A case of eosinophilic granulomatosis with polyangiitis preceded by allergic bullous lesions.

A 62-year-old man with a history of diabetes mellitus was hospitalised with numbness of lower limbs, bullous lesions of the whole body, kidney dysfunction, presence of eosinophils, and elevated antineutrophil cytoplasmic antibodies to myeloperoxidase and anti-bullous pemphigoid 180 antibodies and was diagnosed with mononeuritis multiplex. Kidney and muscle biopsies showed vasculitis with fibrinoid necrosis, whereas skin biopsies showed only blister formation between the epidermis and dermis; a high eosinophilic infiltrate was present in all three tissues. These findings led to a diagnosis of eosinophilic granulomatosis with polyangiitis combined with allergic bullous lesions. Immunohistological examination indicated cytolytic eosinophils and extracellular traps, suggesting the presence of eosinophil extracellular trap cell death (eosinophil ETosis) in diseased tissue.

Relationship between MRI findings and renal histopathology in IgG4-related tubulointerstitial nephritis.

BACKGROUND: MRI is expected to be a valuable tool for evaluating disease activity in immunoglobulin G4 (IgG4)-related tubulointerstitial nephritis (IgG4-TIN). However, the correlation between MRI findings and renal histopathological findings remains to be elucidated. PURPOSE: This study aimed to clarify the correlation between MRI findings and renal histopathological findings in IgG4-TIN. METHOD: This retrospective cross-sectional study investigated 26 patients with biopsy-proven IgG4-TIN who underwent simultaneous percutaneous kidney biopsies and abdominal MRI examinations at Toranomon Hospital or Toranomon Hospital Kajigaya between December 2007 and November 2022. We reviewed kidney biopsy specimens and scored the degree of inflammatory cell infiltration and interstitial fibrosis. We assessed abdominal MRI, specifically examining T1WI, T2WI, and DWI, for the presence of abnormal signals in the inferior pole of the kidney on the side where the kidney biopsy was performed. Spearman's correlation coefficient test was conducted to examine the relationship between the images and histological findings. RESULT: For T1WI, eight cases showed a positive low-intensity signal, and 18 cases were negative. For T2WI, 19 cases were positive for a low-intensity signal, and seven cases were negative. In DWI, 23 cases were positive for a high-intensity signal, and one was negative. T1WI low-intensity signal and T2WI low-intensity signal were significantly correlated with interstitial fibrosis score (correlation coefficient 0.52 and 0.64). DWI revealed IgG4-TIN detected IgG4-TIN lesions with the highest sensitivity; however, the correlation with inflammatory cell infiltration score was not significant. CONCLUSION: Low-intensity signal on T2WI is useful for predicting the degree of fibrosis in IgG4-TIN.

A case report of dipeptidyl peptidase 4 inhibitor-related kidney disease combined with renal cancer.

A kidney biopsy was performed in a 64-year-old woman with type 2 diabetes mellitus and less than 1 g of proteinuria who rapidly progressed to end-stage renal failure after approximately 2 years of treatment with two dipeptidyl peptidase 4 (DPP-4) inhibitors for type 2 diabetes mellitus. The biopsy revealed not only a coincidental diagnosis of renal cell carcinoma, which was not evident on pre-biopsy computed tomography, but also severe thrombotic microangiopathy (TMA)-like glomerular endothelial cell damage in the noncancerous areas. These results suggest that DPP4 inhibitors may have been involved in two kidney diseases.

Renal cell carcinoma preceded by a rheumatoid­like paraneoplastic syndrome: A case report.

A man with polycystic kidney disease and a history of renal transplantation at the age of 55 years developed seronegative rheumatoid arthritis (RA) at the age of 68 years. Treatment with a biological derivative led to remission; however, the patient relapsed 2 years later. After being switched to baricitinib, the patient again achieved remission. After 2 years, when the patient was aged 72 years, RA recurred, and the right native kidney became enlarged due to the presence of a large tumor. Surgical nephrectomy was performed, and the tumor was classified as renal cell carcinoma (RCC), not otherwise specified. The cancer tissue comprised sarcomatoid and rhabdoid cells with marked neutrophil infiltration, and the tumor cells were positive for interleukin-6. The patient, aged 73 years, experienced a resolution of joint pain following surgical intervention; however, they died because of systemic metastases ~10 weeks post-operation. Based on the clinical course, the RA-like lesions and subsequent RCC were considered to represent a paraneoplastic syndrome.

Long-term clinicopathological characteristics of TAFRO syndrome and its relapse: a case series study.

Introduction: This study aimed to analyze the clinical course of TAFRO syndrome in patients through extended follow-up, focusing on recurrent cases and long-term remission. Methods: This was a retrospective case series study. We assessed the clinical course of patients diagnosed with TAFRO syndrome between January 2012 and September 2022 at Toranomon Hospital or Toranomon Hospital Kajigaya, excluding those patients who died during the initial hospitalization. Results: Twelve patients were included. Baseline characteristics, laboratory findings, treatment modalities, and outcomes were assessed. During the median follow-up period of 1474 days, two patients experienced recurrence following a reduction in tocilizumab (TCZ) dose, whereas two achieved remission for >400 days without TCZ treatment. The remaining eight patients maintained remission under the continued TCZ therapy. Recurrence diagnosis was complicated by the non-simultaneous presentation of the five manifestations of TAFRO syndrome. The patients who experienced recurrence showed milder manifestations and faster recovery than the initial onset. Glomerular endotheliopathy was evident in kidney biopsies during recurrence, which was similar to the initial presentation. In a case where only inflammation preceded other manifestation, a kidney biopsy was pivotal in distinguishing TAFRO syndrome relapse from other inflammatory conditions such as infection. Pretreatment serum IL-6 levels were within the reference range only in patients who experienced long-term remission without TCZ treatment. Conclusions: This is the first study to perform kidney biopsies on recurrent TAFRO cases, highlighting recurrence after TCZ dosage reduction, non-simultaneous manifestation of symptoms, the utility of kidney biopsies in recurrence diagnosis, and potential non-IL-6 pathogenesis factors. Pretreatment serum IL-6 levels may help identify patients suitable for maintenance therapy without TCZ. Further investigation is warranted to identify stratified treatment approaches based on individual etiologic factors.

Development of a nomogram to predict recurrence scores obtained using Oncotype DX in Japanese patients with breast cancer.

BACKGROUND: Chemotherapy is crucial for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and its survival benefits may outweigh adverse events. Oncotype DX (ODX) assesses this balance; however, it is expensive. Using nomograms to identify cases requiring ODX may be economically beneficial. We aimed to identify clinicopathological variables that correlated with the recurrence score (RS) and develop a nomogram that predicted the RS. METHODS: We included 457 patients with estrogen receptor-positive, HER2-negative breast cancer with metastases in fewer than four axillary lymph nodes who underwent surgery and ODX at our hospital between 2007 and 2023. We developed nomograms and internally validated them in 310 patients who underwent surgery between 2007 and 2021 and validated the model's performance in 147 patients who underwent surgery between 2022 and 2023. RESULTS: Logistic regression analysis revealed that progesterone receptor (PgR) level, histological grade (HG), and Ki67 index independently predicted the RS. A nomogram was developed using these variables to predict the RS (area under the curve [AUC], 0.870; 95% confidence interval [CI], 0.82-0.92). The nomogram was applied to the model validation group (AUC, 0.877; 95% CI, 0.80-0.95). When the sensitivity of the nomogram was 90%, the model was able to identify 52.3% low-RS and 41.2% high-RS cases not requiring ODX. CONCLUSIONS: This was the first nomogram model developed based on data from a cohort of Japanese women. It may help determine the indications for ODX and the use of nomogram to identify cases requiring ODX may be economically beneficial.

A case of immunoglobulin G4-related kidney disease manifesting after dipeptidyl peptidase-4 inhibitor treatment.

A 68-year-old man with type 2 diabetes mellitus was admitted with decreased renal function. He had high IgG4 (1070 mg/dL) and hypocomplementemia (CH50, 25 U/mL). Kidney biopsy showed tubulointerstitial nephritis with IgG4-positive plasma cell infiltration. Four years later, a second kidney biopsy revealed a new manifestation of membranous nephropathy and tubulointerstitial nephritis with exacerbated fibrosis formation. Six years later, the patient developed bullous pemphigoid, which was thought to be caused by DPP4 inhibitors, so DPP4 inhibitor treatment was discontinued. The use of DPP4 inhibitors correlated with changes in renal function, and the patient was diagnosed with IgG4-related kidney disease related to DPP4 inhibitors.

A case of hypertensive emergency with alveolar hemorrhage and thrombotic microangiopathy.

A 28-year-old woman with a 5-year history of untreated hypertension was admitted for respiratory distress, hemoptysis, and retinopathy. Computed tomography showed diffuse plaques in both lung fields. Acute kidney injury, hemolytic anemia, and thrombocytopenia were noted. Kidney biopsy showed thrombosis with fibrinoid necrosis and edematous intimal thickening and luminal narrowing of the small renal artery, indicating thrombotic microangiopathy; the majority of glomeruli were collapsed. After 8 weeks of treatment with antihypertensive drugs, serum creatinine decreased to 1.0 mg/dL, and the patient recovered. In the absence of any other underlying disease, malignant nephrosclerosis associated with a hypertensive emergency was diagnosed.

De novo posttransplant membranous nephropathy after COVID-19 vaccination 9 years after renal transplantation in a patient with polycystic kidney disease.

A 63-year-old man with polycystic kidney disease underwent kidney transplantation from his wife. Nine years later, after the first and second doses of the COVID-19 vaccination, he developed proteinuria, hematuria, and elevated C-reactive protein. Kidney biopsy 7 months after the initial appearance of proteinuria showed immunoglobulin (Ig)-G granular stain, predominantly IgG1, and spike formation in the glomerular basement membrane. Electron microscopy revealed mainly subepithelial deposits, which corresponds to membranous nephropathy (MN) stage 3 of the Ehrenreich-Churg classification indicating chronic disease, but it also showed electron-dense deposits and endothelial damage. Because a kidney biopsy was performed 1 h after renal transplantation and a biopsy of the patient's native kidney showed intact glomeruli, atypical de novo posttransplant membranous nephropathy (MN) was diagnosed, and a close relationship with COVID-19 vaccination was assumed. Clinicians should consider the involvement of COVID-19 vaccination in de novo posttransplant MN with unclear pathogenesis.

Is Podocytopathy Associated with Gross Hematuria after COVID-19 Vaccination in Patients with Immunoglobulin A Nephropathy?

We experienced three cases of a fever and subsequent severe, prolonged gross hematuria after COVID-19 vaccination. A kidney biopsy revealed immunoglobulin A (IgA) nephropathy, and electron microscopy showed two types of podocytopathy (podocyte damage): loss of foot processes from the glomerular basement membrane and foot process effacement. Mesangial interposition was also present in cases 1 and 3 but not in case 2. Podocytopathy is known to be a cause of proteinuria; however, the reactions to COVID-19 vaccination described here suggest that it may also be related to hematuria in IgA nephropathy.

Gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder after kidney transplantation: A case report.

We report on a 53-year-old Japanese man diagnosed with gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder (B-PTLD) after endoscopy for gastric discomfort 28 months after the patient underwent renal transplantation in Ethiopia. Serum Epstein-Barr virus (EBV) tests were negative before transplantation, but the tumor cells collected from a gastric biopsy showed positive EBV-encoded small RNAs (EBER) at B-PTLD onset. Intensive treatment started with R(rituximab)-CHOP therapy and continued with DA-EPOCH-R therapy has been effective, and relapse has not yet occurred. Burkitt lymphoma has a poor prognosis, but B-PTLD may be effectively treated with high-dose chemotherapy. This is a rare case of gastric B-PTLD in a Japanese patient.

Autopsy of a 45-year-old Man with Liver Failure Due to Polycystic Liver Disease.

A 37-year-old man with autosomal polycystic kidney disease (ADPKD) was admitted to our hospital with a liver volume of 8,000 cm3. Hepatic arterial embolization was performed using a microcoil but was ineffective. Eight years later, the hepatomegaly progressed to liver failure and death. At autopsy, the liver weighed 21.5 kg, and the entire liver had been replaced by cysts; in the few remaining areas of liver parenchyma, microscopic, small cysts of various sizes and fibrosis were evident, with only a few normal hepatocytes observed. Hepatic arterial branches developed; however, the portal vein could not be observed.

Immunoglobulin G4-related Dacryoadenitis Successfully Treated with Baricitinib.

A 48-year-old woman visited our hospital because of bilateral lacrimal gland enlargement. Her serum immunoglobulin G4 (IgG4) level was high, and positron emission tomography-computed tomography showed significant positive findings in the bilateral lacrimal gland. A biopsy revealed a considerable increase in IgG4/CD138, leading to a diagnosis of IgG4-related dacryoadenitis. The disease did not respond to steroid therapy, so treatment was started with baricitinib because of exacerbation of the original atopic dermatitis and dacryoadenitis after the second dose of the coronavirus disease 2019 (COVID-19) vaccine. Baricitinib was effective for resolving both dermatitis and dacryoadenitis, and steroids were able to be discontinued. The IgG4 level also improved.

Anti-factor H antibody-positive C3 glomerulonephritis secondary to poststreptococcal acute glomerulonephritis with diabetic nephropathy.

Poststreptococcal acute kidney glomerulonephritis (PSAGN) has been seen in adults in recent years, especially in patients with type 2 diabetes mellitus, and the renal prognosis has not always been good. There have been cases of PSAGN in which complete remission was not achieved and hematuria and proteinuria persisted, leading to end-stage renal disease. Previous reports showed that the patients subjected to PSAGN have an underlying defect in regulating the alternative pathway of complement, and they identified that antibodies to the C3 convertase, C3 nephritic factors (C3NeF), are involved. C3NeF stabilizes C3 convertase, sustains C3 activation, and causes C3 glomerulonephritis (C3GN). On the other hand, factor H is a glycoprotein that suppresses the overactivation of the alternative pathway by decaying the C3 convertase. Anti-factor H (aFH) antibodies interfere with factor H and cause the same activation of the alternative pathway as C3NeF. However, a limited number of reports describe the clinical course of C3GN with aFH antibodies. We encountered a 49-year-old Japanese man with type 2 diabetes mellitus. He was referred to our hospital because of his elevated serum creatinine, proteinuria, hematuria, and developed edema on both legs. He was diagnosed as PSAGN at the first kidney biopsy, and his renal function improved and edema and hematuria disappeared, but proteinuria persisted after 5 months. He was diagnosed as C3GN at the second kidney biopsy. In our case, no C3NeF was detected. However, a high titer of aFH antibodies was detected in stored serum from the initial presentation, providing a unified diagnosis of aFH antibody-positive C3GN secondary to PSAGN. He progressed to end-stage renal disease (ESRD) and hemodialysis was started. The persistence of high levels of aFH autoantibodies may have caused C3GN secondary to PSAGN due to activating the alternative complement pathway, which eventually worsened the nephropathy and led to ESRD.

Histologically Proven Recurrent Synovitis after Nivolumab Treatment.

A 58-year-old woman with rheumatoid arthritis was diagnosed with methotrexate-associated Hodgkin lymphoma. After receiving several chemotherapy regimens, she started nivolumab treatment. Two weeks later, she was hospitalized with worsening finger, wrist, and elbow joint pain. A synovial biopsy of the wrist joint showed villous synovial proliferation and linear infiltration of CD68-/CD3-positive T cells (with more CD8 than CD4 T cells) but no CD20-positive B cells or CD138-positive macrophages. These findings corresponded to synovitis associated with immune-related adverse events, which are induced mainly by T cells and are different from typical rheumatoid arthritis (RA), in which B cells play a central role.

Gene expression profiling of pancreatic neuroendocrine carcinoma and mixed neuroendocrine-non-neuroendocrine neoplasm.

Pancreatic neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) are rare pancreatic malignant tumors, and comprehensive gene analyses are scarce. In this study, six NECs and six MiNENs were collected, immunohistochemistry for synaptophysin, chromogranin A, INSM1, Ki-67, and Rb was conducted, and KRAS mutational status was examined. Among these cases, comprehensive gene expression analysis of oncogene pathways using nCounter® were performed with six NECs and four MiNENs, and those data were compared with that of three pancreatic ductal adenocarcinomas (PDACs), with that of three normal pancreatic ducts, and with each other. By dividing NEC and MiNEN cases into KRAS-mutated group and KRAS-wild group, the difference of clinicopathological data and gene expression profiling data were examined between the two groups. Compared to the data of normal pancreatic epithelium, all 13 cancer-related pathways were upregulated in PDAC, MiNEN, and NEC group with more upregulation in this order. Compared to the data of PDAC, genes of DNA Damage repair pathway was most upregulated both in NECs and MiNENs. Regarding the difference between KRAS-mutated and KRAS-wild groups, several genes were differentially expressed between the two, where MMP7 was the upregulated gene with highest p-value and NKD1 was the downregulated gene with highest p-value in KRAS-mutated group. From the extent of upregulation of 13 pathways, MiNEN was considered more progressed stage than PDAC, and NEC was considered more progressed than MiNEN. From the comparison of KRAS-mutated and KRAS-wild NECs and MiNENs, several differentially expressed genes were identified in this study.

A case of bullous pemphigoid and renal disease after dipeptidyl peptidase 4 inhibitor administration.

A 62-year-old man with type 2 diabetes was admitted because of a decrease in estimated glomerular filtration rate from 72 to 17.5 mL/min/1.73 m2 in 10 years and development of widespread bullous skin lesions. His hemoglobin A1c level had been maintained at 6.0-7.0% for 10 years with a dipeptidyl peptidase (DPP)-4 inhibitor. Skin biopsy showed typical bullous pemphigoid, and kidney biopsy showed tubulointerstitial nephritis with eosinophilic infiltration and glomerular endothelial cell proliferation. After discontinuing the DPP-4 inhibitor, skin lesions improved, and renal decline slowed. This case indicates that DPP-4 inhibitors can cause not only skin lesions but also renal disease.

A Case of Glomerular Microangiopathy-like Nephropathy Caused by Hyperthyroidism.

A 49-year-old Japanese woman was admitted to our hospital with weight loss of 15 kg, nephrotic-range proteinuria (4.5 g/g.Cre), and hematuria over a 6-month period. She had received two doses of the COVID-19 vaccine one year before the onset of the disease, after which the estimated glomerular filtration rate increased. Laboratory tests and other tests led to a diagnosis of hyperthyroidism, and a kidney biopsy showed thrombotic microangiopathy-like glomerular microangiopathy comprising mainly glomerular endothelial cell damage. Thiamazole (30 mg) was started for the hyperthyroidism. Three months later, the thyroid function normalized, and two months later, the proteinuria and hematuria disappeared, suggesting that COVID-19 vaccination and these events were related.

IL25+ macrophages are a key determinant of treatment resistance of IL17RB+ breast cancer.

Recurrence and metastasis are resistant to multimodal treatments, and are the major causes of death in breast cancer. Accumulating evidence suggests that the IL17RB signaling pathway plays a key role in progression and metastasis of breast cancer. Clinical significance of the IL17RB positivity in tumor tissues has been also reported as a poor prognostic factor in breast cancer. However, the molecular mechanisms underlying the poor prognosis of patients with IL17RB+ breast cancer, particularly the immunological aspects, remain to be fully elucidated, and elimination of the IL17RB+ tumors has not been practically achieved in clinical settings. In this study, we identified a distinct molecular mechanism underlying the intractability of the IL17RB+ tumors through tumor biological and immunological investigation using mouse and human breast cancer cells transduced with il17rb gene. IL17RB overexpression in tumor cells confers cancer stemness, including high invasive and self-renewal abilities, and high resistance to CDK4/6 inhibitors that have been considered as a promising agent for treating breast cancer despite the limited efficacy. In the mice implanted with the IL17RB+ tumors, IL25+ macrophages (Møs) are expanded locally in tumor tissues and systemically in spleen, and promote the IL17RB+ tumor progression directly by intensifying the tumor functions, and indirectly via impairment of anti-tumor effector CTLs and NK cells utilizing the secreted IL25. Blocking IL25 with the specific mAb, however, interferes the adverse events, and successfully elicits significant anti-tumor efficacy in combination with CDK4/6 inhibitors providing better survival in murine mammary tumor models. These results suggest that the IL25+ Mø is a key determinant of building the solid treatment resistance of the IL17RB+ breast cancer. Targeting the IL17RB-IL25 axis may be a promising strategy to improve clinical outcomes in the treatment of breast cancer patients, particularly with IL17RB+ tumors.