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Objective: This is a study on the demographics and clinical outcomes including the response to therapy of patients with focal segmental glomerulosclerosis (FSGS) over the past decade., Materials and Methods: All histologically proven FSGS cases diagnosed between 2008 and 2018 were analyzed for their clinical, laboratory, and histological characteristics including treatment that could influence the disease progression and renal outcome of these patients. We used the Columbia Classification for FSGS for the renal biopsy., Results: There were two subgroups of FSGS patients; those with nephrotic syndrome and those without nephrotic syndrome. Patients with FSGS with non-nephrotic syndrome had poorer survival rates compared to the nephrotic group. For those without nephrotic syndrome, the indices responsible for progression involved more tubular and blood vessel lesions in addition to glomerular pathology compared to those with nephrotic syndrome. Patients with FSGS with nephrotic syndrome responded to immunosuppressants more favorably compared to the non-nephrotic group, though both groups responded with decreasing proteinuria. The nephrotic group had a better 10-year long-term survival rate of 92 vs. 72% for the non-nephrotic group (log-rank 0.002). The 10-year survival for the whole group of FSGS patients was 64%., Conclusion: Our data suggest that in FSGS, one of the significant components of the disease is the vascular and tubular damage, apart from the underlying glomerular pathology, resulting in varying responses to therapy, and the difference is reflected in inherently poorer response to immunosuppressant therapy in those without nephrotic syndrome as opposed to those with nephrotic syndrome, who responded to immunosuppressant therapy (IST) with stabilization of renal function and had less blood vessel and tubular lesions.

Introduction: Circulating tumor DNA (ctDNA) has been increasingly recognized as a promising minimally-invasive biomarker that could identify patients with minimal residual disease and a high risk of recurrence after definitive treatment. In this study, we've compared the clinical utility and sensitivity of 2 different approaches to ctDNA analyses: tumor-informed and tumor-agnostic in the management of colorectal (CRC) patients. The clinical benefits of a single timepoint ctDNA analysis compared to serial ctDNA monitoring after definitive treatment were also evaluated to uncover the ideal surveillance protocol., Methods: Patient-paired resected tumor tissues, peripheral blood cells, and a total of 127 pre-operative and serial plasma cell-free DNA (cfDNA) samples after definitive treatment from 38 CRC patients that had undergone curative intent surgery were analyzed using a commercial NGS cfDNA panel., Results: Up to 84% (32/38) of the recruited patients were detected with at least 1 genomic alteration from the tumor tissues that could be monitored using the tumor-informed ctDNA approach and none of the detected alterations were clonal hematopoiesis (CH) related. In contrast, 37% (14/38) of patients were detected with at least 1 monitoring alteration after exclusion of CH mutations using the tumor-agnostic approach. Serial plasma samples after definitive therapy were available for 31 patients. In the landmark ctDNA analysis, 24% (7/29) of patients had detectable ctDNA and were more likely to relapse than ctDNA-negative patients (p < 0.05). The landmark analysis sensitivity and specificity for recurrence were 67% and 87%, respectively. The incorporation of longitudinal ctDNA analysis at 6-months intervals improved the sensitivity to 100%. The median variant allele frequency (VAF) of the ctDNA mutations detected during surveillance was 0.028% (range: 0.018-0.783), where up to 80% (8/10) of the mutations were detected at VAF lower than the tumor-agnostic detection limit of 0.1%. Utilizing the tumor-agnostic approach reduced the recurrence detection sensitivity to 67% (4/6). Serial ctDNA analyses predicted disease recurrence at a median of 5 months ahead of radiological imaging., Conclusion: Longitudinal monitoring using tumor-informed ctDNA testing shows high analytical sensitivity, low probability of false-positive results due to CH mutations, and improved sensitivity in detecting recurrence which may modify the clinical management of CRC., Competing Interests: YC reported as an employee of Cancer Precision Medicine Inc., Japan. S-KL reported consulting or advisory roles with Cancer Precision Medicine Inc., Japan. YN reported consulting and advisory roles with OncoTherapy Science, Inc., Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chan, Nagayama, Otaki, Chin, Fukunaga, Ueno, Nakamura and Low.)

Purpose: Differentiating between diabetic kidney disease (DKD) and non-diabetic kidney disease (NDKD) in patients with Type 2 diabetes mellitus (T2DM) is important due to implications on treatment and prognosis. Clinical methods to accurately distinguish DKD from NDKD are lacking. We aimed to develop and validate a novel nomogram to predict DKD in patients with T2DM and proteinuric kidney disease to guide decision for kidney biopsy., Methods: A hundred and two patients with Type 2 Diabetes Mellitus (T2DM) who underwent kidney biopsy from 1st January 2007 to 31st December 2016 were analysed. Univariate and multivariate analyses were performed to identify predictive variables and construct a nomogram. The discriminative ability of the nomogram was assessed by calculating the area under the receiver operating characteristic curve (AUROC), while calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test and calibration plot. Internal validation of the nomogram was assessed using bootstrap resampling., Results: Duration of T2DM, HbA1c, absence of hematuria, presence of diabetic retinopathy and absence of positive systemic biomarkers were found to be independent predictors of DKD in multivariate analysis and were represented as a nomogram. The nomogram showed excellent discrimination, with a bootstrap-corrected C statistic of 0.886 (95% CI 0.815-0.956). Both the calibration curve and the Hosmer-Lemeshow goodness-of-fit test (p = 0.242) showed high degree of agreement between the prediction and actual outcome, with the bootstrap bias-corrected curve similarly indicating excellent calibration., Conclusions: A novel nomogram incorporating 5 clinical parameters is useful in predicting DKD in type 2 diabetes mellitus patients with proteinuric kidney disease., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Genomic profiling using tumor biopsies remains the standard approach for the selection of approved molecular targeted therapies. However, this is often limited by its invasiveness, feasibility, and poor sample quality. Liquid biopsies provide a less invasive approach while capturing a contemporaneous and comprehensive tumor genomic profile. Recent advancements in the detection of circulating tumor DNA (ctDNA) from plasma samples at satisfactory sensitivity, specificity, and detection concordance to tumor tissues have facilitated the approval of ctDNA-based genomic profiling to be integrated into regular clinical practice. The recent approval of both single-gene and multigene assays to detect genetic biomarkers from plasma cell-free DNA (cfDNA) as companion diagnostic tools for molecular targeted therapies has transformed the therapeutic decision-making procedure for advanced solid tumors. Despite the increasing use of cfDNA-based molecular profiling, there is an ongoing debate about a 'plasma first' or 'tissue first' approach toward genomic testing for advanced solid malignancies. Both approaches present possible advantages and disadvantages, and these factors should be carefully considered to personalize and select the most appropriate genomic assay. This review focuses on the recent advancements of cfDNA-based genomic profiling assays in advanced solid tumors while highlighting the major challenges that should be tackled to formulate evidence-based guidelines in recommending the 'right assay for the right patient at the right time'.

Background: Genomic profiling of tumors from cancer patients facilitates molecular-guided therapy. The turnaround time is one of important issues to deliver results timely for clinical decisions. The Ion Torrent™ Genexus™ Integrated Sequencer automates all next generation sequencing (NGS) workflows and delivers results within a day., Methods: In this study, we conducted a feasibility study to evaluate the detection rate of genomic alterations from cell-free total nucleic acid (cfTNA, containing cfDNA and cfRNA) of 119 non-small cell lung cancer using Oncomine Precision Assay on Genexus™ Integrated Sequencer. Oncomine Precision Assay (OPA) covers actionable mutations, copy number variations and fusion genes and that are applicable for the selection of targeted therapy. cfTNA isolated from plasma (derived from 14 ml of blood) were subjected to the Genexus system for library construction, templating, sequencing, and data analyses., Results: The sequencing resulted in median overall depth of 35,773× and median molecular coverage of 2,192× with cfTNA input ranged from 11 to 36 ng. Among the 119 samples evaluated, we detected at least one genomic alteration in plasma cfTNA of 79 cases (66%). When comparing to standard-of-care testing, the sensitivity and specificity of mutation detection in non-small cell lung cancer related genes using liquid biopsy with Genexus-OPA ranged between 49-67% and 93-100%, respectively. 59% of actionable mutations, which were present in tumor tissues, were detected by the Genexus- Oncomine Precision Assay using plasma cfTNA. Among the 5 mutations detected from liquid biopsy only, three mutations are of level 1 evidence according to OncoKB database, highlighting the clinical utilities of liquid biopsy in addressing tumor heterogeneity. Extrathoracic metastasis and levels of lactate dehydrogenase (LDH), C-reactive protein (CRP) and Carcinoembryonic Antigen (CEA) are found to be associated with increased circulating tumor DNA detection., Conclusions: The Genexus™ Integrated Sequencer system is an automated, accurate NGS system with short turnaround time (TAT) that could assist clinicians to make more timely decision., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-21-981/coif). SKL serves as a scientific advisor and received honorarium from Cancer Precision Medicine Inc. RA receives personal fees for lectures from AstraZeneca, Chugai Pharmaceutical. KU receives personal fees for lectures from AstraZeneca, Brystol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Novartis, Ono Pharmaceutical, and Takeda Pharmaceutical Company Limited, and for manuscript writing from Chugai-Igakusha, Nankodo Co., Ltd., Nanzando Co., Ltd., Yodosha Co., Ltd. KU’s spouse is an employee of Daiichi Sankyo. RH and YMC are Employees of Cancer Precision Medicine, Inc. NY is a medical advisor of Chugai Pharmaceutical and receives lecture’s fee from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, MSD, and Takeda Pharmaceutical Company Limited. YN serves as a scientific advisor of Oncotherapy Science Inc., and possesses stock from Oncotherapy Science Inc. MN receives grants and personal fees from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, MSD, Novartis, Daiichi Sankyo, and Takeda Pharmaceutical Company Limited, personal fees from Boehringer-Ingelheim, Merck Biopharma, Teijin Pharma Limited, and AbbVie. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) significantly improve progression-free survival and have become the standard therapy for estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer patients. Treatment surveillance by radiological imaging has some limitations in detection and repeated biopsy genomic profiling is not clinically feasible. Serial circulating tumor DNA (ctDNA) analysis may provide insights into treatment response. Here we performed serial ctDNA analysis (n = 178) on 33 patients. Serial ctDNA analysis identified disease progression with sensitivity of 75% and specificity of 92%. In eight of 12 patients (61%) responding to CDK4/6i who eventually developed progressive disease, serial sampling every 3 or 6 months captured the initial rise of ctDNA with an average lead time of 3 months. In three of eight patients that did not respond to CDK4/6i (progressive disease at first radiological assessment, 3 months), biweekly sequencing within the first cycle of CDK4/6i treatment (1 month) detected sustained ctDNA levels (≥0.2% variant allele frequency), with lead time of 2 months. Serial ctDNA analysis tracked RECIST response, including clinically challenging scenarios (bone metastases or small-sized target lesions), as well as detecting acquired genetic alterations linked to CDK4/6i resistance in the G 1 to S transition phase. Circulating tumor DNA analysis was more sensitive than carcinoembryonic antigen or cancer antigen 15-3 serum tumor markers at monitoring tumor response to CDK4/6i treatment. Our findings indicated the possible clinical utility of serial ctDNA analysis for earlier progressive disease detection and real-time monitoring of CDK4/6i response., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Umbilical granuloma is a common infantile condition which usually responds to non operative management. Copper sulphate (CuSO 4 ) is often used as chemical cauterization but can cause superficial skin burns. An alternative is table salt (NaCl), which osmotically dehydrates wet granulation tissue causing necrosis. We aimed to compare the effectiveness of NaCl versus CuSO 4 in treating umbilical granuloma., Method: We performed a multi centerrandomized controlled trial involving three regional pediatricsurgical units. We included children who presented with umbilical granuloma from December 2018 to May 2020. Children who received treatment prior to index visit were excluded. They were randomly allocated to receive NaCl (twice/day application for 5 days by caregiver) or CuSO 4 (single application by clinician). Demographic data, compliance in the NaCl group by pill counting method, treatment outcomes, and complications were recorded. Treatment success was defined as complete lesion resolution. Partial or no response was considered treatment failure. Subsequent treatment then reverted to the respective center's routine management., Result: We recruited 70 participants with 6 dropouts (2 defaulters, 1 vitellointestinal duct, 3 urachal remnants), leaving 64 subjects for final analysis: 31 NaCl, 33 CuSO 4 . Compliance rate of 77.4% was recorded for NaCl, with 6 (20%) 'poor compliance' participants stopping therapy before completion owing to complete resolution. NaCl group had a significantly higher complete resolution rate (90.4%) compared to CuSO 4 (69.7%), p = 0.040. No NaCl participant developed complications versus 9% (n = 3) in CuSO 4 (periumbilical superficial skin burn)., Conclusion: Table salt is an ideal treatment choice for umbilical granuloma as it is effective, safe, and readily available., Level of Evidence: II., Competing Interests: Declaration of Competing Interest The authors declare that there are no known conflicts of interest associated with this publication., (Copyright © 2021. Published by Elsevier Inc.)

Background and Aims: Individuals undergoing kidney biopsy are increasingly older and may have concurrent illnesses that cause deranged hematological and renal parameters that are associated with post-biopsy bleeding. We aimed to develop a clinical risk model to quantify bleeding risks in high-risk individuals with multiple risk factors., Methods: Single-center retrospective cohort study of consecutive adults with serum creatinine ≥ 2 mg/dL (176 µmol/L) and had ultrasound-guided percutaneous native kidney biopsies between June 2011 and July 2015 in our tertiary referral center. The primary outcome was major bleeding, defined as need for red cell transfusion, radiological or surgical intervention, or if bleeding led to death within 7 days after kidney biopsy., Results: Among 184 native kidney biopsies with serum creatinine ≥ 2 mg/dL, median age was 54.1 years and eGFR was 18.8 ml/min/1.73 m 2 . Major bleeding occurred in 19 biopsies (10.3%). Multivariate analysis accounting for age, weight, hemoglobin, platelet, prothrombin time and urea found that higher hemoglobin (adjusted OR 0.51, 95% CI 0.33-0.79, p = 0.003) and platelet (adjusted OR 0.99, 95% CI 0.98-0.99, p = 0.01) were independently associated with reduced major bleeding. A risk model that included (1) age ≥ 62 years old, (2) hemoglobin < 10 g/dL and (3) platelets ≤ 216 × 10 9 /L as categorical variables predicted major bleeding post-biopsy., Conclusion: We developed a risk model that included multiple risk factors to quantify bleeding risks in native kidney biopsies with renal impairment., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Aims: Shared decision-making regarding COVID-19 vaccination in IgA nephropathy involves the ability to handle health information regarding potential benefits and risk of flare, but few studies have evaluated health literacy in the context of vaccination. We aimed to evaluate the health literacy and COVID-19 vaccination uptake and acceptance in IgA nephropathy., Methods: Single-center cross-sectional study of 126 consecutive patients with IgA nephropathy. Health literacy was assessed using the HLS-EU-47 questionnaire. Determinants of vaccine acceptance such as contextual influences, individual and group influences, and vaccine-specific issues were adapted from the World Health Organization framework., Results: Forty-eight patients (38.1%) with IgAN nephropathy completed the survey between June and August 2021. The participants' median age was 40.5 (31.6, 52.8) years with median disease duration of 2.8 (1.3, 4.3) years. The median general health literacy index was 31.74 (29.88, 35.82) with significantly greater difficulty in the competency of appraising health information and in the domain of disease prevention ( p < 0.001). Forty-five patients (93.8%) received at least one dose of COVID-19 vaccine between January and August 2021. Among the 3 unvaccinated patients, 2 intended to receive the vaccination while and 1 did not intend to get vaccinated. There was a high level of trust and belief that their government and healthcare providers had their best interests at heart and that the healthcare providers were honest about the vaccine's risk and benefits, although 31.2% did not understand how the vaccine works and 22.9% believed that there were other ways to prevent infection. Most thought there was adequate safety information, were confident in the system for tracking adverse events and had no issues with access to the vaccine., Conclusion: Participants with IgA nephropathy had high health literacy scores and low vaccine hesitancy. The determinants for vaccine acceptance can potentially guide efforts to optimize vaccination coverage., Competing Interests: No relevant conflict of interest for all authors., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Background: Cardiovascular disease causes significant morbidity and mortality in patients with glomerulonephritis, which is increasingly diagnosed in older individuals who may have diabetes mellitus (DM). We evaluated the impact of DM on metabolic profile, renal and cardiovascular outcomes during treatment and follow-up of individuals with glomerulonephritis., Methods: We performed a retrospective cohort study of 601 consecutive adults with biopsy-proven glomerulonephritis for factors associated with kidney failure, hospitalization for cardiovascular events, and death. Biopsies with isolated diabetic nephropathy were excluded., Results: The median patient age was 49.8 years (36.7-60.9 years) with estimated glomerular filtration rate of 56.7 mL/min/1.73 m2 (27.7-93.2 mL/min/1.73 m2). DM was present in 25.4%. The most frequent diagnoses were minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) (29.5%), lupus nephritis (21.3%), immunoglobulin A (IgA) nephropathy (19.1%), and membranous nephropathy (12.1%). The median follow-up was 38.8 months (interquartile range [IQR], 26.8-55.8 months). Among 511 individuals with lupus nephritis, anti-neutrophil cytoplasmic antibody-associated vasculitis, MCD/FSGS, membranous nephropathy, and IgA nephropathy, 52 (10.2%) developed kidney failure at a median 16.4 months (IQR, 2.3-32.2 months), while 29 (5.7%) had cardiovascular-related hospitalizations at 12.9 months (IQR, 4.8-31.8 months) and 31 (6.1%) died at 13.5 months (IQR, 2.5-42.9 months) after diagnosis. Cox regression analysis found that baseline DM was independently associated with kidney failure (adjusted hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.06-4.05, p = 0.03) and cardiovascular-related hospitalization (adjusted HR, 2.69; 95% CI, 1.21-5.98, p = 0.02) but not with mortality., Conclusion: DM was strongly associated with kidney failure and hospitalization for cardiovascular events in patients with biopsy-proven glomerulonephritis.

Objective: In this study, we trace the changes in the clinical and histological pattern of IgA nephritis (IgAN) in Singapore as it has evolved over 4 decades and compare the clinical, demographic, histological, and renal outcome of patients with IgAN from the 1 st decade and the 4 th decade., Materials and Methods: This is a retrospective study of all histologically proven IgAN diagnosed between 1976 and 2018. Clinical, laboratory, and histological characteristics between the 1 st and the 4 th decade, including treatment which could influence the disease progression and renal outcome of these two groups, were compared. We used the Oxford classification to compare the renal biopsy changes for these 2 decades as we were able to retrieve 125 renal biopsy tissues for the 1 st cohort of IgAN studied in the 1970s for the comparative study., Results: The commonest clinical presentation throughout the first 3 decades was asymptomatic hematuria and proteinuria (63, 52, and 49%, respectively). In the 4 th decade, nephrotic syndrome (31%) was the commonest followed by asymptomatic hematuria and proteinuria (30%), hypertension (21%), and chronic renal failure (11%). The data showed that treatment can modify the Oxford MEST - Crescent scores. Renin-angiotensin system (RAS) blockers modified the S scores, immunosuppressants modified the T and C scores, and combination therapy with RAS blockers and immunosuppressants modified the E, S, and T scores., Conclusion: The Oxford MEST classification offers a robust and expressive classification for early and late disease progression with respect to the development of end-stage renal disease (ESRD). E and S seem to be indices of continuing disease activity with progressive glomerulosclerosis, probably still amenable to therapy, but T was a predictive indicator for those destined for ESRD and no longer amenable to therapy.

We present a study to evaluate the feasibility and clinical utility of amplicon-based Oncomine Pan-Cancer cell-free assay to detect circulating tumor DNA (ctDNA) in patients with early or advanced breast cancer. In this study, 109 early and metastatic breast cancer patients were recruited before the initiation of treatment. ctDNA mutation profiles were assessed through unique molecular tagging (UMT) and ultradeep next generation sequencing (NGS). For patients with mutations, DNA from corresponding white blood cells (WBC) was sequenced to exclude variants of clonal-hematopoietic (CH) origin. UMT targeted sequencing from plasma of 109 patients achieved a median total coverage of 55 498X and a median molecular coverage of 4187X. Among 53 ctDNA positive samples, 38% were mutation positive by WBC sequencing, indicating potentially false-positive results contributed by CH origin. Prevalence of CH-related mutations was associated with age (P = 7.51 × 10 -4 ). After exclusion of CH mutations, ctDNA detection rates were 37% for local or locally advanced breast cancer (stage I-III) and 81% for metastatic or recurrent breast cancer. The ctDNA detection rate correlated with disease stage (P = 2.60 × 10 -4 ), nodal spread (P = 6.49 × 10 -3 ) and the status of distant metastases (P = 5.00 × 10 -4 ). ctDNA variants were detected mostly in TP53, PIK3CA and AKT1 genes, with variants showing therapeutic relevance. This pilot study endorses the use of targeted NGS for non-invasive molecular profiling of breast cancer. Paired sequencing of plasma ctDNA and WBC should be implemented to improve accurate interpretation of liquid biopsy., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The use of blood liquid biopsy is being gradually incorporated into the clinical setting of cancer management. The minimally invasive nature of the usage of cell-free DNA (cfDNA) and its ability to capture the molecular alterations of tumors are great advantages for their clinical applications. However, somatic mosaicism in plasma remains an immense challenge for accurate interpretation of liquid biopsy results. Clonal hematopoiesis (CH) is part of the normal process of aging with the accumulation of somatic mutations and clonal expansion of hematopoietic stem cells. The detection of these non-tumor derived CH-mutations has been repeatedly reported as a source of biological background noise of blood liquid biopsy. Incorrect classification of CH mutations as tumor-derived mutations could lead to inappropriate therapeutic management. CH has also been associated with an increased risk of developing cardiovascular disease and hematological malignancies. Cancer patients, who are CH carriers, are more prone to develop therapy-related myeloid neoplasms after chemotherapy than non-carriers. The detection of CH mutations from plasma cfDNA analysis should be cautiously evaluated for their potential pathological relevance. Although CH mutations are currently considered as "false-positives" in cfDNA analysis, future studies should evaluate their clinical significance in healthy individuals and cancer patients.

As the use of next-generation sequencing (NGS) for plasma cell-free DNA (cfDNA) continues to expand in clinical settings, accurate identification of circulating tumor DNA mutations is important to validate its use in the clinical management for cancer patients. Here, we aimed to characterize mutations including clonal hematopoiesis (CH)-related mutations in plasma cfDNA and tumor tissues using the same ultradeep NGS assay and evaluate the clinical significance of CH-related mutations on the interpretation of liquid biopsy results. Ultradeep targeted NGS using Oncomine Pan-Cancer Panel was performed on matched surgically resected tumor tissues, peripheral blood cells (PBCs), and 120 plasma cfDNA samples from 38 colorectal cancer patients. The clinical significance of the CH-related mutations in plasma cfDNA was evaluated by longitudinal monitoring of the postoperative plasma samples. Among the 38 patients, 74 nonsynonymous mutations were identified from tumor tissues and 64 mutations from the preoperative plasma samples. Eleven (17%) of the 64 mutations identified in plasma cfDNA were also detected in PBC DNA and were identified to be CH-related mutations. Overall, 11 of 38 (29%) patients in this cohort harbored at least one CH-related mutation in plasma cfDNA. These CH-related mutations were continuously detected in subsequent postoperative plasma samples from three patients which could be misinterpreted as the presence of residual disease or as lack of treatment response. Our results indicated that it is essential to integrate the mutational information of PBCs to differentiate tumor-derived from CH-related mutations in liquid biopsy analysis. This would prevent the misinterpretation of results to avoid misinformed clinical management for cancer patients., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Objective: This study on the prevalence of diabetic nephropathy (DN) and coexistence of non-diabetic renal disease (NDRD) in a cohort of 255 non-insulin-dependent diabetes mellitus (NIDDM) patients aims to determine the value of performing renal biopsies in these patients and elucidate the factors which could affect their progression to end-stage renal disease (ESRD)., Methods: Among 255 NIDDM patients, 93 had DN alone, 69 had NDRD alone, and the remaining 93 had DN plus NDRD (mixed group). The indications for renal biopsy were based on clinical suspicion of superimposed NDRD, including heavy or rapidly increasing proteinuria, renal impairment even though diabetes is of relatively short duration, rapidly declining renal function, and presence of hematuria with dysmorphic red blood cells suggesting presence of glomerulonephritis., Results: The following were predictors of ESRD: high systolic BP at biopsy, longer duration of diabetes, heavy proteinuria, and presence of diabetic retinopathy. Comparing patients in the NDRD group with the DN group and the mixed group, the NDRD group had lower serum creatinine and higher eGFR with lower urinary proteinuria and higher serum albumin at presentation and on follow-up. Kimmelstiel-Wilson nodules were associated with a poorer prognosis leading to a higher occurrence of ESRD among patients with DN., Conclusion: Renal biopsy is of value in indicating the prognosis of NIDDM patients with DN based on the diabetic lesions. For NIDDM patients with atypical course and suspicion of associated NDRD, a renal biopsy would enable us to diagnose the underlying NDRD and offer appropriate therapy. Most nephrologists would consider renal biopsy for an NIDDM patient based on clinical indications like atypical clinical course and suspicion of an associated NDRD, but they would not perform a routine renal biopsy like for a CKD patient, unless it is for a research indication., Competing Interests: We declare that there are no conflicts of interest pertaining to this work and we have no ethical conflicts to disclose., (Copyright © 2020 by S. Karger AG, Basel.)

Background: Blood-based analysis of circulating tumor DNA (ctDNA) is a promising tool for cancer screening, monitoring relapse/recurrence and evaluating response to treatment. Although plasma is widely used to obtain ctDNA, biorepositories worldwide possess a huge number of serum samples and comparative studies on the use of serum vs plasma as ctDNA sources are essential., Methods: We analyzed cell-free DNA (cfDNA) from matched EDTA-plasma and serum samples from healthy donors and patients with colorectal or lung cancer, and used targeted next-generation sequencing to evaluate mutation detection efficiency and reproducibility. Matched samples from healthy individuals were spiked with reference oligonucleotides and sequenced using the Ion-S5 Oncomine-Pan-Cancer panel. Detection efficiency in matched samples from patients with cancer was evaluated using 2 distinct gene panels and compared to mutations found in tissue-biopsy samples at diagnosis., Results: Mean total cfDNA was 55% higher in serum samples and the presence of longer DNA fragments was significantly increased in serum compared with plasma samples (P = 0.0001 to 0.015). Spiked mutated nucleotides were detected in both samples, but allele frequencies (AF) were approximately half in serum compared with plasma, suggesting ctDNA from serum was more diluted by DNA of noncancerous origins. Matched samples from patients with cancer revealed that up to 44.8% of mutations with low AF were missed in serum samples and concordance rates with somatic mutations found in tissue biopsy at diagnosis was better in plasma samples., Conclusion: The use of serum in retrospective studies should consider the limitations for detecting low AF mutations. Plasma is clearly preferable for prospective clinical applications of liquid biopsy., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Glomerulonephritis is often treated with kidney-saving, but potentially diabetogenic immunosuppressants such as glucocorticosteroids and calcineurin inhibitors. Unfortunately, there are little data on dysglycemia before and after diagnosis and during treatment of glomerulonephritis. We aimed to evaluate the occurrence and risk factors for pre-diabetes and incident diabetes among non-diabetic patients with glomerular disease with or without treatment with immunosuppressants., Methods: A single-center, retrospective cohort study was performed on 229 non-diabetic immunosuppressantnaïve adults diagnosed with glomerulonephritis and renal vasculitis. Patients with known diabetes and prior immunosuppressant treatment were excluded. Outcomes of new-onset pre-diabetes and new-onset diabetes were defined according to American Diabetic Association criteria., Results: Pre-diabetes was present pre-biopsy in 74 of the 229 patients (32.3%). During the median follow-up of 34.0 (23.3-47.5) months, 29 patients (12.7%) developed new-onset diabetes and 58 (25.3%) had new-onset prediabetes. Immunosuppressive therapy in patients with pre-existing pre-diabetes was associated with increased odds of new-onset diabetes compared to those without either risk factor (26.0% versus 5.0%; odds ratio, 6.67; 95% confidence interval [CI], 1.41 to 31.64), P = 0.02)., Conclusion: New-onset diabetes after immunosuppressant treatment occurred in one-quarter of patients with glomerulonephritis and pre-existing pre-diabetes. Physicians should screen for pre-diabetes when planning treatment with immunosuppressants, as its presence significantly increases the risk of diabetes mellitus.

Introduction: Percutaneous renal biopsy remains critical for the workup of renal allograft dysfunction but is associated with the risk of bleeding. Prophylactic intravenous desmopressin has been proposed to reduce bleeding risk in native renal biopsies, but its efficacy in the renal transplant population is unclear and adverse events such as severe hyponatraemia have been reported., Materials and Methods: We conducted a single-centre retrospective cohort study involving adult (≥21 years old) renal transplant recipients with impaired renal function (serum creatinine ≥150 µmol/L) who underwent ultrasound-guided renal allograft biopsies from 2011‒2015 to investigate the effect of prebiopsy desmopressin on the risk of bleeding and adverse events., Results: Desmopressin was administered to 98 of 195 cases who had lower renal function, lower haemoglobin and more diuretic use. Postbiopsy bleeding was not significantly different between the 2 groups (adjusted odds ratio [OR] 0.79, 95% confidence interval [CI] 0.26‒2.43, P = 0.68) but desmopressin increased the risk of postbiopsy hyponatraemia (sodium [Na] <135 mmol/L) (adjusted OR 2.24, 95% CI 1.10‒4.59, P = 0.03). Seven cases of severe hyponatraemia (Na <125 mmol/L) developed in the desmopressin group, while none did in the non-desmopressin group. Amongst those who received desmopressin, risk of hyponatraemia was lower (OR 0.26, 95% CI 0.09‒0.72, P = 0.01) if fluid intake was <1 L on the day of biopsy., Conclusion: Prophylactic desmopressin for renal allograft biopsy may be associated with significant hyponatraemia but its effect on bleeding risk is unclear. Fluid restriction (where feasible) should be recommended when desmopressin is used during renal allograft biopsy. A randomised controlled trial is needed to clarify these outcomes.

Genome-wide association studies (GWAS) have successfully identified about 70 genomic loci associated with breast cancer. Owing to the complexity of linkage disequilibrium and environmental exposures in different populations, it is essential to perform regional GWAS for better risk prediction. This study aimed to investigate the genetic architecture and to assess common genetic risk model of breast cancer with 6,669 breast cancer patients and 21,930 female controls in the Japanese population. This GWAS identified 11 genomic loci that surpass genome-wide significance threshold of P < 5.0 × 10 -8 with nine previously reported loci and two novel loci that include rs9862599 on 3q13.11 (ALCAM) and rs75286142 on 21q22.12 (CLIC6-RUNX1). Validation study was carried out with 981 breast cancer cases and 1,394 controls from the Aichi Cancer Center. Pathway analyses of GWAS signals identified association of dopamine receptor medicated signaling and protein amino acid deacetylation with breast cancer. Weighted genetic risk score showed that individuals who were categorized in the highest risk group are approximately 3.7 times more likely to develop breast cancer compared to individuals in the lowest risk group. This well-powered GWAS is a representative study to identify SNPs that are associated with breast cancer in the Japanese population.

Objective: The pattern of glomerulonephritis (GN) in Singapore is compared with that of 19 other countries to review changing trends in the evolution of GN in Asian, Eastern, and Western countries., Method: Three thousand two hundred and eighty-nine renal biopsies in Singapore were reviewed and compared with that of 19 other countries., Results: IgA nephritis is on the decline in many countries, including Singapore, though it still remains the commonest GN in Singapore. Membranous GN that if used to be more frequently present in Western countries has also declined though it continues a rising trend in countries such as Singapore and China. Worldwide, the frequency of focal sclerosing glomerulosclerosis (FSGS) continues to increase in many countries, but in some countries, the frequency is still low with mesangiocapillary GN remaining indigenous., Conclusion: Urbanization and socioeconomic changes and less exposure to parasitic and other infestations have transformed Singapore's pattern, which is tending toward that of more developed countries. Antigenic exposure due to lifestyle changes, environmental, and industrial pollution are significant contributory factors that affect the evolutionary trend of GN in many countries. The rising trend in the frequency of FSGS may reflect aging and obesity., Competing Interests: We declare that there are no conflicts of interest pertaining to this work, and we have no ethical conflicts to disclose., (Copyright © 2019 by S. Karger AG, Basel.)

Cancer pharmacogenomics is the science concerned with understanding genetic alterations and its effects on the pharmacokinetics and pharmacodynamics of anti-cancer drugs, with the aim to provide cancer patients with the precise medication that will achieve a good response and cause low/no incidence of adverse events. Advances in biotechnology and bioinformatics have enabled genomic research to evolve from the evaluation of alterations at the single-gene level to studies on the whole-genome scale using large-scale genotyping and next generation sequencing techniques. International collaborative efforts have resulted in the construction of databases to curate the identified genetic alterations that are clinically significant, and these are currently utilized in clinical sequencing and liquid biopsy screening/monitoring. Furthermore, countless clinical studies have accumulated sufficient evidence to match cancer patients to therapies by utilizing the information of clinical-relevant alterations. In this review we summarize the importance of germline alterations that act as predictive biomarkers for drug-induced toxicity and drug response as well as somatic mutations in cancer cells that function as drug targets. The integration of genomics into the medical field has transformed the era of cancer therapy from one-size-fits-all to cancer precision medicine.

Background: Desmopressin is used to reduce bleeding complications for kidney biopsies with azotemia but little is known about desmopressin-induced hyponatremia in these individuals. We aimed to evaluate the impact of desmopressin prophylaxis on severe hyponatremia and bleeding after kidney biopsies in individuals with renal impairment., Method: This is a single-center retrospective cohort study of consecutive adults with serum creatinine ≥ 150 µmol/L and had ultrasound-guided percutaneous native or transplant kidney biopsies between June 2011 and July 2015. Data were retrieved from electronic medical records. Primary outcomes were the use of desmopressin prophylaxis and severe hyponatremia (serum sodium ≤ 125 mmol/L) within 7 days post-biopsy. Secondary outcome was post-biopsy bleeding., Results: 240 native kidney and 196 allograft biopsies were performed. Median age was 51 (IQR 42.3, 60) years and eGFR was 21.9 (12.9, 30.1) ml/min/1.73 m 2 . Although patients prescribed desmopressin prophylaxis (n = 226) had higher serum creatinine [279 (201, 392) vs. 187 (160, 241), p < 0.001], bleeding (15.0% vs. 13.3%, p = 0.60) was not significantly different with and without desmopressin. Severe hyponatremia occurred in 30 biopsies (6.9%) with nadir serum sodium level of 122 (119, 124) mmol/L at 3 (2, 5) days after biopsy, more frequently among those with desmopressin prophylaxis (10.7% vs. 3.0%, p = 0.002). Multi-variate analysis found that pre-biopsy serum sodium level [adjusted OR 0.80 (95% CI 0.72, 0.90), p < 0.001] and desmopressin prophylaxis [adjusted OR 4.02 (95% CI 1.58, 10.21), p = 0.003] were independently associated with severe hyponatremia after kidney biopsy., Conclusion: Pre-biopsy desmopressin was associated with severe hyponatremia in individuals with renal impairment; hence, susceptible patients given desmopressin should be closely monitored.

Background: The male predominance in the incidence of nasopharyngeal carcinoma (NPC) suggests the contribution of the X chromosome to the susceptibility of NPC. However, no X-linked susceptibility loci have been examined by genome-wide association studies (GWASs) for NPC by far., Methods: To understand the contribution of the X chromosome in NPC susceptibility, we conducted an X chromosome-wide association analysis on 1615 NPC patients and 1025 healthy controls of Guangdong Chinese, followed by two validation analyses in Taiwan Chinese (n = 562) and Malaysian Chinese (n = 716)., Results: Firstly, the proportion of variance of X-linked loci over phenotypic variance was estimated in the discovery samples, which revealed that the phenotypic variance explained by X chromosome polymorphisms was estimated to be 12.63% (non-dosage compensation model) in males, as compared with 0.0001% in females. This suggested that the contribution of X chromosome to the genetic variance of NPC should not be neglected. Secondly, association analysis revealed that rs5927056 in DMD gene achieved X chromosome-wide association significance in the discovery sample (OR = 0.81, 95% CI 0.73-0.89, P = 1.49 × 10 -5 ). Combined analysis revealed rs5927056 for DMD gene with suggestive significance (P = 9.44 × 10 -5 ). Moreover, the female-specific association of rs5933886 in ARHGAP6 gene (OR = 0.62, 95%CI: 0.47-0.81, P = 4.37 × 10 -4 ) was successfully replicated in Taiwan Chinese (P = 1.64 × 10 -2 ). rs5933886 also showed nominally significant gender × SNP interaction in both Guangdong (P = 6.25 × 10 -4 ) and Taiwan datasets (P = 2.99 × 10 -2 )., Conclusion: Our finding reveals new susceptibility loci at the X chromosome conferring risk of NPC and supports the value of including the X chromosome in large-scale association studies.

This review of 3,289 native kidney biopsies over the past four decades in Singapore documents the changing pattern of biopsy-proven glomerulonephritis (GN)from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative GN was the most common form of primary GN, similar to the Asian region. In the 2nd decade, the percentage of mesangial proliferative GN decreased, but membranous GN became more common, as was seen in China and Thailand. In the 3rd decade, focal segmental glomerulosclerosis (FSGS) and membranous nephropathy continued to rise, but it was only recently, in the 4th decade, that FSGS prevalence increased dramatically, although membranous nephropathy continues to increase in some Asian countries. In the last decade in Singapore, Malaysia, and Japan, prevalence of IgA nephritis has decreased but remains the most common GN. The percentage of FSGS continues to increase in many countries like in Italy, United States of America, United Kingdom, China, and Malaysia. We surmise that socioeconomic factors play significant roles in the evolution of the renal biopsy pattern.
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Background: Glomerulonephritis commonly causes kidney failure. Immunosuppressant treatment may be diabetogenic, but data on hyperglycaemia in glomerulonephritis treated with usual clinical care are scant., Aim: To assess the epidemiology, risk factors and outcomes for new-onset diabetes among patients with glomerular disease (NODAG)., Methods: A single-centre retrospective cohort of nondiabetic adults diagnosed with glomerulonephritis between January 2011 and July 2015. Clinical, laboratory and pharmacotherapy data were retrieved from electronic medical records. Using modified American Diabetes Association criteria, the primary outcome of NODAG was present if fasting venous glucose was ≥7 mmol/L for at least two readings, HbA1c was ≥6.5% or if patient required antidiabetic medications. Secondary outcomes were end-stage renal disease, cardiovascular disease and death., Results: NODAG occurred in 48 patients (10.7%); 22 required antidiabetic medication at median 6.2 (interquartile range 1.7, 20.0) months after glomerulonephritis diagnosis. Patients with NODAG had higher prebiopsy fasting glucose, greater proteinuria and lower fasting high-density lipoprotein cholesterol levels. Methylprednisolone and cyclophosphamide were more commonly used among patients with NODAG. In multivariate logistic regression, greater proteinuria (odds ratio 1.08 (95% confidence interval 1.01, 1.16), P = 0.02) and methylprednisolone use (odds ratio 4.02 (95% confidence interval 1.76, 9.18), P = 0.001) were significantly associated with NODAG, independent of the triglyceride/high-density lipoprotein cholesterol ratio as a surrogate measure of insulin resistance. Median follow up was 39.6 (26.9, 57.2) months. Secondary outcomes were not significantly different in patients with and without NODAG., Conclusion: Proteinuria and methylprednisolone were associated with incident diabetes among patients with glomerular disease treated with usual care. At-risk patients should be appropriately counselled and monitored for hyperglycaemia., (© 2018 Royal Australasian College of Physicians.)

Background: Renal involvement is common among Asians with systemic lupus erythematosus and long-term renal outcomes have been described in homogeneous Caucasian and East Asian populations with lupus nephritis, but data are scarce for other ethnicities., Aim: To evaluate the incidence and risk factors for progressive chronic kidney disease (CKD) in multi-ethnic Southeast Asians with lupus nephritis., Methods: This is a single-centre retrospective cohort study of adults with biopsy-proven lupus nephritis diagnosed between May 2001 and May 2009. Demographic and clinical data were retrieved from electronic medical records. Patients were excluded if baseline comorbid, renal function or pharmacotherapy data were incomplete or if they default follow-up within 3 months from time of diagnosis. Primary outcome was progressive CKD, defined by end-stage renal disease or persistent doubling of serum creatinine or reduction in eGFR ≥50% for ≥3 months from baseline., Results: We studied 113 patients with newly diagnosed biopsy-proven lupus nephritis. Median age was 42 (interquartile range 29-52) years; the majority were Chinese (76%; Malay 13% and others 11%) and female (81%). Two-thirds had International Society of Nephrology and Renal Pathology Society Class III or IV nephritis; serum creatinine was 86 (67-125) μmol/L with heavy proteinuria (6.3 (2.5-12.2) g/g creatinine). Median follow-up was 110 (83-142) months. Remission (partial and complete) occurred in 96% at 3.1 (1.6-5.2) months after diagnosis. Among patients who achieved remission, 56% had disease relapse at 19.0 (6.0-40.2) months after remission. Patients with progressive CKD (n = 13, 11%) had lower baseline CKD Epidemiology Collaboration estimated glomerular filtration rate (37.3 (16.5-82.0) vs 79.4 (57.5-101.0) mL/min/1.73 m 2 , P = 0.03) and higher chronicity index (5 (3-6) vs 3 (2-3), P = 0.04) than those who did not. Remission, early remission within 6 months, complete remission and non-relapse were less frequently associated with progressive CKD (P < 0.01)., Conclusion: Multi-ethnic Southeast Asians with biopsy-proven lupus nephritis had high remission rates and low incidence of progressive CKD. Progressive CKD was associated with poorer baseline renal function, higher histological chronicity index, failure to achieve remission and occurrence of relapse., (© 2018 Royal Australasian College of Physicians.)

Covariate misclassification is well known to yield biased estimates in single level regression models. The impact on hierarchical count models has been less studied. A fully Bayesian approach to modeling both the misclassified covariate and the hierarchical response is proposed. Models with a single diagnostic test and with multiple diagnostic tests are considered. Simulation studies show the ability of the proposed model to appropriately account for the misclassification by reducing bias and improving performance of interval estimators. A real data example further demonstrated the consequences of ignoring the misclassification. Ignoring misclassification yielded a model that indicated there was a significant, positive impact on the number of children of females who observed spousal abuse between their parents. When the misclassification was accounted for, the relationship switched to negative, but not significant. Ignoring misclassification in standard linear and generalized linear models is well known to lead to biased results. We provide an approach to extend misclassification modeling to the important area of hierarchical generalized linear models.

Subpopulations of nasopharyngeal carcinoma (NPC) contain cells with differential tumourigenic properties. Our study evaluates the tumourigenic potential of CD24, CD44, EpCAM and combination of EpCAM/CD44 cells in NPC. CD44br and EpCAMbr cells enriched for higher S-phase cell content, faster-growing tumourigenic cells leading to tumours with larger volume and higher mitotic figures. Although CD44br and EpCAMbr cells significantly enriched for tumour-initiating cells (TICs), all cells could retain self-renewal property for at least four generations. Compared to CD44 marker alone, EpCAM/CD44dbr marker did not enhance for cells with faster-growing ability or higher TIC frequency. Cells expressing high CD44 or EpCAM had lower KLF4 and p21 in NPC subpopulations. KLF4-overexpressed EpCAMbr cells had slower growth while Kenpaullone inhibition of KLF4 transcription increased in vitro cell proliferation. Compared to non-NPC, NPC specimens had increased expression of EPCAM, of which tumours from advanced stage of NPC had higher expression. Together, our study provides evidence that EpCAM is a potentially important marker in NPC.

Circular RNAs (circRNAs) have recently emerged as a large class of novel non-coding RNA species. However, the detailed functional significance of the vast majority of them remains to be elucidated. Most functional characterization studies targeting circRNAs have been limited to resting cells, leaving their role in dynamic cellular responses to stimuli largely unexplored. In this study, we focus on the LPS-induced cytoplasmic circRNA, mcircRasGEF1B, and combine targeted mcircRasGEF1B depletion with high-throughput transcriptomic analysis to gain insight into its function during the cellular response to LPS stimulation. We show that knockdown of mcircRasGEF1B results in altered expression of a wide array of genes. Pathway analysis revealed an overall enrichment of genes involved in cell cycle progression, mitotic division, active metabolism, and of particular interest, NF-κB, LPS signaling pathways, and macrophage activation. These findings expand the set of functionally characterized circRNAs and support the regulatory role of mcircRasGEF1B in immune response during macrophage activation and protection against microbial infections.

Aim: Lupus nephritis (LN) is associated with significant morbidity and mortality and hence usually treated aggressively with immunosuppressants. This predisposes LN patients to increased infections, yet few studies have evaluated LN patients for infective complications. We aimed to describe the epidemiology and identify risk factors for infections requiring hospitalization among patients with biopsy-proven LN., Methods: This was a single-centre retrospective cohort study of patients with biopsy-proven LN between 1 January 2000 and 31 May 2009. Patients were excluded if they were <16 years old at time of biopsy, had previous kidney transplant or if pharmacotherapy data were incomplete. Hospitalizations for infections, bacteraemia and polymicrobial infections were recorded until patients' last visit or when they received immunosuppression for non-glomerulonephritis indications, such as solid organ transplant or chemotherapy., Results: We studied 189 patients who had biopsy-proven lupus nephritis. Median age at diagnosis was 36.9 (IQR: 27.4, 47.5) years and 82% were female. Most patients received at least one immunosuppressant after LN diagnosis, including glucocorticosteroids in 94.2%. One hundred and four patients (60.3%) had at least one hospitalization for infection at 11 (1, 53) months from diagnosis. Bacteraemia occurred in 26 patients (13.8%) and 32 patients (16.9%) had polymicrobial infections. On multivariate analysis, LN relapse was associated with hospitalization for infection (OR 2.33 (1.18, 4.60), P = 0.01) and bacteraemia (OR 3.47 (1.05, 11.45), P = 0.04). Infection-related mortality occurred in 10 patients (5.3%)., Conclusion: Serious infections are common among patients with LN and are associated with mortality., (© 2016 Asian Pacific Society of Nephrology.)

Large consortia efforts and genome-wide association studies (GWASs) have linked a number of genetic variants within the 6p21 chromosomal region to non-Hodgkin lymphoma (NHL). Complementing these efforts, we genotyped previously reported SNPs in the human leukocyte antigen (HLA) class I (rs6457327) and class II (rs9271100, rs2647012 and rs10484561) regions in a total of 1,145 subjects (567 NHL cases and 578 healthy controls) from two major ethnic groups in Malaysia, the Malays and the Chinese. We identified a NHL-associated (P NHL&#95;add  = 0.0008; OR NHL&#95;add  = 0.54; 95% CI = 0.37-0.77) and B-cell associated (P Bcell&#95;add  = 0.0007; OR Bcell&#95;add  = 0.51; 95% CI = 0.35-0.76) SNP rs2647012 in the Malaysian Malays. In silico cis-eQTL analysis of rs2647012 suggests potential regulatory function of nearby HLA class II molecules. Minor allele rs2647012-T is linked to higher expression of HLA-DQB1, rendering a protective effect to NHL risk. Our findings suggest that the HLA class II region plays an important role in NHL etiology., Competing Interests: The authors declare no competing financial interests.

Background: In 1985 we reported that 11% of a cohort of 151 patients with IgA nephritis (IgAN) had developed end-stage renal disease (ESRD) after a follow-up period of 5 years. 15 years later, 35% had developed ESRD., Methods: We retrieved 125 stored renal biopsy paraffin blocks of the original cohort. From these, 102 patients were included in the present study and scored according to the Oxford classification as 21 specimens with less than 8 glomeruli were excluded and in 2 others, tissue samples were too tiny for a re-block. ESRD was ascertained by linking the study cohort to the Singapore Renal Registry at the National Registry of Diseases Office., Results: Renal survival curves for each of the Oxford MEST lesions: endocapillary proliferation (E) (p < 0.04), segmental glomerulosclerosis (S) (p < 0.05), tubular atrophy/interstitial fibrosis (p < 0.0001) were significantly associated with ESRD. Mesangial hypercellularity, less commonly associated with progressive chronic kidney disease (CKD) in the study, was independently associated with ESRD at 30 years (p < 0.03). In this cohort, E and S were associated with lower eGFR at presentation and doubling of serum creatinine in the first 5 years. This study's initial 5 years was representative of the "natural history" of IgAN since no renin-angiotensin system (RAS) blockers or immunosuppression were administered. This represents the early phase of disease progression. E and S may be considered "early disease activity predictors"., Conclusion: Mesangial hypercellularity and tubular atrophy/interstitial fibrosis (M1 and T1/T2 lesion) of the Oxford classification independently predicted long term ESRD.
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Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome toward NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene p values derived from differential expression values from GEO2R. Our study identified NPC association in the gene ontology (GO) axonemal dynein complex pathway (pGWAS-GSEA  = 1.98 × 10(-2) ; pExpr-GSEA  = 1.27 × 10(-24) ; pBonf-Combined  = 4.15 × 10(-21) ). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (pAmpliSeq-GSEA  = 6.56 × 10(-4) ). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort., (© 2016 UICC.)

Background: Nasopharyngeal carcinoma (NPC) is a neoplasm of the epithelial lining of the nasopharynx. Despite various reports linking genomic variants to NPC predisposition, very few reports were done on copy number variations (CNV). CNV is an inherent structural variation that has been found to be involved in cancer predisposition., Methods: A discovery cohort of Malaysian Chinese descent (NPC patients, n = 140; Healthy controls, n = 256) were genotyped using Illumina® HumanOmniExpress BeadChip. PennCNV and cnvPartition calling algorithms were applied for CNV calling. Taqman CNV assays and digital PCR were used to validate CNV calls and replicate candidate copy number variant region (CNVR) associations in a follow-up Malaysian Chinese (NPC cases, n = 465; and Healthy controls, n = 677) and Malay cohort (NPC cases, n = 114; Healthy controls, n = 124)., Results: Six putative CNVRs overlapping GRM5, MICA/HCP5/HCG26, LILRB3/LILRA6, DPY19L2, RNase3/RNase2 and GOLPH3 genes were jointly identified by PennCNV and cnvPartition. CNVs overlapping GRM5 and MICA/HCP5/HCG26 were subjected to further validation by Taqman CNV assays and digital PCR. Combined analysis in Malaysian Chinese cohort revealed a strong association at CNVR on chromosome 11q14.3 (Pcombined = 1.54x10-5; odds ratio (OR) = 7.27; 95% CI = 2.96-17.88) overlapping GRM5 and a suggestive association at CNVR on chromosome 6p21.3 (Pcombined = 1.29x10-3; OR = 4.21; 95% CI = 1.75-10.11) overlapping MICA/HCP5/HCG26 genes., Conclusion: Our results demonstrated the association of CNVs towards NPC susceptibility, implicating a possible role of CNVs in NPC development.

Background: Genetic loci within the major histocompatibility complex (MHC) have been associated with nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer, in several GWAS. Results outside this region have varied., Methods: We conducted a meta-analysis of four NPC GWAS among Chinese individuals (2,152 cases; 3,740 controls). Forty-three noteworthy findings outside the MHC region were identified and targeted for replication in a pooled analysis of four independent case-control studies across three regions in Asia (4,716 cases; 5,379 controls). A meta-analysis that combined results from the initial GWA and replication studies was performed., Results: In the combined meta-analysis, rs31489, located within the CLPTM1L/TERT region on chromosome 5p15.33, was strongly associated with NPC (OR = 0.81; P value 6.3 × 10(-13)). Our results also provide support for associations reported from published NPC GWAS-rs6774494 (P = 1.5 × 10(-12); located in the MECOM gene region), rs9510787 (P = 5.0 × 10(-10); located in the TNFRSF19 gene region), and rs1412829/rs4977756/rs1063192 (P = 2.8 × 10(-8), P = 7.0 × 10(-7), and P = 8.4 × 10(-7), respectively; located in the CDKN2A/B gene region)., Conclusions: We have identified a novel association between genetic variation in the CLPTM1L/TERT region and NPC. Supporting our finding, rs31489 and other SNPs in this region have been reported to be associated with multiple cancer sites, candidate-based studies have reported associations between polymorphisms in this region and NPC, the TERT gene has been shown to be important for telomere maintenance and has been reported to be overexpressed in NPC, and an EBV protein expressed in NPC (LMP1) has been reported to modulate TERT expression/telomerase activity., Impact: Our finding suggests that factors involved in telomere length maintenance are involved in NPC pathogenesis., (©2015 American Association for Cancer Research.)

Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is constantly associated with Epstein-Barr virus type 1 (EBV-1) infection. We carried out a genome-wide association study (GWAS) of 575,247 autosomal SNPs in 184 NPC patients and 236 healthy controls of Malaysian Chinese ethnicity. Potential association signals were replicated in a separate cohort of 260 NPC patients and 245 healthy controls. We confirmed the association of HLA-A to NPC with the strongest signal detected in rs3869062 (p = 1.73 × 10(-9)). HLA-A fine mapping revealed associations in the amino acid variants as well as its corresponding SNPs in the antigen peptide binding groove (p(HLA-A-aa-site-99) = 3.79 × 10(-8), p(rs1136697) = 3.79 × 10(-8)) and T-cell receptor binding site (p(HLA-A-aa-site-145) = 1.41 × 10(-4), p(rs1059520) = 1.41 × 10(-4)) of the HLA-A. We also detected strong association signals in the 5'-UTR region with predicted active promoter states (p(rs41545520) = 7.91 × 10(-8)). SNP rs41545520 is a potential binding site for repressor ATF3, with increased binding affinity for rs41545520-G correlated with reduced HLA-A expression. Multivariate logistic regression diminished the effects of HLA-A amino acid variants and SNPs, indicating a correlation with the effects of HLA-A*11:01, and to a lesser extent HLA-A*02:07. We report the strong genetic influence of HLA-A on NPC susceptibility in the Malaysian Chinese., (© 2014 UICC.)

We evaluated the association of two IL10 single nucleotide polymorphisms (SNPs) (rs1800896 and rs1800871) with non-Hodgkin lymphoma (NHL) risk in the three major races of the Malaysian population (Malay, Chinese and Indian; 317 cases and 330 controls). Our initial screening demonstrated that rs1800871 but not rs1800896 was significantly associated with increased NHL risk in Malays (pMalay-Rec = 0.007) and Chinese only (pChinese-Rec = 0.039). Subsequent combined analysis of the Malay and Chinese revealed significant association of rs1800871 with all (ALL) NHL subtypes (pMeta-ALL-NHL-Rec = 0.001), ALL B-cell subtypes (pMeta-ALL-B-cell-Rec = 0.003), diffuse large B-cell lymphoma (DLBCL) subtype (pMeta-DLBCL-Rec = 0.002) and ALL T-cell subtypes (pMeta-ALL-T-cell-Rec = 0.031). SNP rs1800896 showed increased risk only in follicular lymphoma (FL) (pMeta-FL-Dom = 0.0004). We also detected a male-specific association of rs1800871 with increased NHL risk (pMeta-Male-ALL-NHL-Rec = 0.006) in the combined analysis. To our knowledge, this is the first report on the association of IL10 promoter SNPs with NHL susceptibility in the three major races of Malaysia.

Although a positive association is found between HIV prevalence and intimate partner violence, a causal interpretation is hard to establish due to the endogeneity of HIV prevalence. Using the distance from the origin of the virus as an instrument, I find that an exogenous increase in HIV prevalence in a cluster has a sizable positive effect on the risk of physical and sexual violence against women within marriage. The results of this study confirm a gender-specific negative externality of the disease and encourage policy efforts to incorporate services for violence against women into existing HIV programs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: This paper presents the results of a community survey on urinary abnormalities which covered 1/80th of the population of Singapore in 1975. These findings were compared with the data from the Singapore National Service Registrants in 1974 as well as data from a recent survey in Singapore and that of other Asian and Western countries., Materials and Methods: The study covered 18,000 persons aged 15 years and above, representing a sampling fraction of 1/80th of the population. A total of 16,808 respondents attended the field examination centres, of whom 16,497 had their urine sample tested representing 92.7% of the sample population., Results: In the dipstick urine testing at the field examination centres, 769 subjects (4.6%) were found to have urinary abnormalities. Two hundred and eighty-two (36.7%) of these 769 subjects were found to have urinary abnormalities based on urine microscopy constituting a prevalence of 1.71%. The prevalence of proteinuria was 0.63% and for both haematuria and proteinuria was 0.73%. The prevalence for hypertension was 0.43% and renal insufficiency was 0.1%., Discussion: The consensus is that routine screening for chronic kidney disease (CKD) in the general population is not cost effective as the yield is too low. Whilst, most studies showed that screening of the general population was not cost effective, it has been suggested that screening for targeted groups of subjects could help to identify certain risk groups who may benefit from early intervention to prevent or retard the progression of CKD., Conclusion: The prevalence of urinary abnormalities in Singapore has remained the same, now and three decades ago.