FOXP3+ regulatory T cells, mismatch repair proteins and BRAF V600E status in young-onset colorectal cancer.

INTRODUCTION: Young onset colorectal cancer (YOCRC) is a heterogenous CRC phenotype with an increasing trend globally. This study aims to determine FOXP3+ Treg cells, Mismatch Repair (MMR) proteins, and proto-oncogene B-Raf (BRAF) V600E status among YOCRC patients at Hospital Universiti Sains Malaysia. MATERIALS AND METHODS: This was a retrospective study of YOCRC (<50 years) over 8 years (January 2013 to December 2021). Immunohistochemistry staining of FOXP3, BRAFV600E, and MMR protein expression was performed using monoclonal antibodies. The staining intensity and percentage of positive cells were used to evaluate the staining using immunoreactive scoring. All data were analysed using descriptive and correlation statistics. A p-value of ≤ 0.05 was taken as statistically significant. RESULTS: A total of 65 YOCRC patients were diagnosed, out of which 53.8% had proficient MMR (pMMR) with a mean age of 41, while 46.2% had deficient MMR (dMMR) with a mean age of 35.5. The pMMR with the BRAFV600E+ group expressed higher FOXP3+Tregs (54.2%) than the dMMR with the BRAFV600E+ group (22.9%). Patients with lower FOXP3+Tregs were observed more in dMMR with BRAFV600E- (47%) than in pMMR with BRAFV600E- (5.9%). There was a statistically significant association between the density of expressed FOXP3+Tregs with MMR and BRAFV600E status (p=0.002). CONCLUSION: While most of the YOCRC had pMMR, others exhibited dMMR with loss of one or more MMR proteins. The presence of BRAFV600E demonstrated the YOCRC's sporadic nature. A high FOXP3+Treg expression was significantly associated with MMR and BRAFV600E status. Future research must be expanded to cover other hospitals to increase the sample size and include MLH1 hypermethylation testing.

Evaluation of quantitative point-of-care test for measurement of glucose-6-phosphate dehydrogenase enzyme activity in Malaysia.

INTRODUCTION: The treatment of Plasmodium vivax malaria with 8-aminoquinolines is contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals due to the risk of acute haemolytic anaemia. Effective G6PD screening is paramount to avoid adverse drug reactions. This study aimed to evaluate the performance of novel quantitative point-of-care (POC) tests as a new screening method for G6PD deficiency in Malaysia. MATERIALS AND METHODS: A total of 153 neonatal cord blood, 99 peripheral blood of older children aged between 1 month to 12-years old, and 62 peripheral adult blood were screened for G6PD deficiency using two quantitative POC tests, CareStartTM biosensor (Carestart) and CareStartTM Biosensor 1 (S1). The results were compared with OSMMR2000D kit as a reference assay. Two statistical analyses were performed in this study to evaluate the POC test performances, the Spearman's correlation test and the Cohen's kappa method. RESULTS: Both Carestart and S1 tests showed significant positive correlations to OSMMRS000D with r2 = 0.7916 and r2 = 0.7467. Their measurement of agreement showed a kappa (κ) value of 0.805 (p<0.001, 95% CI), and 0.795 (p<0.001, 95% CI), respectively. Analysis of the area under the Receiver Operating Curve (ROC) at 60% cut-off illustrated that the Carestart had 90.2% sensitivity, 98.9% specificity, 98.3% positive predictive value (PPV), and 93.8% negative predictive value (NPV). The corresponding values for the S1 were 95.2%, 100%, 100%, and 96.8%, respectively. CONCLUSION: This study showed that the Carestart and S1 biosensors have high-performance reliability for screening of G6PD deficiency, which can guide safe prescriptions of anti-malaria medications and hence, eradication of Plasmodium vivax malaria.

Effectiveness of Decision Aid in Men with Localized Prostate Cancer: a Multicenter Randomized Controlled Trial at Tertiary Referral Hospitals in an Asia Pacific Country.

There are several treatment options for localized prostate cancer with very similar outcome but vary in terms of technique and side effect profiles and risks. Considering the potential difficulty in choosing the best treatment, a patient decision aid (PDA) is used to help patients in their decision-making process. However, the use and applicability of PDA in a country in Asia Pacific region like Malaysia is still unknown. This study aims to evaluate the effectiveness of a PDA modified to the local context in improving patients' knowledge, decisional conflict, and preparation for decision making among men with localized prostate cancer. Sixty patients with localized prostate cancer were randomly assigned to control and intervention groups. A self-administered questionnaire, which evaluate the knowledge on prostate cancer (23 items), decisional conflict (10 items) and preparation for decision-making (10 items), was given to all participants at pre- and post-intervention. Data were analyzed using independent T test and paired T test. The intervention group showed significant improvement in knowledge (p = 0.02) and decisional conflict (p = 0.01) from baseline. However, when compared between the control and intervention groups, there were no significant differences at baseline and post-intervention on knowledge, decisional conflict and preparation for decision-making. A PDA on treatment options of localized prostate cancer modified to the local context in an Asia Pacific country improved patients' knowledge and decisional conflict but did not have significant impact on the preparation for decision-making. The study was also registered under the Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12614000668606 registered on 25/06/2014.

Colorectal cancer in patient younger than 50-year-old in Kelantan: Two case reports.

Although young-onset colorectal cancer (CRC) is commonly linked to genetic predispositions such as Lynch syndrome, there has been an increasing trend in the prevalence of sporadic type youngonset CRC. We highlighted two cases of young patients diagnosed with CRC. Both patients came at the late stage of presentation with right sided colon tumour and local lymph nodes involvement. Loss of MLH1 expression with positive BRAF V600E was seen on immunohistochemistry staining. Additionally, they have no chronic disease or familial history of malignancy. The follow-up surveillance CT scan and the surveillance colonoscopy of case 1 showed no local recurrence and distant metastasis. However, another patient defaulted on the subsequent follow-up. In this report, we review the clinicopathological characteristics of these two cases and discuss the importance of the screening for the BRAF V600E and the four MMR proteins to characterise the sporadic and hereditary subgroups of young-onset CRC.

Metastatic leiomyosarcoma of the thyroid: A rare entity.

Cancer metastasis to the thyroid gland from non-thyroid sites is a rare presentation in clinical practice. The most frequent primary cancers that metastasise to the thyroid are renal cell carcinoma, followed by colorectal, lung and breast. We report a case of a 64-year-old Malay lady who presented with anterior neck swelling 4 years after an initial diagnosis of uterine leiomyosarcoma. She had undergone a hysterectomy procedure four years ago. Fine needle aspiration cytology of the thyroid mass suggested undifferentiated thyroid carcinoma. After multi-disciplinary discussion, the patient underwent thyroidectomy and the final histopathological diagnosis was metastatic leiomyosarcoma of the thyroid. The diagnosis was aided by an immunohistochemistry panel of positive myogenic markers, negative epithelial markers as well as the previous medical history of uterine leiomyosarcoma. Metastatic leiomyosarcoma of the thyroid may mimic primary undifferentiated (anaplastic) thyroid carcinoma (UTC) with a sarcomatoid pattern, medullary thyroid carcinoma (MTC) with spindle cells morphology and spindle cell tumour with thymus-like differentiation (SETTLE). Hence, a multidisciplinary approach must be practised by pathologists, surgeons and radiologists to consider metastatic lesions of the thyroid gland, especially when a previous history of cancer exists or is suspected.

H396P mutation in chronic myeloid leukaemia patient on nilotinib - A case report.

INTRODUCTION: The advent of BCR-ABL1-targeted therapy with the tyrosine kinase inhibitor (TKI), for example, imatinib and nilotinib, marked a turning point in the therapy of chronic myeloid leukaemia (CML). However, a substantial proportion of patients experience primary or secondary disease resistance to TKI. There are multifactorial causes contributing to the treatment failure of which BCR-ABL1 kinase domain mutation being the most common. Here, we describe a case of a CML patient with H396P mutation following treatment with nilotinib. CASE: A 60-year-old woman presented with abdominal discomfort and hyperleukocytosis. She was diagnosed as CML in the chronic phase with positive BCR-ABL1 transcripts. Due to the failure to obtain an optimal response with imatinib treatment, it was switched to nilotinib. She responded well to nilotinib initially and achieved complete haematological and cytogenetic responses, with undetectable BCR-ABL1 transcripts. However, in 4 years she developed molecular relapse. Mutation analysis which was done 70 months after commencement of nilotinib showed the presence of BCRABL1 kinase domain mutation with nucleotide substitution at position 1187 from Histidine(H) to Proline(P) (H396P). Currently, she is on nilotinib 400mg twice daily. Her latest molecular analysis showed the presence of residual BCR-ABL1 transcripts at 0.22%. DISCUSSION/CONCLUSION: This case illustrates the importance of BCR-ABL1 mutation analysis in CML patients with persistent BCR-ABL1 positivity in spite of treatment. Early detection and identification of the type of BCRABL1 mutation are important to guide appropriate treatment options as different mutation will have different sensitivity to TKI.

Siriraj I Gγ(Aγδß)0-thalassaemia causing severe thalassaemia intermedia in compound heterozygous state with IVS1-1(G→T) mutation.

The Siriraj I Gγ(Aγδß)0-thalassaemia is a novel mutation involving a 118kb deletion of the ß-globin gene cluster. It was first reported in 2012 in two unrelated families from the southern part of Thailand. The carriers in the heterozygous state are clinically asymptomatic. Nonetheless, its complex interaction with other ß-thalassaemia could give rise to different clinical phenotypes, ranging from mild thalassaemia intermedia to thalassaemia major. We report here a case of a six-year-old Malay boy, presented with pallor, growth failure and hepatosplenomegaly. His haemoglobin at presentation was 9.2g/dL with a mean cell haemoglobin of 22.6pg and a mean cell volume of 69.9fl. His peripheral blood smear showed features of thalassaemia intermedia. Haemoglobin (Hb) analysis revealed markedly raised Hb F (83%), normal HbA2 levels and absent HbA. Deoxyribonucleic acid (DNA) analysis showed compound heterozygous IVS1-1 (G→T) ß-globin gene mutation and Siriraj I Gγ(Aγδß)0-deletion (genotype ßIVS1-1/ ß Siriraj I deletion). Both his father and elder sister are carriers of Siriraj I Gγ(Aγδß)0-thalassaemia while his mother carries IVS1-1 (G→T) gene mutation. Clinically, the patient is transfusion dependent on six weekly regime. To the best of our knowledge, this is the first reported case in Malaysia involving unique Siriraj I Gγ(Aγδß)0-thalassaemia and IVS1-1 (G→T) in a compound heterozygous state. In summary, detection of Siriraj I Gγ(Aγδß)0-thalassaemia is essential as this deletion can lead to severe disease upon interaction with a ß-thalassemia point mutation as demonstrated in our case. The establishment of effective carrier screening and genetic counselling is important to prevent its adverse consequences.

Expression of IGFBP-rP1 in ovarian and breast cancers in association with diabetes mellitus status.

INTRODUCTION: Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is an important component of the IGF system that regulates insulin resistance-related to tumour development. The aim of this study is to investigate the expression of IGFBP-rP1 among female cancer patients who are known or not known to have Type 2 Diabetes Mellitus (T2DM). MATERIALS AND METHODS: Using a cross-sectional design, cases of ovarian and breast cancer with clinical status of T2DM were selected over a 10-year period in Hospital Universiti Sains Malaysia. Immunohistochemical staining for IGFBP-rP1 was performed on paraffin-embedded tissues and the results were correlated with the patient's demographic and clinicopathological data. RESULTS: A total of 152 breast cancer patients were recruited into the current study with 33.5% (51/152) patients were positive T2DM. Most of the breast cancer patients with T2DM were IGFBP-rP1-negative (66.7%, 34/51). The IGFBP-rP1 expression was significantly difference between breast cancer subjects with and without T2DM (p<0.001). There was no significant association of IGFBP-rP1 expression with data on the demographic and clinicopathological profiles of patients with breast cancer. Meanwhile, positive IGFBP-rP1 expression was evident in 44 out of 108 (40.74%) ovarian cancer cases. Among these cases, 36 were T2DM. In contrast to breast cancer cases, IGFBP-rP1 was mostly expressed among ovarian cancer patients with T2DM (66.7%, 24/36, p < 0.001). However, the -positive expression was not significantly associated with any sociodemographic and clinicopathological features of ovarian cancers. CONCLUSIONS: Majority of breast cancer patients with T2DM did not express IGFBP-rP1. In contrast, majority of the ovarian cancer patients with T2DM expressed IGFBP-rP1.

Relapse of B-cell acute lymphoblastic leukaemia presenting as right aural polyp with facial and mandibular nerves palsy.

A patient presenting with an ear polyp is a common finding in otorhinolaryngology practice. The common causes include chronic otitis media and cholesteatoma. We report an adult female patient with a history of acute leukaemia presenting with chronic otitis media symptoms and right ear polyp. She was subsequently diagnosed as relapse of B-cell acute lymphoblastic leukaemia based on histopathological examination. The presentation may be similar to an inflammatory pathology of the middle ear, making it misleading.

Genetic Modifiers of Fetal Haemoglobin (HbF) and Phenotypic Severity in ß-Thalassemia Patients.

BACKGROUND: The phenotypic severity of ß-thalassemia is highly modulated by three genetic modifiers: ß-globin (HBB) mutations, co-inheritance of α-thalassemia and polymorphisms in the genes associated with fetal haemoglobin (HbF) production. This study was aimed to evaluate the effect of HbF related polymorphisms mainly in the HBB cluster, BCL11A (B-cell CLL/lymphoma 11A) and HBS1L-MYB (HBS1-like translational GTPase-MYB protooncogene, transcription factor) with regards to clinical severity. METHODS: A total of 149 patients were included in the study. HBA and HBB mutations were characterised using multiplex PCR, Sanger sequencing and multiplex ligationdependent probe amplification. In addition, 35 HbF polymorphisms were genotyped using mass spectrometry and PCR-restriction fragment length polymorphism (PCRRFLP). The genotype-phenotype association was analysed using SPSS version 22. RESULTS: Twenty-one HBB mutations were identified in the study population. Patients with HBB mutations had heterogeneous phenotypic severity due to the presence of other secondary modifiers. Co-inheritance of α-thalassemia (n = 12) alleviated disease severity of ß-thalassemia. In addition, three polymorphisms (HBS1LMYB, rs4895441 [P = 0.008, odds ratio (OR) = 0.38 (0.18, 0.78)], rs9376092 [P = 0.030, OR = 0.36 (0.14, 0.90)]; and olfactory receptor [OR51B2] rs6578605 [P = 0.018, OR = 0.52 (0.31, 0.89)]) were associated with phenotypic severity. Secondary analysis of the association between single-nucleotide polymorphisms with HbF levels revealed three nominally significant SNPs: rs6934903, rs9376095 and rs9494149 in HBS1L-MYB. CONCLUSION: This study revealed 3 types of HbF polymorphisms that play an important role in ameliorating disease severity of ß-thalassemia patients which may be useful as a predictive marker in clinical management.

Lupus masquerading as CAPD peritonitis.

Abdominal serositis and mesenteric vasculitis are complications of SLE. We report a case of SLE presenting as abdominal pain in a CAPD patient. Lupus serositis/mesenteric vasculitis should be considered in the differential diagnosis of a CAPD patient with SLE who presents with abdominal pain but benign cell counts and cultures. This is especially important since untreated mesenteric vasculitis can lead to bowel perforation and death.

The dental identification of victims of an aircraft accident in Malaysia.

On 15 September 1995 a Malaysian Airlines (MAS) Fokker 50 plane plunged while descending and crashed, killing thirty-four passengers aboard. The dental disaster victim identification team comprising dental surgeons from the Dental faculty, University of Malaya; Ministry of Health, Sabah; and the Malaysian Defence Forces played an active role in the identification process. Most of the bodies were badly mutilated, disfigured and severely incinerated. Problems were encountered due to inadequate facilities and space at the mortuary. Difficulties were also encountered during the procurement and deciphering of information from dental records. This disaster has however created greater awareness amongst Malaysians of the important role of forensic odontology in mass disasters.

Brown fat uptake of 18F-FDG on dual time point PET/CT imaging.

The aim of this report was to assess the changes in the 18F-fluorodeoxyglucose (18F-FDG) uptake of brown fats on integrated positron emission tomography/computed tomography (PET/CT) imaging. The patient presented with an enlargement of the neck lymph nodes, and was suspicious for tuberculous lymphadenitis. A whole body PET/CT imaging was performed, followed by a delayed imaging of the neck and thoracic regions. A visually increased 18F-FDG uptake was taken as a positive finding. A semi-quantitative evaluation was performed using a maximum standardised uptake value (SUVmax), with a cut-off value above 2.5. There were a number of 18F-FDG avid activity areas seen at the supraclavicular, mediastinal, paravertebral and perirenal regions. These are in keeping with the physiological 18F-FDG uptake in brown fat. The differences in SUVmax between the two images ranged from -20 percent to +20 percent. Based on our observations, dual time point imaging may not be a reliable method for assessing the 18F-FDG uptake of brown fat.

PET-CT as an effective imaging modality in the staging and follow-up of post-transplant lymphoproliferative disorder following solid organ transplantation.

INTRODUCTION: To establish the role of positron-emission tomography (PET)-computed tomography (CT) in post-transplant lymphoproliferative disorder (PTLD) patients, compared to conventional imaging (ultrasonography/CT/magnetic resonance imaging) in relation to its accuracy, sensitivity and specificity. METHODS: 30 patients (26 males and 4 females), with a median age of 49.5 (range 18-74) years, were retrospectively evaluated. In 29 cases, the diagnosis was confirmed by histopathology. Malignant lymphoma was detected in 20 cases, polymorphic lymphoproliferative disorder in six cases, multiple myeloma in two cases and Hodgkin's disease in one case. A total of 49 PET-CTs (13 studies for staging at diagnosis and 36 studies at follow-up as assessment post-therapy) were compared to conventional imaging. Imaging results in accordance with disease status were assessed at a median follow-up of 17.8 (range 1.5-42.2) months post-PET-CT. RESULTS: In 41 of 49 examinations performed for staging and on follow-up, PET-CT and conventional imaging findings were concordant. Compared to conventional imaging, PET-CT showed comparable sensitivity (75 percent vs. 83 percent), similar specificity (100 percent in both modalities) and comparable accuracy (77 percent vs. 85 percent) during staging at diagnosis. PET-CT was found to be superior to conventional imaging modalities at follow-up, with greater sensitivity (100 percent vs. 81 percent), specificity (80 percent vs. 100 percent) and accuracy (97 percent vs. 83 percent). CONCLUSION: PET-CT is an accurate diagnostic tool for staging and for the follow-up of PTLD patients. It represents a good alternative imaging method to avoid contrast-related nephrotoxicity in patients who often develop impaired renal function secondary to chronic immunosuppressive therapy. However, further studies are recommended before considering PET-CT as a routine diagnostic tool in PTLD.

18F-FDG positron emission tomography/computed tomography and the "underground map" appearance in imaging Horton's arteritis.

A majority of the clinical use of positron emission tomography (PET)-computed tomography (CT) is related to cancer management. Its application in evaluating inflammatory diseases and pyrexia of unknown origin is becoming popular. We reviewed the fluorine-18-fluorodeoxyglucose PET-CT findings of an 80-year-old woman with nonspecific clinical presentation consisting of generalised malaise, moderately high fever and weight loss. Prior CT and magnetic resonance imaging were not helpful in providing a clinical diagnosis. The diagnosis was Horton's arteritis, and the patient responded well to high-dose steroids.

A rare primary malignant vaginal melanoma detected by 18 [F]-FDG PET/CT imaging

A malignant melanoma in the vagina is a rare entity, for which there is little evidence-based literature for guiding clinicians to understand the importance of disease staging via noninvasive imaging strategy. Conventional imaging techniques i.e. computed tomography (CT) may be suboptimal in evaluating a small volume tumour, which may lead to inaccurate staging of a loco-regional tumour. A multimodality imaging exploiting a glucose biomarker, i.e. 18 [F]FDG PET/CT, is being increasingly used for tumour staging, particularly when the other imaging modalities have failed, although its precise role in the T- staging remains to be defined. This paper reports a 51-year-old lady who presented with pervaginal bleeding for 3 months. She has no constitutional symptoms or history of bleeding tendency. Examination of the vagina revealed blood clots without discernible mucosal abnormalities. CT abdomen revealed no perceptible abnormalities aside for an asymmetry of the anterior vaginal fornices. A 18[F]-FDG PET/CT showed a focus of an FDG-avid lesion embedded in the right anterior vaginal fornix without lymphatic or distant metastasis. Histological sections of the tumour lesion confirmed the diagnosis of a primary malignant vaginal melanoma. This report documents the importance of FDG-PET/CT in delineating a small volume tumour which is imperceptible on CT imaging.

Plexiform granular cell odontogenic tumor: unicystic variant.

Plexiform granular cell odontogenic tumor of the mandible has recently been described. The cardinal histopathologic feature, as its name suggests, is a monophasic plexiform pattern of granular cells; the principal tumor in the differential diagnosis is granular cell ameloblastoma. Unlike the two previously reported cases of plexiform granular cell odontogenic tumor, which occurred as solid tumors in elderly men, the lesion reported here is a unicystic variant occurring in a middle-aged woman.

Factors influencing the in-vitro sensitivity of Ureaplasma urealyticum to tetracyclines.

The sensitivity of 23 strains of Ureaplasma urealyticum to doxycycline was measured by a metabolism-inhibition technique. The minimal inhibitory concentrations were not influenced by using, as inocula in the tests, organisms either directly from the patient or after culture, providing that the numbers of organisms in the inocula were about the same in both. All the strains were sensitive to doxycycline but an apparent increase in the resistance of the cultured organisms occurred when the number, expressed as colour-changing units (ccu), in the inoculum was 10(5) or more/ml. Tests may be undertaken on cultured organisms of U. urealyticum but it is recommended that a standard inoculum of 10(3)-10(4) ccu/ml should be used.

Infection of the epididymis by Ureaplasma urealyticum.

Ureaplasma urealyticum organisms (ureaplasmas) were isolated from the urethra and epididymal aspirate of a man aged 24 who had acute right sided epididymitis. No other microorganisms were detected, and he had no chlamydial antibody response. A fourfold antibody response to the epididymal ureaplasma isolate was detected by two methods, however, and the patient responded clinically to doxycycline, to which the ureaplasmal isolates were susceptible in vitro. These findings suggest that U urealyticum had a causative role.

Synthesis and Antifungal Activity of Some Organotin(IV) Carboxylates.

Six diorganotin(IV) carboxylates prepared by reacting diorganotin(IV) dichlorides with the respective silver carboxylate have been tested for antifungal activity against Aspergillus. niger, Aspergilluus flavus and Pencillium. citrinum in Sabourand dextrose broth. The compounds generally exhibit greater fungitoxicity than the diorganotin(IV) dichlorides and the carboxylic acids from which they were synthesized. In keeping with the generally accepted notion that the organotin moiety plays an important role in deciding the antifungal activity of an organotin compound, the diphenyltin(IV) compounds were more active than their di-n-butyltin(IV) analogues. However, the order of increasing fungitoxicity of the compounds parallels that of the uncomplexed carboxylic acids. The implications of the results are discussed.