Cost-effectiveness analysis of the nonavalent human papillomavirus vaccine for the prevention of cervical cancer in Singapore.

BACKGROUND: The nonavalent human papillomavirus (HPV) vaccine has been shown to extend protection against oncogenic HPV types 31/33/45/52/58 (HPV-OV) not covered by the bivalent and quadrivalent HPV vaccines. Besides its clinical benefit, evidence on the economic value of the nonavalent vaccine is required to inform local vaccination strategies and funding decisions. This study evaluated the cost-effectiveness of replacing the bivalent vaccine with the nonavalent vaccine in the national school-based HPV vaccination programme in Singapore. METHODS: An existing age-structured dynamic transmission model coupled with stochastic individual-based simulations was adapted to project the health and economic impact of vaccinating 13-year-old girls with two doses of the nonavalent or bivalent HPV vaccines in Singapore. Direct costs (in Singapore dollars, S$) were obtained from public healthcare institutions in Singapore, while health state utilities were sourced from the literature. Incremental cost-effectiveness ratios (ICERs) were estimated over a lifetime horizon, from a healthcare system perspective. Probabilistic sensitivity analysis was performed to obtain the ICERs and corresponding variations across variable uncertainty. Particularly, this study tested the scenarios of lifelong and 20-year vaccine-induced protection, assumed 96.0% and 22.3% cross-protection against HPV-OV by nonavalent and bivalent vaccines respectively, and fixed vaccine prices per dose at S$188 for nonavalent and S$61.50 for bivalent vaccines. RESULTS: Compared with the bivalent vaccine, the use of the nonavalent vaccine was associated with an ICER of S$61,629 per quality-adjusted life year gained in the base case. The result was robust across a range of plausible input values, and to assumptions regarding the duration of vaccine protection. CONCLUSION: Given the high ICER, the nonavalent vaccine is unlikely to represent a cost-effective option compared with the bivalent vaccine for school-based HPV vaccination of 13-year old female students in Singapore. Substantial price reductions would be required to justify its inclusion in the school-based programme in the future.

Cost-effectiveness analysis of atezolizumab in advanced triple-negative breast cancer.

BACKGROUND: The IMpassion130 trial demonstrated that adding atezolizumab to nanoparticle albumin-bound (nab)-paclitaxel improved the survival of patients with untreated, advanced, programmed death ligand 1 (PDL1)-positive triple-negative breast cancer (TNBC). In view of the high cost of immunotherapy, it is important to examine its value with respect to both benefits and costs. In this study, the cost-effectiveness of atezolizumab/nab-paclitaxel combination therapy relative to nab-paclitaxel monotherapy was evaluated for the first-line treatment of advanced, PDL1-positive TNBC, from a healthcare system perspective. METHODS: A three-state partitioned-survival model was developed to compare the clinical and economic outcomes of treatment with atezolizumab/nab-paclitaxel combination therapy with nab-paclitaxel monotherapy in patients with advanced TNBC. Clinical data were obtained from the IMpassion130 trial and extrapolated to 5 years. Health state utilities were retrieved from the literature, while direct costs (in Singapore dollars, S$) were sourced from public healthcare institutions in Singapore. The primary outcomes of the model were life years (LYs), quality-adjusted LYs (QALYs), costs and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses and scenario analyses were conducted to explore the impact of specific assumptions and uncertainties. RESULTS: Adding atezolizumab to nab-paclitaxel resulted in an additional 0.361 QALYs (0.636 LYs) at an ICER of S$324,550 per QALY gained. The ICER remained high at S$67,092 per QALY even when atezolizumab was priced zero. One-way sensitivity analysis showed that the ICER was most sensitive to variations in the cost of atezolizumab and the time horizon. Scenario analyses confirmed that the ICERs remained high even under extremely favourable assumptions. CONCLUSIONS: Given the exceedingly high ICER, adding atezolizumab to nab-paclitaxel was unlikely to represent good value for money for the treatment of advanced PDL1-positive TNBC. Our findings will be useful in informing funding policy decisions alongside other considerations such as comparative effectiveness, unmet need and budget impact.

Metabolomic prediction of treatment outcome in pancreatic ductal adenocarcinoma patients receiving gemcitabine.

PURPOSE: Resistance to gemcitabine remains a key challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC), necessitating the constant search for effective strategies for a priori prediction of clinical outcome. While the existing studies focused on aberration of drug disposition genes and proteins as molecular predictors of gemcitabine treatment outcomes, the metabolic aberration associated with chemoresistance in clinical PDAC has been neglected. This exploratory study investigated the potential role of tissue metabolomics in characterizing the clinical treatment outcome of gemcitabine therapy. METHODS: Surgically resected tumors from PDAC patients who underwent gemcitabine-based adjuvant chemotherapy (n = 25) were subjected to metabotyping using gas chromatography/time-of-flight mass spectrometry (GC/TOFMS). RESULTS: A partial least-squares discriminant analysis (PLS-DA) model clearly distinguished patients who had favorable survival [overall survival (OS) > 24 months] from those who exhibited poorer survival (OS < 16 months) (Q 2 = 0.302). Receiver-operating characteristic analysis demonstrated the robustness of the PLS-DA model with an area under the curve of 1. PLS-DA revealed 19 marker metabolites (e.g., lactic acid, proline, and pyroglutamate) that shed insights into the chemoresistance of gemcitabine in PDAC. Particularly, tissue levels of lactic acid complemented transcript expression levels of human equilibrative nucleoside transporter 1 in distinguishing patients according to their overall survival. CONCLUSION: This work established proof-of-principle for GC/TOFMS-based global metabotyping of PDAC and laid the foundation for future discovery of metabolic biomarkers predictive of gemcitabine resistance in PDAC chemotherapy.

Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer.

Mutations in oncogenes along the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the resistance to cetuximab in patients with metastatic colorectal cancer (mCRC). However, the relative significance of these mutations based on their frequencies of occurrence in the Singaporean population remains unclear. In the present study, the prevalence of Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), phosphoinositide 3-kinase (PI3K) and EGFR somatic mutations were determined among Singaporean patients with mCRC. DNA extracted from 45 pairs of surgically resected tumor and normal mucosa samples was subjected to direct sequencing or restriction fragment length polymorphism. Associations of the genetic mutations with various clinicopathological parameters were further explored. Mutations in either codon 12 or 13 of KRAS were confirmed as prominent phenomena among the included Singaporean mCRC patients, at a prevalence comparable with that of Caucasian and patients of other Asian ethnicities [33.3% (90% confidence interval, 21.8-44.9%)]. KRAS mutation was not associated with clinicopathological features, including age, gender and ethnicity of patients, or the tumor site, differentiation and mucinous status. Conversely, the prevalence of BRAF (0%), PI3K (2.2%) and EGFR (0%) mutations were low. The results of the present study indicate that KRAS mutations are prevalent among the studied population, and confirm the low prevalence of BRAF, PI3K and EGFR mutations. KRAS should be prioritized as an investigational gene for future studies of predictive biomarkers of cetuximab response among Singaporean patients with mCRC.

Gastrointestinal Symptoms and Altered Intestinal Permeability Induced by Combat Training Are Associated with Distinct Metabotypic Changes.

Physical and psychological stress have been shown to modulate multiple aspects of gastrointestinal (GI) physiology, but its molecular basis remains elusive. We therefore characterized the stress-induced metabolic phenotype (metabotype) in soldiers during high-intensity combat training and correlated the metabotype with changes in GI symptoms and permeability. In a prospective, longitudinal study, urinary metabotyping was conducted on 38 male healthy soldiers during combat training and a rest period using gas chromatography-mass spectrometry. The urinary metabotype during combat training was clearly distinct from the rest period (partial least-squares discriminant analysis (PLSDA) Q(2) = 0.581), confirming the presence of a unique stress-induced metabotype. Differential metabolites related to combat stress were further uncovered, including elevated pyroglutamate and fructose, and reduced gut microbial metabolites, namely, hippurate and m-hydroxyphenylacetate (p < 0.05). The extent of pyroglutamate upregulation exhibited a positive correlation with an increase in IBS-SSS in soldiers during combat training (r = 0.5, p < 0.05). Additionally, the rise in fructose levels was positively correlated with an increase in intestinal permeability (r = 0.6, p < 0.005). In summary, protracted and mixed psychological and physical combat-training stress yielded unique metabolic changes that corresponded with the incidence and severity of GI symptoms and alteration in intestinal permeability. Our study provided novel molecular insights into stress-induced GI perturbations, which could be exploited for future biomarker research or development of therapeutic strategies.

Global fecal microRNA profiling in the identification of biomarkers for colorectal cancer screening among Asians.

Fecal microRNAs (miRNAs) are increasingly explored as non-invasive markers of colorectal cancer (CRC). However, its holistic profile in Asian CRC patients remains elusive. In the present study, the global human fecal miRNAs in Asian Chinese CRC patients was assayed to elucidate novel diagnostic fecal markers. Additionally, the influence of blood in stool on fecal miRNA levels was investigated for the first time. Microarray analysis was applied to profile the fecal miRNAs extracted from CRC patients and healthy subjects. Concurrently, surgically resected tumor and matched normal mucosae were analyzed. Potential fecal miRNA markers were further confirmed using real-time PCR in 17 CRC patients and 28 healthy subjects. Global miRNA profiling uncovered 17 fecal markers (p<0.05) differentially regulated in CRC. Fecal miR-223 and miR-451 represented robust markers in distinguishing CRC patients from healthy subjects, as evident from areas under the receiver operator characteristic curves of 0.939 and 0.971, respectively. Blood in stool affected fecal miR-451, miR-223 and miR-135b levels to a varying extent and substantially impacted the interpretation of the clinical data. Notably, a discrete set of aberrant miRNAs occurred within the tumor, indicating the presence of contributors beyond the exfoliation of tumor cells to the fecal miRNA profile. In summary, the utility of a global miRNA screening approach was successfully demonstrated in elucidating diagnostic markers of CRC. In particular, fecal miR-223 and miR-451 hold promise in detecting CRC.

Non-invasive fecal metabonomic detection of colorectal cancer.

Colorectal cancer (CRC) is a major cause of mortality in many developed countries. Effective screening strategies were called for to facilitate timely detection and to promote a better clinical outcome. In this study, the role of fecal metabonomics in the non-invasive detection of CRC was investigated. Gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) was utilized for the metabolic profiling of feces obtained from 11 CRC patients and 10 healthy subjects. Concurrently, matched tumor and normal mucosae surgically excised from CRC patients were profiled. CRC patients were differentiated clearly from healthy subjects based on their fecal metabonomic profiles (orthogonal partial least squares discriminant analysis [OPLS-DA], 1 predictive and 3 Y-orthogonal components, R (2)X = 0.373, R (2)Y = 0.995, Q (2) [cumulative] = 0.215). The robustness of the OPLS-DA model was demonstrated by an area of 1 under the receiver operator characteristic curve. OPLS-DA revealed fecal marker metabolites (e.g., fructose, linoleic acid, and nicotinic acid) that provided novel insights into the tumorigenesis of CRC. Interestingly, a disparate set of CRC-related metabolic aberrations occurred at the tissue level, implying the contribution of processes beyond the direct shedding of tumor cells to the fecal metabotype. In summary, this work established proof-of-principle for GC/TOFMS-based fecal metabonomic detection of CRC and offered new perspectives on the underlying mechanisms.

Global gas chromatography/time-of-flight mass spectrometry (GC/TOFMS)-based metabonomic profiling of lyophilized human feces.

Gas chromatography mass spectrometry (GC/MS)-based fecal metabonomics represents a powerful systems biology approach for elucidating metabolic biomarkers of lower gastrointestinal tract (GIT) diseases. Unlike metabolic profiling of fecal water, the profiling of complete fecal material remains under-explored. Here, a gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) method was developed and validated for the global metabonomic profiling of human feces. Fecal and fecal water metabotypes were also profiled and compared. Additionally, the unclear influence of blood in stool on the fecal metabotype was investigated unprecedentedly. Eighty milligram of lyophilized feces was ultrasonicated with 1mL of methanol:water (8:2) for 30min, followed by centrifugation, drying of supernatant, oximation and trimethylsilylation for 45min. Lyophilized feces demonstrated a more comprehensive metabolic coverage than fecal water, based on the number of chromatographic peaks. Principal component analysis (PCA) indicated occult blood (1mgHb/g feces) exerted a negligible effect on the fecal metabotype. Conversely, a unique metabotype related to feces spiked with gross blood (100mgHb/g feces) was revealed (PCA, R(2)X=0.837, Q(2)=0.794), confirming the potential confounding effect of gross GIT bleeding on the fecal metabotype. This pertinent finding highlights the importance of prudent interpretation of fecal metabonomic data, particularly in GIT diseases where bleeding is prevalent.

Investigating the role of nucleoside transporters in the resistance of colorectal cancer to 5-fluorouracil therapy.

Resistance to 5-fluorouracil (5FU) poses a constant challenge to the management of colorectal cancer (CRC). Consistent efforts were called for to identify molecular markers that can effectively predict patients' response. This study investigated the role of nucleoside transporters, particularly human equilibrative nucleoside transporter 1 (hENT1), in predicting clinical treatment outcome with 5FU-based therapy. Expression of a panel of nucleoside transporters in biopsied tumors from 7 CRC patients was measured by real-time PCR prior to 5FU-based chemotherapy. To provide mechanistic support for the role of hENT1 in 5FU resistance, cell viability of Caco-2 cells was measured, following incubation with varying concentrations of 5FU and a hENT1 inhibitor. Biopsied tumors were further subjected to global metabonomic profiling using gas chromatography/mass spectrometry. High hENT1 levels in tumor tissue correlated with poor clinical response to 5FU. Corroborating with the clinical findings, chemical inhibition of hENT1 in Caco-2 cells resulted in an augmentation of 5FU efficacy. Metabonomic profiling revealed that the pretreatment metabotype associated with non-responders to 5FU therapy was distinct from metabotype of responders (partial least-squares discriminant analysis Q(2) (cumulative) = 0.898, R(2)X = 0.513, R(2)Y = 0.996). This is the first clinical report on the relationships of intratumoral expression of nucleoside transporters and tumor metabotype with response to 5FU among CRC patients. Coupled to the in vitro findings, our preliminary data suggested hENT1 to be a potential codeterminant of clinical response to 5FU.

Investigation of the drug-drug interaction between alpha-lipoic acid and valproate via mitochondrial beta-oxidation.

PURPOSE: To investigate the potential drug-drug interaction (DDI) between lipoic acid (LA) and valproate (VA) via the mitochondrial beta-oxidation pathway in rats. METHODS: In vitro mitochondrial assays were performed to compare the biotransformation of VA to valproyl-CoA (VA-CoA), in the absence and presence of LA. In vitro microsomal and protein binding assays were performed to elucidate their potential DDI at the microsomal metabolism and distribution levels. A pharmacokinetic study was conducted in Lister Hooded rats to ascertain the in vivo DDI between LA and VA. RESULTS: LA was shown to decrease significantly (p < 0.05) the in vitro formation of VA-CoA in a concentration-dependent manner. Our in vitro assay results confirmed that there was minimal interaction between LA and VA in microsomal metabolism and protein binding. Based on the pharmacokinetic data, the absolute bioavailability of VA was determined to be 1.3 in the presence of LA. CONCLUSIONS: Our study demonstrated for the first time that there is a potential DDI between LA and VA at the mitochondrial beta-oxidation level. While further clinical study is essential, our preliminary finding suggested that medical practitioners need to be prudent when managing epileptic patients who are co-administered with both VA and LA.