Prognostic implication of the neoadjuvant rectal score and other biomarkers of clinical outcome in Hong Kong Chinese patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy is a standard treatment for locally advanced rectal cancer, for which pathological complete response is typically used as a surrogate survival endpoint. Neoadjuvant rectal score is a new biomarker that has been shown to correlate with survival. The main objectives of this study were to investigate factors contributing to pathological complete response, to validate the prognostic significance of neoadjuvant rectal score, and to investigate factors associated with a lower neoadjuvant rectal score in a cohort of Hong Kong Chinese. METHODS: Data of patients with locally advanced rectal cancer who received neoadjuvant chemoradiotherapy from August 2006 to October 2018 were retrieved from hospital records and retrospectively analysed. RESULTS: Of 193 patients who had optimal response to neoadjuvant chemoradiotherapy and surgery, tumour down-staging was the only independent prognostic factor that predicted pathological complete response (P<0.0001). Neoadjuvant rectal score was associated with overall survival (hazard ratio [HR]=1.042, 95% confidence interval [CI]=1.021-1.064; P<0.0001), disease-free survival (HR=1.042, 95% CI=1.022-1.062; P<0.0001), locoregional recurrence-free survival (HR=1.070, 95% CI=1.039-1.102; P<0.0001) and distant recurrence-free survival (HR=1.034, 95% CI=1.012-1.056; P=0.002). Patients who had pathological complete response were associated with a lower neoadjuvant rectal score (P<0.0001), but pathological complete response was not associated with survival. For patients with intermediate neoadjuvant rectal scores, late recurrences beyond 72 months from diagnosis were observed. CONCLUSION: Neoadjuvant rectal score is an independent prognostic marker of survival and disease recurrence in a cohort of Hong Kong Chinese patients who received neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

Comparison of antral follicle count and serum anti Müllerian hormone level for determination of gonadotropin dosing in in-vitro fertilization: randomized trial.

OBJECTIVE: To compare the proportion of women achieving a desired ovarian response following ovarian stimulation when gonadotropin dosing was determined based on antral follicle count (AFC) vs serum anti-Müllerian hormone (AMH) level, in women undergoing in-vitro fertilization (IVF) using the gonadotropin-releasing hormone (GnRH) antagonist protocol. METHODS: This was a randomized double-blind trial carried out in a university-affiliated assisted reproduction unit. A total of 200 women undergoing their first IVF cycle using the GnRH-antagonist protocol between April 2016 and February 2018 were randomized to determination of gonadotropin dosing based on either AFC or serum AMH level measured in the pretreatment cycle 1 month before the IVF cycle. Patients underwent IVF as per our center's standard protocol. The proportion of subjects achieving a desired ovarian response, defined as retrieval of six to 14 oocytes, was compared between the two study arms. Subgroup analysis of patients with baseline AFC > 5 and those with baseline AFC ≤ 5 was performed. Concordance in AFC and AMH categorization between the pretreatment cycle and the ovarian-stimulation cycle was assessed using Cohen's kappa (κ). RESULTS: There was no significant difference in the proportion of patients achieving a desired ovarian response between the AFC (54%) and AMH (49%) groups (P = 0.479). The median number of oocytes retrieved was nine vs seven (P = 0.070), and the median follicular output rate was 0.54 vs 0.55 (P = 0.764) in the AFC and AMH groups, respectively. Similar findings were observed on subgroup analysis of subjects with AFC ≤ 5 and AFC > 5 at the start of ovarian stimulation (P > 0.05 for all comparisons). There was moderate concordance between AFC and AMH measured in the pretreatment cycle and the stimulation cycle (κ = 0.478 and 0.587, respectively). CONCLUSION: The proportion of women achieving a desired ovarian response following ovarian stimulation using the GnRH-antagonist protocol is similar when the gonadotropin-dosing algorithm used is based on AFC or serum AMH level. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Comparación del recuento de folículos sinusales y el nivel de la hormona antimulleriana en el suero para la determinación de la dosis de gonadotrofina en la fecundación in vitro: ensayo aleatorizado OBJETIVO: Comparar la proporción de mujeres que logran una respuesta ovárica deseada tras la estimulación del ovario cuando se determinó la dosis de gonadotrofina en función del recuento de folículos sinusales (AFC, por sus siglas en inglés) frente al nivel de la hormona antimulleriana (HAM) en el suero, en mujeres que se sometieron a una fecundación in vitro (FIV) mediante el protocolo de antagonistas de la hormona liberadora de gonadotropina (GnRH, por sus siglas en inglés). MÉTODOS: Se trata de un ensayo aleatorizado doble ciego realizado en una unidad de reproducción asistida afiliada a una universidad. Un total de 200 mujeres que se sometieron a su primer ciclo de FIV y utilizaron el protocolo de antagonistas de la GnRH entre abril de 2016 y febrero de 2018 fueron asignadas al azar a la determinación de la dosis de gonadotrofina basada en el nivel de AFC o de HAM en suero, medidos en el ciclo de pretratamiento un mes antes del ciclo de FIV. Las pacientes se sometieron a una FIV según el protocolo estándar de nuestro centro. La proporción de mujeres que lograron una respuesta ovárica deseada, definida como la recuperación de seis a 14 ovocitos, se comparó entre las dos ramas del estudio. Se realizó un análisis de subgrupos de las pacientes con AFC de base >5 y de aquellas con AFC de base ≤5. La concordancia en la categorización del AFC y la HAM entre el ciclo de pretratamiento y el ciclo de estimulación ovárica se evaluó utilizando la medida estadística kappa de Cohen (κ). RESULTADOS: No hubo diferencias significativas en la proporción de pacientes que lograron una respuesta ovárica deseada entre los grupos de AFC (54%) y HAM (49%) (P=0,479). La mediana del número de ovocitos recuperados fue de nueve frente a siete (P=0,070), y la mediana de la tasa de producción folicular fue de 0,54 frente a 0,55 (P=0,764) en los grupos AFC y HAM, respectivamente. Se observaron hallazgos similares en el análisis de subgrupos de pacientes con AFC ≤5 y AFC >5 al comienzo de la estimulación ovárica (P>0,05 para todas las comparaciones). Se observó una concordancia moderada entre el AFC y la HAM medidos en el ciclo de pretratamiento y el ciclo de estimulación (κ=0,478 y 0,587, respectivamente). CONCLUSIÓN: La proporción de mujeres que logran una respuesta ovárica deseada después de la estimulación ovárica utilizando el protocolo de antagonistas de la GnRH es similar cuando el algoritmo de dosificación de gonadotrofina utilizado se basa en el nivel del AFC o de la HAM en suero.

Predicting first-episode psychosis patients who will never relapse over 10 years.

BACKGROUND: Although relapse in psychosis is common, a small proportion of patients will not relapse in the long term. We examined the proportion and predictors of patients who never relapsed in the 10 years following complete resolution of positive symptoms from their first psychotic episode. METHOD: Patients who previously enrolled in a 12-month randomized controlled trial on medication discontinuation and relapse following first-episode psychosis (FEP) were followed up after 10 years. Relapse of positive symptoms was operationalized as a change from a Clinical Global Impression scale positive score of <3 for at least 3 consecutive months to a score of ⩾3 (mild or more severe). Baseline predictors included basic demographics, premorbid functioning, symptoms, functioning, and neurocognitive functioning. RESULTS: Out of 178 first-episode patients, 37 (21%) never relapsed during the 10-year period. Univariate predictors (p ⩽ 0.1) of patients who never relapsed included a duration of untreated psychosis (DUP) ⩽30 days, diagnosed with non-schizophrenia spectrum disorders, having less severe negative symptoms, and performing better in logical memory immediate recall and verbal fluency tests. A multivariate logistic regression analysis further suggested that the absence of any relapsing episodes was significantly related to better short-term verbal memory, shorter DUP, and non-schizophrenia spectrum disorders. CONCLUSIONS: Treatment delay and neurocognitive function are potentially modifiable predictors of good long-term prognosis in FEP. These predictors are informative as they can be incorporated into an optimum risk prediction model in the future, which would help with clinical decision making regarding maintenance treatment in FEP.

In vitro fertilisation in Hong Kong: the situation in 2019.

The popularity of in vitro fertilisation has continuously increased throughout the past 40 years owing to an increased incidence of infertility and delayed planning for pregnancy. The aim of this paper is to review the current situation of in vitro fertilisation in Hong Kong. In Hong Kong, in 2018, 7995 women underwent 5055 fresh and 5050 frozen-thawed embryo in vitro fertilisation cycles, resulting in an ongoing pregnancy rate of 33.7% per transfer. However, in vitro fertilisation is associated with several problems, including a high rate of multiple pregnancies and risks associated with cross-border reproductive care. Single embryo transfer is a simple strategy to reduce multiple pregnancies without compromising the cumulative live birth rate.

The effect of complex interventions on supporting self-care among community-dwelling older adults: a systematic review and meta-analysis.

Background: self-care is critical to enable community-dwelling older adults to live independently. Complex interventions have emerged as a strategy to support self-care, but their effectiveness is unknown. Our objective was to review systematically their effectiveness on both positive (increased scores in self-rated health, Activities of Daily Living, Instrumental Activities of Daily Living, quality of life) and negative aspects (increased incidence of falls, fear of falling, hospital and nursing home admission, increased depression score), and to determine which intervention components explain the observed effects. Methods: CINAHL, MEDLINE, British Nursing Index, PsycInfo and Cochrane CENTRAL were searched from January 2006 to October 2016. Randomised controlled trials providing at least two of these components: individual assessment, care planning or provision of information were reviewed. Outcomes were pooled by random-effects meta-analysis. Results: twenty-two trials with 14,364 participants were included with a low risk of bias. Pooled effects showed significant benefits on positive aspects including self-rated health [standardised mean difference (SMD) 0.09, 95% confidence interval (CI) 0.01-0.17] and the mental subscale of quality of life (SMD 0.44, 95% CI 0.09-0.80) as well as on the negative aspect of incidence of falls [odds ratio (OR) 0.60, 95% CI 0.46-0.79]. There was no significant improvement in ADL, IADL, overall quality of life, fear of falling, reduction in health service utilisation or depression levels. Meta-regression and subgroup analysis did not identify any specific component or characteristic in complex interventions which explained these effects. Conclusion: based on current evidence, supporting self-care in community-dwelling older adults using complex interventions effectively increases self-rated health, reduces the occurrence of falls and improves the mental subscale of quality of life.

A study of human neutrophil antigen genotype frequencies in Hong Kong.

BACKGROUND: Alloantibodies against human neutrophil antigens (HNA) are associated with a variety of clinical conditions. Over the past decade, the allelic and genotypic frequencies of the five HNA systems have been evaluated. Although the HNA system is less polymorphic than human leukocyte antigens (HLA), significant differences in the genotypic and allele frequencies still exist in different populations, even those living in close proximity. OBJECTIVES: To delineate HNA genotypic and allele frequencies to provide vital information on estimating the risk of HNA-associated diseases for our local population. METHODS: Using a validated, in-house-developed assay, genotyping for HNA-1, HNA-3, HLA-4 and HNA-5 was performed on 300 samples from Chinese blood donors from Hong Kong. In addition, the frequency of the HNA-2 c.843A > T allele was also determined. RESULTS: The allele frequencies of HNA-1a, -1b and -1c alleles were 67·8, 31·5 and 0%, respectively, whereas the frequencies of HNA-3a and HNA-3b were 71·0 and 29·0%, respectively. The frequencies of HNA-4a and -4b alleles were 99·5 and 0·5%, respectively, and for HNA-5a and -5b, alleles were 85·2 and 14·8%, respectively. Homozygotes for the HNA-2 c.843 TT variant were absent in our population, whereas only <4% of the population were c.843AT heterozygote carriers. CONCLUSIONS: This is the first study to define HNA genotype and allele frequencies using a validated modified in-house PCR-SSP method in the Hong Kong Chinese blood donor population. Our approach provides a cost-effective assay for conducting routine HNA typing and facilitates the incorporation of these assays into routine clinical service. Our results are comparable with those reported in the Guangzhou Chinese population, but the allele frequencies in our Hong Kong Chinese population are significantly different from the reported European frequencies, confirming that a geographical difference exists for HNA allele frequencies.

Effect of paternal age on semen parameters and live birth rate of in-vitro fertilisation treatment: a retrospective analysis.

OBJECTIVE: To determine the effect of paternal age on semen parameters and the live birth rate from in-vitro fertilisation (IVF) treatment. METHODS: We performed a retrospective cohort study of couples undergoing a first IVF cycle between 2004 and 2014 in a tertiary assisted reproduction centre in Hong Kong. RESULTS: We analysed 3549 cases. Paternal age ≥40 years was negatively correlated with semen volume, progressive motility, total motility and total normal motile count (P<0.005) and positively correlated with sperm concentration (P<0.001). There was no correlation with sperm count, normal morphology, or total motile count. Subgroup analyses in Chinese men only and in men with normal versus abnormal semen parameters showed the same correlations. Paternal age was positively associated with maternal age (P<0.001) and miscarriage (P=0.006), and negatively associated with ongoing pregnancy and live birth (P<0.001). Logistic regression showed that maternal age, total number of oocytes retrieved, and number of embryos transferred were significant factors which independently predicted the likelihood of live birth from IVF (all P<0.001). CONCLUSION: Paternal age was negatively correlated with some semen parameters, which showed a significant decline after age 40 years. However, paternal age is not predictive of the live birth from IVF treatment.

Hyperglycemia impedes definitive endoderm differentiation of human embryonic stem cells by modulating histone methylation patterns.

Exposure to maternal diabetes during fetal growth is a risk factor for the development of type II diabetes (T2D) in later life. Discovery of the mechanisms involved in this association should provide valuable background for therapeutic treatments. Early embryogenesis involves epigenetic changes including histone modifications. The bivalent histone methylation marks H3K4me3 and H3K27me3 are important for regulating key developmental genes during early fetal pancreas specification. We hypothesized that maternal hyperglycemia disrupted early pancreas development through changes in histone bivalency. A human embryonic stem cell line (VAL3) was used as the cell model for studying the effects of hyperglycemia upon differentiation into definitive endoderm (DE), an early stage of the pancreatic lineage. Hyperglycemic conditions significantly down-regulated the expression levels of DE markers SOX17, FOXA2, CXCR4 and EOMES during differentiation. This was associated with retention of the repressive histone methylation mark H3K27me3 on their promoters under hyperglycemic conditions. The disruption of histone methylation patterns was observed as early as the mesendoderm stage, with Wnt/ß-catenin signaling being suppressed during hyperglycemia. Treatment with Wnt/ß-catenin signaling activator CHIR-99021 restored the expression levels and chromatin methylation status of DE markers, even in a hyperglycemic environment. The disruption of DE development was also found in mouse embryos at day 7.5 post coitum from diabetic mothers. Furthermore, disruption of DE differentiation in VAL3 cells led to subsequent impairment in pancreatic progenitor formation. Thus, early exposure to hyperglycemic conditions hinders DE development with a possible relationship to the later impairment of pancreas specification.

Human varicella zoster virus is not present in the semen of a man affected by chickenpox during the in vitro fertilisation of his wife.

Human varicella zoster virus (VZV) is a member of the herpes virus family and affects humans only. Information about the presence of the virus in the semen samples of men affected by chickenpox is rather limited in the literature. Here, we reported a husband was affected by VZV during in vitro fertilisation treatment of his wife treated in our centre. The semen sample was checked for the presence of VZV by the PCR technique. The PCR result found no detectable viral DNA in the semen sample. The semen sample was then used for conventional IVF insemination and subsequently a healthy baby boy was born. This single case report suggests that the semen sample of men affected by chickenpox may be safe to use for assisted reproduction methods during the VZV infective period.

Preimplantation genetic diagnosis and screening by array comparative genomic hybridisation: experience of more than 100 cases in a single centre.

INTRODUCTION: Preimplantation genetic screening has been proposed to improve the in-vitro fertilisation outcome by screening for aneuploid embryos or blastocysts. This study aimed to report the outcome of 133 cycles of preimplantation genetic diagnosis and screening by array comparative genomic hybridisation. METHODS: This study of case series was conducted in a tertiary assisted reproductive centre in Hong Kong. Patients who underwent preimplantation genetic diagnosis for chromosomal abnormalities or preimplantation genetic screening between 1 April 2012 and 30 June 2015 were included. They underwent in-vitro fertilisation and intracytoplasmic sperm injection. An embryo biopsy was performed on day-3 embryos and the blastomere was subject to array comparative genomic hybridisation. Embryos with normal copy numbers were replaced. The ongoing pregnancy rate, implantation rate, and miscarriage rate were studied. RESULTS: During the study period, 133 cycles of preimplantation genetic diagnosis for chromosomal abnormalities or preimplantation genetic screening were initiated in 94 patients. Overall, 112 cycles proceeded to embryo biopsy and 65 cycles had embryo transfer. The ongoing pregnancy rate per transfer cycle after preimplantation genetic screening was 50.0% and that after preimplantation genetic diagnosis was 34.9%. The implantation rates after preimplantation genetic screening and diagnosis were 45.7% and 41.1%, respectively and the miscarriage rates were 8.3% and 28.6%, respectively. There were 26 frozen-thawed embryo transfer cycles, in which vitrified and biopsied genetically transferrable embryos were replaced, resulting in an ongoing pregnancy rate of 36.4% in the screening group and 60.0% in the diagnosis group. CONCLUSIONS: The clinical outcomes of preimplantation genetic diagnosis and screening using comparative genomic hybridisation in our unit were comparable to those reported internationally. Genetically transferrable embryos replaced in a natural cycle may improve the ongoing pregnancy rate and implantation rate when compared with transfer in a stimulated cycle.

Frameless stereotactic radiosurgery for brain metastases: a review of outcomes and prognostic scores evaluation.

INTRODUCTION: Stereotactic brain radiosurgery provides good local control in patients with limited brain metastases. A newly developed frameless system allows pain-free treatment. We reviewed the effectiveness of this frameless stereotactic brain radiosurgery and identified prognostic factors that may aid better patient selection. METHODS: Medical records of patients with brain metastases treated with linear accelerator-based frameless stereotactic brain radiosurgery between January 2010 and July 2015 in a university affiliated hospital in Hong Kong were reviewed. Outcomes including local and distant brain control rate, progression-free survival, and overall survival were analysed. Prognostic factors were identified by univariable and multivariable analyses. Association of outcomes with four common prognostic scores was performed. RESULTS: In this study, 64 patients with 94 lesions were treated with a median dose of 18 Gy (range, 12-22 Gy) in a single fraction. The median follow-up was 11.5 months. One-year actuarial local and distant brain control rates were 72% and 71%, respectively. The median overall survival was 13.0 months. On multivariable analysis, Karnofsky performance status score (>50 vs ≤50) and number of lesions (1-2 vs ≥3) were found to associate significantly with distinct brain progression-free survival (P=0.022, hazard ratio=0.20, 95% confidence interval 0.05-0.80 and P=0.003, hazard ratio=0.31, 95% confidence interval 0.14-0.68, respectively). Overall survival was associated significantly with Basic Score for Brain Metastases (P=0.031), Score Index for Radiosurgery in Brain Metastases (P=0.007), and Graded Prognostic Assessment (P=0.003). Improvement in overall survival was observed in all groups of different prognostic scores. CONCLUSION: Frameless stereotactic brain radiosurgery is effective in patients with oligo-metastases of brain and should be increasingly considered in patients with favourable prognostic scoring.

Comparative evaluation of three new commercial immunoassays for anti-Müllerian hormone measurement.

STUDY QUESTION: How do the three new anti-Müllerian hormone (AMH) assay methods, manufactured by Beckman Coulter, Roche and Ansh Labs compare with each other and with the Gen II assay? SUMMARY ANSWER: The three new AMH assays are well correlated among themselves and with the Gen II assay, although differences in calibration do exist. WHAT IS KNOWN ALREADY: The Gen II assay has been the mainstay method for AMH measurement in the past few years. Recently, a few new AMH measurement methods have come to the market. STUDY DESIGN, SIZE, DURATION: This was a prospective assay evaluation performed on 178 human serum samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMH concentration was measured in residual serum samples donated by female patients in a reproductive medicine centre. The three new assay methods were tested in parallel and the numerical values obtained were compared among themselves and with those obtained by the Gen II assay. The assay stability upon different sample storage conditions, intra-assay and inter-assay precision, linearity and dilution recovery, and diagnostic performance for polycystic ovary syndrome (PCOS) of the three new AMH assay methods were also compared. MAIN RESULTS AND THE ROLE OF CHANCE: AMH values measured by the Gen II kit and the three new assay methods have good correlations (R > 0.9 for all pairwise correlations). Values measured by the Ansh Labs assay were significantly higher, whereas those by the Roche assay were significantly lower, than those from the Gen II and Beckman-Coulter automated assays (P < 0.05). AMH values were significantly different when measured on the fresh and frozen-thawed serum sample (at -20oC and -80oC) for all three new methods (P < 0.05), but the magnitude of difference was very small with the Beckman-Coulter automated assay and Roche assay. The intra-assay coefficients of variation (CVs) were 0.7-2.2%, 0.5-1.4%, and 1.4-5.4% for the Beckman-Counter automated, Roche and Ansh Labs assays, respectively. Their inter-assay CVs were 0.9-2.5%, 0.7-1.9%, and 6.2-13.5%, respectively. All three new assay methods showed acceptable linearity, and provided excellent discrimination of PCOS from controls. LIMITATIONS, REASONS FOR CAUTION: The precision and dilution linearity experiments involved a small sample size, although these were not the primary outcome measures and have been properly evaluated in previous publications. The study was not designed or powered for determining diagnostic cut-off values. WIDER IMPLICATIONS OF THE FINDINGS: The results demonstrate that the three new AMH assay methods are all valid methods to be adopted in the field of reproduction and are a basis for further work on their clinical application. STUDY FUNDING/COMPETING INTERESTS: The authors have no competing interest to declare. The execution of this study was funded by the Department of Obstetrics and Gynaecology, The University of Hong Kong.

Sperm retrieval rate and pregnancy rate in infertile couples undergoing in-vitro fertilisation and testicular sperm extraction for non-obstructive azoospermia in Hong Kong.

OBJECTIVE: There are currently no local data on the sperm retrieval and pregnancy rates in in-vitro fertilisation and testicular sperm extraction cycles, especially with regard to the presence of genetic abnormalities. This study aimed to determine the sperm retrieval and pregnancy rates in infertile couples who underwent in-vitro fertilisation and testicular sperm extraction for non-obstructive azoospermia. METHODS: This retrospective case series was conducted at a tertiary assisted reproduction unit in Hong Kong. Men with non-obstructive azoospermia who underwent in-vitro fertilisation and testicular sperm extraction between January 2001 and December 2013 were included. The main outcome measures were sperm retrieval and pregnancy rates. RESULTS: During the study period, 89 men with non-obstructive azoospermia underwent in-vitro fertilisation and testicular sperm extraction. Sperm was successfully retrieved in 40 (44.9%) men. There was no statistically significant difference in the sperm retrieval rate of those with karyotypic abnormalities (2/5, 40.0% vs 28/61, 45.9%; P=1.000) and AZFc microdeletion (3/6, 50.0% vs 28/61, 45.9%; P=1.000) compared with those without. Sperms were successfully retrieved in patients who had mosaic Klinefelter syndrome (2/3, 66.7%) but not in the patient with non-mosaic Klinefelter syndrome. No sperms were found in men with AZFa or AZFb microdeletions. Pregnancy test was positive in 15 (16.9%) patients and the clinical pregnancy rate was 13.5% (12/89) per cycle. The clinical pregnancy rate per transfer was 34.3% (12/35). CONCLUSIONS: The sperm retrieval rate and clinical pregnancy rate per initiated cycle in men undergoing in-vitro fertilisation and testicular sperm extraction in our unit were 44.9% and 13.5%, respectively. No sperms could be retrieved in the presence of AZFa and AZFb microdeletions, but karyotype and AZFc microdeletion abnormalities otherwise did not predict the success of sperm retrieval in couples undergoing in-vitro fertilisation and testicular sperm extraction. Genetic tests are important prior to testicular sperm extraction for patient selection and genetic counselling.