Background Pharmacogenetic-based dosing support tools have been developed to personalize antidepr... more Background Pharmacogenetic-based dosing support tools have been developed to personalize antidepressantprescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. Objective To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. Materials and methods A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n = 119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Results Among remitters (n = 95), there was a strong concordance (Kendall's τ-b = 0.84, P = 0.0001; Cohen's κ = 0.82, P = 0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Conclusion Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing. Pharmacogenetics and Genomics
Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as... more Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as an adjunct to monitoring patients taking thiopurine drugs. This special report describes the clinical implications for this type of testing for patients with inflammatory bowel disease who are taking thiopurine drugs. A total of 10% of patients were found to be intermediate metabolizers and the mean dosage (in mg/kg equivalent) was lower in intermediate metabolizers than extensive metabolizers. The metabolite levels did not correlate with scores measuring clinical severity but levels of 6-methylmercaptopurine were related to the dosage of the drugs. Despite considerable study of thiopurine methyltransferase testing in the literature, it is still not widely used in many geographical areas. This study adds to the evidence about using such testing as well as expanding the role of simultaneously measuring thiopurine metabolites. Further work is planned to evaluate the uptake when such testi...
Purpose Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated w... more Purpose Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated with potential safety concerns. An efficacious but less toxic balloon coating may reduce these outcomes. We evaluated a novel DEBc, Epi-Solve, coated with metacept-3 (MCT-3), a member of the histone deacetylase inhibitor (HDACi) class of epigenetic agents, in a large animal model of neointimal hyperplasia (NIH). Methods Plain balloon angioplasty (PABA) catheters were ultrasonically coated with MCT-3 to generate Epi-Solve DEBc. An ovine model of NIH formation was established utilising partial left common carotid artery (LCA) ligation. Twenty-eight days post neointima (NI) induction, PABA, Epi-Solve or PTX-coated DEBc were deployed at the site of induced NI formation. Twenty-eight days post-intervention, ligated vessels were evaluated for attenuation of NI formation, gene expression profiles and immunohistochemical analysis. Results Epi-Solve DEBc demonstrated attenuation of NIH over no intervention and a trend to inhibition of NIH over PABA. Gene expression analysis and immunohistochemical studies identified significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA. Conclusions Epi-Solve is a novel HDACi-coated DEBc which demonstrates significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA in an ovine model and may afford endothelial protection.
to examine health and cost burden of HPV-related diseases to understand the potential impact of i... more to examine health and cost burden of HPV-related diseases to understand the potential impact of introducing HPV vaccine. OBJECTIVES: We aimed to evaluate the longterm health and cost burden associated with cervical cancer, cervical intraepitherial neoplasia (CIN) and genital warts from health-care provider perspective in Thailand. METHODS: We developed a state-transition Markov model to simulate the epidemiology of stages of cervical cancer, CIN and genital warts in a hypothetical cohort of 100,000 12-year-old girls. Costs included diagnosis and treatment costs of HPV related diseases. Probabilities at each chance node in the model were derived from the Thailand health-care context. RESULTS: The highest incidence of CIN and genital warts was observed among women aged 20-30 years. For cervical cancer, the highest incidence was observed among women aged 45-55 years.
We report a case of varicella-zoster virus (VZV) mye-litis in a woman with relapsing-remitting mu... more We report a case of varicella-zoster virus (VZV) mye-litis in a woman with relapsing-remitting multiplesclerosis(RRMS)receivingnatalizumab,ahumanizedmonoclonal antibody that induces an immunosup-pression localized to the CNS.Case report. A32-year-oldwomanwastreatedwithna-talizumab for highly active RRMS. After the fourth infu-sion, she complained of a right radicular pain in a L5/S1territory.Afewdayslater,theneurologicexaminationdis-closed a distal weakness (3/5 Medical Research Council[MRC]) in the right leg with signs of pyramidal irritationsuggestingaspinalcordrelapse.ThespinalcordMRIdis-closed focal cervical and dorsal T2 hyperintensities and aT2 hypersignal in the conus region with contrastenhancement (figure). A spinal cord relapse was consid-ered. HighdosesofIVmethylprednisolonewereinitiatedfor3days.Twoweekslater,thepatientdeteriorated,withan increase of leg weakness (2/5 MRC) and bladder dys-function. She received another series of IV methylpred-nisolone for 3 days, without improvement. Because ofthis unusualevolution, weperformedalumbar puncture,which revealed a lymphocytic pleocytosis (18 elements),normal proteins, and glycorrhachia. VZV DNA detectedby PCR amplification was positive in CSF. Cytomegalo-virus and herpes simplex virus (HSV) PCR in the CSFwere negative. HIV screeningwasnegative.VZVimmu-noglobulin G in the blood was positive before this acuteepisode (tested in January 2012). No skin rash was notedor reported by the patient. A second spinal cord MRIshowed progression of lesion size, persistent contrastenhancement in the conus region, and new contrast en-hancementsindorsallesions(figure).AcuteVZVmyelitiswas diagnosed. The patient was treated with IV acyclovir10 mg/kg/8 h for 3 weeks and then switched to valacy-clovir, which resulted in a c linical improvement (4/5MRC in right lower limb and recovery of subnormalbladder function but persistent sensory loss in the leftlower limb). CSF at 1 month was normal (4 elements,negative VZV PCR). Spinal cord MRI at 2 months wasclearly improved (figure). Natalizumab was discontinued.Discussion. If cases of HSV encephalitis and meningi-tis have been previously reported,
The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) ... more The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood-brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Singlenucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N ¼ 113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonintransporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P ¼ 0.0001). This equates to a 2.0-(95% confidence interval ¼ 1.5-3.4; Po0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio ¼ 6.69; 95% confidence interval ¼ 1.72-25.9, P ¼ 0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.
Common polymorphisms in the genes encoding CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes have an imp... more Common polymorphisms in the genes encoding CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes have an important role in predicting the occurrence of adverse effects and the efficacy of substrate medications. Drug-induced changes to the enzyme's phenotype, a process called phenoconversion, comprise another important factor contributing to interindividual variability in drug response. To date, there is lack of data on the frequency of these common polymorphisms and phenoconversion in the pan-ethnic Australian population. The aim of this study was to (1) describe allele, genotype and phenotype frequencies for CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes in the pan-ethnic Australian population and (2) evaluate the frequency of actionable pharmacogenomic (PGx) variants and phenoconversion. Frequencies were calculated using the records of 5408 Australian patients (obtained from myDNA's propriety database), who were consecutively tested with the DNAdose PGx test which included the CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. In 2509 patients with listed medications at the time of testing, phenoconversion frequencies were calculated for CYP2D6, CYP2C19 and CYP2C9 enzymes. Allele, genotype and phenotype frequencies in our Australian patients correlated with a Caucasian population. Approximately 96% of patients had at least one actionable PGx variant. A five-fold increase in the frequency of poor metabolisers (PMs) for CYP2D6 and CYP2C19 was predicted by phenoconversion. Our study results indicate a high frequency of actionable PGx variants in our Australian population. With the addition of drug-induced phenoconversion, our results provide further support for the utilisation of PGx testing in clinical practice as another tool assisting prescribers in the application of personalised medicine.
11108 Background: Accurate identification of the primary tumor in cases of cancer of unknown prim... more 11108 Background: Accurate identification of the primary tumor in cases of cancer of unknown primary (CUP) is required for effective treatment selection and improved patient outcomes. Here we present the development and clinical validation of a histology-guided gene expression classifier. Methods: RNA from 450 formalin-fixed paraffin embedded tissue samples of known origin comprising 18 tumor groups were used to train and develop the classifier. Whole-genome expression data was collected from each sample using Illumina DASL bead-based arrays. A hierarchical tumor classifier utilizing both conventional histopathology and gene expression data was developed using a binary support vector machine, together with recursive feature elimination. The classifier was then validated on an independent cohort of 94 tumors of known origin and 58 CUP samples. Results: Based on the validation set of tumors, the classifier demonstrated an accuracy of 89% for the highest predicted tumor class, increasing to 98% for the corre...
Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-pres... more Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Among remitters (n=95), there was a strong concordance (Kendall's τ-b=0.84, P=0.0001; Cohen's κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Findings prov...
Aim Carcinomas of unknown primary (CUP) account for 3–5% of all malignancies. Although the progno... more Aim Carcinomas of unknown primary (CUP) account for 3–5% of all malignancies. Although the prognosis for patients with CUP is poor, identifying the primary site of the tumour can allow for more specific treatment selection and may prolong survival. We aimed to develop a gene expression based assay to determine the origin of metastatic carcinomas of unknown primary. Methods RNA was extracted from formalin fixed, paraffin embedded (FFPE) samples containing known metastatic tumours of various classes. Whole genome expression analysis was performed and a binary support vector machine was used as the classification method. Results 405 tumours of 16 classes were analysed. Following a cross validation strategy, we demonstrated an assay accuracy of 82% (93% within top three primary site predictions). Accuracies for individual tumour classes ranged from 72% to 93% for single site predictions, and between 83% and 100% for top three primary predictions. Conclusion Although further assay refinement and validation using an independent test cohort of known metastatic and CUP tumours is required, our preliminary data suggest that a gene expression-based diagnostic could aid in identifying the tumour of origin in patients with CUP.
Clinical Psychopharmacology and Neuroscience, 2015
Objective: Previous studies suggest child abuse and serotonergic polymorphism influence depressio... more Objective: Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and antidepressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. Methods: Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. Results: No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 ＜26; n=26) remitted (p＜0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85-514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. Conclusion: The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.
P-glycoprotein Polymorphisms Predict Antidepressant Dose to Remit. Original hypothesis and empiri... more P-glycoprotein Polymorphisms Predict Antidepressant Dose to Remit. Original hypothesis and empirical study by: Dr Ajeet Bhagat Singh (DOB 24-01-1973) 'Singh Patent 1' Patent Application Number: 2012201179 Abstract The P-glycoprotein (Pgp) transporter is a key component of the blood brain barrier (BBB). Many antidepressants are subject to Pgp efflux. Functional polymorphisms of the gene encoding Pgp may influence CNS bioavailability of antidepressants subject to efflux. Single nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of the Pgp gene have been associated with efflux pump efficiency. This may help explain inter-individual variation in antidepressant dose needed to remit. In this study 113 patients with DSM-IV major depressive disorder (MDD) and of either Caucasian or Chinese heritage where treated with escitalopram (ESCIT) or venlafaxine (VEN) in a naturalistic setting over 8 weeks. 17-item Hamilton Depression Rating Scale (HDRS) scale was assessed serially and blind to genotype. SNP rs1045642(C3435T) of the Pgp gene along with two SNPs previously reported to be in linkage disequilibrium (LD) with it (rs2032582 and rsl 128503) where genotyped. Hepatic P450 2D6 and 2C19 metaboliser status and 5-HTTLPR genotype were controlled for along with demographic and clinical factors. 12.5% of VEN treated subjects with CC allele at rs1045642(C3435T) remitted compared to 73.3% for TT subjects odds ratio (OR) = 6.69 (p=0.006). This was significant with Bonferroni correction. ESCIT average dose needed to remit was 24mg for subjects carrying the TC allele and only 11mg for subjects carrying the TT allele (p = 0.0001) at rs1045642(C3435T). These are these first known data indicating antidepressant dose needed to remit can be predicted by a Pgp SNP. This has potential clinical implications for initial dose selection and sooner remission from MDD.
As the available in vitro and in vivo data suggest that interleukin (IL)-4 and IL-10 have immunos... more As the available in vitro and in vivo data suggest that interleukin (IL)-4 and IL-10 have immunosuppressive activity, our hypothesis was that serum IL-4 and IL-10 levels would correlate inversely with parameters of inflammation in patients with inflalmnatory arthritis. IL-4 was detected in the serum of 12 out of 140 patients with rheumatoid arthritis (RA), which was increased compared to the proportion found with patients with osteoarthritis (OA; P < 0.02). In addition, IL-4 was detected in the serum of 2 of 19 patients with systemic lupus erythematosus (SLE), 2 of 24 patients with psoriatic arthritis and 1 of 5 patients with Behget's syndrome. No IL-4 was detected in patients with the following conditions: OA (58 patients), gout (17 patients), ankylosing spondylitis (6 patients), Reiter's syndrome (6 patients), polymyalgia rheumatica (6 patients), temporal arteritis (5 patients) and scleroderma (3 patients). No IL-10 was detected in any of the sera tested. We discuss the possible relevance of these results to the regulation of the immune response evident in inflammatory arthritis.
This study aimed to ascertain the ability of the microbiology laboratory to detect and identify c... more This study aimed to ascertain the ability of the microbiology laboratory to detect and identify catalase-negative Grampositive cocci with particular reference to vancomycinresistant enterococci (VRE). Twenty-seven reference strains and 42 prospectively collected catalase-negative Grampositive cocci were screened by agar dilution breakpoint susceptibility and linked biochemical methods in routine use. Ability to speciate organisms was then compared using: (i) a multiplex polymerase chain reaction, designed to detect gene sequences specific to Enterococcus faecalis and E. faecium, and vancomycin resistance (van) genes; (ii) a commercial ªAPI 20 strepº (iii) an algorithm using individual tests from a commercial API 20 strep strip; and (iv) the same algorithm utilising traditional phenotyping methods. All vancomycin resistant catalase-negative Gram-positive cocci were detected by an agar dilution screening plate containing 4 mg/ml of vancomycin. Polymerase chain reaction (PCR) detected all enterococci with van genes, speciated all vancomycin-sensitive E. faecalis and E. faecium isolates and excluded non-enterococcal vancomycin-resistant catalase-negative Gram-positive cocci. Algorithm-based methods speciated 41 of the 42 study isolates (98%). The API 20 strep correctly identified only 25 (60%) of these organisms, 38 of which were vancomycin-sensitive E. faecalis. VRE are detected by current screening methods for vancomycin-resistant catalase-negative Gram-positive cocci in this laboratory. API 20 strep, currently used to speciate catalase-negative Gram-positive cocci, is less reliable and should be replaced. Algorithm-based phenotyping by either method tested is more reliable for speciation than API 20 strep in its recommended form. Compared to the other methods tested, PCR is a rapid, accurate and inexpensive method of detecting and speciating vancomycin-resistant enterococci and it provides important extra information impacting on clinical therapy and infection control.
The clinical management of patients with cancer of unknown primary (CUP) is hampered by the absen... more The clinical management of patients with cancer of unknown primary (CUP) is hampered by the absence of a definitive site of origin. We explored the utility of massively-parallel (next-generation) sequencing for the diagnosis of a primary site of origin and for the identification of novel treatment options. DNA enrichment by hybridisation capture of 701 genes of clinical and/or biological importance, followed by massively-parallel sequencing, was performed on 16 CUP patients who had defied attempts to identify a likely site of origin. We obtained high quality data from both fresh-frozen and formalin-fixed paraffin-embedded samples, demonstrating accessibility to routine diagnostic material. DNA copy number obtained by massively-parallel sequencing was comparable to that obtained using oligonucleotide microarrays or quantitatively hybridized fluorescently tagged oligonucleotides. Sequencing to an average depth of 458-fold enabled detection of somatically acquired single nucleotide mutations, insertions, deletions and copy number changes, and measurement of allelic frequency. Common cancer causing mutations were found in all cancers. Mutation profiling revealed therapeutic gene targets and pathways in 12/16 cases, providing novel treatment options. The presence of driver mutations that are enriched in certain known tumour types, together with mutational signatures indicative of exposure to sunlight or smoking, added to clinical, pathological, and molecular indicators of likely tissue of origin. Massively-parallel DNA sequencing Accepted Article This article is protected by copyright. All rights reserved. can therefore provide comprehensive mutation, DNA copy number and mutational signature data that is of significant clinical value for a majority of CUP patients, providing both cumulative evidence for the diagnosis of primary site and options for future treatment.
Background Pharmacogenetic-based dosing support tools have been developed to personalize antidepr... more Background Pharmacogenetic-based dosing support tools have been developed to personalize antidepressantprescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. Objective To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. Materials and methods A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n = 119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Results Among remitters (n = 95), there was a strong concordance (Kendall's τ-b = 0.84, P = 0.0001; Cohen's κ = 0.82, P = 0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Conclusion Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing. Pharmacogenetics and Genomics
Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as... more Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as an adjunct to monitoring patients taking thiopurine drugs. This special report describes the clinical implications for this type of testing for patients with inflammatory bowel disease who are taking thiopurine drugs. A total of 10% of patients were found to be intermediate metabolizers and the mean dosage (in mg/kg equivalent) was lower in intermediate metabolizers than extensive metabolizers. The metabolite levels did not correlate with scores measuring clinical severity but levels of 6-methylmercaptopurine were related to the dosage of the drugs. Despite considerable study of thiopurine methyltransferase testing in the literature, it is still not widely used in many geographical areas. This study adds to the evidence about using such testing as well as expanding the role of simultaneously measuring thiopurine metabolites. Further work is planned to evaluate the uptake when such testi...
Purpose Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated w... more Purpose Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated with potential safety concerns. An efficacious but less toxic balloon coating may reduce these outcomes. We evaluated a novel DEBc, Epi-Solve, coated with metacept-3 (MCT-3), a member of the histone deacetylase inhibitor (HDACi) class of epigenetic agents, in a large animal model of neointimal hyperplasia (NIH). Methods Plain balloon angioplasty (PABA) catheters were ultrasonically coated with MCT-3 to generate Epi-Solve DEBc. An ovine model of NIH formation was established utilising partial left common carotid artery (LCA) ligation. Twenty-eight days post neointima (NI) induction, PABA, Epi-Solve or PTX-coated DEBc were deployed at the site of induced NI formation. Twenty-eight days post-intervention, ligated vessels were evaluated for attenuation of NI formation, gene expression profiles and immunohistochemical analysis. Results Epi-Solve DEBc demonstrated attenuation of NIH over no intervention and a trend to inhibition of NIH over PABA. Gene expression analysis and immunohistochemical studies identified significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA. Conclusions Epi-Solve is a novel HDACi-coated DEBc which demonstrates significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA in an ovine model and may afford endothelial protection.
to examine health and cost burden of HPV-related diseases to understand the potential impact of i... more to examine health and cost burden of HPV-related diseases to understand the potential impact of introducing HPV vaccine. OBJECTIVES: We aimed to evaluate the longterm health and cost burden associated with cervical cancer, cervical intraepitherial neoplasia (CIN) and genital warts from health-care provider perspective in Thailand. METHODS: We developed a state-transition Markov model to simulate the epidemiology of stages of cervical cancer, CIN and genital warts in a hypothetical cohort of 100,000 12-year-old girls. Costs included diagnosis and treatment costs of HPV related diseases. Probabilities at each chance node in the model were derived from the Thailand health-care context. RESULTS: The highest incidence of CIN and genital warts was observed among women aged 20-30 years. For cervical cancer, the highest incidence was observed among women aged 45-55 years.
We report a case of varicella-zoster virus (VZV) mye-litis in a woman with relapsing-remitting mu... more We report a case of varicella-zoster virus (VZV) mye-litis in a woman with relapsing-remitting multiplesclerosis(RRMS)receivingnatalizumab,ahumanizedmonoclonal antibody that induces an immunosup-pression localized to the CNS.Case report. A32-year-oldwomanwastreatedwithna-talizumab for highly active RRMS. After the fourth infu-sion, she complained of a right radicular pain in a L5/S1territory.Afewdayslater,theneurologicexaminationdis-closed a distal weakness (3/5 Medical Research Council[MRC]) in the right leg with signs of pyramidal irritationsuggestingaspinalcordrelapse.ThespinalcordMRIdis-closed focal cervical and dorsal T2 hyperintensities and aT2 hypersignal in the conus region with contrastenhancement (figure). A spinal cord relapse was consid-ered. HighdosesofIVmethylprednisolonewereinitiatedfor3days.Twoweekslater,thepatientdeteriorated,withan increase of leg weakness (2/5 MRC) and bladder dys-function. She received another series of IV methylpred-nisolone for 3 days, without improvement. Because ofthis unusualevolution, weperformedalumbar puncture,which revealed a lymphocytic pleocytosis (18 elements),normal proteins, and glycorrhachia. VZV DNA detectedby PCR amplification was positive in CSF. Cytomegalo-virus and herpes simplex virus (HSV) PCR in the CSFwere negative. HIV screeningwasnegative.VZVimmu-noglobulin G in the blood was positive before this acuteepisode (tested in January 2012). No skin rash was notedor reported by the patient. A second spinal cord MRIshowed progression of lesion size, persistent contrastenhancement in the conus region, and new contrast en-hancementsindorsallesions(figure).AcuteVZVmyelitiswas diagnosed. The patient was treated with IV acyclovir10 mg/kg/8 h for 3 weeks and then switched to valacy-clovir, which resulted in a c linical improvement (4/5MRC in right lower limb and recovery of subnormalbladder function but persistent sensory loss in the leftlower limb). CSF at 1 month was normal (4 elements,negative VZV PCR). Spinal cord MRI at 2 months wasclearly improved (figure). Natalizumab was discontinued.Discussion. If cases of HSV encephalitis and meningi-tis have been previously reported,
The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) ... more The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood-brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Singlenucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N ¼ 113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonintransporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P ¼ 0.0001). This equates to a 2.0-(95% confidence interval ¼ 1.5-3.4; Po0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio ¼ 6.69; 95% confidence interval ¼ 1.72-25.9, P ¼ 0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.
Common polymorphisms in the genes encoding CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes have an imp... more Common polymorphisms in the genes encoding CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes have an important role in predicting the occurrence of adverse effects and the efficacy of substrate medications. Drug-induced changes to the enzyme's phenotype, a process called phenoconversion, comprise another important factor contributing to interindividual variability in drug response. To date, there is lack of data on the frequency of these common polymorphisms and phenoconversion in the pan-ethnic Australian population. The aim of this study was to (1) describe allele, genotype and phenotype frequencies for CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes in the pan-ethnic Australian population and (2) evaluate the frequency of actionable pharmacogenomic (PGx) variants and phenoconversion. Frequencies were calculated using the records of 5408 Australian patients (obtained from myDNA's propriety database), who were consecutively tested with the DNAdose PGx test which included the CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. In 2509 patients with listed medications at the time of testing, phenoconversion frequencies were calculated for CYP2D6, CYP2C19 and CYP2C9 enzymes. Allele, genotype and phenotype frequencies in our Australian patients correlated with a Caucasian population. Approximately 96% of patients had at least one actionable PGx variant. A five-fold increase in the frequency of poor metabolisers (PMs) for CYP2D6 and CYP2C19 was predicted by phenoconversion. Our study results indicate a high frequency of actionable PGx variants in our Australian population. With the addition of drug-induced phenoconversion, our results provide further support for the utilisation of PGx testing in clinical practice as another tool assisting prescribers in the application of personalised medicine.
11108 Background: Accurate identification of the primary tumor in cases of cancer of unknown prim... more 11108 Background: Accurate identification of the primary tumor in cases of cancer of unknown primary (CUP) is required for effective treatment selection and improved patient outcomes. Here we present the development and clinical validation of a histology-guided gene expression classifier. Methods: RNA from 450 formalin-fixed paraffin embedded tissue samples of known origin comprising 18 tumor groups were used to train and develop the classifier. Whole-genome expression data was collected from each sample using Illumina DASL bead-based arrays. A hierarchical tumor classifier utilizing both conventional histopathology and gene expression data was developed using a binary support vector machine, together with recursive feature elimination. The classifier was then validated on an independent cohort of 94 tumors of known origin and 58 CUP samples. Results: Based on the validation set of tumors, the classifier demonstrated an accuracy of 89% for the highest predicted tumor class, increasing to 98% for the corre...
Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-pres... more Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Among remitters (n=95), there was a strong concordance (Kendall's τ-b=0.84, P=0.0001; Cohen's κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Findings prov...
Aim Carcinomas of unknown primary (CUP) account for 3–5% of all malignancies. Although the progno... more Aim Carcinomas of unknown primary (CUP) account for 3–5% of all malignancies. Although the prognosis for patients with CUP is poor, identifying the primary site of the tumour can allow for more specific treatment selection and may prolong survival. We aimed to develop a gene expression based assay to determine the origin of metastatic carcinomas of unknown primary. Methods RNA was extracted from formalin fixed, paraffin embedded (FFPE) samples containing known metastatic tumours of various classes. Whole genome expression analysis was performed and a binary support vector machine was used as the classification method. Results 405 tumours of 16 classes were analysed. Following a cross validation strategy, we demonstrated an assay accuracy of 82% (93% within top three primary site predictions). Accuracies for individual tumour classes ranged from 72% to 93% for single site predictions, and between 83% and 100% for top three primary predictions. Conclusion Although further assay refinement and validation using an independent test cohort of known metastatic and CUP tumours is required, our preliminary data suggest that a gene expression-based diagnostic could aid in identifying the tumour of origin in patients with CUP.
Clinical Psychopharmacology and Neuroscience, 2015
Objective: Previous studies suggest child abuse and serotonergic polymorphism influence depressio... more Objective: Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and antidepressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. Methods: Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. Results: No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 ＜26; n=26) remitted (p＜0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85-514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. Conclusion: The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.
P-glycoprotein Polymorphisms Predict Antidepressant Dose to Remit. Original hypothesis and empiri... more P-glycoprotein Polymorphisms Predict Antidepressant Dose to Remit. Original hypothesis and empirical study by: Dr Ajeet Bhagat Singh (DOB 24-01-1973) 'Singh Patent 1' Patent Application Number: 2012201179 Abstract The P-glycoprotein (Pgp) transporter is a key component of the blood brain barrier (BBB). Many antidepressants are subject to Pgp efflux. Functional polymorphisms of the gene encoding Pgp may influence CNS bioavailability of antidepressants subject to efflux. Single nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of the Pgp gene have been associated with efflux pump efficiency. This may help explain inter-individual variation in antidepressant dose needed to remit. In this study 113 patients with DSM-IV major depressive disorder (MDD) and of either Caucasian or Chinese heritage where treated with escitalopram (ESCIT) or venlafaxine (VEN) in a naturalistic setting over 8 weeks. 17-item Hamilton Depression Rating Scale (HDRS) scale was assessed serially and blind to genotype. SNP rs1045642(C3435T) of the Pgp gene along with two SNPs previously reported to be in linkage disequilibrium (LD) with it (rs2032582 and rsl 128503) where genotyped. Hepatic P450 2D6 and 2C19 metaboliser status and 5-HTTLPR genotype were controlled for along with demographic and clinical factors. 12.5% of VEN treated subjects with CC allele at rs1045642(C3435T) remitted compared to 73.3% for TT subjects odds ratio (OR) = 6.69 (p=0.006). This was significant with Bonferroni correction. ESCIT average dose needed to remit was 24mg for subjects carrying the TC allele and only 11mg for subjects carrying the TT allele (p = 0.0001) at rs1045642(C3435T). These are these first known data indicating antidepressant dose needed to remit can be predicted by a Pgp SNP. This has potential clinical implications for initial dose selection and sooner remission from MDD.
As the available in vitro and in vivo data suggest that interleukin (IL)-4 and IL-10 have immunos... more As the available in vitro and in vivo data suggest that interleukin (IL)-4 and IL-10 have immunosuppressive activity, our hypothesis was that serum IL-4 and IL-10 levels would correlate inversely with parameters of inflammation in patients with inflalmnatory arthritis. IL-4 was detected in the serum of 12 out of 140 patients with rheumatoid arthritis (RA), which was increased compared to the proportion found with patients with osteoarthritis (OA; P < 0.02). In addition, IL-4 was detected in the serum of 2 of 19 patients with systemic lupus erythematosus (SLE), 2 of 24 patients with psoriatic arthritis and 1 of 5 patients with Behget's syndrome. No IL-4 was detected in patients with the following conditions: OA (58 patients), gout (17 patients), ankylosing spondylitis (6 patients), Reiter's syndrome (6 patients), polymyalgia rheumatica (6 patients), temporal arteritis (5 patients) and scleroderma (3 patients). No IL-10 was detected in any of the sera tested. We discuss the possible relevance of these results to the regulation of the immune response evident in inflammatory arthritis.
This study aimed to ascertain the ability of the microbiology laboratory to detect and identify c... more This study aimed to ascertain the ability of the microbiology laboratory to detect and identify catalase-negative Grampositive cocci with particular reference to vancomycinresistant enterococci (VRE). Twenty-seven reference strains and 42 prospectively collected catalase-negative Grampositive cocci were screened by agar dilution breakpoint susceptibility and linked biochemical methods in routine use. Ability to speciate organisms was then compared using: (i) a multiplex polymerase chain reaction, designed to detect gene sequences specific to Enterococcus faecalis and E. faecium, and vancomycin resistance (van) genes; (ii) a commercial ªAPI 20 strepº (iii) an algorithm using individual tests from a commercial API 20 strep strip; and (iv) the same algorithm utilising traditional phenotyping methods. All vancomycin resistant catalase-negative Gram-positive cocci were detected by an agar dilution screening plate containing 4 mg/ml of vancomycin. Polymerase chain reaction (PCR) detected all enterococci with van genes, speciated all vancomycin-sensitive E. faecalis and E. faecium isolates and excluded non-enterococcal vancomycin-resistant catalase-negative Gram-positive cocci. Algorithm-based methods speciated 41 of the 42 study isolates (98%). The API 20 strep correctly identified only 25 (60%) of these organisms, 38 of which were vancomycin-sensitive E. faecalis. VRE are detected by current screening methods for vancomycin-resistant catalase-negative Gram-positive cocci in this laboratory. API 20 strep, currently used to speciate catalase-negative Gram-positive cocci, is less reliable and should be replaced. Algorithm-based phenotyping by either method tested is more reliable for speciation than API 20 strep in its recommended form. Compared to the other methods tested, PCR is a rapid, accurate and inexpensive method of detecting and speciating vancomycin-resistant enterococci and it provides important extra information impacting on clinical therapy and infection control.
The clinical management of patients with cancer of unknown primary (CUP) is hampered by the absen... more The clinical management of patients with cancer of unknown primary (CUP) is hampered by the absence of a definitive site of origin. We explored the utility of massively-parallel (next-generation) sequencing for the diagnosis of a primary site of origin and for the identification of novel treatment options. DNA enrichment by hybridisation capture of 701 genes of clinical and/or biological importance, followed by massively-parallel sequencing, was performed on 16 CUP patients who had defied attempts to identify a likely site of origin. We obtained high quality data from both fresh-frozen and formalin-fixed paraffin-embedded samples, demonstrating accessibility to routine diagnostic material. DNA copy number obtained by massively-parallel sequencing was comparable to that obtained using oligonucleotide microarrays or quantitatively hybridized fluorescently tagged oligonucleotides. Sequencing to an average depth of 458-fold enabled detection of somatically acquired single nucleotide mutations, insertions, deletions and copy number changes, and measurement of allelic frequency. Common cancer causing mutations were found in all cancers. Mutation profiling revealed therapeutic gene targets and pathways in 12/16 cases, providing novel treatment options. The presence of driver mutations that are enriched in certain known tumour types, together with mutational signatures indicative of exposure to sunlight or smoking, added to clinical, pathological, and molecular indicators of likely tissue of origin. Massively-parallel DNA sequencing Accepted Article This article is protected by copyright. All rights reserved. can therefore provide comprehensive mutation, DNA copy number and mutational signature data that is of significant clinical value for a majority of CUP patients, providing both cumulative evidence for the diagnosis of primary site and options for future treatment.
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