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G‐quadruplex (G4), a non‐canonical higher‐order structure formed by guanine‐rich nucleic acid sequences, affects various genetic events in cis, including replication, transcription and translation. Whereas up‐regulation of innate immune/interferon‐stimulated genes (ISGs) is implicated in cancer progression, G4‐forming oligonucleotides that mimic telomeric repeat‐containing RNA suppress ISG induction in three‐dimensional (3D) culture of cancer cells. However, it is unclear how G4 suppresses ISG expression in trans. In this study, we found that G4 binding to splicing factor 3B subunit 2 (SF3B2) down‐regulated STAT1 phosphorylation and ISG expression in 3D‐cultured cancer cells. Liquid chromatography‐tandem mass spectrometry analysis identified SF3B2 as a G4‐binding protein. Either G4‐forming oligonucleotides or SF3B2 knockdown suppressed ISG induction, whereas Phen‐DC3, a G4‐stabilizing compound, reversed the inhibitory effect of G4‐forming oligonucleotides on ISG induction. Phen‐DC3 inhibited SF3B2 binding to G4 in vitro. SF3B2‐mediated ISG induction appeared to occur independently of RNA splicing because SF3B2 knockdown did not affect pre‐mRNA splicing under the experimental conditions, and pharmacological inhibition of splicing by pladienolide B did not repress ISG induction. These observations suggest that G4 disrupts the ability of SF3B2 to induce ISGs in cancer. We propose a new mode for gene regulation, which employs G4 as an inhibitory trans‐element., We demonstrate that a splicing factor SF3B2 mediates interferon‐stimulated gene (ISG) expression in cancer cells. G‐quadruplex‐forming oligonucleotides bind to SF3B2 and suppress ISG up‐regulation. The findings provide a mechanism for the function of G‐quadruplex as a trans‐element of gene regulation.

Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from a lack of alpha-galactosidase A (AGALA) activity in lysosomes. We herein report a patient with FD revealed by a renal biopsy who survived seven years after the introduction of peritoneal dialysis despite having severe heart failure due to left ventricular hypertrophy (LVH). FD was diagnosed based on a renal biopsy and biochemical analysis showing a low enzymatic activity of AGALA. A microscopic examination at the autopsy revealed marked hypertrophy and vacuolation of cardiac muscle cells. In our case, cardiac involvement determined the prognosis. Peritoneal dialysis is the modality of choice in the long-term management of dialysis patients with FD.

A 60-year-old Japanese woman was admitted because of the polycystic mass with right flank pain localized in the upper portion of the right kidney. Right nephrectomy was performed because the mass lesion had continuously increased in size over the past 10 years. A surgical specimen showed histology consistent with a mixed epithelial and stromal tumor, which is closely related to multilocular cystic nephroma, and was diagnosed by a defined capsule between the cystic mass lesion and normal renal tissue by CT and MRI, and histology. Localized renal cystic disease that does not have a capsule was excluded from differential diagnosis.

Case 1: A 59-year-old Japanese woman with rheumatoid arthritis (RA) for 36 years was admitted for evaluation of deteriorating renal function. Her serum creatine was 4.2 mg/dL, and proteinuria was 6.5 g daily. Renal and duodenal biopsy revealed AA amyloidosis. After treatment with tocilizumab (a humanized anti-interleukin-6 receptor antibody), proteinuria decreased to 1.1 g daily. The patient's renal function subsequently remained stable for 8 years. Case 2: A 71-year-old Japanese man with RA for 30 years was admitted due to deterioration of renal function. Serum creatine was 2.9 mg/dL, and urinary protein excretion was 0.06 g daily. Renal and duodenal biopsy identified AA amyloidosis. Tocilizumab was initiated, and his renal function remained stable for 6 years. The 2nd duodenal biopsy showed a marked decrease of AA amyloid deposits. Conclusion: These two cases suggest that tocilizumab may preserve renal function in the setting of end-stage kidney disease and shift the point of no return for RA patients with AA amyloidosis and renal dysfunction.

Background Chronic hypersensitivity pneumonitis (CHP) remains a diagnostic challenge. The process of collecting and extracting serum and droppings from causative animals for the inhalation challenge test is complicated and the risk of inducing disease progression exists. Objective To investigate the utility and safety of an inhalation challenge test using pigeon eggs. Methods Pigeon eggs were pasteurized and mixed with a saline solution to produce an inhalation fluid. An inhalation challenge test was conducted on 19 patients with bird-related CHP and 17 patients with interstitial lung disease other than bird-related CHP. To identify antigens in pigeon eggs, the antigen-antibody responses of the pigeon eggs and serum from patients were evaluated using Western blotting. Results The mean changes in C-reactive protein, alveolar-arterial oxygen difference, erythrocyte sedimentation rate, and lactate dehydrogenase significantly increased by 0.32 mg/dL (P = .014), 7.8 Torr (P = .002), 1.4 mm/h (P = .012), and 5.4 U/mL (P = .0019), respectively, in bird-related CHP group compared to the control 24 hours after the inhalation challenge test. Furthermore, within 24 hours of the inhalation test, the mean forced vital capacity decreased by 2.3% in the bird-related CHP group compared with a decline of 0.05% in the control group (P = .035). Serum collected from seven bird-related CHP patients who underwent the inhalation challenge test and reacted to antigens with molecular weights of 37-75 KDa, and these molecular weights were consistent with egg albumin and globulin. Conclusion Since a mild response was observed after the inhalation challenge test using pigeon eggs, this test was an obvious candidate for diagnosing bird-related CHP.

Interstitial pneumonia (IP) is a major risk factor for lung adenocarcinoma (LADC). IP-related LADC predominantly develops in the bronchiolar metaplasia lining in honeycomb lesions. Kirsten rat sarcoma virus (

Purpose To investigate the impact of hemodialysis on survival in renal cell carcinoma (RCC) patients. Methods We studied 388 patients who underwent radical or partial nephrectomy for RCC at Toranomon Hospital from 2005 to 2013. Survival curves were drawn according to the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model to assess the prognostic influence of hemodialysis on cancer-specific survival. Result Of the 388 patients, 66 were on hemodialysis and 322 were not on dialysis. In the hemodialysis patients, incidental diagnosis of RCC was less frequent than in the non-dialysis patients. In addition, RCC was more likely to be multicentric (41% vs 1.2%), bilateral (14% vs 0.6%), and papillary (18% vs 7%) in hemodialysis patients. Moreover, tumors were smaller, the stage was lower, and the Fuhrman nuclear grade was higher in the patients on hemodialysis. The 5-year cancer-specific survival rate was 82.8% for hemodialysis patients and 93.5% for nondialysis patients. Multivariate analysis indicated that hemodialysis, stage, and Fuhrman nuclear grade were independent prognostic factors for RCC. Conclusions This study suggested that hemodialysis was an independent prognostic factor for cancer-specific survival in RCC patients, along with the tumor stage and Fuhrman nuclear grade.

A renal histology of an 81-year-old man with a 30-year history of diabetes mellitus (DM), as well as diabetic retinopathy and neuropathy, was examined. The patient’s blood pressure was controlled within the normal range (less than 140/75 mmHg) using antihypertensive agents including angiotensin receptor blocker. Edematous management was achieved by a strict salt diet (less than 6 g/per day). However, this patient’s glycemic control was poor with HbA1c 8–10%. Serum creatinine was 0.87 mg/dL and estimated globular filtration rate (eGFR) was 64 ml/min/1.73m2. Urinary protein excretion was 1.5 g/day. This patient’s renal biopsy showed linear staining for IgG along the GBM by immunofluorescence microscopy, but light microscopy showed almost intact glomeruli, and the GBM was not thickened as revealed by electron microscopy with a width of 288–368 nm (

Background Myositis and interstitial lung disease (ILD) frequently occur in patients with anti-aminoacyl-tRNA synthetase (ARS) antibodies. Nearly half of ARS-ILD patients have the acute or subacute form of the disease, and one-third of these patients show a deterioration in pulmonary function over the long-term course because of frequent recurrences and refractoriness to therapy. Several reports recently described different characteristics depending on the individual anti-ARS antibodies, and the anti-asparaginyl tRNA synthetase (KS) antibody was strongly linked to ILD rather than to myositis. We therefore hypothesized that KS-ILD may have clinical characteristics that differ from those of other ARS-ILDs. The aim of this study was to clarify the clinical, radiological, and pathological features of KS antibody-positive ILD. Methods We retrospectively analyzed 19 consecutive patients with KS-ILD who underwent initial clinical measurements and high-resolution computed tomography and pathological assessments. We also analyzed disease behavior based on pulmonary function test results during the follow-up period. Results Our KS-ILD cohort included patients with dermatomyositis (10.5%), primary Sjogren syndrome (5.3%), and idiopathic ILD (84.2%). Most patients presented with chronic onset (89.5%) and a nonspecific pattern of interstitial pneumonia at each radiological and pathological assessment (89.4% and 85.7%, respectively). The pulmonary function test results showed that the mean changes from the initial %forced vital capacity and %diffusing capacity of the lung for carbon monoxide at 3 years were 3.7% ± 2.9% and 9.35% ± 3.0%, respectively. Conclusions Most KS-ILD patients showed a tendency for chronic disease onset and long-term stabilization of pulmonary function.

Introduction Thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a severe subtype of idiopathic multicentric Castleman’s disease, characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, and organomegaly. Renal complication of this disease can be life-threatening and sometimes requires hemodialysis, but it has not been elucidated in detail. Methods Case-series was designed to evaluate the renal histology of patients with TAFRO syndrome treated at our hospital. Results Seven patients were eligible to the criteria. All of them had severe diuretic-resistant anasarca and 6 of 7 had mild proteinuria (, Graphical abstract

Monoclonal B-cell lymphocytosis (MBL) is an early or precursor asymptomatic proliferation of chronic lymphocytic lymphoma (CLL)-like B-cells. Lymphoplasmacytic lymphoma (LPL), often clinically associated with Waldenstrom macroglobulinemia, is a B-cell neoplasm characterized by frequent MYD88 L265P mutation. Here, we report a rare composite MBL and LPL in a patient with IgM light chain (AL) amyloidosis. A 74-year-old male with a known IgM monoclonal protein developed proteinuria. No lymphocytosis was detected. Renal biopsy showed deposition of AL λ amyloid in the glomeruli and vessels. Subsequent bone marrow biopsy revealed nodular atypical CLL-like small B-cell proliferation and scattered peripheral LPL. Immunohistochemistry and/or flow cytometry revealed that the atypical CLL-like population expressed CD19, CD20, CD5, weak CD23, LEF-1 and diminished surface Igκ. The LPL was positive for CD19, CD20 and surface Igλ. Using laser-capture microdissection and allele-specific polymerase chain reaction, we confirmed that MYD88 L265P was detectable in the LPL but not in the atypical CLL-like population. Thus, we demonstrated that these two populations were clonally independent, and made the diagnosis of composite MBL and LPL. An integrated clinical, pathological, immunophenotypic and genetic assessment is essential in such complicated cases, and especially 'clone-specific' MYD88 genotyping may facilitate the differential diagnoses of low-grade B-cell lymphomas.

The molecular pathogenesis of human amyloidosis has been elucidated greatly during the last 20 years. Based on the understanding of the molecular mechanisms of amyloid fibril formation and deposition, various kinds of new drugs and therapeutics have been emerging to improve the prognosis of amyloidosis and even cure this disease. In this review article, we first summarize the pathogenesis and state-of-the-art therapeutics of representative types of systemic human amyloidosis, that is, immunoglobulin light chain-related, transthyretin-related, amyloid A-associated and β2 -microglobulin-related amyloidosis. Next, we describe the essential roles of pathological diagnosis, especially the typing diagnosis of amyloidosis to appropriately guide type-specific therapies of amyloidosis patients. Finally, we introduce the activities of the government-funded group for surveys and research of amyloidosis in Japan, especially the nation-wide pathology consultation system of amyloidosis, which started in April 2018. The nation-wide improvement of the typing diagnosis of amyloidosis is essential for the appropriate treatment and care of amyloidosis patients in Japan.

Severe hepatic failure is rarely a cause of death in patients with immunoglobulin light chain (AL) amyloidosis. We herein report a case of AL amyloidosis involving a bleeding tendency due to factor X deficiency and marked hepatic involvement of amyloidosis. The patient died due to severe liver dysfunction two weeks after admission. The diagnosis was confirmed histologically by AL-λ amyloidosis, with the liver and spleen as the main lesions, on an autopsy. As treatment-related toxicity is strong in advanced cases, appropriate treatments are required to improve the prognosis of AL amyloidosis with severe liver dysfunction.

The effects of structural factors on the delamination of the stacked via in high-density multilayer printed wiring boards were investigated by a statistical approach. Although reducing the height of via or the number of via stacks is effective to prevent the delamination, if these cannot be reduced, the risk of the delamination is eased by increasing the pitch of the stacked via.

Propionibacterium acnes is a potential etiologic agent of sarcoidosis and a dysregulated immune response to the commensal bacterium is suspected to cause granuloma formation. P. acnes-derived insoluble immune complexes were recently demonstrated in sinus macrophages of sarcoidosis lymph nodes, suggesting local proliferation of the bacterium in affected organs. In the present study, we developed a method for detecting P. acnes-derived immune complexes in human blood by measuring the concentration of P. acnes-specific lipoteichoic acid (PLTA) detectable after an antigen retrieval pretreatment of plasma samples. Before pretreatment, anti-PLTA antibody was detected and PLTA could not be detected, in all plasma samples from 51 sarcoidosis patients and 35 healthy volunteers. After pretreatment, however, a significant level of PLTA (&gt, 105 ng/mL) was detected in 33 (65%) sarcoidosis patients and 5 (14%) control subjects, with 86% specificity and 65% sensitivity for sarcoidosis. In both groups, plasma anti-PLTA antibody titers did not differ between samples with and without detection of PLTA. PLTA levels were abnormally increased (&gt, 202 ng/mL) in 21 (41%) sarcoidosis patients. These findings suggest that P. acnes-derived circulating immune complexes present in human blood are abnormally increased in many sarcoidosis patients, presumably due to local proliferation of the bacterium in the affected organs.

Background and purpose We examined whether advances in treatment strategies from older disease-modifying antirheumatic drugs (DMARDs) to new biologic agents and methotrexate improved renal complications and outcome in patients with rheumatoid arthritis (RA). Methods We reviewed records of 156 patients with RA who underwent kidney biopsy at our institute between January 1990 and December 2019. All patients were assigned to one of three periods: period 1, 1990–1999 (n = 48); period 2, 2000–2009(n = 57); period 3, 2010–2019 (n = 51). Results Membranous nephropathy, nephrosclerosis, AA-amyloidosis, and IgA nephropathy were the four major renal manifestations of RA. AA-amyloidosis was diagnosed by kidney biopsy in 21 patients: period 1, 7 patients (15%); period 2, 10 patients (18%); and period 3, 4 patients (8%). The 4 patients in period 3 were in the years 2010–2014, and no new case of AA-amyloidosis was recorded from 2015 to 2019. In all 21 of the patients with AA-amyloidosis, neither a biologic agent nor methotrexate was administered. Fifteen of the 21 patients required dialysis, and 13 died in periods 1–3 because of amyloid-related cardiac dysfunction less than 2 years after the initiation of dialysis. Two of them are doing well using biologic agent despite dialysis. The remaining three patients who received a biologic agent or methotrexate does not progress to end-stage renal failure. In addition, the other renal complications showing progression to dialysis also decreased over time. Conclusion Advances in treatment strategies have improved renal outcome and reduced mortality in patients with RA.

Propionibacterium acnes is implicated in the pathogenesis of sarcoidosis. We investigated the usefulness of immunohistochemistry (IHC) with a commercially available P. acnes-specific monoclonal antibody (PAB antibody) for differentiating sarcoidosis from other granulomatous diseases. Formalin-fixed paraffin-embedded tissue samples from 94 sarcoidosis patients and 30 control patients with other granulomatous diseases were examined by the original manual IHC method. We also compared the detection frequency of P. acnes in sarcoid granulomas between manual and automated IHC methods. P. acnes was detected in sarcoid granulomas of samples obtained by transbronchial lung biopsy (64%), video-associated thoracic surgery (67%), endobronchial-ultrasound-guided transbronchial-needle aspiration (32%), lymph node biopsy (80%), and skin biopsy (80%) from sarcoidosis patients, but not in any non-sarcoid granulomas of the samples obtained from control patients. P. acnes outside granulomas, however, was frequently detected in both groups. The detection status of P. acnes in granulomas did not correlate with the clinical characteristics of sarcoidosis patients. The automated Leica system exhibited the best detection sensitivity (72%) and almost an identical localization for P. acnes in sarcoid granulomas compared with the manual method. IHC with a PAB antibody is useful for differentiating sarcoidosis from other granulomatous diseases by detecting P. acnes in granulomas. An automated method by the Leica system can be used in pathology laboratories for differential diagnosis of granulomas by IHC with the PAB antibody.

Pneumocyte injury is a crucial factor influencing the severity of interstitial lung disease (ILD). In this study, we investigated the potential of hepatocyte nuclear factor α (HNF4α) as an immunohistochemical marker to detect pneumocyte injury and as a prognostic marker. Surgical lung biopsy specimens were collected from 309 patients with different types of ILDs (61 idiopathic pulmonary fibrosis (IPF), 173 non-IPF, and 75 unclassifiable ILD). HNF4α expression were examined and the frequency of positive cells (per mm2 ) was calculated. HNF4α was strongly expressed in regenerating pneumocytes present on fibroblastic foci, Masson bodies/organizing alveoli. In the non-IPF and unclassifiable ILD groups, cases with high frequency expression showed significantly poorer outcome. Particularly, in the unclassifiable ILD group, the prognostic impact was more significant (death due to ILD, log-rank test, p

The present study aimed to elucidate the mechanisms underlying the histogenesis of interstitial pneumonia (IP)-related lung adenocarcinoma (LADC). We focused on the methylation of thyroid transcription factor 1 (TTF-1). The TTF-1 locus was highly methylated in IP-LADCs compared to non-IP-LADCs. Among the IP-LADCs, the non-terminal respiratory unit (TRU) LADCs showed marked hypermethylation in CpG sites in a particular intragenic region. This region was also found to be highly methylated in the IP lungs. The hierarchical dendrogram based on methylation levels divided the IP lungs into three different clusters. One of them showed a methylation profile similar to that of non-TRU LADCs. The non-TRU LADCs developed from this cluster with a significantly higher frequency. Moreover, bronchiolar metaplasia lining honeycomb/cystic lesions in IP lungs, IP-related non-TRU LADCs, and bronchiolar epithelia in healthy lungs were separately collected by microdissection and examined for methylation. Bronchiolar metaplasia showed hypermethylation, but bronchiolar epithelia did not. The methylation patterns in bronchiolar metaplasia were similar to those in non-TRU LADCs. In summary, a particular region of TTF-1 was highly methylated in IP-related non-TRU LADCs and bronchiolar metaplasia, supporting the theory that IP-related non-TRU LADCs may develop from bronchiolar metaplasia lining honeycomb/cystic lesions.

A 74-year-old Japanese woman diagnosed with autosomal dominant polycystic kidney disease (ADPKD) was admitted to our institute for the further examination of right-side groin pain developing in the past week. The patient was diagnosed with polymyositis (PM). Diagnostic imaging showed a mass lesion measuring 8 cm and a renal stone in the right kidney. Immediately following surgical resection of the right kidney, the patient's serum CK decreased to the normal range. A histopathological analysis showed well-differentiated squamous cell carcinoma. In conclusion, this case showed a close relationship between the occurrence of squamous cell carcinoma and the development of PM in an ADPKD patient.

Nevi are benign melanocytic tumors, and some nevi are considered to develop into malignant melanomas. Most nevi arise in the skin, but nevi occasionally occur in the conjunctiva, esophageal mucosa, or at other sites. Pulmonary melanocytic nevi are extremely rare, and only one case has been reported in the literature. Here, we present a case of pulmonary melanocytic nevus, involving a BRAF gene mutation (V600E), and we discuss the potential significance of this condition as a precursor to pulmonary malignant melanoma.

We report a 58-year-old Japanese woman who presented with nephrotic syndrome. Steroid therapy and cyclosporine A administration were initiated, but hematological remission and renal response were not achieved. Renal biopsy revealed amyloid deposits in the mesangial region and the small arteries. Proteomic analysis based on laser microdissection and mass spectrometry showed that the amyloid deposits were composed of the constant region of the lambda light chain. She received vincristine, adriamycin, and dexamethasone therapy followed by high-dose melphalan and autologous stem cell transplantation, resulting in hematological complete remission and renal response with negative urinary Bence-Jones protein and proteinuria. Renal biopsy was performed four times during follow-up, demonstrating that amyloid deposits decreased gradually, while glomeruli showing global sclerosis increased from 3 to 62%. This case suggests that glomerular amyloid deposits can be cleared via tissue remodeling, if stem cells producing amyloid precursors are completely replaced by unrelated cells after stem cell transplantation.

Background Cystinuria is a rare autosomal recessive metabolic disorder that affects renal and intestinal cystine transport. Cystine stones are found in only 1–2% of all stone formers. Patients with cystinuria are at high risk for nephrolithiasis and subsequent morbidity. In spite of the various medical and surgical treatments that are currently available for cystinuria, some patients gradually develop kidney failure, with only a few reported cases regarding kidney transplantation (KTx) to treat end-stage renal disease (ESRD) secondary to cystinuria. Cystinuria is likely not to be a systemic disease; thus, renal replacement with transplantation seems a good therapeutic option for ESRD. However, few cystinuria patients have undergone KTx due to ESRD. Case presentation We herein describe the case of a 49-year-old man with cystinuria, frequent stone events, and ESRD who underwent pre-emptive ABO-incompatible kidney transplantation. At 2 years and 6 months post-transplantation, the patient remains asymptomatic with no prophylactic therapy for cystinuria, and the allograft function has been preserved without evidence of rejection. Conclusions In conclusion, a cystinuria patient with nephrolithiasis-related ESRD was successfully treated by transplantation. Although additional cases are required to confirm the efficacy of this approach, renal replacement may be useful for treating ESRD in patients with rare hereditary forms of kidney stone disease.

In sarcoidosis, renal involvement includes hypercalcemia-related nephrocalcinosis and granulomatous tubulointerstitial nephritis. Hypercalcemia is thought to be due to increased production of 1,25 dihydroxyvitamin D (1-25D), but 1-25D levels have not been evaluated in sarcoidosis patients with renal dysfunction. We enrolled 9 sarcoidosis patients who underwent renal biopsy, and compared the serum 1-25D concentration and eGFR with those in 428 non-sarcoidosis patients who had renal dysfunction (stage 2 or higher CKD with an estimated glomerular filtration rate

An 88-year-old Japanese man received bevacizumab for colorectal cancer with liver and peritoneal metastasis, during which nephrotic range proteinuria occurred (7.66 g/day). Renal biopsy showed endothelial damage with subendothelial swelling and a double contour of the glomerular basement membrane, which indicated a diagnosis of thrombotic microangiopathy (TMA). After bevacizumab was stopped, proteinuria decreased to 1 g/day. During the clinical course, this patient had no extrarenal manifestations. This case suggests that renal injury induced by bevacizumab is characterized by nephrotic range proteinuria and histological TMA, and is a renal-limited condition that differs from systemic TMA related to thrombotic thrombocytopenic purpura.

Cholesterol crystal embolism (CCE) causes renal damage, and there is an extremely high risk of end-stage renal disease. However, the time course of CCE-related renal deterioration varies and little is known about the subsequent risk of dialysis among patients with biopsy-proven CCE. We performed a retrospective cohort study of 38 Japanese patients in whom a histological diagnosis of CCE was made from September 1992 to July 2005. Competing risk regression analysis was used to investigate the association between declining renal function ( ≥ 1.5 elevation of serum creatinine within 26 weeks after CCE) or its subtypes (acute [

Background This study was performed to determine whether the urinary albumin excretion rate (%UAE) could distinguish myeloma cast nephropathy (MCN) without glomerular amyloid deposition from MCN with glomerular amyloid deposition. Materials and methods We retrospectively reviewed clinicopathological data on 16 patients with MCN diagnosed by renal biopsy at Toranomon Hospital from 2004 to 2014. Results A total of 10 patients had pure MCN without glomerular amyloid deposition (group 1), and 6 patients had MCN with glomerular amyloid deposition (group 2). In all 10 patients from group 1, the underlying disease was multiple myeloma (MM), while 4 patients had MM, and 2 patients had lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) in group 2. Total protein did not show a significant difference between the two groups, but serum albumin was significantly higher in group 1 than group 2 (p = 0.0101). Serum-adjusted calcium did not show a significant difference between the groups, while serum creatinine (Cre) was significantly higher in group 1 than group 2 (p = 0.0343). Although urinary protein excretion did not differ significantly between the groups, the %UAE was significantly lower in group 1 than group 2 (p = 0.00198). In group 2, 3 of the 4 patients with MM died within 15 months of diagnosis, but the 2 patients with LPL/WM are alive after 32 months. In group 1, only 1 patient died (of unknown causes) within 15 months after diagnosis. Conclusion In patients with MCN, %UAE may be a useful marker for the detection of coexistence of glomerular lesions, such as amyloidosis, which are associated with a poor outcome.

A 32-year-old Japanese woman was admitted to our hospital for evaluation of microscopic hematuria with a positive family history. Percutaneous renal biopsy was performed under real-time ultrasound guidance using a 16-gauge automated needle and three specimens were obtained. She had no risk factors for hemorrhage. However, macroscopic hematuria developed from 5 days after biopsy and persisted for 4 days. Her Hb decreased markedly from 15.0 to 8.1 g/dL. Enhanced computed tomography revealed urinary tract hematoma, while the early arterial phase showed inflow of contrast medium into the left renal vein from a pseudoaneurysm on a branch left renal artery. Renal transcatheter arterial embolization was performed using platinum microcoils and the arteriovenous fistula was occluded. The patient did not require blood transfusion. Severe renal bleeding that causes urinary tract hematoma usually occurs within 24 h after renal biopsy, but the possibility of late-onset renal bleeding should be kept in mind.

Background: The senescence-associated secretory phenotype (SASP) develops due to cellular senescence during conditions such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). However, studies comparing the degree of cellular senescence and SASP between COPD and IPF are limited. Furthermore, to the best of our knowledge, no study has examined cellular senescence and/or SASP in connective tissue disease-associated interstitial lung disease (CTD-ILD). Methods: To compare the degree of cellular senescence among COPD, IPF, and CTD-ILD, tissue samples from surgical lung biopsies or noncancerous tissue from lobectomy specimens of patients with lung cancer were subjected to immunostaining for p16 and p21. Double-staining for p16 and phosphorylated NF-κB was performed to verify the relationship between cellular senescence and SASP. Results: There was a greater degree of enhancement of p16 and p21 expression in patients with IPF than in those with COPD and controls. Immunostaining for p16 revealed an enhanced expression of this marker in patients with COPD compared with that in controls. No significant differences were observed in the phosphorylated NF-κB expression rate of p16-positive and p16-negative cells among patients with IPF, CTD-ILD, and COPD. Conclusions: Epithelial cells in patients with IPF express higher levels of both cellular senescence and SASP than those in patients with COPD or controls.

Objectives In lupus nephritis, the immune complex plays a very important role in kidney disease progression, and immunoglobulin G subclass 3 (IgG3) may play an important role in endothelial damage as lupus nephropathy progresses. We evaluated the association between IgG3 positivity and lupus nephritis activity. Materials and methods We identified 71 biopsies taken from 57 patients who had lupus nephritis with enough tissue to allow light and immunofluorescence microscopy. We compared the intensity of IgG subclass staining (on a scale of 0 - 3+) with IgG subclass dominance among lupus nephritis classes as defined by the ISN/RPS 2003 classification. Results The proportion of IgG3-positive patients with capillary loop lesion was significantly higher in the class IV group compared with other groups (p l 0.01). Interestingly, in most patients IgG1 was the strongest subclass; in class IV groups, IgG3 was the strongest in 21% of the biopsies. IgG3 deposition in capillary loops was significantly associated with C1q deposition in those loops. According to Kaplan-Meier analysis, renal survival rates in the patients with IgG3 deposition was lower (82.2%) than in patients without IgG3 deposition (93.3%), but the difference was not significant. Conclusion Our results suggest that capillary loop deposition of IgG3 is associated with disease activity in lupus nephritis. .

Background Application of next-generation DNA sequencing (NGS) has recently become increasingly common in the field of clinical oncology in several countries around the world. In Japan also, a system for applying NGS to routine clinical practice is gradually being established. During this process, we introduced in Japan the tumor-profiling MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) assay. Methods We present here our initial experience with the use of MSK-IMPACT in 68 patients selected from two institutions in Japan between June 2016 and October 2017. Results MSK-IMPACT sequencing was successful and yielded results in specimens obtained from 64 of the 68 patients, representing an overall assay success rate of 94.1%. The top three cancer types tested were endometrial cancer (17.2%), pancreatic cancer (15.6%) and colorectal cancer (12.5%). Evaluation of the clinical actionability of the genetic alterations revealed that 25.0% of patients (n = 16) harbored at least one actionable alteration. However, enrolling the patients in a genomically matched clinical trial was difficult, mainly because most clinical trials are limited to tumors arising from a specific organ/site. One patient with microsatellite instability-high status, as determined by MSK-IMPACT, was treated with pembrolizumab and showed partial response. Conclusions Although tumor profiling by NGS and administration of genomically matched therapy is a promising strategy, because of its high cost, we need to consider how we can fit it into the Japanese medical system. Towards this end, we believe that it is important to share our initial experience for furthering precision medicine in Japan.

Renal hemosiderosis occurs in the context of severe intravascular hemolysis, with the most common cause being paroxysmal nocturnal hematuria. Patients with cold agglutinin disease (CAD) have relatively mild hemolysis, and acute kidney injury (AKI) due to renal hemosiderosis has not been reported. We encountered a patient with CAD caused by lymphoplasmacytic lymphoma who developed AKI secondary to renal hemosiderosis after an excessive alcohol intake.

Background Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disease characterized by systemic inflammatory reactions associated with the dysregulated production of interleukin-6 (IL-6). In patients with MCD, renal involvement is uncommon, with only one report published regarding kidney transplantation (KTx) to treat end-stage renal disease (ESRD) secondary to MCD. Recent clinical observations have shown that IL-6 production is implicated in allograft rejection, while IL-6 receptor blockade (with tocilizumab [TCZ]) reduces alloantibody generation and thereby improves graft survival; however, the efficacy and safety of TCZ in MCD patients undergoing KTx is still unknown. Case presentation Herein, we describe the case of a 50-year-old man with MCD who received living-donor KTx for ESRD. Post-operative immunosuppression consisted of a triple-drug regimen (tacrolimus, mycophenolate mofetil and methylprednisolone) with TCZ that was administered intravenously every 2 weeks. At 17 months post-transplantation, the patient remains asymptomatic, and the allograft pathology has shown no evidence of rejection and no development of de novo donor-specific antibody (DSA). Conclusions To our knowledge, this is the second reported case of an MCD patient with ESRD who underwent successful KTx. TCZ safely supported the patient during the perioperative period, and this drug may be useful for blocking the generation of donor-specific antibodies and reducing the risk of rejection episodes. KTx in combination with TCZ is thus considered a viable treatment option for ESRD due to MCD.

The present study aimed to discern the molecular alterations involved in the progression of EGFR-mutated lung adenocarcinoma (LADC). We previously demonstrated that the micropapillary (mPAP) element is the most important histological factor for assessing malignant grades in LADCs. Therefore, mPAP and other elements were separately collected from three cases of EGFR-mutated LADC using laser capture microdissection and subjected to a comprehensive mRNA expression analysis. We focused on DYRK2 in this study because its level showed a substantial increase in EGFR-mutated LADCs with mPAP. We also immunohistochemically examined 130 tumors for the expression of DYRK2. The results confirmed a strong expression of DYRK2 in EGFR-mutated LADC with mPAP. Fluorescent in situ hybridization (FISH) analyses targeting the DYRK2 locus revealed frequent gene amplification in EGFR-mutated LADC, specifically occurring in the high-grade components, like mPAP. In summary, the results of this study suggest that DYRK2 overexpression through gene amplification is one of the molecular mechanisms responsible for promoting the progression of EGFR-mutated LADC.

A 93-year-old woman was admitted with a 10-day history of cough and prostration. Thoracic computed tomography revealed extensive ground-glass opacities in both the lungs. The polymerase chain reaction test of sputum for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was positive. She was treated with antiviral agents and steroid pulse therapy. However, her oxygen saturation gradually declined, and she died 10 days after hospitalization. The most important autopsy finding was fuzzily segmented diffuse alveolar damage (DAD) that expanded from the subpleural to the medial area. No remarkable changes were observed in organs other than the lungs. Therefore, pneumocytes were suggested as the primary target for SARS-CoV-2, which might explain why coronavirus infectious disease-19 is a serious condition. Thus, early treatment is essential to prevent viral replication from reaching a level that triggers DAD.

To clarify the significance of quantitative analyses of amyloid proteins in clinical practice and in research relating to systemic amyloidoses, we applied mass spectrometry-based quantification by isotope-labeled cell-free products (MS-QBIC) to formalin-fixed, paraffin-embedded (FFPE) tissues. The technique was applied to amyloid tissues collected by laser microdissection of Congo red-stained lesions of FFPE specimens. Twelve of 13 amyloid precursor proteins were successfully quantified, including serum amyloid A (SAA), transthyretin (TTR), immunoglobulin kappa light chain (IGK), immunoglobulin lambda light chain (IGL), beta-2-microglobulin (B2M), apolipoprotein (Apo) A1, Apo A4, Apo E, lysozyme, Apo A2, gelsolin, and fibrinogen alpha chain; leukocyte cell-derived chemotaxin-2 was not detected. The quantification of SAA, TTR, IGK, IGL, and B2M confirmed the responsible proteins, even when the immunohistochemical results were not decisive. Considerable amounts of Apo A1, Apo A4, and Apo E were deposited in parallel amounts with the responsible proteins. Quantification of amyloid protein by MS-QBIC is feasible and useful for the classification of and research on systemic amyloidoses.

Background The significance of anti-ribonucleoprotein (RNP) antibody and anti-Smith (anti-Sm) antibody remains unclear in patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MCTD). Methods Thirty patients were retrospectively enrolled in this study. They were all positive for antinuclear antibody (ANA) and anti-RNP antibody, were diagnosed with SLE(n = 25) or MCTD(n = 5), and underwent renal biopsy at our hospital between January 1990 and December 2014. These 30 patients were classified into 4 groups based on their anti-dsDNA and anti-Sm status. Renal histology was classified into 3 patterns, including pure subepithelial membranous nephropathy (MN), mesangial and/or subendothelial lesions (MES), and MN combined with MES. Results Comparison between groups A [dsDNA(-)and SM(-)] and B༻dsDNA(-)and SM(+)༽ revealed that group A was with pure MN(n = 5) + MN + MES(n = 4) + MES(n = 1) and normocomplementemia, while group B was with MES + MN(n = 2) + MES(n = 5) and hypocomplementemia. Comparison between groups C༻dsDNA(+)and SM(-)༽ and D༻dsDNA(+)and SM(+)༽showed that group C was with pure MES and normocomplementemia, while group D was with MN + MES(n = 4) + pure MES(n = 3) and hypocomplementemia. Among 10 patients in group A, all 5 patients with MCTD were categorized as pure MN, while the 5 patients with SLE were MN + MES or pure MES. Conclusion Among patients showing positivity for anti-RNP antibody alone, those with MCTD seem likely to develop pure MN, while those with SLE tend to have MES as well as MN.

AIMS Proliferative activity, evaluated from the Ki-67 index, is a strong prognostic factor in lung adenocarcinoma (LADC). Here, we optimised a procedure to measure the Ki-67 index and establish the best cut-off value. METHODS AND RESULTS We examined 342 stage I LADCs for the immunohistochemical expression of Ki-67 using different antibodies, MIB1 and SP6. The results revealed the superior specificity of SP6; therefore, SP6 was used in subsequent analyses. Slides were scanned with a virtual slide system. Using software, tumour cells were counted in a whole tumour. Thereafter, the tumour was evenly subdivided into 0.25-mm2 tiles. The frequency of positive cells was counted in each tile of an invasive area or the whole tumour. We calculated the number of tumour cells required to produce a 95% confidence interval (CI) 70% and CI of

Background Primary malignant melanoma of the lung (PML) is extremely rare. No precursor lesions of PML have been identified, and little is known about the genetic mutations associated with the disease. Typically, 15–20% of malignant melanomas possess NRAS gene mutations, but no cases of NRAS-mutated PML have been reported in the English literature. We present a case of PML involving an NRAS mutation. Case presentation Clinical summary A 74-year-old Japanese female presented with worsening dyspnea and was admitted to hospital. Computed tomography (CT) revealed a right lung (S10) mass and pleural dissemination. Cytology of the pleural effusion in the right lung was performed, and malignant melanoma or clear cell sarcoma was suspected. A dermatological examination and gallium scintigraphy were conducted to determine the primary tumor site, but no suspicious lesions, expect for the right lung mass, were found. After admission, CT showed complicating bilateral pneumonia, and an antibiotic drug was administered, but the pleural effusion got worse. About 2 weeks later, the patient died of respiratory failure and cardiac arrest. An autopsy was performed to determine the histological diagnosis. Autopsy findings A 26x15x20-mm black and pale yellow mass was found in the right lower lobe. Many disseminated nodules were found in the right lobe. The tumor had invaded the right diaphragm. Subcarinal lymph node metastasis was also detected. Immunohistochemically, the tumor cells exhibited positivity for S-100 and HMB45 staining. The patient was diagnosed with malignant melanoma. Sanger sequencing of the tumor detected an NRAS mutation. Conclusions We found an NRAS D54N mutation in PML, which has not been reported previously anywhere in the world. Previous reports indicated that most cases of PML can be classified into the triple-wild-type, but BRAF mutation status was only analyzed in a few cases. We should analyze the mutation patterns of PML to determine whether any subtypes other than the triple-wild-type exist. PML might be a form of de novo cancer.

A 79-year-old Japanese male with a history of type 2 diabetes mellitus (T2DM) for 16 years was admitted to evaluate possible renal disease. The T2DM was well controlled in this patient using nutrition therapy without the need for any diabetes medication, and both diabetes retinopathy and proteinuria were negative. At the age of 78 advanced colorectal cancer (stage IIIa) was diagnosed and laparoscopic-assisted colectomy was performed. Following this procedure, the patient began treatment with tegafur/gimeracil/oteracil (S-1), 80 mg twice daily for 28 days of 42-day cycle. The patient received S-1 for 6 months, during which time, serum albumin decreased from 3.0 g/dL to 1.1 g/dL, urinary protein increased from negative to 3.0 g/day, and serum creatinine increased from 0.9 mg/dL to 2.1 mg/dL. Treatment with S-1 was discontinued, and furosemide 180 mg and prednisolone 30 mg treatment was initiated; however, serum creatinine levels continued to increase to 7.2 mg/dL and proteinuria continued to increase reaching a nephrotic range. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity was decreased to 27.0%. Renal biopsy showed Kimmelstiel–Wilson nodules, while immunofluorescence intensity of IgG subclass was IgG1 dominant, which was not compatible with diabetic nephropathy (DN). Plasma exchange was not affected. However, hemodialysis was initiated. The results of this investigation suggest that when S-1 monotherapy is performed in the case with DN, rapidly progressive glomerulonephritis (RPGN) may develop due to a condition similar to thrombotic microangiopathy, even in patients with a minor risk factor of DN.

Tonsillectomy performed on patients with Immunoglobulin A glomerulonephritis (IgAN) improved the clinical remission rate as defined by urinary protein. But the number of times steroid pulse therapies (SP) should be administered remained poorly understood. Multicenter, observational, retrospective cohort study at four hospitals in the Tokyo metropolitan area between March 1981 and December 2013. We divided patients into two groups: those treated with SP three times and those treated without SP or with SP only once or twice, and we analyzed standard Cox proportional hazard model unadjusted and adjusted the confounding covariates to estimate the hazard ratio for the primary outcome, the 30% estimated decline in glomerular filtration rate, in four models: model 1, unadjusted; model 2, adjusted for age, sex, body mass index, estimated glomerular filtration rate, biopsy year, proteinuria, hematuria, Japanese historical grade, systolic blood pressure, smoking history, and diabetes as a comorbidity; model 3, adjusted for propensity score, which was estimated by multiple logistic regressions; model 4, multilevel mixed-effects parametric survival models, whose facilities comprise the second level. Patients that received three times SP therapy were significantly associated with better renal outcome compared with patients with less number of SP therapy (HR 0.66; 95% CI 0.37–1.17 in model 1, 0.40 (0.20–0.78) in model 2, 0.46 (0.25–0.88) in model 3, 0.36 (0.18–0.71) in model 4). For treatment of IgAN, SP administered three times after tonsillectomy was associated with better renal prognosis compared with SP administered only once or twice.

A 72-year-old Japanese woman with a history of autoimmune hepatitis-associated liver cirrhosis and portosystemic shunt was admitted to our hospital for evaluation of renal dysfunction, nephrotic range proteinuria, a high titer of anti-double-stranded DNA antibody, and hypocomplementemia. Renal biopsy showed massive subendothelial deposits (wire loop lesions), and class IV-G (A/C) lupus nephritis was diagnosed. Immunosuppressants, such as steroids (including intravenous methylprednisolone pulse therapy) and mycophenolate mofetil, could not prevent renal dysfunction. It was assumed that circulating immune deposits produced in the gastrointestinal tract entered the systemic circulation from the portal vein via the portosystemic shunt without hepatic clearance, resulting in massive subendothelial and mesangial accumulation compared to lupus nephritis patients without a shunt and causing renal injury. Keywords: Lupus nephritis, Systemic lupus erythematosus, Autoimmune hepatitis-associated liver cirrhosis, Portosystemic shunt, Wire loop lesion

A 42-year-old woman with systemic lupus erythematosus (SLE) was admitted to our hospital for evaluation of severe thrombocytopenia. She was treated with steroids, intravenous cyclophosphamide, intravenous immunoglobulin, and plasma exchange, but her thrombocytopenia did not improve. Renal biopsy showed class IV-S(C) + V lupus nephritis, according to the classification of the International Society of Nephrology/Renal Pathology Society. The PA-IgG and serum thrombopoietin (TPO) levels were elevated. Her thrombocytopenia responded to off-label administration of eltrombopag, which was discontinued after 42 months. At 18 months after stopping eltrombopag, the platelet count was 19.3 × 104/μL. Eltrombopag may be a therapeutic option for SLE patients with severe thrombocytopenia refractory to conventional therapy.