Biomarkers and a tailored approach for immune monitoring in kidney transplantation

A literature review on immune monitoring in kidney transplantation produced dozens of research articles and a multitude of promising biomarkers,all in the quest for the much sought after-but perennially elusive-"holy grail" of kidney biomarkers able to unequivocally predict acute transplant rejection vs non-rejection.Detection methodologies and study designs were many and varied.Hence the motivation for this editorial,which espouses the notion that in today's kidney transplantation milieu,the judicious use of disease classifiers tailored to specific patient immune risks may be more achievable and productive in the long run and confer a greater advantage for patient treatment than the pursuit of a single "omniscient" biomarker.In addition,we desire to direct attention toward greater scrutiny of biomarker publications and decisions to implement biomarkers in practice,standardization of methods in the development of biomarkers and consideration for adoption of "biomarker-driven" biopsies.We propose "biomarkerdriven" biopsies as an adjunctive to and/or alternative to random surveillance(protocol) biopsies or belated indication biopsies.The discovery of a single kidney transplantation biomarker would represent a major breakthrough in kidney transplantation practice,but until that occurs-if ever it does occur,other approaches offer substantial potential for unlocking prognostic,diagnostic and therapeutic options.We conclude our editorial with suggestions and recommendations for productively incorporating current biomarkers into diagnostic algorithms and for testing future biomarkers of acute rejection in kidney transplantation.

Histopathological analysis of infiltrating T cell subsets in acute T cell-mediated rejection in the kidney transplant

AIM To compare the differential immune T cell subset com-position in patients with acute T cell-mediated rejection in the kidney transplant with subset composition in the absence of rejection, and to explore the association of their respective immune profiles with kidney transplant outcomes.METHODS A pilot cross-sectional histopathological analysis of the immune infiltrate was performed using immunohistochemistry in a cohort of 14 patients with acute T cellmediated rejection in the kidney transplant and 7 kidney transplant patients with no rejection subjected to biopsy to investigate acute kidney transplant dysfunction. All patients were recruited consecutively from 2012 to 2014 at the Singapore General Hospital. Association of the immune infiltrates with kidney transplant outcomes at up to 54 mo of follow up was also explored prospectively.RESULTS In a comparison to the absence of rejection, acute T cell-mediated rejection in the kidney transplant was characterised by numerical dominance of cytotoxic T lymphocytes over Foxp3^+ regulatory T cells, but did not reach statistical significance owing to the small sample size in our pilot study. There was no obvious difference in absolute numbers of infiltrating cytotoxic T lymphocytes, Foxp3^+ regulatory T cells and Th17 cells between the two patient groups when quantified separately. Our exploratory analysis on associations of T cell subset quantifications with kidney transplant outcomes revealed that the degree of Th17 cell infiltration was significantly associated with shorter time to doubling of creatinine and shorter time to transplant loss.CONCLUSION Although this was a small pilot study, results support our suspicion that in kidney transplant patients the immune balance in acute T cell-mediated rejection is tilted towards the pro-rejection forces and prompt larger and more sophisticated studies.

Live birth rates of assisted reproductive technology treatment and spontaneous conception among subfertile couples in Singapore: A follow-up study

Objective: To explore the potential predictors of a live birth (LB) outcome among subfertile couples of Asian ethnicity undergoing the first fertility treatment cycle;to assess the cumulative live birth rates after successive cycles;and to determine the incidence rate of spontaneous conception (SC).Methods:Subfertile couples were grouped according to treatment modalities at the first fertility treatment cycle: intrauterine insemination (IUI),in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and no treatment, and were followed-up for duration up to seven years. Multivariable logistic regression analysis was used for statistical analyses. Results: Age of female subjects [35-38 years, odds ratio (OR): 0.39;≥39 years, OR: 0.14], uterine factor subfertility (OR: 5.24), and treatment modalities (ORs: IUI 0.25, IVF 2.33 and ICSI 1.91) significantly predicted a LB outcome (P<0.05). The cumulative live birth rates were 11.7% IUI, 41.5% IVF, 27.5% ICSI and 22.6% from frozen embryo transfer cycles. The cumulative SC rate was 24.6% in the non-treated group and 10.7% in the treated group. All LBs from IVF cycles were delivered by the second cycle and within four years, compared to SC delivery of within five years in the non-treated group and six years in the treated group. Conclusions:Age of female subject, uterine factor and modalities of treatment are significant predictors for LB outcome at the first cycle. Higher delivery rates could be achieved following fewer successive IVF cycles and within a shorter duration compared to SC.

Human epidermal growth factor receptor 2 positive rates in invasive lobular breast carcinoma: The Singapore experience

BACKGROUND Invasive lobular carcinomas(ILC)form 5%-10%of breast cancer and rarely show overexpression of human epidermal growth factor receptor 2(HER2).AIM To describe the prevalence and prognostic factors of HER2 positive(HER2+)ILC in an Asian population.METHODS A retrospective review of patients with ILC seen between January 1985 and March 2018 at various SingHealth medical institutions was conducted.Demographic and clinical data were collected from medical records.We examined clinicopathological characteristics and survival in relation to HER2 status.RESULTS A total of 864 patients were included.Prevalence of HER2 positivity was 10.1%(87 patients).Compared with HER2 negative(HER2-)ILC,HER2+ILC was associated with a higher proportion of estrogen receptor negative(24.4%vs 5.9%,P<0.001),progesterone receptor negative(PR-)(40.2%vs 24%,P=0.002)and grade 3 tumours(Grade 3,29.0%vs 10.2%,P<0.001).Overall survival rate was poorer in patients with HER2+compared to HER2-ILC(56.7%vs 72.9%alive at 10 years;hazard ratio 1.87,95%confidence interval:1.21-2.90,P=0.004).Based on multivariate analysis,negative prognostic factors for overall survival included HER2 positivity,PR negativity,older age,Indian ethnicity and higher tumour stage.CONCLUSION Prevalence of HER2+ILC was 10.1%.HER2+ILC was more likely to have poorer prognostic features such as estrogen receptor negative,PR-and higher tumour grade,and have a poorer survival.

Prevalence and Factors Associated with Concomitant Chinese Medicine Use by Rheumatoid Arthritis Patients in A Multi-Ethnic Asian Population

Objective:To determine the prevalence,factors associated with and patterns of concomitant Chinese medicine(CM)with Western treatment use among patients with rheumatoid arthritis(RA)in a tertiary referral centre(Singapore General Hospital)in Singapore.Methods:We conducted a cross-sectional intervieweradministered survey of a consecutive sample of patients with RA in Singapore General Hospital centre regarding their CM use including data on patient demographics,disease characteristics,concomitant use of CM and reasons,concerns and disclosure patterns from March to August 2015.Univariate and multivariate logistic regression analyses were performed to determine the associations of CM use.Results:Prevalence of CM use among the 258 patients surveyed(male:female 42:216;Chinese:Malay:Indian 191:29:34;mean age:61 years;mean duration of RA:10 years)was 46.1%(119/258).On muutivariate analysis,Chinese ethnicity(OR,95%CI:4.11,1.49-11.36),Chinese speakers(OR,95%CI:2.35,1.03-5.54),middle-income group(OR,95%CI:2.53,1.01-6.31)and greater learned helplessness(OR,95%CI:1.13,1.04-1.22)were significantly associated with CM use.More CM users disclosed their CM use to CM physicians(87.3%,96/110),sought advice from them on treatment interactions(59.4%,57/96)and how best to combine treatments(49.0%,47/96)than did so with rheumatologists(42.0%,50/119;40.0%,20/50;and 42.0%,21/50,respectively).Forty-two percentage(29/69)of patients who concealed CM use from rheumatologists because their rheumatologists did not specifically enquire about CM use.Conclusions:Concomitant CM use among patients with RA treated in a tertiary referral centre in Singapore is high but voluntary disclosure is low.The associations identified can help doctors identify and enquire about CM use,minimizing potential adverse interactions.

Bi-weekly docetaxel and 5-fluorouracil:an effective and feasible treatment for advanced gastric cancer with poor performance status

Background:The survival benefits from cytotoxic chemotherapy have been demonstrated in advanced gastric cancer(AGC).A large proportion of AGC patients initially present poor performance status(PS);however,most of the clinical evidence comes from trials on patients with good PS.A better-designed regimen is greatly needed for AGC patients with poor PS.Objective:To evaluate the efficacy and safety of a modified combination regimen with docetaxel plus 5-fluorouracil(5-FU)every two weeks as first-line treatment in AGC patients with poor PS.Methods:From September 2011 to December 2013,12 patients diagnosed with AGC with Eastern Cooperative Oncology Group(ECOG)PS scores of 3 or 4 were included in this study.All the patients received docetaxel 60 mg/m^(2) on Day 1,5-FU 400mg/m^(2) intravenous(i.v.)bolus on Day 1,and a 46-hour continuous i.v.infusion of 5-FU 2400mg/m^(2) every two weeks,until disease progressed or patients experienced unacceptable toxicity or declined treatment.Detailed clinical,pathologic and survival data were all recorded.Results:Eleven out of 12 patients were assessable for responses,whereas nine cases(75%)achieved partial response,one(8.3%)achieved stabilized disease,and one(8.3%)had progressive disease.The median progression-free survival was 6.5 months(95%CI:4.8–8.2).The median overall survival was 12.0 months(95%CI:9.0–15.0).The most common Grade 3/4 toxicities were anemia in seven patients(58.3%).No patient experienced febrile neutropenia.Conclusion:The novel modification of bi-weekly docetaxel and 5-FU is a promising treatment option for AGC with poor PS,showing great efficacy and acceptable toxicity.

Identification of novel loci influencing refractive error in East Asian populations using an extreme phenotype design

The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies(GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent(SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou(631 <-6.00 D and 574 > 0.00 D) and Wenzhou(593 <-6.00 D and54 >-1.75 D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci, which show genome-wide significant associations with SE, including 1 q25.2 FAM163 A, 10 p11.22 NRP1/PRAD3, and 10 p11.21 ANKRD30 A/MTRNR2 L7, together explaining 3.34% of SE variance. 10 p11.21 is successfully replicated.The allele frequencies of all three loci show significant differences between major continental groups(P < 0.001). The SE reducing(more myopic) allele of rs10913877(1 q25.2 FAM163 A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans(EAS = 0.60,EUR = 0.20, and AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5, and ARPP19. These results provide new insights into myopia pathogenesis and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.