Harris Abdullah Ngow

Clinical relevance of VKORC1 (G‐1639A and C1173T) and CYP2C9*3 among patients on warfarin

What is known and Objectives:  Testing for cytochrome P450‐2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles is recommended by the FDA for dosing of warfarin. However, dose prediction models derived from data obtained in one population may not be applicable to another. We therefore studied the impact of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dose requirement in Malaysia.

Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients.

Background: Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine catabolic enzyme involved in the initial and rate-limiting step of the catabolic pathway of toxic metabolites of 5-fluorouracil (5-FU). Several studies have reported that deficiency of DPD and polymorphisms of its gene are related to 5-FU toxicities and death. Association between serum concentration of 5-FU and its related toxicity has also been previously demonstrated. Hence, this study aims to understand the role of DPYD variants in serum level of 5-FU and the risk of developing toxicity to prevent adverse reactions and maximize therapy outcome for personalized medicine. Methods: A total of 26 patients comprising 3 different ethnic groups (Malay, Chinese, and Indian) diagnosed with colorectal cancer and treated with 5-FU chemotherapy regimen from local hospital were recruited. Polymerase chain reaction and denaturing high-performance liquid chromatography methods were developed to screen polymorphisms of DPYD gene. High-performance liquid chromatography–based quantification assay was developed to measure the serum concentration of 5-FU among these patients. Results: Patients with DPYD genotypes of deficient enzyme activity had higher median serum levels of 5-FU compared with normal DPD group (median, 11.51 mcg/mL; 95% confidence interval, 10.18–16.11 versus median, 0.83 mcg/mL; 95% confidence interval, 0.55–5.90, Mann–Whitney U test; P = 0.010). Patients with neutropenia (n = 11) had significantly higher serum concentrations of 5-FU as compared with those with normal white blood cell count (n = 15) (Mann–Whitney U test, P = 0.031). Combined regression analysis showed that the predictive power of DPYD*5 (rs1801159) and 1896 T>C (rs17376848) for serum concentrations of 5-FU in the studied group was 36.6% (P = 0.04). Similarly, DPYD*5 and 1896 T>C accounted for 29.9% of the occurrences of neutropenia (analysis of variance, P = 0.017). Conclusions: This study revealed that DPYD*5 (rs1801159) and 1896 T>C (rs17376848) are potentially useful predictive markers of patients’ responses to 5-FU chemotherapy. Pharmacogenotyping is therefore recommended to guide dosing of 5-FU and prevent neutropenia.

Role of pharmacodiagnostic of CYP2C9 variants in the optimization of warfarin therapy in Malaysia: a 6-month follow-up study

1. A retrospective study was conducted to explore the importance of CYP2C9 genotyping for the initiation and maintenance therapy of warfarin in clinical practice. A total of 191 patients on warfarin therapy in a local hospital were recruited after written informed consent. Their medical records were reviewed and no intervention of warfarin dose was performed. 2. A total of 5 ml of blood were taken from each subject for DNA extraction and identification of *1, *2, *3 and *4 CYP2C9 alleles, using a nested-allele-specific-multiplex-polymerase chain reaction (PCR). Half the patients were Malays and the remaining were Chinese. 3. Two genotypes were detected; 93.2% had CYP2C9*1/*1 and 6.8% were CYP2C9*1/* 3. Warfarin doses were higher in patients with CYP2C9*1/*1. Patients with the *1/* 3 genotype experienced a higher rate of serious and life-threatening bleeding; 15.4 versus 6.2 per 100 patients per 6 months. 4. The observation clearly highlights the inadequacy of the current dosing regimens and the need to move toward a more individualized approach to warfarin therapy. Prospective clinical studies are now being conducted to assess dosing algorithms that incorporate the contribution of the genotype to allow the individualization of warfarin dose.

Right atrial tuberculoma: a diagnosis too late.

Solitary intra-cardiac cavity tuberculoma is extremely rare and often only diagnosed during a post-mortem. We report a case of right atrial tuberculoma causing right atrial outflow tract obstruction in an immune-compromised man. The diagnosis of cardiac tuberculoma was made through the detection of mycobacterium tuberculosis DNA by tuberculosis-polymerase chain reaction in the pericardial fluid. The patient succumbed five days after admission but an autopsy was refused by his family.

Bacillus cereus endocarditis in native aortic valve

Bacillus cereus endocarditis is rare. It has been implicated in immunocompromised individuals, especially in intravenous drug users as well as in those with a cardiac prosthesis. The patient was a 31-year-old ex-intravenous drug addict with a past history of staphylococcal pulmonary valve endocarditis, who presented with symptoms of decompensated cardiac failure. Echocardiography showed severe aortic regurgitation with an oscillating vegetation seen on the right coronary cusp of the aortic valve. The blood cultures grew Bacilluscereus. We report this as a rare case of Bacillus cereus endocarditis affecting a native aortic valve.

Cardiac mass in a patient with sigmoid adenocarcinoma : a metastasis? : case report - online article

Cardiac metastasis from a bowel malignancy seldom occurs and there is a limited number of case reports published on this subject. Although colorectal cancer is the third commonest malignancy in Malaysia, the incidence of cardiac metastasis has never been reported. We report a case of an elderly man with recently diagnosed adenocarcinoma of the sigmoid colon, who presented with congestive cardiac failure secondary to mechanical obstruction by a right atrial mass. The intractable shock led to his sudden death before any intervention could be planned. If an intra-cavity cardiac mass is detected in a patient with an underlying metastatic malignancy, cardiac metastasis should be suspected. However, primary cardiac tumour or thrombus could also be the differential diagnosis. In our case, the definitive cardiac pathology remained unsolved as an autopsy was refused.

Isolated right atrium tuberculoma causing complete heart block

Myocardial tuberculosis was rare even in the era before effective anti-tuberculous chemotherapy was available. It is becoming even rarer with improved anti-tuberculous treatment. It was usually an incidental finding during necropsy. In a case series reported by Custer and Charr,1 they reviewed more than 14 000 deaths due to tuberculosis and found only 64 cases (0.5%) of tuberculosis involving the heart. In most cases the infection is either part of miliary tuberculosis or an extension of pericardial involvement. In the absence of these, it is presumed to be due to haematogenous or lymphatic dissemination.2 There is almost always a tuberculous focus elsewhere in the body; single isolated tuberculoma are very rare indeed. Complete heart block as a complication of myocardial tuberculosis has been described only rarely in medical literature. Thus far, only a limited number of cases have been reported,3–7 and none of these was due to a tuberculoma in the right atrium. A 35-year-old immunocompromised man was admitted with progressively worsening heart failure of 1-month duration. He had been diagnosed 3 months previously as having HIV and hepatitis C infection, but had defaulted on follow-up since then. History of note includes poor appetite, weight loss and intermittent low-grade fever for 1 week before admission. There was progressive worsening of pedal oedema and reduced effort tolerance during this period. He was an active intravenous drug user, but claimed that he had quit a year ago. He denied any syncope or loss of consciousness. He had previously been well and denied any history of contact with tuberculosis. …

Atrial myxoma: histological confirmation.

Atrial myxoma is uncommon, with an overall prevalence in the developed world of 0.02%.1 It is often undiagnosed until complications such as cardiac death or stroke occur. The incidence of primitive tumours of the heart at autopsy is between 0.0017% and 0.03%, and of these 50% are myxomas.1 2 We describe a case of left atrial myxoma which was only diagnosed after histopathological examination. A 69-year-old woman with chronic hypertension and diabetes presented with cardiorespiratory arrest. She was well prior to the acute presentation. She was not a smoker and had no symptoms of malignancy. The family history was unremarkable. She appeared neither cachexic nor cushingoid. She did not have any features suggestive of Carneys complex. She was electively ventilated and successfully resuscitated. The praecordium examination was normal with absence of cardiac murmur or ‘plop.’ There was generalised crepitation in the lungs. The neurological examination was normal without any localising signs. Her complete blood count showed mild lymphocytosis. …

An unsual finding of brain magnetic resonance imaging in a hypertensive patient

Brain edema in patients with hypertensive encephalopathy frequently affects the parietooccipital white matter. Hypertensive encephalopathy is thus included as a differential diagnosis in reversible posterior leukoencephalopathy syndrome. Diffuse white matter involvement rarely occurs. We report a 41-year old woman with hypertensive encephalopathy with diffuse and non-enhancing white matter hyper-intensities throughout the whole brain on magnetic resonance imaging (MRI). These hyperintensities spared the grey matter on T2-weighted and FLAIR sequence. These unusual finding on brain MRI was attributed to severe vasogenic cerebral edema resulting from accelerated hypertension.