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Introduction Double‐negative prostate cancer, an androgen receptor–independent prostate cancer without features of neuroendocrine tumors, is refractory to treatment but could be an ideal candidate for individualized treatment. Case presentation An 85‐year‐old patient with metastatic castration‐resistant prostate cancer without prostate‐specific antigen progression presented with local recurrence and liver and lung metastases 6 months after orchiectomy and apalutamide. A liver tumor biopsy led to a diagnosis of double‐negative prostate cancer. FoundationOne® CDx showed BRCA2 mutation and high tumor mutation burden. Olaparib and pembrolizumab were administered sequentially, and the patient responded to each treatment for 5 months until radiographic progression. Conclusion Sequential use of olaparib and pembrolizumab may be effective for double‐negative prostate cancer with BRCA2 mutations and high tumor mutation burden.

Background/Aims: Asymptomatic esophageal eosinophilia (aEE), characterized by eosinophil infiltration in the esophagus without clinical symptoms, has been reported as a precursor of eosinophilic esophagitis (EoE). Nevertheless, no report exists on the long-term clinical course of the disease. Therefore, this study aimed to investigate the long-term clinical course of aEE over 5 years, including the symptomatic conversion rate and the effect of treatments. Methods: We reviewed 28 patients with aEE who had been followed up for over 5 years with endoscopic monitoring. The basal characteristics of patients were compared with those of 58 patients diagnosed with EoE during the same period. Patients’ clinicopathological findings were collected and examined. Results: No significant differences in basal characteristics and histopathological findings were observed between the patients with aEE and those with EoE. The median follow-up duration was 64 months. Among the 28 patients with aEE, seven were treated with proton pump inhibitor or potassium-competitive acid blocker and the remaining 21 opted for follow-up with no medication. Among the treated patients, six (85.7%) exhibited endoscopic and pathologic improvements. Among the cases followed up without medication, the findings worsened in two (9.5%), improved spontaneously in seven (33.3%), and were unchanged in 12 (57.1%), and three (14.3%) developed symptoms at a mean time of 40 months. Symptoms developed in cases where endoscopic and pathologic findings remained unchanged or worsened during follow-up. Conclusion : s: Some patients with aEE had improved findings without treatment, whereas others developed symptoms, emphasizing the importance of long-term monitoring and individualized treatment decisions.

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.

Background: Cardiac amyloidosis is a fatal disease of severe heart failure caused by the accumulation of amyloid in the myocardium. This disease is often advanced by the time cardiac symptoms appear; therefore, early detection and treatment are critical for a good prognosis. Recently, it has been suggested that cardiac amyloidosis is implicated in several orthopedic diseases, including carpal tunnel syndrome (CTS), which is often reported to precede cardiac dysfunction. Shoulder disease has also been suggested to be associated with cardiac amyloidosis; however, there have been no reports investigating the rate of amyloid deposition in shoulder specimens and the simultaneous prevalence of cardiac amyloidosis. Herein, we investigated the prevalence of intraoperative specimen amyloid deposition and cardiac amyloidosis in shoulder disease and CTS to determine the usefulness of shoulder specimen screening as a predictor of cardiac amyloidosis development. Methods: A total of 41 patients undergoing arthroscopic shoulder surgery and 33 patients undergoing CTS surgery were enrolled in this study. The shoulder group included rotator cuff tears, contracture of the shoulder, synovitis, and calcific tendonitis. In the shoulder group, a small sample of synovium and the long head of the biceps brachii tendon were harvested, while the transverse carpal ligament was harvested from the CTS group. The intraoperative specimens were pathologically examined for amyloid deposition, and patients with amyloid deposition were examined for the presence of cardiac amyloidosis by cardiac evaluation. Results: In the shoulder group, three cases (7.3%) of transthyretin amyloid deposition were found, all of which involved rotator cuff tears. None of these three cases with amyloid deposition were associated with cardiac amyloidosis. When examining the specimens, the amyloid deposition rate in the long head of the biceps brachii tendon was higher than that in the synovium. In the CTS group, 12 cases (36.4%) of transthyretin amyloid deposition were observed. Of these cases, seven underwent cardiac evaluation and two were identified with cardiac amyloidosis. Conclusion: While the prevalence of amyloid deposition and cardiac amyloidosis in the CTS group was consistent with previous reports, the shoulder group showed a lower deposition rate and no concomitant cardiac amyloidosis. Therefore, it remains debatable whether investigating amyloid deposition in samples obtained from shoulder surgery is beneficial for the early detection of cardiac amyloidosis.

Background/Aims: Asymptomatic esophageal eosinophilia (aEE) is considered to be a potential precursor of eosinophilic esophagitis (EoE). However, there are few clinical parameters that can be used to evaluate the disease. Therefore, we aimed to clarify the factors involved in the symptoms of EoE by examining the clinicopathological differences between aEE and EoE. Methods: We reviewed 41 patients with esophageal eosinophilia who underwent endoscopic ultrasonography and high-resolution manometry. They were divided into the aEE group (n=16) and the EoE group (n=25) using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease score. The patients’ clinicopathological findings were collected and examined. Results: The median Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease score was 3.0 in the aEE group and 10.0 in the EoE group. There was no significant difference in patient characteristics, endoscopic findings and pathological findings. The cutoff value for wall thickening was 3.13 mm for the total esophageal wall thickness and 2.30 mm for the thickness from the surface to the muscular layer (total esophageal wall thickness: 84.0% sensitivity, 75.0% specificity; thickness from the surface to the muscular layer: 84.0% sensitivity, 68.7% specificity). The high-resolution manometry study was abnormal in seven patients (43.8%) in the aEE group and in 12 (48.0%) in the EoE group. The contractile front velocity was slower in the EoE group (p=0.026). Conclusions: The esophageal wall thickening in the lower portion of the esophagus is an important clinical factors related to the symptoms in patients with EoE.

Abstract Fibronectin (FN) glomerulopathy (FNG), a rare autosomal hereditary renal disease, is characterized by proteinuria resulting from the massive accumulation of FN in the glomeruli. It typically affects individuals aged 10–50 years. In this report, we describe the case of a 57-year-old man who was diagnosed with FNG through genetic analysis and histological examination that revealed membranoproliferative glomerulonephritis. Despite treatment with prednisolone, the therapeutic response was unsatisfactory. Prednisolone was subsequently tapered and discontinued because the patient had pulmonary thromboembolism. Subsequent comprehensive genetic testing, which was initially not conducted because the patient’s parents did not have a history of kidney disease, identified a known disease-causing variant in the FN1 gene, indicating a de novo variant. FNG was further confirmed by positive staining of glomeruli with FN using an IST-4 antibody. Although corticosteroid therapy is commonly employed as the initial treatment for MPGN, its appropriateness depends on the underlying etiology. Thus, clinicians must be aware of potential rare genetic causes underlying MPGN.

Gastric cancer is one of the most common cancers worldwide, and new therapeutic strategies are urgently needed. Ferroptosis is an intracellular iron-dependent cell death induced by the accumulation of lipid peroxidation, a mechanism different from conventional apoptosis and necrosis. Therefore, induction of ferroptosis is expected to be a new therapeutic strategy. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) have been identified as the major inhibitors of ferroptosis. Herein, we performed immunohistochemistry for GPX4, FSP1, and 4-HNE using tissues from patients with gastric cancer and investigated the relationship between these factors and prognosis. Patients with high GPX4 expression or high GPX4 expression and low 4-HNE accumulation tended to have a poor prognosis (p = 0.036, 0.023), whereas those with low FSP1 expression and high 4-HNE accumulation had a good prognosis (p = 0.033). The synergistic induction of cell death by inhibiting GPX4 and FSP1 in vitro was also observed, indicating that the cell death was non-apoptotic. Our results indicate that the expression and accumulation of lipid peroxidation-related factors play an important role in the clinicopathological significance of gastric cancer and that novel therapeutic strategies targeting GPX4 and FSP1 may be effective in treating patients with gastric cancer who have poor prognosis.

Summary: In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.

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.

Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer; therefore, new therapeutic approaches are required to improve the prognosis of LSCC. Although immunotherapies targeting B7 family molecules were explored as treatments for several cancer types, the expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated in detail. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression using 110 surgically resected pathological specimens retrospectively. We examined the correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells. High B7-H3 expression in tumor cells was associated with a better prognosis and a significant increase in the number of CD163+PD-L1+ macrophages. Quantitative analysis revealed that there is a positive correlation between B7-H3 and PD-L1 expression in tumor and stromal cells, as well as in intratumoral tumor-infiltrating lymphocytes and tumor-associated macrophages in the same cells. CD68+, CD163+, and CK+ cells with PD-L1+ phenotypes had higher B7-H3 expression compared to PD-L1− cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies.

Abstract Background As messenger RNA (mRNA)-based vaccines for coronavirus disease 2019 (COVID-19) have been administered to millions of individuals worldwide, cases of de novo and relapsing glomerulonephritis after mRNA COVID-19 vaccination are increasing in the literature. While most previous publications reported glomerulonephritis after the first or second dose of an mRNA vaccine, few reports of glomerulonephritis occurring after the third dose of an mRNA vaccine currently exist. Case presentation We report a case of rapidly progressive glomerulonephritis in a patient following the third dose of an mRNA COVID-19 vaccine. A 77-year-old Japanese man with a history of hypertension and atrial fibrillation was referred to our hospital for evaluation of anorexia, pruritus, and lower extremity edema. One year before referral, he received two mRNA vaccines (BNT162b2) for COVID-19. Three months before the visit, he received a third mRNA vaccine (mRNA-1273) for COVID-19. On admission, the patient presented severe renal failure with a serum creatinine level of 16.29 mg/dL, which had increased from 1.67 mg/dL one month earlier, prompting us to initiate hemodialysis. Urinalysis showed nephrotic-range proteinuria and hematuria. Renal biopsy revealed mild mesangial proliferation and expansion, a lobular appearance, and double contours of the glomerular basement membrane. Renal tubules had severe atrophy. Immunofluorescence microscopy showed strong mesangial staining for IgA, IgM, and C3c. Electron microscopy exhibited mesangial and subendothelial electron-dense deposits, leading to a diagnosis of IgA nephropathy with membranoproliferative glomerulonephritis-like changes. The kidney function remained unchanged after steroid therapy. Conclusions Although the link between renal lesions and mRNA vaccines remains unclear, a robust immune response induced by mRNA vaccines may play a role in the pathogenesis of glomerulonephritis. Further studies of the immunological effects of mRNA vaccines on the kidney are warranted.

Introduction Several retrospective studies have demonstrated the efficacy of progressive site‐directed therapy for oligoprogressive castration‐resistant prostate cancer. However, eligible patients for progressive site‐directed therapy in these studies were limited to oligoprogressive castration‐resistant prostate cancer with bone or lymph node metastases without visceral metastases, and little is known about the efficacy of progressive site‐directed therapy for oligoprogressive castration‐resistant prostate cancer with visceral metastases. Case presentation We report a case with castration‐resistant prostate cancer previously treated with enzalutamide and docetaxel, in which only a solitary lung metastasis was identified throughout the course of treatment. The patient underwent thoracoscopic pulmonary metastasectomy with a diagnosis of repeat oligoprogressive castration‐resistant prostate cancer. Only androgen deprivation therapy was continued and his prostate‐specific antigen levels remained undetectable for 9 months after surgery. Conclusion Our case suggests that progressive site‐directed therapy may be effective for carefully selected repeat OP‐CRPC with a lung metastasis.

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.

Herein, we report a child with COVID-19 and seemingly no underlying disease, who died suddenly. The autopsy revealed severe anemia and thrombocytopenia, splenomegaly, hypercytokinemia, and a rare ectopic congenital coronary origin. Immunohistochemical analysis demonstrated that the patient had acute lymphoblastic leukemia of the B-cell precursor phenotype (BCP-ALL). The complex cardiac and hematological abnormalities suggested the presence of an underlying disease; therefore, we performed whole-exome sequencing (WES). WES revealed a leucine-zipper-like transcription regulator 1 (LZTR1) variant, indicating Noonan syndrome (NS). Therefore, we concluded that the patient had underlying NS along with coronary artery malformation and that COVID-19 infection may have triggered the sudden cardiac death due to increased cardiac load caused by high fever and dehydration. In addition, multiple organ failure due to hypercytokinemia probably contributed to the patient’s death. This case would be of interest to pathologists and pediatricians because of the limited number of NS patients with LZTR1 variants; the complex combination of an LZTR1 variant, BCP-ALL, and COVID-19; and a rare pattern of the anomalous origin of the coronary artery. Thus, we highlight the significance of molecular autopsy and the application of WES with conventional diagnostic methods.

A man in his 20s initiated intermittent peritoneal dialysis in the late 1960s. He subsequently transitioned to hemodialysis and survived for more than 50 years, spanning low-flux and high-flux hemodialysis eras. He underwent surgery for cervical and lumbar spinal canal stenosis after 30 and 35 years, respectively, and both surgeries revealed similar degrees of severe amyloid deposition. At autopsy, significant improvement was seen in lumbar amyloid deposition. During the previous 25 years, serum β2 microglobulin levels had decreased from 40 mg/L and been maintained at 20 mg/L. This case indicates that advances in dialysis therapy aimed at lowering β2 microglobulin concentrations have reduced highly deposited amyloid.

Accumulation of 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation, has various favorable and unfavorable effects on cancer cells; however, the clinicopathological significance of its accumulation in hepatocellular carcinoma (HCC) and its metabolic pathway remain unknown. This study analyzed 4-HNE accumulation and its clinicopathological significance in HCC. Of the 221 cases, 160 showed relatively low accumulation of 4-HNE in HCC tissues, which was an independent prognostic predictor. No correlation was found between 4-HNE accumulation and the expression of the antioxidant enzymes glutathione peroxidase 4, ferroptosis suppressor protein 1, and guanosine triphosphate cyclohydrolase 1. Therefore, we hypothesized that 4-HNE metabolism is up-regulated in HCC. A database search was focused on the transcriptional regulation of aldo-keto reductases, alcohol dehydrogenases, and glutathione-S-transferases, which are the metabolic enzymes of 4-HNE, and seven candidate transcription factor genes were selected. Among the candidate genes, the knockdown of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) increased 4-HNE accumulation. Immunohistochemical analysis revealed an inverse correlation between 4-HNE accumulation and SMARCA4 expression. These results suggest that SMARCA4 regulates 4-HNE metabolism in HCC. Therefore, targeting SMARCA4 provides a basis for a new therapeutic strategy for HCC via 4-HNE accumulation and increased cytotoxicity.

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,

Abstract Background Dermoid cysts are well-known lesions that manifest as subcutaneous tumors around the lateral sides of the eyebrows in young patients. Computed tomography or magnetic resonance imaging (MRI) is often performed to confirm the diagnosis. On the other hand, a lipoma is usually a circular lesion, which is sometimes observed in the upper part of the face. The signals of both T1-weighted and T2-weighted images of MRI of a lipoma are, in general, relatively highly homogenous, and the signals decrease in fat-suppressed images. Therefore, differential diagnosis between a dermoid cyst and a lipoma is usually made with MRI, especially based on fat-suppressed images. Here, we present a case of misdiagnosis of a dermoid cyst as a lipoma because of atypical magnetic resonance images. Case presentation We report a case of a 24-year-old Japanese woman with a dermoid cyst around the lateral edge of the eyebrow. The cyst had been gradually increasing in size for the past 2 years. On MRI, it showed high internal signals on T1- and T2-weighted images. However, the signal intensity decreased homogeneously in the fat-suppressed T2-weighted images. The observed tumor had a yellowish appearance under the endoscope. On the basis of these findings, the lesion was considered a lipoma until it ruptured intraoperatively. The pathological diagnosis confirmed it to be a dermoid cyst. Conclusion Some dermoid cysts contain lipid-rich liquid, and these may be misdiagnosed as lipomas by MRI. When a tumor is located at a common site for a dermoid cyst, the MRI images should be validated carefully if it appears like a lipoma, and the differential diagnosis should be considered carefully.

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.

Giant cell tumor of soft tissue (GCTST) is a defined disease entity that has a morphology similar to giant cell tumor of bone (GCTB). The malignant transformation of GCTST has not been reported, and a kidney primary is extremely rare. We report the case of a 77-year-old Japanese male, who was diagnosed with primary GCTST of the kidney and showed peritoneal dissemination, considered to be a malignant transformation of GCTST, in 4 years and 5 months. Histologically, the primary lesion showed characteristics of round cells with not prominent atypia, multi-nucleated giant cells, and osteoid formation, and carcinoma components were not found. The peritoneal lesion was characterized by osteoid formation and round to spindle-shaped cells, but differed in nuclear atypia, and multi-nucleated giant cells were not detected. Immunohistochemical and cancer genome sequence analysis suggested these tumors were sequential. This is a first report of a case that we could diagnose as primary GCTST of the kidney and could be determined as malignant transformation of GCTST in the clinical course. Analysis of this case will be examined in the future when genetic mutations and the disease concepts of GCTST are established.

Background. Cag A-positive Helicobacter pylori isolated from human gastric mucosa is categorized as a Western or East Asian allele-type based on whether the cagA gene encodes an EPIYA-C or EPIYA-D motif. We aimed to differentiate between the 2 types of H. pylori by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) gastric biopsy samples. Materials and Methods. We developed 2 monoclonal antibodies (mAbs) that detect either the EPIYA-C or EPIYA-D motif of the H. pylori CagA protein by IHC using FFPE tissues. FFPE tissue sections from 30 Japanese and 39 Brazilian gastric biopsy samples with H. pylori infection confirmed by Giemsa staining (moderate/severe in the Sydney classification system) were examined by IHC with the novel mAbs followed by polymerase chain reaction (PCR) for EPIYA-C or EPIYA-D using DNA extracted from adjacent tissue sections. Results. Differentiation among Western and East Asian types and CagA-negative H. pylori was successful in most (97%) samples by IHC with the novel mAbs and commercially available mAbs that react with a species-specific lipopolysaccharide or a common CagA motif of H. pylori. The detection status of EPIYA-C/D motifs by IHC with the novel mAbs was consistent with the PCR results in 61 (88%) of 69 samples: EPIYA-C(+)/D(−) in zero Japanese and 26 Brazilian samples, EPIYA-C(−)/D(+) in 26 Japanese and 1 Brazilian sample, and EPIYA-C(−)/D(−) in 1 Japanese and 7 Brazilian samples. The detection sensitivity and specificity of IHC with each novel mAb compared with the PCR results were, respectively, 84% and 97% for EPIYA-C, and 97% and 95% for EPIYA-D. Conclusions. The novel mAbs specific to each EPIYA-C or EPIYA-D motif differentiated between Western and East Asian types of CagA-positive H. pylori by IHC using FFPE tissues. Applying these novel mAbs to large numbers of archived pathology samples will contribute to elucidating the association of these allele types with gastric cancer.

Abstract 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.

The purpose of this paper is to explore the interrelationship between tourism and migration by the case study on Russian-speaking tourism phenomena observed in Nha Trang, Vietnam. The case challenges us to reexamine our static interpretations of tourism/migration concepts and to focus on the interpenetration of them. This paper tries to educe the multiple intermediate forms of human mobility that go beyond the simple framework of binominal confrontation between tourism and migration.

We report the renal histology of a 66-year-old man with hypertension, cardiovascular disease, and a 30-year history of type 2 diabetes mellitus with proliferative diabetic retinopathy, diabetic neuropathy, and diabetic foot status post toe amputation. Urinary protein excretion was 1.4 g/gCr, serum creatinine level 0.86 mg/dL, estimated glomerular filtration rate 69 mL/min/1.73 m2, and HbA1c 13–15%, despite using insulin. Light microscopy showed global glomerulosclerosis in 37% of the glomeruli, but the remaining glomeruli were intact. Significant polar vasculosis was present, while arteriolar sclerosis was mild. Electron microscopy revealed a thickened glomerular basement membrane, which is compatible with the early stage of diabetic glomerulopathy. The presented case was unique because glomerular changes seen typically in diabetes were not seen in the patient, despite the long-standing history of diabetes and diabetic comorbidities, while prominent polar vasculosis was found. Polar vascular formation helps preserve the glomeruli by allowing hyperosmotic blood bypass the glomeruli; this decreases intraglomerular pressure and minimizes glomerular endothelial damage.

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint inhibitors, acts as a suppressive signal for the surrounding immune system; however, its expression and effect on TAMs and the clinical outcome in breast cancer are unknown. In this study, we used high-throughput multiple immunohistochemistry to spatially and quantitatively analyze TAMs. We subjected 81 breast cancer specimens to immunostaining for CD68, CD163, PD-1, PD-L1, CD20, and pan-CK. In both stromal and intratumoral areas, the triple-negative subtype had significantly more CD68/CD163, CD68/PD-L1, and CD163/PD-L1 double-positive cells than the estrogen receptor (ER)/progesterone receptor (PR) subtype. Interestingly, a higher number of CD68+/PD-L1+/CK-/CD163- TAMs in the intratumoral area was correlated with a favorable recurrence rate (p = 0.048). These findings indicated that the specific subpopulation and localization of TAMs in the TME affect clinical outcomes in breast cancer.

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 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.

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.

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.

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.

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

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare complication of cancer. It is histologically characterized by fibrocellular intimal proliferation in small pulmonary arteries and arterioles in patients with metastatic carcinoma. It is most frequently caused by adenocarcinoma. We report a case of PTTM caused by uterine carcinosarcoma in a 62-year-old female, who exhibited reductions in blood pressure and oxygen saturation. This is the first case report about uterine carcinosarcoma-induced PTTM. Histologically, the primary uterine carcinosarcoma included serous carcinoma and homologous sarcoma components. Many tumor emboli were observed across large regions of both lungs. PTTM was found in the lower lobes. Interestingly, the embolized tumor cells were all derived from the adenocarcinoma component. Immunohistologically, the primary carcinosarcomaexhibited weak positivity for tissue factor (TF), but was negativefor vascular endothelial growth factor-A (VEGF-A). The PTTM tumor cells were positive for TF and weakly positive for VEGF-A. This case suggests that any tumor containing adenocarcinoma can cause PTTM, and immunostaining of the primary tumor might be worthless for determining whether PTTM will develop. PTTM should always be considered during the differential diagnosis of dyspnea in patients with adenocarcinoma. Keywords: Pulmonary tumor thrombotic microangiopathy, Pulmonary tumor embolism, Vascular endothelial growth factor, Tissue factor, Uterine carcinosarcoma

We report a 33-year-old Japanese man diagnosed with mixed connective tissue disease (MCTD) who developed nephrotic proteinuria. Both speckled antinuclear antibody (ANA) and anti-U1 ribonucleoprotein (RNP) antibody were positive, but anti-double-stranded DNA (dsDNA) antibody and anti-Smith (Sm) antibody were negative, while complement levels were normal. Renal biopsy revealed membranous glomerulonephritis (MGN) with diffuse thickening of the glomerular basement membrane (GBM) plus spike and bubble formation. Immunofluorescence demonstrated granular deposits of IgG and C3 along the GBM. Analysis of IgG subclasses showed predominant deposition of IgG1 and IgG4, unlike typical lupus nephritis in which there is predominant deposition of IgG1, IgG2, IgG3, and C1q. Electron microscopy identified numerous large electron-dense deposits (EDD) of various types in the subepithelial region of the GBM, but there were no EDD localized in the mesangium or subendothelium. Based on these findings, MGN was considered to be closely related to MCTD in this patient. Keywords: Membranous glomerulonephritis, Mixed connective tissue disease

We report the case of a 67-year-old Japanese woman with type 1 diabetes mellitus. At 47 years of age, her hemoglobin A1c (HbA1c) was 10.0%, and she had overt nephropathy. The first renal biopsy yielded a diagnosis of diabetic nephropathy. Intensive glycemic control was initiated and her HbA1c improved to 6.0%. Renal dysfunction showed no progression for 15 years. At 62 years of age, a second renal biopsy was performed. Glomerular lesions did not show progression but tubulointerstitial fibrosis and vascular lesions showed progression compared with the first biopsy. Intensive glycemic control can prevent the progression of glomerular lesions, but might not be effective for interstitial and vascular lesions.

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 (>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 (>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.

Abstract Background Various renal manifestations are known to develop in patients with liver disease, including chronic hepatitis and cirrhosis. Case presentation We evaluated renal disease in two 47-year-old Japanese men with liver cirrhosis and chronic alcoholism for 34 years and 27 years, respectively. Renal biopsy demonstrated massive wire loop-like deposits in the subendothelial space of the glomerular basement membrane and in the mesangium. However, immunofluorescence was only positive for IgA and C3, and electron microscopy did not reveal any organized structures in the electron-dense deposits. IgA nephropathy was diagnosed, although the features were different from primary IgA nephropathy. Both patients had portosystemic shunts associated with liver cirrhosis. Their renal deposits and proteinuria resolved completely after 1 year of steroid therapy. Conclusion Alcohol abuse may have contributed to development of secondary IgA nephropathy in these two patients, probably via their portosystemic shunts.

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.

Abstract Background Non-functioning parathyroid carcinoma is a rare disease that is difficult to distinguish from other diseases based on the lack of hyperparathyroidism. This is a report of non-functioning parathyroid carcinoma diagnosed by reverse transcription polymerase chain reaction (RT-PCR) targeting parathyroid hormone (PTH) messenger RNA. Case Presentation The patient is a 67-year-old male who visited our hospital for the chief complaint of hoarseness. A 5-cm mass was observed in the right lobe of the thyroid gland, and poorly differentiated thyroid carcinoma was suspected according to the fine-needle biopsy results. The laboratory data for thyroid functions, thyroglobulin, anti-thyroglobulin antibodies, calcium, phosphorus, and intact-PTH were all within the normal range. Right recurrent nerve paralysis was observed preoperatively. The patient was diagnosed with poorly differentiated thyroid carcinoma, and total thyroidectomy and central node dissection with partial resection of the right recurrent nerve and esophageal muscle were performed. The pathological findings revealed atypical cells containing clear cells in solid and alveolar structures with broad fibrosis. Mitosis, focal coagulative necrosis, and vascular and capsular invasions were observed. A slightly positive PTH immunohistochemical stain was noted, whereas the RT-PCR results were positive. We finally diagnosed this tumor as non-functioning PTC. No distant metastasis occurred, and the patient is still alive. Conclusions This is a report of a patient with non-functioning parathyroid carcinoma, which is clinically very rare. We diagnosed this tumor as non-functioning parathyroid carcinoma using RT-PCR for PTH mRNA.

A 54-year-old Japanese man presented with recurrent abdominal pain, fever lasting >5 days, and renal failure. AA amyloidosis was proven by renal and gastric biopsy. Symptoms subsided with the administration of colchicine, but a subsequent recurrence of symptoms did not respond to colchicine. Mediterranean fever gene (MEFV) analysis showed that he was heterozygous for mutations in exon 2 (E148Q/R202Q) and exon 3 (P369S/R408Q), although he had none of the exon 10 mutations known to be closely related to AA amyloidosis. He did not respond to infliximab, but tocilizumab therapy was successful. The present case is a rare report of AA amyloidosis associated with familial Mediterranean fever in Japan.

We investigated the significance of MUC21 in EGFR-mutated lung adenocarcinoma (LADC). Two-hundred forty-one surgically resected LADCs (116 EGFR-mutated and 125 wild-type tumors) were examined for immunohistochemical expression of MUC21 protein. A polyclonal antibody and two monoclonal antibodies (heM21C and heM21D) that bind differentially glycosylated MUC21 epitopes were used, and MUC21 proteins detected by these antibodies were named MUC21P, MUC21C, and MUC21D, respectively. MUC21 mRNA levels were semi-quantified and classified into "high" and "low". Among the immunohistochemical expression detected by three different antibodies, high expressors tended to be related to EGFR mutations. The three varieties of the immunohistochemical expressions were related to different histological elements in the EGFR-mutated LADCs. Either MUC21P or MUC21C high expressors had a higher proportion of lepidic elements with low papillary structure and micropapillary elements. MUC21D high expressors had a significantly higher proportion of micropapillary elements (Mann-Whitney test P ≤0.0001). Furthermore, MUC21D high expressors showed high incidence of lymphatic canal invasion and lymph node metastasis (Pearson x2 test, P = 0.0021, P = 0.0125), and a significantly higher recurrence rate (5-year recurrence-free survival 50.7% vs. 73.8%, log-rank test P = 0.0495). MUC21 proteins with a specific glycosylation status may be involved in the progression of EGFR-mutated LADCs, particularly at the stage where tumors are transforming from pure lepidic to micropapillary through low papillary lepidic lesions.

Sarcoidosis may have more than a single causative agent, including infectious and non-infectious agents. Among the potential infectious causes of sarcoidosis, Mycobacterium tuberculosis and Propionibacterium acnes are the most likely microorganisms. Potential latent infection by both microorganisms complicates the findings of molecular and immunologic studies. Immune responses to potential infectious agents of sarcoidosis should be considered together with the microorganisms detected in sarcoid granulomas, because immunologic reactivities to infectious agents reflect current and past infection, including latent infection unrelated to the cause of the granuloma formation. Histopathologic data more readily support P. acnes as a cause of sarcoidosis compared with M. tuberculosis, suggesting that normally symbiotic P. acnes leads to granuloma formation in some predisposed individuals with Th1 hypersensitivity against intracellular proliferation of latent P. acnes, which may be triggered by certain host or drug-induced conditions. Detection of bacterial nucleic acids in granulomas does not necessarily indicate co-localization of the bacterial proteins in the granulomas. In the histopathologic diagnosis of sarcoidosis, M. tuberculosis-associated and P. acnes-associated sarcoidosis will possibly be differentiated in some patients by immunohistochemistry with appropriate antibodies that specifically react with mycobacterial and propionibacterial antigens, respectively, for each etiology-based diagnosis and potential antimicrobial intervention against sarcoidosis.

Previous studies reported that endoscopic resection is effective for the treatment of superficial pharyngeal cancers, as for digestive tract cancers. However, the optimal treatment for superficial cancer of the uvula has not been established because of the rarity of this condition. We present two male patients in their 70s with superficial cancer of the uvula, detected with upper gastrointestinal endoscopy. Both patients underwent surgical resection of the uvula under general anesthesia. The extent of the lesions was determined by means of gastrointestinal endoscopy by using magnifying observation with narrow-band imaging, enabling the performance of minimally invasive surgery. Endoscopic submucosal dissection was performed to achieve en bloc resection of the intramucosal carcinoma that had infiltrated the area adjacent to the uvula. Gastrointestinal endoscopists should carefully examine the laryngopharynx to avoid missing superficial cancers. Our minimally invasive treatment for superficial cancer of the uvula had favorable postoperative outcomes, and prevented postoperative loss of breathing, swallowing, and articulation functions.

The impact of the newly proposed pathological classification by the Japan Renal Pathology Society (JRPS) on renal outcome is unclear. So we evaluated that impact and created a new pathological scoring to predict outcome using this classification.A multicenter cohort of 493 biopsy-proven Japanese patients with diabetic nephropathy (DN) were analyzed. The association between each pathological factor-Tervaert' and JRPS classifications-and renal outcome (dialysis initiation or 50% eGFR decline) was estimated by adjusted Cox regression. The overall pathological risk score (J-score) was calculated, whereupon its predictive ability for 10-year risk of renal outcome was evaluated.The J-scores of diffuse lesion classes 2 or 3, GBM doubling class 3, presence of mesangiolysis, polar vasculosis, and arteriolar hyalinosis were, respectively, 1, 2, 4, 1, and 2. The scores of IFTA classes 1, 2, and 3 were, respectively, 3, 4, and 4, and those of interstitial inflammation classes 1, 2, and 3 were 5, 5, and 4 (J-score range, 0-19). Renal survival curves, when dividing into four J-score grades (0-5, 6-10, 11-15, and 16-19), were significantly different from each other (p

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.

Skin barrier function is often deficient in obese individuals, but the underlying molecular mechanisms remain unclear. This study investigated how skin structure and lipid metabolism, factors strongly associated with barrier function, differed among 50 Japanese women of greatly varying body mass index (BMI). Subjects receiving breast reconstruction surgery were chosen for analysis to obtain skin samples from the same site. The subjects were classified into two groups, control (BMI < 25 kg/m2) and obese (25 kg/m2 ≤ BMI < 35 kg/m2), according to standards in Japan. Hematoxylin and eosin staining was used to assess skin thickness, Ki-67 immunostaining to examine keratinocyte proliferation, and real-time polymerase chain reaction to measure skin expression levels of genes associated with lipid metabolism. Total lipids, cholesterol, and fatty acids were also measured from these same skin samples. In the obese group, structural changes included epidermal thickening and an increase in the number of Ki-67-positive (proliferating) cells. Both skin cholesterol and fatty acid levels exhibited an "inverted-U" relationship with BMI, suggesting that there is an optimal BMI for peak lipid content and barrier function. Decreased lipid levels at higher BMI were accompanied by downregulated expression of PPARδ and other genes related to lipid metabolism, including those encoding acetyl-CoA carboxylase and HMG-CoA reductase, the rate-limiting enzymes for fatty acid and cholesterol synthesis, respectively. Thus, elevated BMI may lead to deficient skin barrier function by suppressing local lipid synthesis.

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.

Glomerular insudative lesions are a pathological hallmark of diabetic nephropathy (DN). However, paratubular basement membrane insudative lesions (PTBMIL) have not attracted much attention, and the association between such lesions and the renal prognosis remains unclear.Among 142 patients with biopsy-proven DN and type 2 diabetes encountered from 1998 to 2011, 136 patients were enrolled in this study. Patients were classified into 3 groups (Group 1: mild, Group 2: moderate, Group 3: severe) according to the extent of cortical and medullary PTBMIL. The endpoint was a decline of the estimated glomerular filtration rate (eGFR) by ≥ 40% from baseline or commencement of dialysis for end-stage renal disease. The Cox proportional hazard model was employed to calculate hazard ratios (HRs) and 95% confidence interval (CIs) for the death-censored endpoint.During a median follow-up period of 1.8 years (IQR: 0.9-3.5), the endpoint occurred in 104 patients. Baseline mean eGFR was 43.9 ± 22.8 ml/min/1.73 m2, and 125 patients (92%) had overt proteinuria. After adjusting for known indicators of DN progression, the HR for the endpoint was 2.32 (95% CI: 1.20-4.51) in PTBMIL Group 2 and 3.12 (1.48-6.58) in PTBMIL Group 3 versus PTBMIL Group 1. Furthermore, adding the PTBMIL Group to a multivariate model including known promoters of DN progression improved prediction of the endpoint (c-index increased by 0.02 [95% CI: 0.00-0.04]).PTBMIL may be useful for predicting the renal prognosis of patients with biopsy-proven DN, but further investigation of these lesions in various stages of DN is needed.

Background and study aims: The aim of this study was to investigate the capability of magnifying endoscopy with narrow-band imaging (ME-NBI) to discriminate between early carcinomas (EC) and low grade adenomas (LGA) in gastric superficial elevated epithelial neoplasias. Patients and methods: We investigated 100 consecutive cases of gastric superficial elevated epithelial neoplasias that were removed using endoscopic submucosal dissection. The pathological diagnostic criteria were based on the revised Vienna classification; category 4 (mucosal high grade neoplasia) and category 5 (submucosal invasion by carcinoma) lesions were diagnosed as EC, whereas category 3 (mucosal low grade neoplasia) lesions were diagnosed as LGA. The associations between the postoperative pathological diagnoses and the ME-NBI findings were analyzed, and included the shape, specification, and area of irregularity in the microvascular architecture (MV) and the microsurface structure (MS). Results: Seventy-nine EC and 21 LGA cases diagnosed postoperatively were evaluated retrospectively. The lesion size (median; range (mm)) was significantly larger in the EC group (14; 2 – 95) compared to the LGA group (5; 2 – 16) (P

The purpose of this study was to define histological features determining the malignant potential of EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P ≤0.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage (stage II, III, or IV) than in the tumor at the early stage (stage I) (Mann-Whitney test, P