Hepatic and Extrahepatic Characteristics of Autoimmune Hepatitis: A 23-year Hospital-Based Cohort Study.

BACKGROUND: The characteristics of autoimmune hepatitis (AIH) in Asia mostly remain elusive. METHODS: A cohort study of liver biopsy-proven AIH patients was conducted in a tertiary care cancer of Taiwan. RESULTS: From 1999 to 2022, of 13,766 patients who underwent liver biopsy, 150 patients with AIH were enrolled. The female-to-male ratio was 2.26. At baseline, the mean age was 51.09 years, mean alanine aminotransferase level was 494.11 U/L, and 17 (11.3%) had cirrhosis. All except one patient had AIH type 1. The females were older and had higher baseline cirrhosis rates than did the males. The 23-year cumulative incidences of cirrhosis, hepatocellular carcinoma (HCC), mortality/liver transplantation, autoimmune diseases and extrahepatic cancer were 64.2%, 13.3%, 23.4%, 30.7% and 21.2%, respectively. The 1-year, 2-year, 3-year, 5-year, 10-year and 20-year postimmunosuppressive therapy relapse rates were 60%, 78.2%, 81.8%, 89.1%, 94.5% and 100%, respectively. Baseline associations were as follows: alkaline phosphatase (Alk-p) levels with postimmunosuppressive therapy flare [hazard ratio (HR): 1.003; 95% CI HR: 1.000-1.005]; age with HCC (1.072; 1.010-1.138) and all-cause cancer (1.041;1.005-1.079); cirrhosis with mortality/liver transplantation (11.933;1.984-71.787); and antinuclear antibody (ANA) titers with mortality/liver transplantation (1.001;1.000-1.003), cirrhosis (1.001;1.000-1.002), and autoimmune diseases (1.001; 1.000-1.002). CONCLUSION: In an Asian country endemic for viral hepatitis, the female-to-male and baseline cirrhosis rates of AIH patients were lower than expected, while over 60% of the patients eventually developed cirrhosis. The high posttherapy relapse rate warrants cautious monitoring, particularly for patients with high baseline Alk-p levels. Baseline age, cirrhosis status and ANA titers are crucial for outcomes.

Presentation of glomerulocystic disease in a young onset diabetes: A case report.

RATIONALE: This case report presents a challenging medical scenario involving a young adult male who exhibited an unusual combination of symptoms, including abrupt weight loss, declining renal function, proteinuria, and concurrent onset of diabetes mellitus. Remarkably, the patient had no previous medical history or family history of similar conditions, necessitating a comprehensive investigation. PATIENT CONCERNS: On March 10, 2021, a 25-year-old male sought medical attention due to the aforementioned symptoms. Initial assessments revealed stage 5 chronic kidney disease, with elevated blood urea nitrogen (BUN) and serum creatinine (Cr) levels, as well as significant proteinuria. The only notable physical finding was obesity, and renal ultrasound showed normal-sized kidneys without cysts. DIAGNOSIS: A treatment plan was initiated to stabilize creatinine levels, including medications such as Glimepiride, Glyxambi, Bisoprolol, Amlodipine, and Valsartan. However, despite diligent medication management, proteinuria persisted, prompting further evaluation. A renal biopsy was performed on April 12th, 2023, leading to the diagnosis of glomerulocystic kidney disease with early-stage changes indicative of diabetic nephropathy. INTERVENTIONS: The patient continues to receive ongoing care and follow-up at our outpatient clinic to optimize therapeutic interventions and elucidate the underlying etiology of this complex clinical scenario. OUTCOMES: Ongoing investigations and therapeutic interventions are crucial to understand the underlying cause and optimize patient care in this intricate clinical scenario. LESSONS: This case underscores the complexity of diagnosing and managing a young adult presenting with concurrent renal dysfunction, proteinuria, and diabetes mellitus in the absence of prior underlying conditions. It highlights the importance of comprehensive evaluation and ongoing care in such challenging cases.

Real-World Evidence of Intra-institutional Performance Variation in Indefinite Diagnosis of Pleural Effusion Cytology.

CONTEXT.­: Pleural effusion cytology has been widely used in the investigation of pathologic fluid accumulation in pleural spaces. However, up to one-tenth of the cases were not given a definitive diagnosis. These cases have largely been neglected in the bulk of the literature. OBJECTIVE.­: To provide real-world data on indefinite diagnoses including "atypia of uncertain significance" (AUS) and "suspicious for malignancy" (SFM) in pleural effusion cytology and to investigate pathologists' practice patterns on using these diagnostic categories. DESIGN.­: We reported the diagnoses of 51 675 cases. Descriptive statistics and correlation coefficients were used to analyze the relationships between different diagnostic categories and pathologists' practice patterns and possible explanatory variables. RESULTS.­: The diagnoses AUS and SFM were reported in 4060 cases (7.86%) and 1554 cases (3.01%) in the cohort, respectively. The mean rates for these indefinite diagnoses varied up to 3-fold between pathologists. Correlations were found between AUS and SFM, as well as between indefinite diagnoses and negative for malignancy (NFM). No correlations were found between pathologists' years of experience or case volume and the rates of indefinite diagnosis or diagnostic certainty. CONCLUSIONS.­: A real-world baseline for the rates of indefinite diagnoses in pleural effusion cytology is provided in this large retrospective study. Pathologists show significant variation in their use of indefinite diagnostic categories, and the tendency to use these ambiguous terms was not correlated with individuals' experience or case volume. How to untangle the intertwined relationship between the uncertainty of indefinite diagnoses and that of NFM requires future prospective studies.

Learning more from the inter-rater reliability of interstitial fibrosis assessment beyond just a statistic.

Interstitial fibrosis assessment by renal pathologists lacks good agreement, and we aimed to investigate its hidden properties and infer possible clinical impact. Fifty kidney biopsies were assessed by 9 renal pathologists and evaluated by intraclass correlation coefficients (ICCs) and kappa statistics. Probabilities of pathologists' assessments that would deviate far from true values were derived from quadratic regression and multilayer perceptron nonlinear regression. Likely causes of variation in interstitial fibrosis assessment were investigated. Possible misclassification rates were inferred on reported large cohorts. We found inter-rater reliabilities ranged from poor to good (ICCs 0.48 to 0.90), and pathologists' assessments had the worst agreements when the extent of interstitial fibrosis was moderate. 33.5% of pathologists' assessments were expected to deviate far from the true values. Variation in interstitial fibrosis assessment was found to be correlated with variation in interstitial inflammation assessment (r2 = 32.1%). Taking IgA nephropathy as an example, the Oxford T scores for interstitial fibrosis were expected to be misclassified in 21.9% of patients. This study demonstrated the complexity of the inter-rater reliability of interstitial fibrosis assessment, and our proposed approaches discovered previously unknown properties in pathologists' practice and inferred a possible clinical impact on patients.

Unsatisfactory reproducibility of interstitial inflammation scoring in allograft kidney biopsy.

Interstitial inflammation scoring is incorporated into the Banff Classification of Renal Allograft Pathology and is essential for the diagnosis of T-cell mediated rejection. However, its reproducibility, including inter-rater and intra-rater reliabilities, has not been carefully investigated. In this study, eight renal pathologists from different hospitals independently scored 45 kidney allograft biopsies with varying extents of interstitial inflammation. Inter-rater reliabilities and intra-rater reliabilities were investigated by kappa statistics and conditional agreement probabilities. Individual pathologists' scoring patterns were examined by chi-squared tests and proportions tests. The mean pairwise kappa values for inter-rater reliability were 0.27, 0.30, and 0.26 for the Banff i score, ti score, and i-IFTA, respectively. No rater pair performed consistently better or worse than others on all three scorings. After dichotomizing the scores into two groups (none/mild and moderate/severe inflammation), the averaged conditional agreements ranged from 47.1% to 50.0%. The distributions of the scores differed, but some pathologists persistently scored higher or lower than others. Given the important role of interstitial inflammation scoring in the diagnosis of T-cell mediated rejection, transplant practitioners should be aware of the possible clinical implications of the far-from-optimal reproducibility.

Nivolumab-induced acute tubular injury: A case report.

Nivolumab belongs to immune checkpoint inhibitors (ICIs). ICIs-induced kidney injury is rare and acute interstitial nephritis (AIN) is the majority. A 58-year-old woman had gastric cancer treated with nivolumab. Her serum creatinine (Cr) increased to 5.94 mg/dL post 2 cycles of nivolumab and co-administered with acemetacin. A kidney biopsy showed acute tubular injury (ATI). Nivolumab rechallenge was done and Cr worsened again. The lymphocyte transformation test (LTT) indicated a strong positive for nivolumab. Although rare, ATI due to ICIs could not be ruled out, and LTT is a tool to identify the culprit.

Bevacizumab-Induced Thrombotic Microangiopathy (TMA) in Metastatic Lung Adenocarcinoma Patients Receiving Nivolumab Combined with Bevacizumab, Carboplatin and Paclitaxel: Two Case Reports.

Anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs), combined with bevacizumab and platinum-based chemotherapy, have shown promising efficacy in treating metastatic non-squamous cell lung cancer in phase 3 clinical trials. However, drug-induced nephrotoxicity is an uncommon but threatening adverse effect when using this combination therapy, and should be evaluated and managed carefully. Here, we present two patients experiencing late-onset asymptomatic heavy proteinuria during the clinical trial. Kidney biopsies performed finally identified bevacizumab-induced thrombotic microangiopathy (TMA), and the proteinuria was decreased after discontinuing bevacizumab permanently. Our report suggests that a kidney biopsy is needed for those receiving ICIs in combination with bevacizumab and chemotherapy and experiencing nephrotoxicity such as heavy proteinuria.

The pathological spectrum of pediatric kidney disease: 18-Year experience from a single tertiary care center in northern Taiwan.

BACKGROUND: Glomerular disease is one of the leading causes of chronic kidney disease in children worldwide. Recent studies outlined the changing spectrum of glomerular disease in certain countries. Therefore, our study aimed to evaluate the histopathological patterns and changes in pediatric kidney disease over the past 18 years in northern Taiwan. METHODS: This was a retrospective chart review study of pediatric patients (≤18 years of age) undergoing percutaneous renal biopsies (PRBs) of native kidneys between January 2002 and July 2020 from a Pediatric Care Center at Chang Gung Memorial Hospital, Taoyuan, Taiwan. RESULTS: This study analyzed a total of 339 pediatric native PRBs. The mean age of the subjects was 13.7 ± 7.0 years (184 girls and 155 boys). The most common indications of PRBs included acute nephritic syndrome (55.7%), idiopathic nephrotic syndrome (22.7%), persistent asymptomatic hematuria (13.9%), and unexplained renal failure (7.7%). Our study revealed that proliferative lupus nephritis (LN), minimal change disease (MCD)-related nephrotic syndrome, and IgA nephropathy (IgAN) were the most frequent biopsy-proven pediatric glomerular diseases. In addition, we showed that severe acute post-streptococcal glomerulonephritis (APSGN) was infrequent and has not even been diagnosed since 2010. CONCLUSION: Our result revealed that the spectrum of biopsy-proven pediatric kidney disease has not changed significantly over the past two decades. Furthermore, proliferative LN, MCD, and primary IgAN continue to be the most common histopathological diagnoses among Taiwanese children.

End-to-end interstitial fibrosis assessment of kidney biopsies with a machine learning-based model.

BACKGROUND: The extent of interstitial fibrosis in the kidney not only correlates with renal function at the time of biopsy but also predicts future renal outcome. However, its assessment by pathologists lacks good agreement. The aim of this study is to construct a machine learning-based model that enables automatic and reliable assessment of interstitial fibrosis in human kidney biopsies. METHODS: Validated cortex, glomerulus and tubule segmentation algorithms were incorporated into a single model to assess the extent of interstitial fibrosis. The model performances were compared with expert renal pathologists and correlated with patients' renal functional data. RESULTS: Compared with human raters, the model had the best agreement [intraclass correlation coefficient (ICC) 0.90] to the reference in 50 test cases. The model also had a low mean bias and the narrowest 95% limits of agreement. The model was robust against colour variation on images obtained at different times, through different scanners, or from outside institutions with excellent ICCs of 0.92-0.97. The model showed significantly better test-retest reliability (ICC 0.98) than humans (ICC 0.76-0.94) and the amount of interstitial fibrosis inferred by the model strongly correlated with 405 patients' serum creatinine (r = 0.65-0.67) and estimated glomerular filtration rate (r = -0.74 to -0.76). CONCLUSIONS: This study demonstrated that a trained machine learning-based model can faithfully simulate the whole process of interstitial fibrosis assessment, which traditionally can only be carried out by renal pathologists. Our data suggested that such a model may provide more reliable results, thus enabling precision medicine.

Association between breast cancer and hepatitis C: A joint study of hospitalized patients and nationwide cohorts.

Whether hepatitis C virus (HCV) infection is associated with breast cancer risk remains elusive, and we aimed to elucidate it. A nationwide population-based cohort study of the Taiwan National Health Insurance Research Database (TNHIRD) was conducted. Additionally, breast cancer risk factors, and HCV core expression were surveyed in breast cancer patients of a tertiary care center. Three TNHIRD cohorts (1:4:4, propensity score-matched, 2003-2012), including HCV-treated (3646 HCV-infected females with interferon-based therapy ≥6 months), HCV-untreated (n = 14,584) and HCV-uninfected (n = 14,584) cohorts, were enrolled. The HCV-untreated cohort had the highest 9-year breast cancer cumulative incidence (2.017%; 95% confidence interval [CI]: 1.382%-2.846%), while the HCV-treated (1.073%; 0.414%-2.356%), and HCV-uninfected (1.453%; 0.785%-2.486%) cohorts showed no difference. Untreated HCV infection (hazard ratio [HR]: 1.701; 95% CI: 1.205%-2.400), urban residency (1.658, 1.183-2.323), and baseline cardiovascular events (1.920; 1.005-3.668) were associated with incident breast cancers. The interaction analysis showed that particularly among patients <49 years, HCV infection was associated with breast cancer development (2.193; 1.097-4.384). Of 12,170 hospitalized breast cancer patients, 4.90% were HCV Ab-positive. HCV Ab-positive patients were older (60.92+/-10.82 vs 53.91+/-11.38 years, P < 0.0001) and had a higher body mass index (25.39+/-5.1 vs 24.5+/-4.3 kg/m2, P = 0.007), rates of diabetes (30.60 vs 19.98%, P < 0.0001), hypertension (46.9 vs 30.39%, P < 0.0001), dyslipidemia (25.52 vs 20.28%, P = 0.031), and hyperuricemia (11.38 vs 5.52%, P < 0.0001) than their counterparts. No HCV core-positive cells were demonstrated in breast cancer tissues. Conclusions: Untreated HCV infection, urbanization, and cardiovascular events were potential risk factors for breast cancer. The HCV-associated risk was most prominent among patients <49 years, might not be associated with in situ HCV core-related oncogenesis but with metabolic alterations, and was reversed by anti-HCV therapy.

Glomerular disease classification and lesion identification by machine learning.

BACKGROUND: Classification of glomerular diseases and identification of glomerular lesions require careful morphological examination by experienced nephropathologists, which is labor-intensive, time-consuming, and prone to interobserver variability. In this regard, recent advance in machine learning-based image analysis is promising. METHODS: We combined Mask Region-based Convolutional Neural Networks (Mask R-CNN) with an additional classification step to build a glomerulus detection model using human kidney biopsy samples. A Long Short-Term Memory (LSTM) recurrent neural network was applied for glomerular disease classification, and another two-stage model using ResNeXt-101 was constructed for glomerular lesion identification in cases of lupus nephritis. RESULTS: The detection model showed state-of-the-art performance on variedly stained slides with F1 scores up to 0.944. The disease classification model showed good accuracies up to 0.940 on recognizing different glomerular diseases based on H&E whole slide images. The lesion identification model demonstrated high discriminating power with area under the receiver operating characteristic curve up to 0.947 for various glomerular lesions. Models showed good generalization on external testing datasets. CONCLUSION: This study is the first-of-its-kind showing how each step of kidney biopsy interpretation carried out by nephropathologists can be captured and simulated by machine learning models. The models were integrated into a whole slide image viewing and annotating platform to enable nephropathologists to review, correct, and confirm the inference results. Further improvement on model performances and incorporating inputs from immunofluorescence, electron microscopy, and clinical data might realize actual clinical use.

TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities.

TAFRO syndrome is an extremely rare form of idiopathic MCD, characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis on bone marrow biopsy, and organomegaly. Like idiopathic MCD, renal involvement is also a common presentation in patients with TAFRO syndrome. Furthermore, membranoproliferative glomerulonephritis (MPGN)-like injury and thrombotic microangiopathy (TMA) are the most reported histopathologic findings of renal biopsy. Several molecular mechanisms have been previously postulated in order to explain the TAFRO syndrome symptoms, including abnormal production of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), etc. The role of these cytokines in renal injury, however, is not well understood. The aim of this review article is to summarize the latest knowledge of molecular mechanisms behind the TAFRO syndrome and their potential role in renal damage.

Combination Biomarker of Immune Checkpoints Predict Prognosis of Urothelial Carcinoma.

In contrast to Western counties, the incidence of urothelial carcinoma (UC) remains mar-edly elevated in Taiwan. Regulatory T cells (Tregs) play a crucial role in limiting immune responses within the tumor microenvironment. To elucidate the relationship between immune checkpoints in the tumor immune microenvironment and UC progression, we utilize the Gene Expression Omnibus (GEO) to analyze a microarray obtained from 308 patients with UC. We observed that the expression level of CD276 or TIM-3 was positively correlated with late-stage UC and poor prognosis. Patients with simultaneously high CD276 and TIM-3 expression in tumors have significantly reduced both univariate and multivariate survival, indicating that mRNA levels of these immune checkpoints could be independent prognostic biomarkers for UC overall survival and recurrence. Our cohort study showed rare CD8+ cytotoxic T-cells and Tregs infiltration during early-stage UC-known as cold tumors. Approximately 30% of late-stage tumors exhibited highly infiltrated cytotoxic T cells with high PD-1 and FOXP3 expression, which implied that cytotoxic T cells were inhibited in the advanced UC microenvironment. Collectively, our findings provide a better prognosis prediction by combined immune checkpoint biomarkers and a basis for early-stage UC standard treatment to convert cold tumors into hot tumors, followed by immune checkpoint therapy.

Successful Identification of Nasopharyngeal Carcinoma in Nasopharyngeal Biopsies Using Deep Learning.

Pathologic diagnosis of nasopharyngeal carcinoma (NPC) can be challenging since most cases are nonkeratinizing carcinoma with little differentiation and many admixed lymphocytes. Our aim was to evaluate the possibility to identify NPC in nasopharyngeal biopsies using deep learning. A total of 726 nasopharyngeal biopsies were included. Among them, 100 cases were randomly selected as the testing set, 20 cases as the validation set, and all other 606 cases as the training set. All three datasets had equal numbers of NPC cases and benign cases. Manual annotation was performed. Cropped square image patches of 256 × 256 pixels were used for patch-level training, validation, and testing. The final patch-level algorithm effectively identified NPC patches, with an area under the receiver operator characteristic curve (AUC) of 0.9900. Using gradient-weighted class activation mapping, we demonstrated that the identification of NPC patches was based on morphologic features of tumor cells. At the second stage, whole-slide images were sequentially cropped into patches, inferred with the patch-level algorithm, and reconstructed into images with a smaller size for training, validation, and testing. Finally, the AUC was 0.9848 for slide-level identification of NPC. Our result shows for the first time that deep learning algorithms can identify NPC.

Acute Iron Deprivation Reprograms Human Macrophage Metabolism and Reduces Inflammation In Vivo.

Iron is an essential metal that fine-tunes the innate immune response by regulating macrophage function, but an integrative view of transcriptional and metabolic responses to iron perturbation in macrophages is lacking. Here, we induced acute iron chelation in primary human macrophages and measured their transcriptional and metabolic responses. Acute iron deprivation causes an anti-proliferative Warburg transcriptome, characterized by an ATF4-dependent signature. Iron-deprived human macrophages show an inhibition of oxidative phosphorylation and a concomitant increase in glycolysis, a large increase in glucose-derived citrate pools associated with lipid droplet accumulation, and modest levels of itaconate production. LPS polarization increases the itaconate:succinate ratio and decreases pro-inflammatory cytokine production. In rats, acute iron deprivation reduces the severity of macrophage-dependent crescentic glomerulonephritis by limiting glomerular cell proliferation and inducing lipid accumulation in the renal cortex. These results suggest that acute iron deprivation has in vivo protective effects mediated by an anti-inflammatory immunometabolic switch in macrophages.

The irreversible HCV-associated risk of gastric cancer following interferon-based therapy: a joint study of hospital-based cases and nationwide population-based cohorts.

BACKGROUND: Hepatitis C virus (HCV) infection causes many extrahepatic malignancies; whether it increases gastric cancer risk and the risk reverses after anti-HCV therapy remain elusive. METHOD: A nationwide population-based cohort study of Taiwan National Health Insurance Research Database (TNHIRD) was conducted. In parallel, the risk factors and HCV-core-protein expressions were surveyed in gastric cancer patients from a tertiary care center. RESULTS: From 2003 to 2012, of 11,712,928 patients, three 1:4:4, propensity-score-matched TNHIRD cohorts including HCV-treated (7545 patients with interferon-based therapy ⩾ 6 months), HCV-untreated (n = 30,180), and HCV-uninfected cohorts (n = 30,180) were enrolled. The cumulative incidences of gastric cancer [HCV-treated: 0.452%; 95% confidence interval (CI): 0.149-1.136%; HCV-untreated: 0.472%; 95% CI: 0.274-0.776%; HCV-uninfected: 0.146%; 95% CI 0.071-0.280%] were lowest in HCV-uninfected cohort (p = 0.0028), but indifferent between treated and untreated cohorts. HCV infection [hazards ratio (HR): 2.364; 95% CI: 1.337-4.181], male sex (HR: 1.823; 95% CI: 1.09-3.05) and age ⩾ 49 years (HR: 3.066; 95% CI: 1.56-6.026) were associated with incident gastric cancers. Among 887 (males: 68.4%; mean age: 66.5 ± 12.9 years, 2008-2018) hospitalized gastric cancer patients, HCV Ab-positive rate was 7.8%. None of the investigated factors exhibited different rates between HCV Ab-positive and Ab-negative patients. No HCV-core-positive cells were demonstrated in gastric cancer tissues. CONCLUSIONS: HCV infection, male sex and old age were risk factors for gastric cancer development. HCV-associated gastric cancer risk might be neither reversed by interferon-based therapy, nor associated with in situ HCV-core-related carcinogenesis.

Effect of celastrol on the progression of polycystic kidney disease in a Pkd1-deficient mouse model.

AIMS: Celastrol, a naturally occurring pentacyclic triterpene, has attracted considerable interest because it exhibits potent anti-inflammatory and anti-tumor properties. However, the effects of celastrol in autosomal dominant polycystic kidney disease (ADPKD) remain uninvestigated. MAIN METHODS: We determined the effects of celastrol on ADPKD progression in a novel Pkd1-hypomorphic mouse model by intraperitoneal injection (postnatal day 35-63). KEY FINDINGS: Pkd1 miRNA transgenic (Pkd1 miR TG) mice treated with 1 mg/kg/day of celastrol exhibited a lower renal cystic index (by 21.5%) than the vehicle-treated controls, but the fractional kidney weights and blood urea nitrogen levels were not significantly affected with celastrol treatment. At a high dose (2 mg/kg/day), celastrol caused marginal weight loss in the treated mice and had no significant effect on renal cystogenesis, thus indicating a potential toxic effect. We further identified that celastrol increased the phosphorylation level of adenosine monophosphate-activated protein kinase (AMPK) in the cystic kidneys. Moreover, celastrol reduced the renal mRNA expression levels of tumor necrosis factor-α, interleukin-1ß, P2RX7, F4/80, CD68, transforming growth factor-ß, collagen-1, and fibronectin, which were high in the Pkd1 miR TG mice. Immunohistological analysis revealed that celastrol suppressed macrophage infiltration in the cystic kidneys; however, the renal fibrosis scores and proliferation indices remained high. SIGNIFICANCE: These results indicate that celastrol could be a potent anti-inflammatory agent and a natural AMPK enhancer. However, celastrol has only modest effects on renal cystogenesis and has a narrow therapeutic window. Further studies are needed to clarify whether celastrol has the potential for the treatment of ADPKD.

Interferon-λ3/4 genetic variants and interferon-λ3 serum levels are biomarkers of lupus nephritis and disease activity in Taiwanese.

BACKGROUND: Type III interferons (IFNs) or IFN-λs are the newly discovered cytokines that primarily target the cells of epithelial and myeloid lineages, which are major components of kidneys. The current study aimed to investigate whether IFN-λs are involved in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis. METHODS: TaqMan allele discrimination assays were used to determine IFNL3/4 SNP genotypes of 1620 healthy controls and 1013 SLE patients (two independent cohorts consisting of 831 and 182 subjects, respectively) from Taiwan. The distributions of IFNL3/4 SNP genotypes and allele frequencies were compared between SLE patients and healthy controls and among SLE patients stratified by clinical phenotypes. ELISA was used to determine the serum IFN-λ3 concentrations of SLE patients. RESULTS: All major IFN3/4 SNP alleles were significantly associated with the risk for lupus nephritis (rs8099917T, PFDR = 0.0021, OR 1.75, 95% CI 1.24-2.47; rs12979860C, PFDR = 0.0034, OR 1.65, 95% CI 1.18-2.30; rs4803217C, PFDR = 0.0021, OR 1.76, 95% CI 1.25-2.48; and ss469415590TT, PFDR = 0.0021, OR 1.73, 95% CI 1.23-2.42) among SLE patients. Similarly, the major IFNL3/4 SNP haplotype rs8099917T-ss469415590TT-rs12979860C-rs4803217C (or T-TT-C-C) was a significant risk factor for lupus nephritis (P = 0.0015, OR 1.68, 95% CI 1.22-2.32). Additionally, all minor IFN3/4 SNP alleles were significantly associated with SLE susceptibility in nephritis-negative SLE patients as compared to normal healthy controls (rs8099917G, PFDR = 0.00177, OR 1.68, 95% CI 1.24-2.28; rs12979860T, PFDR = 0.00299, OR 1.58, 95% CI 1.18-2.32; rs4803217A, PFDR = 0.00176, OR 1.65, 95% CI 1.22-2.23; and ss469415590ΔG, PFDR = 0.00176, OR 1.70, 95% CI 1.26-2.29). Furthermore, the elevated serum levels of IFN-λ3 were significantly correlated with the complement depression and the high SLE disease activities in SLE patients. CONCLUSIONS: IFN-λ3/4 genetic variants play a unique role in the development of lupus nephritis and SLE.

Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function.

Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.

Palliative gastrectomy is beneficial in selected cases of metastatic gastric cancer.

BACKGROUND: Salvage chemotherapy is the mainstay of treatment for metastatic gastric cancer (mGC). This study aimed to clarify the effects of palliative gastrectomy (PG) and identify prognostic factors in mGC patients undergoing PG. METHODS: This was a retrospective review of 333 mGC patients receiving PG or a non-resection procedure (NR) between 2000 and 2010. Clinicopathological factors affecting the prognosis of these patients were collected prospectively and analyzed. RESULTS: One hundred and ninety-three patients underwent PG and 140 NR. The clinicopathological characteristics were comparable between the two groups except for metastatic pattern. There were no significant differences in postoperative morbidity and mortality between the two groups. The PG group had a significantly longer median overall survival compared with the NR group (7.7 months vs. 4.9 months). In the PG group, age ≤58 years, preoperative albumin level >3 g/dL, ratio of metastatic to examined lymph nodes ≤0.58, and administration of chemotherapy were independent prognostic factors in multivariate analysis. CONCLUSIONS: Patients undergoing PG had better outcomes than those undergoing NR. Among the patients undergoing resection, age ≤58 years, a better preoperative nutritional status, less nodal involvement and postoperative chemotherapy independently affected patient survival.