RESUMO
Epigenetic mechanisms are considered to contribute to diabetic nephropathy by maintaining memory of poor glycemic control during the early stages of diabetes. However, DNA methylation changes in the human kidney are poorly characterized, because of the lack of cell type-specific analysis. We examined DNA methylation in proximal tubules (PTs) purified from patients with diabetic nephropathy and identified differentially methylated CpG sites, given the critical role of proximal tubules in the kidney injury. Hypermethylation was observed at CpG sites annotated to genes responsible for proximal tubule functions, including gluconeogenesis, nicotinamide adenine dinucleotide synthesis, transporters of glucose, water, phosphate, and drugs, in diabetic kidneys, whereas genes involved in oxidative stress and the cytoskeleton exhibited demethylation. Methylation levels of CpG sites annotated to ACTN1, BCAR1, MYH9, UBE4B, AFMID, TRAF2, TXNIP, FOXO3, and HNF4A were correlated with the estimated glomerular filtration rate, whereas methylation of the CpG site in RUNX1 was associated with interstitial fibrosis and tubular atrophy. Hypermethylation of G6PC and HNF4A was accompanied by decreased expression in diabetic kidneys. Proximal tubule-specific hypomethylation of metabolic genes related to HNF4A observed in control kidneys was compromised in diabetic kidneys, suggesting a role for aberrant DNA methylation in the dedifferentiation process. Multiple genes with aberrant DNA methylation in diabetes overlapped genes with altered expressions in maladaptive proximal tubule cells, including transcription factors PPARA and RREB1. In conclusion, DNA methylation derangement in the proximal tubules of patients with diabetes may drive phenotypic changes, characterized by inflammatory and fibrotic features, along with impaired function in metabolism and transport.NEW & NOTEWORTHY Cell type-specific DNA methylation patterns in the human kidney are not known. We examined DNA methylation in proximal tubules of patients with diabetic nephropathy and revealed that oxidative stress, cytoskeleton, and metabolism genes were aberrantly methylated. The results indicate that aberrant DNA methylation in proximal tubules underlies kidney dysfunction in diabetic nephropathy. Aberrant methylation could be a target for reversing memory of poor glycemic control.
Assuntos
Ilhas de CpG , Metilação de DNA , Nefropatias Diabéticas , Epigênese Genética , Túbulos Renais Proximais , Fenótipo , Humanos , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos de Casos e Controles , Taxa de Filtração GlomerularRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. New therapeutic strategies are needed for the treatment of refractory DLBCL. 4-Hydroxy-2-nonenal (4-HNE) is a cytotoxic lipid peroxidation marker, which alters intracellular signaling and induces genetic mutations. Lipid peroxidation is associated with nonapoptotic cell death, called ferroptosis. However, the relationship between 4-HNE accumulation and feroptotic regulators in DLBCL has not been fully evaluated. Here, we aimed to evaluate the accumulation of lipid peroxide and the expression of ferroptosis suppressor protein 1 (FSP1) in DLBCL using immunohistochemistry. We found a significant increase in the expression of FSP1 in cases with nuclear 4-HNE accumulation (P = .021). Both nuclear and cytoplasmic 4-HNE accumulation and FSP1 positivity were independent predictors of worse prognosis. In vitro exposure to 4-HNE resulted in its concentration- and time-dependent intracellular accumulation and increased expression of FSP1. Furthermore, short-term (0.25 and 1.0 µM) or long-term (0.25 µM) exposure to 4-HNE induced resistance to not only apoptosis but also ferroptosis. Taken together, regulation of FSP1 through 4-HNE accumulation may attenuate resistance to cell death in treatment-resistant DLBCL and might help develop novel therapeutic strategies for refractory DLBCL.
Assuntos
Aldeídos , Ferroptose , Linfoma Difuso de Grandes Células B , Humanos , Ferroptose/genética , Apoptose , Morte Celular , Linfoma Difuso de Grandes Células B/genéticaRESUMO
Peripheral blood stem cell transplantation (PBSCT) has made amyloid light-chain (AL) amyloidosis treatable. After PBSCT, hematological complete remission (HCR) can be achieved, leading to improved renal prognosis. The purpose of this study was to evaluate whether whole slide imaging of biopsy samples shows a post-treatment reduction in amyloid deposits in patients with AL amyloidosis. Patients were divided into three groups: Group A (n = 8), not eligible for PBSCT and treated with other therapies; Group B (n = 11), treated with PBSCT and achieved HCR; and Group C (n = 5), treated with PBSCT but did not achieve HCR. Clinical findings and amyloid deposition in glomeruli, interstitium, and blood vessels were compared before and after treatment using digital whole-slide imaging. Proteinuria and hypoalbuminemia improved more in Group B than in the other groups, and in Group B, amyloid deposition improved more in the glomeruli than in the interstitium and blood vessels. The long-term renal and survival prognosis was better in Group B than in the other groups. PBSCT can be expected to improve long-term clinical and renal histological prognosis in patients with AL amyloidosis who achieve HCR. Amyloid disappearance from renal tissue may take a long time even after clinical HCR.
RESUMO
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.
Assuntos
Glomerulonefrite Membranoproliferativa , Masculino , Humanos , Pessoa de Meia-Idade , Glomerulonefrite Membranoproliferativa/diagnóstico , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Glomerulonefrite Membranoproliferativa/genética , Glomérulos Renais , Rim , Prednisolona/uso terapêuticoRESUMO
BACKGROUND: Esophageal cancers other than two types, squamous cell carcinoma (SCC) and adenocarcinoma, are commonly referred to as special type of esophageal cancer (STEC). Studies on STECs have been limited because of its low prevalence. Therefore, we aimed to clarify the clinicopathological findings and the long-term outcomes of STECs that were managed with ESD. METHODS: We reviewed 713 patients with 1,089 lesions who underwent ESD for primary esophageal cancer except Barrett's esophageal cancer. Patients were classified into the SCC group and the STEC group, respectively. Their clinicopathological findings and long-term outcomes including disease-specific survival (DSS) were collected and examined. RESULTS: A total of 19 consecutive patients (1.7%) were diagnosed with STEC. Nine patients were diagnosed with basaloid carcinoma, 6 with adenosquamous carcinoma, 2 with mucoepidermoid carcinoma, 2 with salivary duct-type carcinoma, and 1 with neuroendocrine cell carcinoma. There was significantly more pT1b esophageal cancer (47.4% vs. 11.0%, p < 0.01) and lymphovascular invasion (31.6% vs. 10.2%, p = 0.011) in the STEC group. Metastatic relapse and disease-specific mortality were significantly higher in the STEC group (both 15.8% vs. 1.2%, p < 0.01), and the STEC group had shorter DSS with 5-year DSS rates of 90.9%. In a subgroup analysis of patients with pT1a esophageal cancer, the 5-year DSS rate was shorter in the STEC group (p < 0.01). In the multivariate analysis, STEC (HR = 0.24) and tumor depth (HR = 12.60) were the factors associated with DSS. CONCLUSION: STECs are suggested to have high malignant potential and to be an independent negative prognostic factor for DSS.
Assuntos
Adenocarcinoma , Carcinoma de Células Escamosas , Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/patologia , Adenocarcinoma/cirurgia , Adenocarcinoma/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Endoscopic ultrasonography (EUS) is a commonly used tool for preoperative depth diagnosis of superficial esophageal squamous cell carcinoma (ESCC). Probing EUS using the water-filled balloon method is a simple and safe examination. AIM: The aim of this study was to clarify the diagnostic performance of EUS with the water-filled balloon method for superficial ESCC compared to magnifying narrow-band imaging (ME-NBI). METHODS: We retrospectively examined 403 lesions in 393 consecutive patients diagnosed with ESCC and evaluated them with ME-NBI and EUS. Clinicopathological findings were collected, and the accuracy of the preoperative diagnosis was compared between ME-NBI and EUS-B. EUS examiners were not blinded to prior ME-NBI results, and EUS results may have been influenced by ME-NBI results. RESULTS: The pathological tumor depth of the EP/LPM in 152 lesions, MM/SM1 in 130 lesions, and deep submucosa (SM2/SM3) in 121 lesions was examined. The proportion of total lesions with an accurate diagnosis was significantly higher in EUS than in ME-NBI (67.7% versus 62.0%, P = 0.015). When analyzed by clinical depth diagnosis using ME-NBI, the proportion of lesions with an accurate diagnosis was significantly higher for EUS in MM/SM1 (55.7% versus 46.1%, P = 0.033). The sensitivity was significantly higher in EUS for SM2/SM3 lesions (76.0% versus 54.5%, P < 0.001). The accuracy and specificity of EUS, which differentiate MM/SM1 from EP/LPM or SM2/SM3, were significantly higher than those of ME-NBI. The median endoscopic ultrasonography procedure time was approximately 6.5 min. CONCLUSIONS: EUS with the water-filled balloon method is a safe and straightforward method that can be performed on lesions clinically diagnosed as MM/SM1 using ME-NBI. We retrospectively reviewed lesions in patients diagnosed with ESCC and evaluated them using magnifying endoscopy with narrow-band imaging (ME-NBI) and endoscopic ultrasound using the water-filled balloon method (EUS-B). We conclude that EUS-B can increase the diagnostic accuracy.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/diagnóstico por imagem , Neoplasias Esofágicas/patologia , Endossonografia , Carcinoma de Células Escamosas/patologia , Estudos Retrospectivos , Esofagoscopia/métodos , Invasividade Neoplásica/patologia , Imagem de Banda Estreita/métodosRESUMO
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.
Assuntos
COVID-19 , Glomerulonefrite por IGA , Glomerulonefrite Membranoproliferativa , Glomerulonefrite , Masculino , Humanos , Idoso , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite Membranoproliferativa/patologia , Vacinas contra COVID-19 , Vacina BNT162 , COVID-19/complicações , Glomerulonefrite/patologiaRESUMO
BACKGROUND: Esophageal cancers with a histological type other than the two major types, squamous cell carcinoma (SCC) and adenocarcinoma, are referred to as "special type of esophageal cancer" (STEC). STEC is rare and difficult to diagnose preoperatively. Therefore, we aimed to clarify the clinicopathological findings of STEC, including magnifying endoscopy with narrow band imaging (ME-NBI). METHODS: We reviewed 1133 lesions in 936 consecutive cases who underwent endoscopic resection or surgical resection for primary esophageal cancer. Patients were classified into the SCC group and the STEC group, respectively. Factors that predict STEC endoscopically, as well as clinicopathologic features of STEC compared to SCC, were examined. RESULTS: Twenty-eight STECs were diagnosed in 28 patients: 15 with basaloid squamous cell carcinoma, 6 with adenosquamous carcinoma, 4 with mucoepidermoid carcinoma, 1 with carcinosarcoma, 1 with salivary duct-type carcinoma, and 1 with neuroendocrine cell carcinoma. There was significantly more pT1b or deeper cancer (60.7% vs. 12.8%), lymphovascular invasion (50.0% vs. 11.1%) and elevated type (53.6% vs. 16.1%) in the STEC group. The proportion of lesions with type R vessels on ME-NBI was significantly higher in the STEC group (46.4% vs. 3.9%). The STEC group had significantly lower accuracy of ME-NBI for prediction of depth (64.3% vs. 83.5%) and a greater proportion of underestimated lesions (32.1% vs. 9.3%). In the multivariate analysis, the histopathology of STEC was associated with type R vessels on ME-NBI. CONCLUSION: Type R vessels and submucosal tumor-like elevation might be the clinical predictors of STEC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Esofagoscopia/métodos , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/patologia , Imagem de Banda EstreitaRESUMO
Although activation of the renin-angiotensin system and of its glomerular components is implicated in the pathogenesis of diabetic nephropathy, the functional roles of the tubular renin-angiotensin system with AT1 receptor signaling in diabetic nephropathy are unclear. Tissue hyperactivity of the renin-angiotensin system is inhibited by the angiotensin II type 1 receptor-associated protein ATRAP, which negatively regulates receptor signaling. The highest expression of endogenous ATRAP occurs in the kidney, where it is mainly expressed by tubules but rarely in glomeruli. Here, we found that hyperactivation of angiotensin II type 1 receptor signaling in kidney tubules exacerbated diabetic glomerular injury in a mouse model of streptozotocin-induced diabetic nephropathy. These phenomena were accompanied by decreased expression of CD206, a marker of alternatively activated and tissue-reparative M2 macrophages, in the kidney tubulointerstitium. Additionally, adoptive transfer of M2- polarized macrophages into diabetic ATRAP-knockout mice ameliorated the glomerular injury. As a possible mechanism, the glomerular mRNA levels of tumor necrosis factor-α and oxidative stress components were increased in diabetic knockout mice compared to non-diabetic knockout mice, but these increases were ameliorated by adoptive transfer. Furthermore, proximal tubule-specific ATRAP downregulation reduced tubulointerstitial expression of CD206, the marker of M2 macrophages in diabetic mice. Thus, our findings indicate that tubular ATRAP-mediated functional modulation of angiotensin II type 1 receptor signaling modulates the accumulation of tubulointerstitial M2 macrophages, thus affecting glomerular manifestations of diabetic nephropathy via tubule-glomerular crosstalk.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Proteínas Adaptadoras de Transdução de Sinal/genética , Angiotensina II/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Feminino , Humanos , Rim/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , EstreptozocinaRESUMO
G-quadruplex (G4), a non-canonical higher-order structure formed by guanine-rich nucleic acid sequences, affects various genetic events in cis, including replication, transcription and translation. Whereas up-regulation of innate immune/interferon-stimulated genes (ISGs) is implicated in cancer progression, G4-forming oligonucleotides that mimic telomeric repeat-containing RNA suppress ISG induction in three-dimensional (3D) culture of cancer cells. However, it is unclear how G4 suppresses ISG expression in trans. In this study, we found that G4 binding to splicing factor 3B subunit 2 (SF3B2) down-regulated STAT1 phosphorylation and ISG expression in 3D-cultured cancer cells. Liquid chromatography-tandem mass spectrometry analysis identified SF3B2 as a G4-binding protein. Either G4-forming oligonucleotides or SF3B2 knockdown suppressed ISG induction, whereas Phen-DC3, a G4-stabilizing compound, reversed the inhibitory effect of G4-forming oligonucleotides on ISG induction. Phen-DC3 inhibited SF3B2 binding to G4 in vitro. SF3B2-mediated ISG induction appeared to occur independently of RNA splicing because SF3B2 knockdown did not affect pre-mRNA splicing under the experimental conditions, and pharmacological inhibition of splicing by pladienolide B did not repress ISG induction. These observations suggest that G4 disrupts the ability of SF3B2 to induce ISGs in cancer. We propose a new mode for gene regulation, which employs G4 as an inhibitory trans-element.
Assuntos
Quadruplex G , Regulação da Expressão Gênica , Imunidade Inata/genética , Ácidos Nucleicos/metabolismo , Fatores de Processamento de RNA/metabolismo , Linhagem Celular Tumoral , Citocinas/genética , Citocinas/metabolismo , Compostos de Anéis Fundidos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Ontologia Genética , Humanos , Imunidade Inata/efeitos dos fármacos , Ligantes , Modelos Biológicos , Oligonucleotídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Splicing de RNA/efeitos dos fármacos , Splicing de RNA/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ubiquitinas/genética , Ubiquitinas/metabolismoRESUMO
Pneumocyte injury is a crucial factor influencing the severity of interstitial lung disease (ILD). In this study, we investigated the potential of hepatocyte nuclear factor α (HNF4α) as an immunohistochemical marker to detect pneumocyte injury and as a prognostic marker. Surgical lung biopsy specimens were collected from 309 patients with different types of ILDs (61 idiopathic pulmonary fibrosis (IPF), 173 non-IPF, and 75 unclassifiable ILD). HNF4α expression were examined and the frequency of positive cells (per mm2 ) was calculated. HNF4α was strongly expressed in regenerating pneumocytes present on fibroblastic foci, Masson bodies/organizing alveoli. In the non-IPF and unclassifiable ILD groups, cases with high frequency expression showed significantly poorer outcome. Particularly, in the unclassifiable ILD group, the prognostic impact was more significant (death due to ILD, log-rank test, p < 0.0001), with a 10-year survival rate (hazard ratio 11.1, Wald test, p = 0.0003), as compared to the non-IPF group (log-rank test, p = 0.0269; hazard ratio 2.7, Wald test, p = 0.0334). Multivariable analysis focusing on the unclassifiable ILD group confirmed that the frequent HNF4α expression was an independent prognostic factor (hazard ratio 28.6; Wald test, p = 0.0033). Thus, HNF4α can be utilized as an immunohistochemical marker for pneumocyte injury and have prognostic impact particularly in unclassifiable ILD.
Assuntos
Fator 4 Nuclear de Hepatócito/metabolismo , Doenças Pulmonares Intersticiais , Prognóstico , Idoso , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Biomarcadores/metabolismo , Progressão da Doença , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
BACKGROUND AND PURPOSE: We examined whether advances in treatment strategies from older disease-modifying antirheumatic drugs (DMARDs) to new biologic agents and methotrexate improved renal complications and outcome in patients with rheumatoid arthritis (RA). METHODS: We reviewed records of 156 patients with RA who underwent kidney biopsy at our institute between January 1990 and December 2019. All patients were assigned to one of three periods: period 1, 1990-1999 (n = 48); period 2, 2000-2009(n = 57); period 3, 2010-2019 (n = 51). RESULTS: Membranous nephropathy, nephrosclerosis, AA-amyloidosis, and IgA nephropathy were the four major renal manifestations of RA. AA-amyloidosis was diagnosed by kidney biopsy in 21 patients: period 1, 7 patients (15%); period 2, 10 patients (18%); and period 3, 4 patients (8%). The 4 patients in period 3 were in the years 2010-2014, and no new case of AA-amyloidosis was recorded from 2015 to 2019. In all 21 of the patients with AA-amyloidosis, neither a biologic agent nor methotrexate was administered. Fifteen of the 21 patients required dialysis, and 13 died in periods 1-3 because of amyloid-related cardiac dysfunction less than 2 years after the initiation of dialysis. Two of them are doing well using biologic agent despite dialysis. The remaining three patients who received a biologic agent or methotrexate does not progress to end-stage renal failure. In addition, the other renal complications showing progression to dialysis also decreased over time. CONCLUSION: Advances in treatment strategies have improved renal outcome and reduced mortality in patients with RA.
Assuntos
Artrite Reumatoide , Metotrexato , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Fatores Biológicos/uso terapêutico , Humanos , Rim/patologia , Metotrexato/efeitos adversos , Diálise Renal , Estudos RetrospectivosRESUMO
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.
Assuntos
Antígeno B7-H1 , Neoplasias de Mama Triplo Negativas , Macrófagos Associados a Tumor , Humanos , Antígeno B7-H1/metabolismo , Macrófagos/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral , Macrófagos Associados a Tumor/citologia , Biomarcadores TumoraisRESUMO
AIMS: Proliferative activity, evaluated from the Ki-67 index, is a strong prognostic factor in lung adenocarcinoma (LADC). Here, we optimised a procedure to measure the Ki-67 index and establish the best cut-off value. METHODS AND RESULTS: We examined 342 stage I LADCs for the immunohistochemical expression of Ki-67 using different antibodies, MIB1 and SP6. The results revealed the superior specificity of SP6; therefore, SP6 was used in subsequent analyses. Slides were scanned with a virtual slide system. Using software, tumour cells were counted in a whole tumour. Thereafter, the tumour was evenly subdivided into 0.25-mm2 tiles. The frequency of positive cells was counted in each tile of an invasive area or the whole tumour. We calculated the number of tumour cells required to produce a 95% confidence interval (CI) <0.05. Additionally, we calculated coverage probabilities (CP) using two different methods, counting any number or 200 cells per tile. The results showed that we could meet our goal by counting 2000 cells from 10 random tiles (200 cells each) in invasive areas. CONCLUSIONS: We successfully developed an optimal procedure for determination of the Ki-67 labelling index using an SP6 antibody, which provided CP > 70% and CI of <0.05 in more than 90% of cases. Furthermore, we identified an optimal cut-off value of 0.12 with an alternative of 0.15, based on disease recurrence. This procedure and the cut-off values may be used in the routine pathological diagnosis of LADC.
Assuntos
Adenocarcinoma de Pulmão , Antígeno Ki-67/análise , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , PrognósticoRESUMO
Case 1: A 59-year-old Japanese woman with rheumatoid arthritis (RA) for 36 years was admitted for evaluation of deteriorating renal function. Her serum creatine was 4.2 mg/dL, and proteinuria was 6.5 g daily. Renal and duodenal biopsy revealed AA amyloidosis. After treatment with tocilizumab (a humanized anti-interleukin-6 receptor antibody), proteinuria decreased to 1.1 g daily. The patient's renal function subsequently remained stable for 8 years. Case 2: A 71-year-old Japanese man with RA for 30 years was admitted due to deterioration of renal function. Serum creatine was 2.9 mg/dL, and urinary protein excretion was 0.06 g daily. Renal and duodenal biopsy identified AA amyloidosis. Tocilizumab was initiated, and his renal function remained stable for 6 years. The 2nd duodenal biopsy showed a marked decrease of AA amyloid deposits. Conclusion: These two cases suggest that tocilizumab may preserve renal function in the setting of end-stage kidney disease and shift the point of no return for RA patients with AA amyloidosis and renal dysfunction.
Assuntos
Amiloidose/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/complicações , Falência Renal Crônica/fisiopatologia , Rim/efeitos dos fármacos , Receptores de Interleucina-6/imunologia , Proteína Amiloide A Sérica/metabolismo , Idoso , Amiloidose/fisiopatologia , Anticorpos Monoclonais Humanizados/farmacologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Feminino , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-6/antagonistas & inibidoresRESUMO
A 33-year-old Japanese man with no significant past medical history was admitted to our hospital for evaluation of weight gain and pitting edema. A laboratory test confirmed nephrotic-range proteinuria. Renal biopsy showed subepithelial deposits, and membranous nephropathy (MN) was diagnosed. Closer examination clarified an active syphilis infection. After renal biopsy, we prescribed amoxicillin for 8 weeks to treat the syphilis infection. Three weeks later, the patient's proteinuria dramatically decreased. This case is of interest because syphilis can become a cause of acute-onset MN in younger adults, and the incidence of syphilis is increasing in Japan.â©.
Assuntos
Glomerulonefrite Membranosa , Sífilis , Adulto , Amoxicilina/uso terapêutico , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/etiologia , Humanos , Japão , Masculino , Proteinúria , Sífilis/complicações , Sífilis/diagnóstico , Sífilis/tratamento farmacológicoRESUMO
A 60-year-old Japanese woman with polymyositis (PM) developed hemolytic anemia (hemoglobin of 7.3 g/dL), thrombocytopenia (platelet of 9.1×104/µL), and acute kidney injury (Cre of 4.7 mg/dL) at 14 days after starting steroid therapy. Renal biopsy revealed glomerular endothelial swelling with fibrin thrombi and fragmented erythrocytes in the capillary lumens. Hemolytic uremic syndrome (HUS) with thrombotic microangiopathy (TMA) was diagnosed. Hemodialysis and plasma exchange/plasma transfusion were initiated, but HUS did not subside. After 45 days, the patient died of hemorrhagic respiratory failure. Autopsy showed fibrin thrombi filling the glomerular vascular pole and the small arteries in most glomeruli, resulting in glomerular collapse and glomerular basement membrane (GBM) duplication. Although renal involvement by PM is rare, HUS/TMA should be remembered as one of the serious renal complications of PM.
Assuntos
Polimiosite/complicações , Microangiopatias Trombóticas/etiologia , Injúria Renal Aguda/etiologia , Anemia Hemolítica/etiologia , Feminino , Síndrome Hemolítico-Urêmica/etiologia , Humanos , Rim/patologia , Pessoa de Meia-Idade , Polimiosite/patologia , Diálise RenalRESUMO
BACKGROUND: Chronic hypersensitivity pneumonitis (CHP) remains a diagnostic challenge. The process of collecting and extracting serum and droppings from causative animals for the inhalation challenge test is complicated and the risk of inducing disease progression exists. OBJECTIVE: To investigate the utility and safety of an inhalation challenge test using pigeon eggs. METHODS: Pigeon eggs were pasteurized and mixed with a saline solution to produce an inhalation fluid. An inhalation challenge test was conducted on 19 patients with bird-related CHP and 17 patients with interstitial lung disease other than bird-related CHP. To identify antigens in pigeon eggs, the antigen-antibody responses of the pigeon eggs and serum from patients were evaluated using Western blotting. RESULTS: The mean changes in C-reactive protein, alveolar-arterial oxygen difference, erythrocyte sedimentation rate, and lactate dehydrogenase significantly increased by 0.32 mg/dL (P = .014), 7.8 Torr (P = .002), 1.4 mm/h (P = .012), and 5.4 U/mL (P = .0019), respectively, in bird-related CHP group compared to the control 24 hours after the inhalation challenge test. Furthermore, within 24 hours of the inhalation test, the mean forced vital capacity decreased by 2.3% in the bird-related CHP group compared with a decline of 0.05% in the control group (P = .035). Serum collected from seven bird-related CHP patients who underwent the inhalation challenge test and reacted to antigens with molecular weights of 37-75 KDa, and these molecular weights were consistent with egg albumin and globulin. CONCLUSION: Since a mild response was observed after the inhalation challenge test using pigeon eggs, this test was an obvious candidate for diagnosing bird-related CHP.
Assuntos
Alérgenos/administração & dosagem , Pulmão do Criador de Aves/diagnóstico , Testes de Provocação Brônquica , Columbidae/imunologia , Proteínas do Ovo/administração & dosagem , Testes Imunológicos , Pulmão/imunologia , Administração por Inalação , Idoso , Alérgenos/imunologia , Animais , Pulmão do Criador de Aves/sangue , Pulmão do Criador de Aves/imunologia , Pulmão do Criador de Aves/fisiopatologia , Estudos de Casos e Controles , Proteínas do Ovo/imunologia , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Tempo , Capacidade VitalRESUMO
PURPOSE: To investigate the impact of hemodialysis on survival in renal cell carcinoma (RCC) patients. METHODS: We studied 388 patients who underwent radical or partial nephrectomy for RCC at Toranomon Hospital from 2005 to 2013. Survival curves were drawn according to the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model to assess the prognostic influence of hemodialysis on cancer-specific survival. RESULT: Of the 388 patients, 66 were on hemodialysis and 322 were not on dialysis. In the hemodialysis patients, incidental diagnosis of RCC was less frequent than in the non-dialysis patients. In addition, RCC was more likely to be multicentric (41% vs 1.2%), bilateral (14% vs 0.6%), and papillary (18% vs 7%) in hemodialysis patients. Moreover, tumors were smaller, the stage was lower, and the Fuhrman nuclear grade was higher in the patients on hemodialysis. The 5-year cancer-specific survival rate was 82.8% for hemodialysis patients and 93.5% for nondialysis patients. Multivariate analysis indicated that hemodialysis, stage, and Fuhrman nuclear grade were independent prognostic factors for RCC. CONCLUSIONS: This study suggested that hemodialysis was an independent prognostic factor for cancer-specific survival in RCC patients, along with the tumor stage and Fuhrman nuclear grade.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Humanos , Neoplasias Renais/terapia , Estadiamento de Neoplasias , Nefrectomia , Prognóstico , Diálise Renal , Estudos RetrospectivosRESUMO
Monoclonal B-cell lymphocytosis (MBL) is an early or precursor asymptomatic proliferation of chronic lymphocytic lymphoma (CLL)-like B-cells. Lymphoplasmacytic lymphoma (LPL), often clinically associated with Waldenström macroglobulinemia, is a B-cell neoplasm characterized by frequent MYD88 L265P mutation. Here, we report a rare composite MBL and LPL in a patient with IgM light chain (AL) amyloidosis. A 74-year-old male with a known IgM monoclonal protein developed proteinuria. No lymphocytosis was detected. Renal biopsy showed deposition of AL λ amyloid in the glomeruli and vessels. Subsequent bone marrow biopsy revealed nodular atypical CLL-like small B-cell proliferation and scattered peripheral LPL. Immunohistochemistry and/or flow cytometry revealed that the atypical CLL-like population expressed CD19, CD20, CD5, weak CD23, LEF-1 and diminished surface Igκ. The LPL was positive for CD19, CD20 and surface Igλ. Using laser-capture microdissection and allele-specific polymerase chain reaction, we confirmed that MYD88 L265P was detectable in the LPL but not in the atypical CLL-like population. Thus, we demonstrated that these two populations were clonally independent, and made the diagnosis of composite MBL and LPL. An integrated clinical, pathological, immunophenotypic and genetic assessment is essential in such complicated cases, and especially 'clone-specific' MYD88 genotyping may facilitate the differential diagnoses of low-grade B-cell lymphomas.