Somatic mitochondrial DNA mutations in different grades of glioma.

Aim: Mitochondrial DNA (mtDNA) alterations play an important role in the multistep processes of cancer development. Gliomas are among the most diagnosed brain cancer. The relationship between mtDNA alterations and different grades of gliomas are still elusive. This study aimed to elucidate the profile of somatic mtDNA mutations in different grades of gliomas and correlate it with clinical phenotype. Materials & methods: Forty histopathologically confirmed glioma tissue samples and their matched blood were collected and subjected for mtDNA sequencing. Results & conclusion: About 75% of the gliomas harbored at least one somatic mutation in the mtDNA gene, and 45% of these mutations were pathogenic. Mutations were scattered across the mtDNA genome, and the commonest nonsynonymous mutations were located at complex I and IV of the mitochondrial respiratory chain. These findings may have implication for future research to determine the mitochondrial energetics and its downstream metabolomics on gliomas.

Complementary role of p57kip2 immunostaining in diagnosing hydatidiform mole subtypes.

OBJECTIVES: Gestational trophoblastic disease comprises of a spectrum of pregnancy-related tumours which includes complete (CHM) and partial hydatidiform moles (PHM). Accurate diagnosis and subclassification of HM subtypes are crucial as prognosis differs. Histopathological examination using haemotoxylin and eosin (H&E) staining remains the basis for diagnosing HM, with only 80% accuracy. p57kip2 is a cyclin-dependent kinase inhibitor (CDKI) protein and is strongly paternally imprinted, being expressed from maternal allele. Therefore, complete mole (CHM) with only paternal genome has nearly absent expression of p57kip2 compared to partial mole (PHM) having both paternal and maternal genomes. This study is aimed to determine usefulness of p57kip2 immunohistochemistry (IHC) analysis in the diagnosis of HM subtypes. METHODS: A total of 82 archived paraffin embedded HM tissues with subtypes classified based on H&E staining - 39 (47.5%) CHM, 41 (50.0%) PHM and two (2.43%) unclassified molar pregnancy were retrieved. All tissue samples were subjected for p57kip2 IHC analysis and HM subtypes were then reclassified. RESULTS: A total of 66 cases (80.5%) were re-classified as CHM, 14 cases (17.1%) as PHM and two cases (2.4%) were decidual and cystic tissues. Analysis using p57kip2 immunostaining showed a diagnostic discrepancy of 33.0% from routine H&E staining and helps to improve the characterisation of the HM subtypes specifically at early gestations which have less distinctive morphologies. CONCLUSIONS: IHC using p57kip2 monoclonal antibody should be considered as a routine ancillary test to H&E in improving the diagnosis of HM subtypes particularly in developing countries with limited resources.

Prevalence of obstructive sleep apnea in an Asian bariatric population: an underdiagnosed dilemma.

BACKGROUND: Obesity is a growing health problem that has become a global epidemic. Serial population studies have shown the same in Malaysia, where the prevalence of obesity increased rapidly in the last decade. Currently, bariatric surgery is the most effective treatment in patients with morbid obesity. Obstructive sleep apnea (OSA) is the most common type of sleep-related breathing disorder seen in obesity. OBJECTIVES: We aim to ascertain the prevalence and severity of OSA in Asian patients who underwent bariatric surgery and were seen in our center. SETTING: The study was conducted in our university hospital. METHODS: Study approval was obtained from our institutional review board for a retrospective chart review. A total of 226 patients were included in this review. OSA was noted as absent or present and graded from mild to severe. The patient population was stratified by body mass index according to the World Health Organization guidelines for Asian population. RESULTS: The overall sample prevalence of OSA was 80.5%. Of these, 24.3% had mild OSA, 23.9% had moderate OSA, and 32.3% had severe OSA. Only 17.3% have been diagnosed with OSA before bariatric workup. Among men, the prevalence of OSA was 93.7% and 75.5% among women. CONCLUSION: Based on these findings, Asian patients undergoing bariatric workup should be considered for routine polysomnography to enable treatment of OSA.

Behavioral outcome among survivors of childhood brain tumor: a case control study.

BACKGROUND: Advances in the treatment of childhood brain tumors have significantly improved survival rates. With improved survival rates, long-term treatment-related toxicities have become important, and the resulting complications can affect patients' emotion and behavior. This study aimed to 1) evaluate behavioral outcomes among survivors of childhood brain tumors, 2) compare behavioral outcomes among survivors of childhood brain tumors with survivors of childhood leukemia and healthy children, and 3) determine any demographic, disease, and/or treatment-related factors that could affect the behavioral outcomes of survivors of childhood brain tumors. METHODS: A comparative cross-sectional study was conducted over a period of 1 year (June 1st, 2018-May 31st, 2019) in two tertiary referral centers in Kuala Lumpur, Malaysia. Thirty-eight survivors of childhood brain tumors aged 6 to 18 years old who had been off-treatment for at least 1 year and were in remission, 38 age- and gender-matched survivors of childhood leukemia who had been off-treatment for at least 1 year and were in remission, and 38 age- and gender-matched unrelated healthy children were recruited. The Child Behaviour Checklist (CBCL) parent report and Youth Self-Report (YSR) questionnaires were used to assess behavioral outcomes. RESULTS: Survivors of childhood brain tumors showed statistically significantly worse behavioral outcomes than healthy children for social problems and attention problems (p < 0.05, respectively). A significantly worse outcome was found for "social problems" (p < 0.05) in survivors of childhood brain tumors compared to survivors of childhood leukemia. Significant associations were also found between physical disability, visual impairment, education level of survivors, and father's occupation and behavioral outcomes among survivors of childhood brain tumors. CONCLUSIONS: Survivors of childhood brain tumors in our center showed poor behavioral outcomes for social problems and attention problems. Thus, effective psychosocial support interventions tailored to individual patients as soon as treatment is completed are important to prevent potentially debilitating emotional problems.

Effectiveness of Sterilized Symbiotic Drink Containing Lactobacillus helveticus Comparable to Probiotic Alone in Patients with Constipation-Predominant Irritable Bowel Syndrome.

BACKGROUND: This study aimed to objectively investigate whether the addition of polydextrose to sterilized probiotic containing Lactobacillus helveticus will confer benefits to constipation-predominant irritable bowel syndrome patients. METHODS: A total of 163 patients were randomized into two groups: Group A to consume 350 mL of sterilized probiotic with 5.85 g polydextrose daily for 1 week and Group B without polydextrose. Intestinal transit time, fecal pH, fecal weight, and modified Garrigues questionnaires for pre- and post-consumption were assessed. RESULTS: Median intestinal transit time was significantly reduced from 58 (IQR 43-72) to 45 (IQR 24-59) hours and 48 (IQR 31-72) to 30 (IQR 24-49) hours for Groups A and B, respectively (p < 0.01). Fecal pH for Groups A and B was significantly reduced from 6.57 ± 0.96 to 6.13 ± 0.95 (p = 0.003) and 6.58 ± 1.0 to 5.87 ± 0.83 (p < 0.001), respectively. Fecal weight for Group A was significantly increased from 8 g ± 6.4 g to 9.8 g ± 7.6 g (p = 0.003), but it was reduced for Group B from 13.3 g ± 19.4 g to 11.2 g ± 6.6 g (p = 0.308). Constipation-related symptoms were significantly improved for both groups. CONCLUSIONS: The addition of polydextrose to sterilized probiotic containing L. helveticus did not show significant benefits to constipation-predominant irritable bowel syndrome patients. However, daily consumption of sterilized probiotic containing L. helveticus with or without polydextrose for a week alleviated constipation-related symptoms and objectively reduced both fecal pH and intestinal transit time.

Early Experience, Setup, Learning Curve, Benefits, and Complications Associated with Exoscope and Three-Dimensional 4K Hybrid Digital Visualizations in Minimally Invasive Spine Surgery.

STUDY DESIGN: Prospective observational study (n=74). PURPOSE: To evaluate the learning curve for exoscope and three-dimensional (3D) 4K hybrid visualization in terms of operating time, advantages, disadvantages, and surgical complications in tubular-access minimally invasive spine surgery (MISS) and to assess surgeon satisfaction with image quality, ergonomics, and ability to perform target site treatment. OVERVIEW OF LITERATURE: Working through tubular retractors poses a challenge. The extreme angulations during microsurgical decompression, especially contralateral decompression, require surgeons to work non-ergonomically. An exoscope allows surgeons to work ergonomically and independently of the microscope oculars as visualizations are now provided by large 3D 4K monitors. However, the value and efficacy of solely depending on an exoscope and 3D 4K monitors during microsurgical work are still unknown. METHODS: Seventy-four patients (99 levels) underwent trans-tubular MISS between March 2018 and January 2019. Five patients were excluded: one had pyogenic discitis, two had revisions, and two were trans-tubular transoral. In total, we analyzed 69 for operating time, blood loss, and complications. The learning curve graph was plotted using the surgical time for each procedure. Surgeons were asked to rate their satisfaction with image quality, ability to maintain ergonomic posture, and efficient target site treatment. RESULTS: For tubular microdiscectomy, the operating time plateaued after six cases, and for tubular decompression and minimally invasive transforaminal lumbar interbody fusion, the operating time plateaued after nine cases. Mean operating time was significantly reduced after the plateau. Complications included four cases of dural tear. All patients improved symptomatically, and there were no postoperative neurological deficits. CONCLUSIONS: Use of the exoscope has a short learning curve. Surgeons benefit from improved ergonomic posture during surgery, and resident teaching appears to be good. The only drawback is the need to rearrange the operating table setup. Complications were comparable to those when using the surgical microscope. An exoscope with hybrid digital visualization provides excellent visualization, depth perception, clarity, and precision target site treatment.

Serum pepsinogen and gastrin-17 as potential biomarkers for pre-malignant lesions in the gastric corpus.

There is a lack of non-invasive screening modalities to diagnose chronic atrophic gastritis (CAG) and intestinal metaplasia (IM). Thus, the aim of the present study was to determine the sensitivity and specificity of serum pepsinogen I (PGI), PGI:II, the PGI:II ratio and gastrin-17 (G-17) in diagnosing CAG and IM, and the correlations between these serum biomarkers and pre-malignant gastric lesions. A cross-sectional study of 72 patients (82% of the calculated sample size) who underwent oesophageal-gastro-duodenoscopy for dyspepsia was performed in the present study. The mean age of the participants was 56.2±16.2 years. Serum PGI:I, PGI:II, G-17 and Helicobacter pylori antibody levels were measured by enzyme-linked immunosorbent assay. Median levels of PGI:I, PGI:II, the PGI:II ratio and G-17 for were 129.9 µg/l, 10.3 µg/l, 14.7 and 4.4 pmol/l, respectively. Subjects with corpus CAG/IM exhibited a significantly lower PGI:II ratio (7.2) compared with the control group (15.7; P<0.001). Histological CAG and IM correlated well with the serum PGI:II ratio (r=-0.417; P<0.001). The cut-off value of the PGI:II ratio of ≤10.0 demonstrated high sensitivity (83.3%), specificity (77.9%) and area under the receiver operating characteristic curve of 0.902 in detecting the two conditions. However, the sensitivity was particularly low at a ratio of ≤3.0. The serum PGI:II ratio is a sensitive and specific marker to diagnose corpus CAG/IM, but at a high cut-off value. This ratio may potentially be used as an outpatient, non-invasive biomarker for detecting corpus CAG/IM.

Mitochondrial DNA Mutations in Grade II and III Glioma Cell Lines Are Associated with Significant Mitochondrial Dysfunction and Higher Oxidative Stress.

The role of mitochondria in tumorigenesis has regained much attention as it could dysregulate cellular energetics, oxidative stress and apoptosis. However, the role of mitochondria in different grade gliomasis still unknown. This study aimed to identify mitochondrial DNA (mtDNA) sequence variations that could possibly affect the mitochondrial functions and also the oxidative stress status. Three different grades of human glioma cell lines and a normal human astrocyte cell line were cultured in-vitro and tested for oxidative stress biomarkers. Relative oxidative stress level, mitochondria activity, and mitochondrial mass were determined by live cell imaging with confocal laser scanning microscope using CM-H2DCFDA, MitoTracker Green, and MitoTracker Orange stains. The entire mitochondrial genome was sequenced using the AffymetrixGeneChip Human Mitochondrial Resequencing Array 2.0. The mitochondrial sequence variations were subjected to phylogenetic haplogroup assessment and pathogenicity of the mutations were predicted using pMUT and PolyPhen2. The Grade II astrocytoma cells showed increased oxidative stress wherea high level of 8-OHdG and oxidative stress indicator were observed. Simultaneously, Grade II and III glioma cells showed relatively poor mitochondria functions and increased number of mutations in the coding region of the mtDNA which could be due to high levels of oxidative stress in these cells. These non-synonymous mtDNA sequence variations were predicted to be pathogenic and could possibly lead to protein dysfunction, leading to oxidative phosphorylation (OXPHOS) impairment, mitochondria dysfunction and could create a vicious cycle of oxidative stress. The Grade IV cells had no missense mutation but preserved intact mitochondria and excellent antioxidant defense mechanisms thus ensuring better survival. In conclusion, Grade II and III glioma cells demonstrated coding region mtDNA mutations, leading to mitochondrial dysfunction and higher oxidative stress.

A 19-Gene expression signature as a predictor of survival in colorectal cancer.

BACKGROUND: Histopathological assessment has a low potential to predict clinical outcome in patients with the same stage of colorectal cancer. More specific and sensitive biomarkers to determine patients' survival are needed. We aimed to determine gene expression signatures as reliable prognostic marker that could predict survival of colorectal cancer patients with Dukes' B and C. METHODS: We examined microarray gene expression profiles of 78 archived tissues of patients with Dukes' B and C using the Illumina DASL assay. The gene expression data were analyzed using the GeneSpring software and R programming. RESULTS: The outliers were detected and replaced with randomly chosen genes from the 90 % confidence interval of the robust mean for each group. We performed three statistical methods (SAM, LIMMA and t-test) to identify significant genes. There were 19 significant common genes identified from microarray data that have been permutated 100 times namely NOTCH2, ITPRIP, FRMD6, GFRA4, OSBPL9, CPXCR1, SORCS2, PDC, C12orf66, SLC38A9, OR10H5, TRIP13, MRPL52, DUSP21, BRCA1, ELTD1, SPG7, LASS6 and DUOX2. This 19-gene signature was able to significantly predict the survival of patients with colorectal cancer compared to the conventional Dukes' classification in both training and test sets (p < 0.05). The performance of this signature was further validated as a significant independent predictor of survival using patient cohorts from Australia (n = 185), USA (n = 114), Denmark (n = 37) and Norway (n = 95) (p < 0.05). Validation using quantitative PCR confirmed similar expression pattern for the six selected genes. CONCLUSION: Profiling of these 19 genes may provide a more accurate method to predict survival of patients with colorectal cancer and assist in identifying patients who require more intensive treatment.

Nocturia in patients with benign prostatic hyperplasia: evaluating the significance of ageing, co-morbid illnesses, lifestyle and medical therapy in treatment outcome in real life practice.

AIM: The aim of study was to evaluate the influence of ageing, lifestyle, and co morbid illnesses on treatment outcome of nocturia among men with BPH. METHODS: Patients with BPH on medical therapy of least 6 months and up to 48 months were interviewed. Nocturia episodes, co morbid illnesses, beverage intake frequency, medications and work history were documented. Body Mass Index (BMI), waist circumference (WC), prostate volume, and prostate specific antigen (PSA) were recorded. Treatment failure is defined as persistent nocturia despite on medical therapy for BPH. RESULTS: In 156 patients, the prevalence of nocturia was 96.7% while nocturia of 2 or more was 85.9%. Factors associated with treatment failure was older age (p < 0.01), usage of diuretics (p = 0.03), and antimuscarinics (p < 0.01), while active working status (p < 0.01), use of desmopression (p = 0.01), and increased coffee intake (p = 0.02) were associated with nocturia improvement. Co-morbid illnesses, obesity, WC, alcohol intake, PSA, prostate volume, and use of BPH medical therapy did not influence treatment outcome. CONCLUSION: Advancing age has a significance negative outcome on nocturia treatment, while standard BPH medical therapy and co morbid illnesses have an insignificant impact. However, alleviation of bothersome symptoms is possible with the understanding of its patho-physiology and individual-based approach to treatment and expected outcome.

Parental reports of behavioural outcome among paediatric leukaemia survivors in Malaysia: a single institution experience.

OBJECTIVES: To determine the behavioural impact of chemotherapy in survivors of acute lymphoblastic leukaemia (ALL) treated with chemotherapy only and to identify treatment-related or sociodemography-related factors that might be associated with behavioural outcome. METHODS: We examined 57 survivors of childhood ALL, who were off treatment for at least 2 years and were in remission, aged 4-18 years, and 221 unrelated healthy controls. The Child Behaviour Checklist (CBCL) parent report was used either in English or in Bahasa Malaysia (the national language of Malaysia) to assess the behavioural outcome. RESULTS: Childhood ALL survivors had significantly higher scores on externalising behaviour on the CBCL parent report than did controls. Higher problem scores were found in ALL survivors with single parents on 'total problems' (P = 0.03) and subscales 'withdrawn' (P = 0.03), 'social problems' (P < 0.01) and 'delinquent behaviour' (P = 0.03) than in survivors with married parents. Significant associations were seen between a lower education level of the father and the variables representing internalising (withdrawn, anxious/depressed) and externalising (aggressive behaviour). We observed trends on higher scores in all scales in ALL survivors with single parents than in controls with single parents or with fathers with low education level, especially primary education only. CONCLUSIONS: Malaysian childhood ALL survivors had a significantly increased risk for externalising behavioural problems, and there was a trend towards increased risk of problems in many other behavioural scales. Understanding the sociocultural dimension of patients' health is important to be able to design the most appropriate remedy for problem behaviours detected in this multi-ethnic population.

Health-related quality of life (HRQOL) among pediatric leukemia patients in Malaysia.

BACKGROUND: Health-Related Quality of Life (HRQOL) in pediatric leukemia patients in Malaysia has not been studied before. This was mainly due to a lack of databases on patients in the past. Many patients abandoned treatment or were lost to follow up. With more children now fully compliant and completing treatment nowadays, with higher cure rate, HRQOL has become important for our patients. The purpose of the current study was to determine the HRQOL scores in children with acute leukemia and to compare the scores for those on maintenance chemotherapy with those off-treatment as well as to determine factors which might affect HRQOL. METHODS: Seventy-seven children in a pediatric oncology center in Kuala Lumpur, Malaysia diagnosed with acute leukemia were consecutively enrolled, of whom 22 were on maintenance chemotherapy and 55 off-treatment. The Pediatric Quality of Life Inventory (PedsQL™) Scales were used to assess HRQOL. RESULTS: Children on maintenance chemotherapy had significantly lower child self-report HRQOL scores across all domains (P < 0.001) especially psychosocial health compared with those who were off-treatment. Also, parents with children on maintenance chemotherapy reported significantly lower HRQOL scores across all domains (P < 0.05) except social functioning compared with parents with children off-treatment. Younger child age was associated with lower parent proxy-report total score (P = 0.007) CONCLUSIONS: Pediatric acute leukemia patients on maintenance chemotherapy experienced significantly poorer HRQOL compared to those off-treatment.

Clinical characteristics of renal cancer in Malaysia : a ten year review.

Renal cancer is rare and its incidence is 1.9 per 100,000 in the Malaysian population, which consists of three major ethnic groups (Malay, Chinese and Indians). A retrospective study was her conducted to identify clinical characteristics and ethnic background influences on presentation. The study included all renal cancer patients from a single medical institution over ten years, with a total of 75 cases. Seventy-three patients underwent surgery while 2 received only radiotherapy or chemotherapy. The male to female ratio was 2.75:1. Incidence was equal among the Malay (49.3%) and Chinese ethnic groups (45.3%). Mean age of patients were 57.1 (18-93) years old. There were 26 (37.4%) patients with Stage I disease, 14 (18.7%) at Stage II, 23 (30.7%) at Stage III and 12 (16%) at Stage IV. The Chinese race presented at mean older age (p= 0.02) and later stage of disease (p= 0.046). Patients above 40 years old had more advanced stage disease (p= 0.023). Tumour histology were clear cell (72%), urothelial cell (13.3%), sarcomatoid cell and nephroblastoma each contributed 2.7%. The mean tumour size was 8.1 (2-20) cm. There was substantial agreement between the pre and post operative staging (kappa 0.691). In conclusion we observed significant influences of age and race in the clinical presentation of renal cancer in our institution based population. There was larger male to female ratio and mean tumour size as compared to previous epidemiology studies.

Clinicopathological features of bladder tumours in a single institution in Malaysia.

OBJECTIVE: To determine the clinicopathological features of bladder tumours encountered over a five year period in Universiti Kebangsaan Malaysia Medical Centre. METHODS: Medical records of bladder tumour cases from 2005 till 2009 were retrospectively reviewed and tabulated. RESULTS: A total of 83 cases were recorded. The incidence was highest among the Chinese (56.6%), followed by Malays (34.9%), Indians (6%) and other races (2.4%). The male-to-female ratio was 9.4:1. The median age was 65 years (range 30-91 years) and median duration of follow up was 17.2 months (range 2-60 months). The main histopathology was transitional cell carcinoma (TCC) (90.4%), followed by adenocarcinoma (6%), squamous cell carcinoma (1.2%), leiomyoma (1.2%) and myeloid sarcoma (1.2%). For the TCCs, 58.6% were superficial while 41.4% were muscle invasive, and 13.3% had nodal metastasis with distant metastasis in 8%. Of the total, 5.3% were papillary urothelial tumours of low malignant potential, 33.3% pTa, 20% pT1, 10.7% pT2, 12.0% pT3 and 18.7% pT4. Of the superficial tumours, 32.5% were high grade tumours. There were ten radical cystectomies performed for transitional cell carcinomas; two had neobladder reconstruction whereas the other eight had ileal conduits. All the adenocarcinomas and squamous cell carcinomas were treated by radiotherapy due to the advanced stage of the disease while the myeloid sarcoma received chemotherapy. Mean survival of patients with muscle invasive cancer was 33+/-5 months. By the end of the study, 18.1% of patients had died of their cancer. CONCLUSION: The incidence of bladder tumours is highest among the Chinese. When compared to other studies, the incidence of muscle invasive and high-grade superficial tumours was greater.

Prevalence and parental perceptions of complementary and alternative medicine use by children with cancer in a multi-ethnic Southeast Asian population.

BACKGROUND: The purpose of the current study was to determine the prevalence of use of complementary and alternative medicine (CAM) by children with cancer and to compare the characteristics of CAM users and CAM nonusers. METHODS: A cross-sectional study was performed at a pediatric oncology center in Kuala Lumpur, Malaysia. The parents of 97 children with cancer were interviewed using a structured questionnaire. RESULTS: Overall, 84.5% of the respondents had used CAM, and most of them believed that CAM provided a boost to the immune system, and used CAM with the intention to complement conventional treatment. The most frequently used CAM was water therapy (78%), followed by spirulina (33%), vitamin C (27%), multivitamin (23%), visit to traditional healers (22%), sea cucumber (Stichopus horrens) (15%), and Chinese traditional medicine (12%). The Malay (n = 67) were using more often (93%) CAM than non-Malay (n = 30, use 67%, P = 0.001). CONCLUSIONS: CAM use is common among Malaysian children with cancer. Understanding the sociocultural dimension of patients' health beliefs is important to a successful treatment, and pediatric oncologists should ask for the use of CAM.