERIALS AND METHODS: In total, 218 patients given combination therapy for 6 months or more were enrolled in our study. Candidate factors for surgical intervention before dutasteride administration were statistically analyzed. We also examined the proportion of stromal components in resected specimens of the intravesical prostatic protrusion (IPP) portion using the point-counting technique according to IPP grades. RESULTS: Combination therapy was effective and was thus continued in 172 patients, whereas 46 required surgical intervention. The comparison between these two groups, by multivariate analysis, revealed significant differences in IPP and total International Prostate Symptom Score (IPSS). IPP (odds ratio 1.133, P <.001) was the strongest independent factor predicting conversion to surgical intervention. Receiver operating characteristic analysis identified the optimal cutoff value of IPP to be 8 mm (area under the curve: 0.9). This value yielded a sensitivity of 91% and a specificity of 72%. In addition, the mean proportion of stromal components in resected specimens of IPP according to IPP grades was grade I: 96.7%, grade II: 57.8%, and grade III: 21.4% (P <.001 for all), respectively. CONCLUSION: Our results suggest that in lower urinary tract symptoms and/or benign prostatic enlargement associated with severe IPP, combination therapy might have insufficient efficacy due to a low proportion of stromal components, necessitating conversion to surgical intervention.

Outcome of tonsillectomy for recurrent IgA nephropathy after kidney transplantation.

Since 2007, we have performed tonsillectomies for patients with recurrent immunoglobulin A nephropathy (IgAN) after kidney transplantation. Seven patients with primary IgAN showed biopsy-proven recurrent IgAN after living-donor kidney transplantation. They had persistent proteinuria or hematuria for an average of 40.3 months, and tonsillectomy was performed, on average, 75.6 months after kidney transplantation. In six patients with observation periods of more than one year, good remission of urinary findings was observed after tonsillectomy. We classified the seven patients into three types of renal injury based on histological findings: severe, moderate, and mild. Two patients classified with severe renal injury at the time of tonsillectomy had other problems, such as refractory hypertension and bilateral sinusitis. They followed a rapidly progressive clinical course. One case already had moderate histological renal injury. He demonstrated prompt amelioration of urinary findings after tonsillectomy but immediate deviation from remission of proteinuria and hematuria. In the four cases presenting mild renal injury at tonsillectomy, the improved urinary findings and serum creatinine value after tonsillectomy have persisted. In conclusion, tonsillectomy may be a favorable treatment for cases of mild-grade IgAN. However, other treatments such as antihypertensive agents and diet therapy may be necessary in other grades.

[An appropriate distal resection margin for lower rectal cancer after preoperative chemoradiotherapy].

In recent years, with the increase in the adoption of anus-preserving surgery, understanding of residual lower rectal cancer distribution to the anal side after chemoradiotherapy (CRT) has become an increasingly important issue. We aimed to clarify the pathological safe distal resection margin for lower rectal cancer after preoperative CRT. This study included 36 patients with lower third rectal cancer, who underwent preoperative CRT. We classified the gross tumor appearance as type 0-II like, Borrmann type 2, and Borrmann type 5. Whole-mount sections were used for pathological examination. We examined all slides and measured the extent of residual cancer spread. In many cases, residual cancer was observed in the deeper layers of the lesion, and in none of the cases was the cancer limited to the superficial layer. With regard to lateral distribution, tumors with a type 0-II like appearance showed a wider extent of lateral cancer spread from the optimal margin. In conclusion, although CRT contributes to tumor reduction, attention should be paid to both circumferential and lateral residual cancer spread. Our results suggest that the lateral distribution of residual cancer spread could be predicted by gross tumor appearance. This is an ongoing study.

Overlapped glomerular lesions of chronic rejection and recurrent lupus nephritis in transplanted kidney: a case report.

We describe a renal transplant recipient with systemic lupus erythematosus (SLE) who showed continuous proteinuria and low complement levels without clinical evidence of active SLE. Her first renal allograft biopsy, performed nine yr and eight months after transplantation, revealed unusual histological change of glomeruli, and it initially led us to make a contradictory diagnosis based on light and electron microscopic examinations. Diffuse global double- or multi-contour glomerular basement membrane was caused by chronic endothelial injury owing to chronic rejection, and mesangial proliferation associated with mesangial electron-dense deposit was a histological change characteristic of recurrent lupus nephritis (RLN). Immunofluorescence study displayed weak mesangial staining of IgM and C1q. We concluded that this case presented overlapped chronic rejection and RLN. Because both transplant nephropathy and lupus nephritis present constellations of various histologies, it is difficult to diagnose their overlap. Complete morphologic studies with both immunofluorescence and electron microscopic evaluations in addition to microscopic examination should be performed to elucidate complex histological findings.

A case of recurrent focal segmental glomerulosclerosis (FSGS) involving massive proteinuria (>50 g/day) immediately after renal transplantation.

A 15-yr-old girl with end-stage kidney disease caused by primary focal segmental glomerulosclerosis (FSGS) underwent a living-related donor kidney transplantation. The allograft functioned well immediately after reperfusion, but massive proteinuria exceeding 50 g/d appeared on day 3. Treatment with rituximab and plasma exchange (PE) successfully decreased the proteinuria to 10 g/d. A biopsy specimen on day 30 showed no segmental glomerulosclerosis but partial interstitial infiltration of inflammatory cells. An increased number of podocytes showed intracytoplasmic vacuolization, and an electron micrograph showed diffuse mild subendothelial edema and foot process effacement. The podocytes were hypertrophied but were not detached from the basement membrane. As the therapies used to reduce the patient's proteinuria were having a limited effect, intravenous steroid pulse therapy followed by low-density lipoprotein apheresis was performed. A biopsy specimen taken on day 120 showed no segmental glomerulosclerosis. Thrombus formation in one glomerulus and packed lymphocytes in the capillary loop of another glomerulus were detected. The patient's clinical course was compatible with FSGS recurrence. Although the early pathological changes were not typical of FSGS, they might be indicative of the primary lesion that subsequently progresses to typical FSGS.

Findings of graft biopsy specimens within 90 days after ABO blood group incompatible living donor kidney transplantation compared with ABO-identical and non-identical transplantation.

As immunosuppressive therapy has advanced, we have markedly improved the outcome of ABO blood group incompatible living donor kidney transplantation. Consequently, graft survival at early phase after ABO-incompatible transplantation has been favorable than ABO-compatible transplantation in Japan. But in these days, it has been assumed that transplant glomerulopathy within one yr after ABO-incompatible kidney transplantation might be significantly precipitated. That may be because of chronic, active antibody-mediated rejection (AMR). We performed kidney graft biopsies at the early phase within 90 d after living donor kidney transplantation that involved the episode and protocol biopsies and studied findings of graft biopsy specimens when compared with ABO incompatible and compatible involving non-identical and identical transplantations. In ABO-incompatible transplant cases, the ratio occurring glomerulitis, especially severe injury of g 2-3, was significantly higher than that of identical and non-identical transplant cases (p < 0.01). There was no significant difference in t score, i score, ptc score and v score between three transplant groups. The cases occurring AMR were concordant with the cases recognized with severe glomerulitis. AMR was difficult to be diagnosed by C4d analysis in ABO-incompatible transplant cases. Glomerular injury score, g score, may be considered as more significant and the injury should be cured thoroughly.

Gastric leiomyosarcoma manifesting peculiar findings: radiological-pathological correlation.

Reported herein is a gastric leiomyosarcoma, which, nowadays, is extremely rare. Attention was focused not only on pathological findings but also on the histological basis of magnetic resonance imaging (MRI) findings. The patient was a 29-year-old Japanese woman. Preoperative T2-weighted MRI showed a large high-intensity gastric tumor with isointense streaks. The tumor was a broad-based large polypoid lesion and histologically consisted of fascicles of spindled cells having eosinophilic cytoplasm and cigar-shaped nuclei. Immunoreactivity for several smooth muscle markers including desmin on tumor cells, low amplification of both c-kit and PDGFRA cDNA on polymerase chain reaction, and absence of c-kit gene mutation in exons 9 and 11 strongly suggested that the tumor was not a gastrointestinal stromal tumor but a true leiomyosarcoma. In vitro MRI of the fresh tumor was obtained to explain the radiological findings on a morphological basis. In vitro MRI clearly depicted the very high-intensity areas separated by radially extended isointense lines. This radiological finding corresponded best to the most characteristic histological feature, that is, linearly extended fascicles of the tumor cells often with myxedematous change separated by radially elongated thin fibrovascular stroma: in other words, spouting appearance.

Oncocytic renal cell carcinoma having papillotubular growth: rare morphological variant of papillary renal cell carcinoma.

Herein is described a unique renal cell tumor with previously unreported morphological and immunohistochemical features. The patient was a 78-year-old Japanese man. A huge left renal tumor was found on ultrasound during evaluation of left abdominal distention. The tumor was macroscopically characterized by a non-infiltrative border, pale yellow to grayish color, foci of hemorrhage and partial edematous change. Histologically the tumor had an extensive small tubular growth pattern often with papillary fronds mainly composed of oncocytic cells with deeply eosinophilic granular cytoplasm. Clear vacuolated cells were scattered among the oncocytic cells. The present case had an unusual immunohistochemical profile for all known types of renal cell tumors, but both the oncocytic cells and the clear vacuolated cells were strongly immunoreactive for alpha-methylacyl-coenzyme A racemase. It is concluded that the tumor may be a candidate for a rare variant of papillary renal cell carcinoma. Further cases having similar features are awaited for a definitive classification of this tumor as a previously undescribed tumor type.

Extraarticular paravertebral diffuse-type giant cell tumor.

A diffuse-type giant cell tumor (DGCT) of the paravertebral region is a rare condition characterized by an ill-demarcated mass with facet joint involvement. We describe a case of extra-articular DGCT of the paravertebral cervical region without association to the facet joint. A 51-year-old male presented with a headache. Diagnostic imaging showed a dumbbell-shaped mass with enlargement of the right intervertebral foramen between C6 and C7. The tumor was completely resected in multiple fragments with the suspicion that it was a schwannoma. Histologically the tumor consisted chiefly of mononuclear histiocytoid cells, foamy macrophages and multinucleated giant cells, which led to a diagnosis of DGCT. The case alerts one to be aware that DGCT may originate from a paravertebral location as a soft-tissue mass without facet joint involvement.