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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.

We present a 51-year-old male patient with a history of Child-Pugh Grade B alcoholic liver cirrhosis (ALC) who developed renal impairment (serum creatinine of 2.00 mg/dL) and nephrotic syndrome (a urinary protein level of 4.35 g/gCr). The patient was diagnosed with immunoglobulin A nephropathy (IgAN) associated with ALC based on findings from comprehensive evaluations, including markedly elevated serum IgA levels (883.7 mg/dL), a kidney biopsy revealing significant IgA deposition in the para-mesangial area, and a liver diagnosis showing long-standing advanced ALC. Our treatment approach involved initiating dapagliflozin therapy, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, alongside strict alcohol abstinence. Remarkably, the patient demonstrated a dramatic reduction in proteinuria within one week of dapagliflozin administration. No hypoglycemic events were observed. This case adds valuable clinical insights into the potential therapeutic role of SGLT2 inhibitors in IgAN associated with ALC. Specifically, in cases where conventional steroid therapies may be contraindicated due to coexisting comorbidities such as diabetes or obesity, dapagliflozin emerges as a potentially efficacious alternative. Further investigations are warranted to validate these preliminary observations.

Abstract Background Rectal neuroendocrine neoplasms can induce liver metastasis. However, few reports exist on the associated long-term recurrence rates. We report a case of liver metastasis identified 15 years after rectal neuroendocrine neoplasm resection. Case presentation A 50-year-old woman was on semi-annual follow-up after undergoing mastectomy for breast cancer (pT1N0M0) and low anterior resection for grade 1 rectal neuroendocrine neoplasm (pT1b, ly1, v1). Fifteen years postoperatively, a 7-mm hyperechoic mass was identified at liver segment 6. Magnetic resonance imaging revealed a slight growth of the mass. Positron emission tomography/computed tomography revealed radiotracer accumulation in the lesion. Laparoscopic hepatectomy was performed. The histopathological diagnosis was grade 2 neuroendocrine neoplasm. The pathological findings and clinical course indicated the tumor originated in the rectum. Conclusions Our findings highlight the need to reassess the optimal postoperative follow-up period for patients with rectal neuroendocrine neoplasm.

A 63-year-old Japanese woman was admitted to our institute for the evaluation of proteinuria. The patient was diagnosed with medullary sponge kidney, distal type renal tubular acidosis, and renal infection at the age of 37. Thereafter, the patient had repeated renal infections. Urinary proteinuria appeared at around the age of 61 and gradually increased up to 1.0 g daily. In the same period, glycated hemoglobin (HbA1c) increased to 7.0%. On kidney biopsy, light microscopy showed a nodular glomerular lesion and capsular drop. Linear staining for immunoglobulin G along the glomerular basement membrane was observed by immunofluorescence. Electron microscopy showed thickening of the glomerular basement membrane to a width of 800–900 nm. A class III glomerular lesion was diagnosed according to the Tervaert classification. This case indicates that mild but prolonged hyperglycemia for more than 10 years may also contribute to the formation of nodular lesions, although long-standing repeated chronic renal infection and chronic acidosis may have been a precipitating factor in the formation of diabetic nephropathy, including nodular glomerular lesions. This hypothesis is of interest because nodular lesions specific to diabetes are currently considered to be associated with long-term severe hyperglycemia.

Introduction The effectiveness of nivolumab plus ipilimumab for metastatic renal cell carcinoma with inferior vena cava tumor thrombus remains unclear. Case presentation A 75‐year‐old male was diagnosed with metastatic renal cell carcinoma with inferior vena cava tumor thrombus and treated with nivolumab plus ipilimumab. The renal mass and thrombus regressed and all pulmonary nodules except for one lesion diminished. To avoid thrombotic complications, radical nephrectomy and thrombectomy were performed. No viable malignant cells were revealed histopathologically. Although nivolumab was continued after the surgical interventions, the remaining lesion did not change. Considering the discontinuation of nivolumab, metastasectomy was performed, and no viable malignant cells were revealed histopathologically. There has been no recurrence after the discontinuation. Conclusion Nivolumab plus ipilimumab could have effectiveness for metastatic renal cell carcinoma with inferior vena cava tumor thrombus.

PurposePositron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) are useful for detecting axillary lymph node (ALN) metastasis in invasive ductal breast cancer (IDC); however, there is limited clinical evidence to demonstrate the effectiveness of the combination of PET/CT plus MRI. Further axillary surgery is not recommended against ALN micrometastasis (lesion ≤2 mm) seen in sentinel lymph nodes, especially for patients who received proper adjuvant therapy. We aimed to evaluate the efficacy of a prediction model based on PET/CT plus MRI for ALN macrometastasis (lesion >2 mm) and explore the possibility of risk stratification of patients using the preoperative PET/CT plus MRI and biopsy findings.Materials and methodsWe retrospectively investigated 361 female patients (370 axillae; mean age, 56 years ± 12 [standard deviation]) who underwent surgery for primary IDC at a single center between April 2017 and March 2020. We constructed a prediction model with logistic regression. Patients were divided into low-risk and high-risk groups using a simple integer risk score, and the false negative rate for ALN macrometastasis was calculated to assess the validity. Internal validation was also achieved using a 5-fold cross-validation.ResultsThe PET/CT plus MRI model included five predictor variables: maximum standardized uptake value of primary tumor and ALN, primary tumor size, ALN cortical thickness, and histological grade. In the derivation (296 axillae) and validation (74 axillae) cohorts, 54% and 61% of patients, respectively, were classified as low-risk, with a false-negative rate of 11%. Five-fold cross-validation yielded an accuracy of 0.875.ConclusionsOur findings demonstrate the validity of the PET/CT plus MRI prediction model for ALN macrometastases. This model may aid the preoperative identification of low-risk patients for ALN macrometastasis and provide helpful information for PET/MRI interpretation.

A 59-year-old Japanese woman with a 22-year history of long-term hemodialysis was admitted to our hospital for further examination of hyperglycemia and anemia. Five months before hospitalization, her fasting plasma glucose value was 99 mg/dL and her glycated hemoglobin was 5.7%. On admission, her fasting plasma glucose value was 873 mg/dL, glycated hemoglobin was 16.2%, C-peptide reactivity was 22.3 ng/mL (reference range, 0.5-3.0), and homeostasis model assessment of insulin resistance (HOMA-IR) was 10.6 (reference range,

Autosomal dominant tubulointerstitial kidney disease subtype hepatocyte nuclear factor 1β (ADTKD-HNF1B) is a hereditary disease caused by variants of HNF1B that is characterized by a family history of tubulointerstitial nephropathy with concomitant diabetes mellitus. We report on a Japanese man in his early 40s who had ADTKD-HNF1B diagnosed. He had a reduced glomerular filtration rate, borderline diabetes mellitus, multiple small cysts in his bilateral kidneys, and pancreatic hypoplasia. He also had a family history of diabetes and kidney cystic lesions. These phenotypes represent ADTKD-HNF1B and genetic analysis revealed a missense variant of HNF1B. Kidney biopsy demonstrated not only tubulointerstitial fibrosis but also abnormal mitochondrial morphology in tubular cells, a novel finding.

A 71-year-old Japanese woman with a history of rheumatoid arthritis of 50 years’ duration was admitted to our hospital with refractory diarrhea. Endoscopic biopsy revealed AA amyloid deposition in the large intestine. Although the patient had been prescribed 5 tumor necrosis factor inhibitors over the past 10 years, rheumatoid arthritis was poorly controlled, with a Disease Activity Score 28 using C-reactive protein score of 6.52 on admission. Treatment with tocilizumab (8 mg/kg every 2 weeks) was initiated, but this was ineffective. After 3 months, abatacept (cytotoxic T-lymphocyte–associated antigen 4 immunoglobulin) was initiated (750 mg/mo) and the patient’s diarrhea began to improve. After 3 months of abatacept treatment, serum albumin, C-reactive protein, and serum amyloid A levels had all decreased to within normal ranges. After 3 years of abatacept treatment, a repeat biopsy of the large intestine revealed a marked improvement in amyloid deposition. Interleukin 6 is a key factor in AA amyloid formation, but this case suggests that T-cell activation increases the production of cytokines (including interleukin 6) via a mechanism involving cytotoxic T-lymphocyte–associated antigen 4, resulting in a second key factor of AA amyloid formation.

Abstract Background While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy. Methods To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions. Results The study population consisted of 277 patients who had received a median of 10 doses (range, 1–79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77–4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF. Conclusions We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) may manifest non-nephrotic range proteinuria, but is rarely complicated with nephrotic syndrome. Limited number of reports describe the histology of ADPKD with nephrotic syndrome in detail. Case presentation We encountered a 23-year-old man with polycystic kidney disease (PKD) with small kidney volume and nephrotic syndrome, which eventually progressed to end-stage renal disease. Renal histology showed typical focal segmental glomerulosclerosis and remarkable glomerular cyst formation, but did not reveal tubular cysts. PKD1 mutation was detected in him and his father, who also had PKD with small kidney volume. Conclusions In contrast to tubular cysts which develop along ADPKD progression, glomerular cysts may likely be associated with ADPKD with slower volume progression manifesting small kidney volume. Although previous investigations report that ADPKD with smaller kidney volume is attributed to slower decline in renal function, coexistence of nephrotic-range proteinuria implies complication of other glomerular diseases and needs histological evaluation since it may lead to poor renal outcome.

Abstract 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.

Abstract Background Pseudoprogression refers to a specific pattern of response sometimes observed in malignant melanoma patients receiving treatment with immune-checkpoint inhibitors. Although cases with pseudoprogression documented once have been reported previously, there have been no case reports yet of pseudoprogression events documented twice during treatment. Case presentation A 55-year-old man underwent surgery for locally advanced esophageal malignant melanoma and received postoperative adjuvant interferon therapy. However, he presented with multiple liver and bone metastases at 6 months after the surgery, and was initiated on treatment with nivolumab 2 mg/kg every 3 weeks as the first-line treatment for recurrent disease. Follow-up computed tomography revealed that the liver metastases initially increased transiently in size, but eventually regressed. However, while the liver metastases continued to shrink, a new peritoneal nodule emerged, that also subsequently shrinked during the course of treatment with nivolumab. With only grade 1 pruritus, the patient continues to be on nivolumab treatment at 15 months after the induction therapy, with no progression observed after the second episode of pseudoprogression in the liver and peritoneal nodule. Conclusions We present the case of a patient with metastatic malignant melanoma who showed the unique response pattern of serial pseudoprogression during treatment with nivolumab. This case serves to highlight the fact that development of a new lesion may not always signify failure of disease control during treatment with nivolumab.

Octamer transcription factor 1 (OCT1) is a transcriptional factor reported to be a poor prognostic factor in various cancers. However, the clinical value of OCT1 in breast cancer is not fully understood. In the present study, an immunohistochemical study of OCT1 protein was performed using estrogen receptor (ER)-positive breast cancer tissues from 108 patients. Positive OCT1 immunoreactivity (IR) was associated with the shorter disease-free survival (DFS) of patients (p = 0.019). Knockdown of OCT1 inhibited cell proliferation in MCF-7 breast cancer cells as well as its derivative long-term estrogen-deprived (LTED) cells. On the other hand, the overexpression of OCT1 promoted cell proliferation in MCF-7 cells. Using microarray analysis, we identified the non-structural maintenance of chromosomes condensin I complex subunit H (NCAPH) as a novel OCT1-taget gene in MCF-7 cells. Immunohistochemical analysis showed that NCAPH IR was significantly positively associated with OCT1 IR (p < 0.001) and that positive NCAPH IR was significantly related to the poor DFS rate of patients (p = 0.041). The knockdown of NCAPH inhibited cell proliferation in MCF-7 and LTED cells. These results demonstrate that OCT1 and its target gene NCAPH are poor prognostic factors and potential therapeutic targets for patients with ER-positive breast cancer.

There have been a limited number of biopsy-based studies on diabetic nephropathy, and therefore the clinical importance of renal biopsy in patients with diabetes in late-stage chronic kidney disease (CKD) is still debated. We aimed to clarify the renal prognostic value of pathological information to clinical information in patients with diabetes and advanced CKD.We retrospectively assessed 493 type 2 diabetics with biopsy-proven diabetic nephropathy in four centers in Japan. 296 patients with stage 3-5 CKD at the time of biopsy were identified and assigned two risk prediction scores for end-stage renal disease (ESRD): the Kidney Failure Risk Equation (KFRE, a score composed of clinical parameters) and the Diabetic Nephropathy Score (D-score, a score integrated pathological parameters of the Diabetic Nephropathy Classification by the Renal Pathology Society (RPS DN Classification)). They were randomized 2:1 to development and validation cohort. Hazard Ratios (HR) of incident ESRD were reported with 95% confidence interval (CI) of the KFRE, D-score and KFRE+D-score in Cox regression model. Improvement of risk prediction with the addition of D-score to the KFRE was assessed using c-statistics, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI).During median follow-up of 1.9 years, 194 patients developed ESRD. The cox regression analysis showed that the KFRE,D-score and KFRE+D-score were significant predictors of ESRD both in the development cohort and in the validation cohort. The c-statistics of the D-score was 0.67. The c-statistics of the KFRE was good, but its predictive value was weaker than that in the miscellaneous CKD cohort originally reported (c-statistics, 0.78 vs. 0.90) and was not significantly improved by adding the D-score (0.78 vs. 0.79, p = 0.83). Only continuous NRI was positive after adding the D-score to the KFRE (0.4%; CI: 0.0-0.8%).We found that the predict values of the KFRE and the D-score were not as good as reported, and combining the D-score with the KFRE did not significantly improve prediction of the risk of ESRD in advanced diabetic nephropathy. To improve prediction of renal prognosis for advanced diabetic nephropathy may require different approaches with combining clinical and pathological parameters that were not measured in the KFRE and the RPS DN Classification.

Many of the tripartite motif (TRIM) proteins function as E3 ubiquitin ligases and are assumed to be involved in various events, including oncogenesis. In regard to tripartite motif-containing 44 (TRIM44), which is an atypical TRIM family protein lacking the RING finger domain, its pathophysiological significance in breast cancer remains unknown. We performed an immunohistochemical study of TRIM44 protein in clinical breast cancer tissues from 129 patients. The pathophysiological role of TRIM44 in breast cancer was assessed by modulating TRIM44 expression in MCF-7 and MDA-MB-231 breast cancer cells. TRIM44 strong immunoreactivity was significantly associated with nuclear grade (p = 0.033), distant disease-free survival (p = 0.031) and overall survival (p = 0.027). Multivariate analysis revealed that the TRIM44 status was an independent prognostic factor for distant disease-free survival (p = 0.005) and overall survival (p = 0.002) of patients. siRNA-mediated TRIM44 knockdown significantly decreased the proliferation of MCF-7 and MDA-MB-231 cells and inhibited the migration of MDA-MB-231 cells. Microarray analysis and qRT–PCR showed that TRIM44 knockdown upregulated CDK19 and downregulated MMP1 in MDA-MB-231 cells. Notably, TRIM44 knockdown impaired nuclear factor-kappa B (NF-κB)-mediated transcriptional activity stimulated by tumor necrosis factor α (TNFα). Moreover, TRIM44 knockdown substantially attenuated the TNFα-dependent phosphorylation of the p65 subunit of NF-κB and IκBα in both MCF-7 and MDA-MB-231 cells. TRIM44 would play a role in the progression of breast cancer by promoting cell proliferation and migration, as well as by enhancing NF-κB signaling.

We performed a postmortem bone histomorphometric analysis of iliac bone on a 38-year-old man who had been bedridden for the nine months before his death because of orthostatic hypotension and severe malnutrition related to amyloidκ-light-chain amyloidosis. Cancellous bone volume was greatly decreased, with a trabecular bone volume to total bone volume ratio of 6.77% (normal value, 19.56% ± 5.62%). Trabecular thinning was also apparent, with a trabecular thickness of 78.9 μm (normal value, 131.3 ± 28.1 μm), although the trabecula was still preserved. Cortical bone width was normal, although areas of porosity area were clear throughout the cortical bone. Our findings indicate that immobilization-related osteoporosis may be closely associated with loss of cancellous bone.