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1.
Res Aging ; 45(2): 210-220, 2023 02.
Article in English | MEDLINE | ID: mdl-35466812

ABSTRACT

This study aimed to examine whether changes in generalized trust (GT) and particularized trust (PT) predict changes in depressive symptoms (CES-D 8), and whether changes in self-rated health (SRH), family support (FS), and life satisfaction (LS) mediate the relationship between changes in the two types of trust and depressive symptoms in Chinese older adults. Structural equation modeling was employed to analyze two-wave data on 3770 participants aged 65 and over. Our results showed that in a context where GT was low and PT was high, an increase in GT was associated with more depressive symptoms, while an increase in PT was associated with fewer depressive symptoms. As such, GT cannot be viewed as protective against depression in older adults in a given context. LS partially mediated the relationship between changes in PT and depressive symptoms. The findings support psychosocial processes rather than health-problem and support pathways.


Subject(s)
Depression , Family Support , Humans , Aged , Depression/diagnosis , Trust , East Asian People , Personal Satisfaction
2.
Radiography (Lond) ; 29(1): 184-189, 2023 01.
Article in English | MEDLINE | ID: mdl-36469993

ABSTRACT

INTRODUCTION: The use of computed tomography (CT) in healthcare institutions has increased rapidly in recent years. The Singapore Health Services (SingHealth) cluster of healthcare institutions has taken the first step in establishing a local cluster-wide CT Diagnostic Reference Levels (DRL) in Singapore. CT dose data from each institution were collected through two primary dosimetry metrics: volume CT dose index (CTDIvol measured in mGy) and dose-length product (DLP measured in mGy.cm). METHODS: Data from 19 CT scanners in seven institutions under one of Singapore healthcare cluster were retrospectively collected and analysed. The five common adult CT examinations analysed were CT Brain (non-contrast enhanced), CT Chest (IV contrast enhanced), CT Kidney-Ureter-Bladder (CT KUB, non-contrast enhanced), CT Pulmonary Angiogram (CT PA, IV contrast enhanced) and CT Abdomen-Pelvis (CT AP, IV contrast enhanced, single phase). Median CTDIvol and DLP values for the five CT examinations from each institution were derived, with the cluster DRLs determined as the 75th percentile of the distribution of the institution median dose values. RESULTS: A total of 2413 dose data points were collected over a six-month period from June to November 2020. The cluster CT DRLs for the five CT examinations were determined to be 47 mGy and 820 mGy.cm for CT Brain, 5.4 mGy and 225 mGy.cm for CT Chest, 6.7 mGy and 248 mGy.cm for CT PA, 4.6 mGy and 190 mGy.cm for CT KUB and 6.9 mGy and 349 mGy.cm for CT AP. CONCLUSION: The establishment of the cluster CT DRLs provided individual institutions with a better understanding if their CT doses are unusually high or low, while emphasising that these DRLs are not meant as hard dose limits or constraints to follow strictly.


Subject(s)
Diagnostic Reference Levels , Tomography, X-Ray Computed , Adult , Humans , Radiation Dosage , Retrospective Studies , Singapore , Tomography, X-Ray Computed/methods , Delivery of Health Care
3.
J Neurol ; 268(10): 3878-3885, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33830335

ABSTRACT

OBJECTIVE: Niemann Pick disease type C (NPC) is a rare progressive neurovisceral lysosomal disorder caused by autosomal recessive mutations in the NPC1 or NPC2 genes. 18F-fluorodeoxyglucose (FDG) is a positron-emitting glucose analogue for non-invasive imaging of brain metabolism. FDG PET is commonly used for dementia imaging but its specific application to NPC is rarely described. METHODS: This is a retrospective study of all baseline brain FDG PET performed for NPC patients. Images were assessed using a normal database statistical comparison of metabolic changes expressed in standard deviations and three-dimensional Stereotactic Surface Projection maps. Typical hypometabolic patterns in NPC were identified. We further investigated any correlation between the degree of regional brain hypometabolism and the Iturriaga clinical severity scale. RESULTS: Brain FDG PET images of 14 adolescent-adult NPC patients were analysed, with mean age of 35 years. We found significant frontal lobe hypometabolism in 12 patients (86%), thalamic hypometabolism in eight patients (57%) and variable parietal lobe hypometabolism in 13 patients (93%). Hypometabolic changes were usually bilateral and symmetric. Ten out of 13 ataxic patients showed cerebellar or thalamic hypometabolism (sensitivity 77%, specificity 100%). Linear regression analysis showed frontal lobe hypometabolism to have the best correlation with the Iturriaga clinical scale (R2 = 0.439; p = 0.01). CONCLUSIONS: We found bilateral symmetric hypometabolism of the frontal lobes, thalami and parietal lobes (especially posterior cingulate gyrus) to be typical of adolescent-adult NPC. Ataxia was commonly associated with cerebellar or thalamic hypometabolism. Frontal lobe hypometabolism showed the best inverse correlation with clinical severity.


Subject(s)
Fluorodeoxyglucose F18 , Niemann-Pick Disease, Type C , Adolescent , Adult , Brain/diagnostic imaging , Humans , Niemann-Pick Disease, Type C/diagnostic imaging , Positron-Emission Tomography , Retrospective Studies
5.
Int J Infect Dis ; 77: 34-39, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30292892

ABSTRACT

OBJECTIVE: The objective of this study was to evaluate the effects of earlier intervention by an antimicrobial stewardship team (AST) on antimicrobial use, antimicrobial resistance rates, and the clinical outcomes, without changing the weekly intervention schedule. METHODS: A retrospective study was conducted at Fukuoka University Hospital between April 2013 and March 2016. The effects were compared among three study periods (SP): SP1 (patients receiving anti-methicillin-resistant Staphylococcus aureus agents and carbapenems for ≥14 days), SP2 (patients receiving specific antimicrobials for ≥14 days), and SP3 (patients receiving specific antimicrobials regardless of the duration of treatment). RESULTS: The timing of AST intervention was shortened from an average of 15.5days after administration in SP1 to 4.2 days in SP3. The antimicrobial use density (AUD) of carbapenems and piperacillin-tazobactam decreased significantly (SP2 vs. SP3, p<0.05), and the costs of specific antimicrobials decreased (SP1, US$ 1080000; SP2, US$ 944000; SP3, US$ 763000). The rates of carbapenem resistance among Pseudomonas aeruginosa isolates showed a significant reduction from 16.2% in SP2 to 8.7% in SP3 (p<0.05). The mortality rate and length of stay did not change during the study period. CONCLUSIONS: Earlier intervention by an AST could contribute to the proper use of antimicrobials without adversely affecting patient outcomes.


Subject(s)
Anti-Infective Agents/therapeutic use , Antimicrobial Stewardship , Anti-Infective Agents/economics , Carbapenems/economics , Carbapenems/therapeutic use , Daptomycin/therapeutic use , Drug Resistance, Microbial , Fluoroquinolones/therapeutic use , Humans , Linezolid/therapeutic use , Methicillin-Resistant Staphylococcus aureus/drug effects , Piperacillin, Tazobactam Drug Combination/economics , Piperacillin, Tazobactam Drug Combination/therapeutic use , Pseudomonas aeruginosa/drug effects , Retrospective Studies , Teicoplanin/therapeutic use , Time Factors , Treatment Outcome , Vancomycin/therapeutic use
8.
Singapore Med J ; 59(12): 661, 2018 12.
Article in English | MEDLINE | ID: mdl-30631880
9.
Ann Oncol ; 27(12): 2210-2215, 2016 12.
Article in English | MEDLINE | ID: mdl-27681866

ABSTRACT

BACKGROUND: Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with Child-Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand-foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes. CONCLUSION: The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation. CLINICALTRIALSGOV IDENTIFIER: NCT01029418.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Benzimidazoles/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzimidazoles/adverse effects , Carcinoma, Hepatocellular/pathology , Disease-Free Survival , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Kaplan-Meier Estimate , Liver Neoplasms/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Niacinamide/administration & dosage , Niacinamide/adverse effects , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Sorafenib
11.
Australas Phys Eng Sci Med ; 38(3): 381-98, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25894289

ABSTRACT

The history of medical physics in Asia-Oceania goes back to the late nineteenth century when X-ray imaging was introduced, although medical physicists were not appointed until much later. Medical physics developed very quickly in some countries, but in others the socio-economic situation as such prevented it being established for many years. In others, the political situation and war has impeded its development. In many countries their medical physics history has not been well recorded and there is a danger that it will be lost to future generations. In this paper, brief histories of the development of medical physics in most countries in Asia-Oceania are presented by a large number of authors to serve as a record. The histories are necessarily brief; otherwise the paper would quickly turn into a book of hundreds of pages. The emphasis in each history as recorded here varies as the focus and culture of the countries as well as the length of their histories varies considerably.


Subject(s)
Biophysics/history , Asia , History of Medicine , History, 19th Century , History, 20th Century , History, 21st Century , Humans , Oceania
12.
Nucl Med Commun ; 36(4): 356-62, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25569865

ABSTRACT

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is caused by excessive hormone synthesis and release (AIT I), a destructive thyroiditis (AIT II), or a combination of both (AIT Ind). Although no gold-standard diagnostic test is available, technetium-99m sestamibi thyroid scintigraphy (99mTc-STS) has been previously reported to be an accurate tool for differentiating subtypes with important therapeutic implications. However, the information to guide reporting of 99mTc-STS is qualitative and highly subjective. This study aims to compare the interobserver reliability of 99mTc-STS before and after the use of quantitative thyroid-to-background ratios (TBRs) displayed on a time-activity curve for differentiation of AIT subtypes. METHODS: A retrospective audit of Nuclear Medicine Departments at Royal Melbourne Hospital (Parkville, Victoria, Australia) and Cabrini Hospital (Malvern, Victoria, Australia) identified 15 consecutive 99mTc-STS studies performed for AIT. Four nuclear medicine physicians reported the studies according to previously established criteria (series 1). Quantitative TBR and estimated 'normal' range TBR were subsequently provided before the studies were reordered and reported again (series 2). Interobserver reliability was calculated using Fleiss' κ statistic for each assessment. RESULTS: The overall percentage of agreement (PoA) and κ statistics for use of conventional 99mTc-STS for diagnosis of AIT improved from 47 to 80% and from 0.30 to 0.67 following the use of quantitative TBR displayed on a time-activity curve with reference to a normal population. Interobserver reliability improved substantially under all diagnostic comparisons, particularly for differentiation of either AIT I (PoA 80% to 94%, κ: 0.48 to 0.84) or AIT Ind (PoA 47% to 82%, κ: -0.05 to 0.51) from other types of AIT. CONCLUSION: Use of quantitative TBR improves the interobserver reliability of reporting 99mTc-STS for investigation of different types of AIT. There is 'almost perfect' agreement upon differentiation of AIT I from AIT II and AIT Ind, with important implications for rationalizing the use of corticosteroid therapy. Prospective identification of AIT Ind is improved from 'poor' to a 'moderate' level of agreement to facilitate rational use of combination therapy at diagnosis.


Subject(s)
Amiodarone/adverse effects , Technetium Tc 99m Sestamibi , Thyroid Gland/diagnostic imaging , Thyrotoxicosis/chemically induced , Thyrotoxicosis/diagnostic imaging , Aged , Aged, 80 and over , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Observer Variation , Radionuclide Imaging , Reproducibility of Results , Retrospective Studies
13.
Chem Sci ; 6(8): 5053-5058, 2015 Aug 01.
Article in English | MEDLINE | ID: mdl-29142729

ABSTRACT

A new class of 'soft' particles, micelles, is detected electrochemically via 'nano-impacts' for the first time. Short, sharp bursts of current are used to indicate the electrical contact of a single CTAB (cetyltrimethylammonium bromide) micelle with an electrode via the oxidation of the bromide content. The variation in CTAB concentration for such 'nano-impact' experiments shows that a significant number of 'spikes' are observed above the CMC (critical micelle concentration) and this is attributed to the formation of micelles. A comparison with dynamic light scattering is also reported.

14.
Cell Death Discov ; 1: 15032, 2015.
Article in English | MEDLINE | ID: mdl-27551463

ABSTRACT

Hepatocellular carcinoma (HCC) is a deadly cancer because of its commonly late diagnosis and limited treatment options. SAG (sensitive to apoptosis gene)-dependent UPS (ubiquitin-proteasome system) is a key switch between immune-mediated apoptosis and overactivation-mediated protumorigenesis, prompting us to hypothesize that SAG-UPS modulates chronic inflammation-induced tumorigenesis. Here, we investigated the molecular mechanism by which SAG-UPS regulates death/survival of liver cancer cells. By retrospective studies, we found reciprocal expressions of anti-/proapoptotic factors: SAG/SARM and SAG/Noxa in human primary HCC tissues - the antiapoptotic SAG was significantly upregulated whereas the proapoptotic SARM and Noxa were markedly downregulated, suggesting their involvement in hepatocarcinogenesis. Upregulated SAG-UPS effectively manipulates the levels of high-molecular-weight ubiquitinated SARM and Noxa in carcinoma tissues compared with corresponding normal tissues. SAG-overexpressing HCC cell lines display reduced SARM and Noxa (but not Bcl-2, Bax and Bcl-xL), suggesting that SARM and Noxa are specific substrates of SAG-dependent ubiquitination. SARM overexpression activated caspase-3 and caspase-9, reducing cell viability. SAG knockdown significantly elevated apoptosis with increased cytosolic cytochrome c, confirming SAG-mediated antiapoptosis in HCC. SAG overexpression stimulated protumorigenic cytokines, IL-1ß, IL-6 and TNF, but not antitumorigenic IL-12p40 and anti-inflammatory IL-10. This is consistent with higher proinflammatory cytokines (IL-1ß, IL-6 and TNF) in hepatoma compared with healthy tissues. Altogether, early stage-upregulated SAG-UPS exacerbates hepatocarcinogenesis progression, through: (1) ubiquitination-mediated degradation of proapoptotic SARM and Noxa; and (2) production of protumorigenic cytokines that induce a protumorigenic microenvironment, conferring survival advantage to HCC cells. Thus, we propose SAG-UPS to be an early diagnostic marker for HCC, and a potential target for therapeutics development.

15.
Eur J Cancer ; 49(5): 999-1008, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23265712

ABSTRACT

BACKGROUND & AIMS: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma. METHODS: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume. RESULTS: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume. CONCLUSIONS: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Sirolimus/pharmacokinetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Dose-Response Relationship, Drug , Female , Hepatectomy , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Maximum Tolerated Dose , Middle Aged , Sirolimus/administration & dosage , Sirolimus/adverse effects , Treatment Outcome
16.
Ann Oncol ; 23(4): 997-1005, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21821548

ABSTRACT

BACKGROUND: Individuals with metastatic Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) continue to have poor outcomes. To evaluate the ability of a dendritic cell (DC) vaccine to target subdominant EBV antigens LMP1 and LMP2 expressed by NPC cells, we vaccinated patients using autologous DCs transduced with an adenovirus encoding a truncated LMP1 (ΔLMP1) and full-length LMP2 (Ad-ΔLMP1-LMP2). MATERIALS AND METHODS: Sixteen subjects with metastatic NPC received Ad-ΔLMP1-LMP2 DC vaccines i.d. biweekly for up to five doses. Toxicity, immune responses and clinical responses were determined. RESULTS: Most patients had extensive disease, with a median of three visceral sites of involvement (range 1-7). No significant toxicity was observed. Ad-ΔLMP1-LMP2 DCs induced delayed type hypersensitivity responses in 9 out of 12 patients, but although these DCs activated LMP1/2-specific T cells in vitro, no such increase in the frequency of peripheral LMP1/2-specific T cells was detected. Three patients had clinical responses including one with partial response (for 7½ months) and two with stable disease (for 6½ and 7½ months). CONCLUSIONS: Ad-ΔLMP1-LMP2 transduced DCs can be successfully generated and safely administered to patients with advanced NPC. Since efficacy was limited, future studies should focus on DC vaccines with greater potency administered to subjects with less tumor burden.


Subject(s)
Adenoviridae/genetics , Cancer Vaccines/administration & dosage , Carcinoma/therapy , Dendritic Cells/immunology , Nasopharyngeal Neoplasms/therapy , Viral Matrix Proteins/immunology , Adult , Cancer Vaccines/adverse effects , Cancer Vaccines/immunology , Carcinoma/mortality , Carcinoma/virology , Cells, Cultured , Coculture Techniques , Dendritic Cells/metabolism , Dendritic Cells/transplantation , Dendritic Cells/virology , Disease-Free Survival , Epstein-Barr Virus Infections/complications , Female , Genetic Vectors , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/mortality , Nasopharyngeal Neoplasms/virology , Sequence Deletion , Treatment Outcome , Viral Matrix Proteins/genetics , Viral Matrix Proteins/metabolism
17.
Curr Cancer Drug Targets ; 11(8): 944-53, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21834756

ABSTRACT

Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest malignancy. Sorafenib has demonstrated 44% survival advantage over placebo and has emerged as a standard of care in advanced HCC. The therapeutic effects of sorafenib are however transient and hence additional treatment options are warranted. In this study, we aimed to compare the efficacy of sunitinib relative to sorafenib, two potent inhibitors of protein tyrosine kinases involved in tumor growth, metastasis, or angiogenesis. We reported that sorafenib and sunitinib suppressed tumor growth, angiogenesis, cell proliferation, and induced apoptosis in both orthotopic and ectopic models of HCC. However, the antitumor effect of 50 mg/kg sorafenib was greater than that of 40 mg/kg sunitinib. Sorafenib inhibited p-eIF4E Ser209, p-p38 Thr180/Tyr182 and reduced survivin expression. This was not seen with sunitinib. In addition, the antitumor and apoptotic effects of sorafenib, which are associated with upregulation of fast migrating Bim and ASK1 and downregulation of survivin, were greater than that of sunitinib. These observations explained in part the apparent superior anti-tumor activity of sorafenib compared to sunitinib. In conclusion, sunitinib demonstrated an inferior anti-tumor activity compared to sorafenib in ectopic and orthotopic models of human HCC. It remains to be seen whether such observations would be recapitulated in humans.


Subject(s)
Antineoplastic Agents/therapeutic use , Benzenesulfonates/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Indoles/therapeutic use , Liver Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Pyrroles/therapeutic use , Xenograft Model Antitumor Assays/methods , Angiogenesis Inhibitors/therapeutic use , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, SCID , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neovascularization, Pathologic/prevention & control , Niacinamide/analogs & derivatives , Phenylurea Compounds , Protein-Tyrosine Kinases/antagonists & inhibitors , Random Allocation , Sorafenib , Sunitinib
18.
Ann Oncol ; 22(11): 2516-2522, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21385886

ABSTRACT

BACKGROUND: The objective of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. PATIENTS AND METHODS: Dose-escalating cohorts of three to six patients received SB939 orally thrice weekly for 3 weeks in a 4-week cycle. Acetylated histone H3 (acH3) was measured in peripheral blood mononuclear cells (PBMCs). RESULTS: Thirty patients treated at one of five doses (10-80 mg/day) received 79 cycles of SB939 (range, 1-12 cycles). Dose-limiting toxic effects were fatigue, hypokalemia, troponin T elevation, and QTc prolongation. Peak plasma concentration (C(max)) and area under the concentration-time curve extrapolated to infinity increased dose proportionally. The MTD of SB939 was 80 mg/day. The mean elimination half-life and oral clearance of SB939 were 7.2 ± 0.6 h and 53.0 ± 8.5 l/h, respectively, with no substantial accumulation on day 15. An increase in acH3 was observed at hour 3 and correlated with dose and C(max). Stable disease was seen in several tumor types treated at ≥40 mg. HDAC inhibition was consistently observed at 60 mg, the recommended dose. CONCLUSIONS: SB939 can be safely administered at the recommended dose and reaches plasma levels that strongly inhibit HDAC in PBMCs. These data support further efficacy studies of SB939.


Subject(s)
Benzimidazoles/administration & dosage , Histone Deacetylase Inhibitors/administration & dosage , Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Benzimidazoles/adverse effects , Benzimidazoles/pharmacokinetics , Dose-Response Relationship, Drug , Female , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylase Inhibitors/pharmacokinetics , Histone Deacetylases/metabolism , Humans , Male , Middle Aged , Neoplasms/enzymology , Neoplasms/metabolism
19.
Bone Marrow Transplant ; 46(4): 573-9, 2011 Apr.
Article in English | MEDLINE | ID: mdl-20661236

ABSTRACT

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4-1147) days, the median PFS was 100 days (95% confidence interval (CI), 66-128 days), and median OS was 209 days (95% CI, 128-236 days). Patients with chronic GVHD had better survival-median OS 426 days (95% CI, 194-NE days) vs 143 days (95% CI, 114-226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC.


Subject(s)
Graft vs Tumor Effect , Nasopharyngeal Neoplasms/therapy , Peripheral Blood Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Adult , Cyclophosphamide/therapeutic use , Female , Humans , Lymphocyte Depletion , Male , Middle Aged , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/radiotherapy , Neoplasm Metastasis , Peripheral Blood Stem Cell Transplantation/mortality , Survival Analysis , Transplantation Chimera , Transplantation, Homologous
20.
Br J Cancer ; 102(6): 981-6, 2010 Mar 16.
Article in English | MEDLINE | ID: mdl-20160718

ABSTRACT

BACKGROUND: Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population. METHODS: Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg(-1) on day 1 and capecitabine 800 mg m(-2) twice daily on days 1-14 every 3 weeks as first-line therapy. RESULTS: A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand-foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score < or =3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients. CONCLUSION: The bevacizumab-capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Deoxycytidine/analogs & derivatives , Fluorouracil/analogs & derivatives , Liver Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Capecitabine , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Disease Progression , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Survival Analysis , Treatment Outcome , Young Adult
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