ORCID Profile
0000-0003-3779-3705
Current Organisation
Bond University
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Publisher: BMJ
Date: 2007
DOI: 10.1111/J.1525-1438.2007.00763.X
Abstract: Gemcitabine and oxaliplatin have shown single-agent activity in relapsed ovarian cancer. This combination was used to determine response rates, time-to-event efficacy measures, and toxicity in patients with recurrent ovarian cancer. Patients with prior platinum-based chemotherapy who had measurable lesions and/or elevated CA-125 levels were identified as group A (platinum-refractory latinum-resistant patients) and group B (platinum-sensitive patients). All patients received gemcitabine 1000 mg/m 2 on days 1 and 8 and oxaliplatin 130 mg/m 2 on day 8 every 21 days for up to eight cycles. Seventy-five patients (21 in group A and 54 in group B), with a median age of 58 years (range, 37–78), were enrolled. A median of six cycles (range, 1–8) was administered. By intent-to-treat analysis, 15 patients with measurable disease achieved partial response for an overall best response rate of 20.0% (9.5% in group A and 24.1% in group B). CA-125 response was observed in 48.4% patients (30.0% in group A and 57.1% in group B). Median time to progressive disease was 7.1 months (95% CI, 5.6–9.0 months) with 5.0 months in group A and 8.3 months in group B. Median overall survival was 17.8 months (95% CI, 12.9–21.3 months) with 9.2 months for group A and 20.0 months for group B. Major grade 3/4 toxicities were neutropenia (61.3%), leukopenia (24.0%), nausea (16.0%), and vomiting (22.7%). We conclude that the combination of oxaliplatin and gemcitabine is active in patients with recurrent ovarian cancer, but the regimen is unsatisfactory for further study due to modest response and relatively high toxicity.
Publisher: Wiley
Date: 27-03-2014
DOI: 10.1111/AJCO.12184
Abstract: Primary adenoid cystic carcinoma of the lung is a rare subtype of lung cancer with a prolonged natural history but is difficult to completely resect surgically due to its proximal location. Hence radiotherapy plays a role for local control of these cancers. The role of systemic therapies in the treatment of adenoid cystic carcinoma of the lung remains unclear. Isolated case reports have previously described the treatment of primary adenoid cystic carcinoma of the lung with tamoxifen, resulting in partial control. We report the first case of primary adenoid cystic carcinoma of the lung treated with primary chemoradiotherapy due to unresectable location of the tumor, and disease stabilization with symptomatic response to tamoxifen following tumor recurrence. There is a need for further studies to investigate the role of anti-hormonal therapies in the treatment of adenoid cystic carcinoma of the lung.
Publisher: Wiley
Date: 23-05-2011
DOI: 10.1111/J.1743-7563.2011.01390.X
Abstract: This multicentre phase II trial examined the combination of gemcitabine and oxaliplatin in patients with advanced non-small cell lung cancer (NSCLC). The effect of sequence administration was randomized and pharmacokinetics (PK) assessed. Eligible patients had stage IIIB or IV or recurrent NSCLC, no prior chemotherapy, World Health Organization performance status ≤2 and measurable disease. Treatment comprised: gemcitabine (1250 mg/m(2)) and oxaliplatin (70 mg/m(2)), each given on days 1 and 8 of a 21-day cycle. Patients were randomized 1:1 to the sequencing of the two drugs for the duration of their treatment. The primary end-point was response rate (RR). Secondary end-points included progression-free survival (PFS), overall survival (OS), toxicity, PK and the effect of drug sequencing. A total of 46 patients were enrolled of whom 43 were evaluable for response. Overall 13 patients (30%) achieved a partial response, PFS was 4.2 months (95% CI 2.8-5.8 months), and OS was 6.8 months (95% CI 4.4-10.1 months). There was only one case of grade 3 neurosensory toxicity despite a median cumulative oxaliplatin dose in excess of 500 mg/m(2) . No differences in clinical or PK end-points were observed between the two different sequencing arms. This oxaliplatin and gemcitabine schedule has shown activity in advanced NSCLC with modest toxicity. Neither clinical nor PK outcomes were influenced by the sequencing of these agents, although definite conclusions are limited by small patient numbers. The favorable toxicity profile of this doublet, in light of an encouraging RR, warrants its further investigation in NSCLC.
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.2165/00129784-200505040-00003
Abstract: Cardiac toxicity of chemotherapeutic agents is a rapidly evolving area of increasing significance because of the increasing pool of long-term cancer survivors. The spectrum of cardiotoxicity with chemotherapeutic agents includes hypertension, QTc prolongation, acute cardiomyopathy, and bradyarrhythmias. The most common issue to arise has been cardiomyopathy with anthracyclines. Preventative strategies that have met with some success have included the use of less cardiotoxic analogs such as epirubicin and liposomal anthracycline preparations. The cardioprotectant agent dexrazoxane reduces cardiomyopathy but there are significant toxicity issues. Therefore, the main strategy for preventing cardiotoxicity remains careful monitoring with radionuclide angiography or echocardiography. The role of investigational markers of myocardial injury, such as troponin T or brain natriuretic peptide, remains of great interest. Management is according to conventional management of congestive heart failure. Trastuzumab is an antibody therapy directed against the human epidermal growth factor receptor-2 (HER2) receptor, which increases survival in patients with metastatic breast cancer and is under evaluation in the adjuvant setting. It also causes a decrease in left ventricular ejection fraction (LVEF) in a minority of patients. Incidence is increased if trastuzumab is given in conjunction with paclitaxel or anthracyclines. It differs from anthracycline cardiotoxicity in that it is not cumulative dose-dependent and often improves after withdrawal of treatment. Re-treatment with trastuzumab is often possible. Novel agents under development offer a different spectrum of toxicity to existing anticancer drugs and it appears likely that cardiovascular toxicity will be an important issue for many of these drugs, particularly those that target the tumor vasculature.
Publisher: Wiley
Date: 24-10-2008
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.LUNGCAN.2010.12.016
Abstract: Clinical trials combining epidermal growth factor receptor (EGFR) inhibitors with gemcitabine-based chemotherapy in non-small cell lung cancer (NSCLC) have not produced a survival advantage. This may be caused by antagonism between the two drugs or mutations that promote such, possibly RAS mutation. Furthermore, ERK, a critical growth regulator downstream of RAS, may play a role. This study aimed to explore the relationship between ERK, synergy/antagonism and cell cycle arrest in combination treatment. A549 (mutant KRAS), H322 (wildtype KRAS) and siRNA-mediated KRAS knockdown A549 were treated with gemcitabine and/or the EGFR inhibitor AG1478 and analyzed with median effect analysis. Cell cycle distribution and ERK phosphorylation were assessed using flow cytometry and ELISA, respectively. Effect on cytotoxicity after ERK inhibition by U0126 was also assessed. Cytotoxic interaction was dose dependent with antagonism at high dose AG1478. G1 arrest was observed with both high dose AG1478 and high dose gemcitabine and therefore was inconsistently associated with antagonism. Furthermore, ERK phosphorylation was increased by gemcitabine and its suppression by AG1478 was related to antagonism particularly in H322. ERK's effect in antagonism was further confirmed by using U0126. Greater antagonism was observed in the KRAS mutant cell line and KRAS knockdown by siRNA resulted in increased sensitivity to AG1478 as well as combination treatment. Our findings are consistent with a model in which ERK phosphorylation favors synergy and the outcome depends on the balance between gemcitabine-induced and AG1478-inhibited ERK phosphorylation. KRAS mutation confers resistance to AG1478 as well as combination treatment.
Publisher: Wiley
Date: 07-2019
DOI: 10.1111/IMJ.14351
Publisher: Wiley
Date: 10-2013
DOI: 10.1111/IMJ.12251
Abstract: A new national guideline for the management of febrile patients with severe neutropenia uses a risk stratification score to tailor treatment. To evaluate the implementation of this guideline in a metropolitan teaching hospital. A protocol was developed for implementation of the national guidelines for patients with neutropenic fever or at risk because of recent chemotherapy. Medical records of all patients presenting with fever to the haematology and oncology service for 3 months in 2011 were audited. Patients with a neutrophil count between 0.5 and 1.0 × 10(9) /L were classified as borderline neutropenia. Eighty-one episodes of fever were treated on the protocol. Forty-three per cent of patients were neutropenic. Uptake of the policy was low (35%) despite concerted efforts. The sensitivity and specificity of the Multinational Association for Supportive Care in Cancer score was 86% and 24% respectively. The readmission rate with fever was 19.2%. Median time to antibiotics was 60 min. Outcomes were similar for the neutropenic fever and borderline groups. Increasing treatment complexity was the major barrier to implementation. The majority of presentations with cancer and fever following chemotherapy do not have neutropenia but have similar outcomes when treated on the same pathway. The utility of the Multinational Association for Supportive Care in Cancer score was limited by uptake and specificity. Reducing time to antibiotics administration and readmission rates were identified as priorities. Implementation was labour-intensive and faced significant barriers. Prioritisation of evidence for translation requires attention to local priorities and implementation complexity. These results argue for a single sepsis guideline with treatment of cancer as a high-risk group.
Publisher: Springer Science and Business Media LLC
Date: 1999
DOI: 10.2165/00003495-199957030-00003
Abstract: Dose-limiting toxicity secondary to antineoplastic chemotherapy is due to the inability of cytotoxic drugs to differentiate between normal and malignant cells. The consequences of this may include impairment of patient quality of life, because of toxicity, and reduced tumour control because of the inability to deliver adequate dose-intensive therapy against the cancer. Specific ex les of toxicity against normal tissues include cisplatin-related neurotoxicity and nephrotoxicity, myelotoxicity secondary to treatment with alkylating agents and carboplatin, oxazaphosphorine-induced haemorrhagic cystitis, and cumulative dose-related cardiac toxicity secondary to anthracycline treatment. Chemoprotectants have been developed as a means of ameliorating the toxicity associated with cytotoxic agents by providing site-specific protection for normal tissues, without compromising antitumour efficacy. Clinical trials with toxicity protectors must include sufficient dose-limiting events for study, and assessment of both toxicity (allowing for measurement of efficacy of protection) and antitumour effect. Several chemoprotective compounds have now been extensively investigated, including dexrazoxane, amifostine, glutathione, mesna and ORG 2766. Dexrazoxane appears to complex with metal co-factors including iron, to reduce the incidence of anthracycline-induced cardiotoxicity, allowing the delivery of higher cumulative doses of anthracyclines without the expected consequence of cardiomyopathy. Numerous studies have demonstrated that sulfur-containing nucleophiles, including amifostine, glutathione, and mesna can specifically bind cisplatin- or alkylating agent-generated free radicals or alkylating agent metabolites to reduce the incidence of cisplatin-associated neurotoxicity and nephrotoxicity, or alkylating agent-associated myelosuppression and urothelial toxicity. These studies, in the majority of instances, have not revealed any evidence of reduction in antitumour efficacy. Further randomised trials are required to identify the optimal role of chemoprotectants when used alone or in combination with other toxicity modifiers including haemopoietic growth factors.
Publisher: Wiley
Date: 30-12-2011
DOI: 10.1111/J.1743-7563.2010.01354.X
Abstract: Controversy exists over the optimal dosing for the nucleoside analogue gemcitabine. A pharmacological advantage is achieved by prolonging infusion times but evidence for a clinical benefit has been conflicting. We hypothesized that polymorphisms in genes involved in gemcitabine accumulation, particularly the cytidine deaminase CDA c.79A>C, may influence the optimal dosing regimen in in idual patients. DNA was collected from 32 patients participating in a randomized crossover study comparing 30-min with 100-min infusions of gemcitabine. The relationships between seven polymorphisms among three genes (CDA, RRM1 and DCK) and (i) gemcitabine triphosphate accumulation (ii) gemcitabine-induced toxicity and (iii) dose delivery were examined for each infusion time and week of administration. There were trends for increased accumulation of gemcitabine-triphosphate (GEM-TP) with the variant alleles of CDA c.79A>C, and RRM1-37C>A and -524T>C but none of these reached statistical significance in a univariate analysis. In a multivariable model there were significant effects of infusion duration and week of administration on GEM-TP accumulation. There were significant interactions between CDA c.79A>C (P=0.01) and RRM1-37C>A (P=0.019) genotypes, infusion time, and arm. More patients with one or two CDA c.79 variant alleles had doses delays (57 vs 13 %, P=0.03) and a pharmacological advantage for prolonged infusion after week 1. It is important to consider both pharmacokinetics and pharmacogenetics in optimizing gemcitabine accumulation. This represents a classical interaction between genes and environment and provides support for the consideration of both CDA genotype and infusion duration in development of an in idualized dosing strategy.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-06-2015
Abstract: We examined the impact of different epidermal growth factor receptor (EGFR) mutations and clinical characteristics on progression-free survival (PFS) in patients with advanced EGFR-mutated non–small-cell lung cancer treated with EGFR tyrosine kinase inhibitors (TKIs) as first-line therapy. This meta-analysis included randomized trials comparing EGFR TKIs with chemotherapy. We calculated hazard ratios (HRs) and 95% CIs for PFS for the trial population and prespecified subgroups and calculated pooled estimates of treatment efficacy using the fixed-effects inverse-variance-weighted method. All statistical tests were two sided. In seven eligible trials (1,649 patients), EGFR TKIs, compared with chemotherapy, significantly prolonged PFS overall (HR, 0.37 95% CI, 0.32 to 0.42) and in all subgroups. For tumors with exon 19 deletions, the benefit was 50% greater (HR, 0.24 95% CI, 0.20 to 0.29) than for tumors with exon 21 L858R substitution (HR, 0.48 95% CI, 0.39 to 0.58 P interaction .001). Never-smokers had a 36% greater benefit (HR, 0.32 95% CI, 0.27 to 0.37) than current or former smokers (HR, 0.50 95% CI, 0.40 to 0.63 P interaction .001). Women had a 27% greater benefit (HR, 0.33 95% CI, 0.28 to 0.38) than men (HR, 0.45 95% CI, 0.36 to 0.55 treatment-sex interaction P = .02). Performance status, age, ethnicity, and tumor histology did not significantly predict additional benefit from EGFR TKIs. Although EGFR TKIs significantly prolonged PFS overall and in all subgroups, compared with chemotherapy, greater benefits were observed in those with exon 19 deletions, never-smokers, and women. These findings should enhance drug development and economic analyses, as well as the design and interpretation of clinical trials.
Publisher: Elsevier BV
Date: 10-1995
DOI: 10.1016/S0748-7983(95)97083-5
Abstract: Cimetidine has demonstrated a survival benefit in a randomized trial as adjuvant therapy for gastric cancer. We have demonstrated expression of histamine receptors on colon cancer cell lines and inhibition of their growth with cimetidine. Cimetidine also activates suppressor T cells and stimulates cell-mediated immunity. We therefore performed a randomized controlled clinical trial to determine the effect of cimetidine 400 mg given twice daily in conjunction with chemotherapy vs chemotherapy alone. Thirty-eight patients were randomized and 35 patients were eligible for further analysis. Both groups were well matched for pre-treatment characteristics. There was no difference in overall response. There was, however, a significantly increased rate of CEA response in the cimetidine group. Four of 11 patients (36%) in the cimetidine group had a CEA response compared to none of eight in the control. Meaningful comparisons of overall survival cannot yet be made. This study demonstrates that cimetidine has encouraging activity in increasing CEA response in patients with metastatic colorectal cancer treated with chemotherapy. This observation needs to be extended in a larger randomized study, which is currently underway.
Publisher: Springer Science and Business Media LLC
Date: 18-12-2013
Publisher: AMPCo
Date: 05-2014
DOI: 10.5694/MJA14.00400
Publisher: Springer Science and Business Media LLC
Date: 27-04-2007
Publisher: Cambridge University Press (CUP)
Date: 25-10-1999
DOI: 10.1017/S1462399499001099X
Abstract: Resistance to anti-cancer drugs (drug resistance) can be defined in the laboratory by the amount of anti-cancer drug that is required to produce a given level of cell death (drug response). Clinical drug resistance can be defined either as a lack of reduction of the size of a tumour following chemotherapy or as the occurrence of clinical relapse after an initial ‘positive’ response to anti-tumour treatment. Many studies of tumour s les do not directly measure drug resistance in the laboratory (because it is difficult to perform functional assays on tumour tissue) instead, key proteins or genes that are involved in particular mechanisms of drug resistance have been proposed as ‘markers’ of drug resistance. In this review, we have focused on the problems that can arise when attempts are made to relate the relevance of laboratory-identified molecular mechanisms of drug resistance to anti-cancer drug resistance that occurs in patients.
Publisher: InTech
Date: 20-04-2012
DOI: 10.5772/33330
Publisher: Wiley
Date: 03-2006
DOI: 10.1111/J.1445-2197.2006.03579.X
Abstract: Peritoneal dissemination of malignancy is usually considered incurable. The purpose of the present study was to evaluate the efficacy of intraperitoneal chemohyperthermia and cytoreductive surgery. The present article is a retrospective review of prospectively recorded data in 60 patients who underwent 71 peritonectomy procedures between January 1996 and May 2004. Hospital records, a database and department notes were studied. Conditions treated were pseudomyxoma peritoneii (PMP) and appendiceal cancer (23), mesothelioma (7), colorectal cancer (CRC, 15), ovarian cancer (6) and other forms of malignancy (9). Following cytoreductive surgery, early postoperative intraperitoneal chemotherapy (EPIC) was given in 47 procedures, five with added i.v. mitomycin C. In 34 procedures, heated intraperitoneal chemotherapy (HIPEC) was administered. A policy change was made from intravenous to intraperitoneal mitomycin C chemotherapy in December 2001. Peritoneal cancer index (PCI) was calculated for all procedures. Of the procedures, 23 had PCI 20. The median operation time was 9 h. Blood units transfused and length of hospital stay have declined. Mortality was 4/60 patients (6.7%), caused by pancytopenia and sepsis. Morbidity occurred in 28/71 procedures. The 3-year survival rate for the HIPEC group was 71% compared with 28% for the no HIPEC group. In the complete excision group, the 3-year survival rate was 52% compared with 13% for the incomplete excision group. The 3-year survival rate for PMP and appendiceal cancer was 74%. The 2-year survival rate for ovarian cancer was 67%, mesothelioma 57%, and CRC 50%, respectively. Morbidity is significantly associated with duration of surgery and units of blood transfused. Our findings are consistent with the international experience in patients treated with combined peritonectomy and HIPEC.
Publisher: Wiley
Date: 06-2006
DOI: 10.1111/J.1445-2197.2006.03749.X
Abstract: This study aims to assess the survival of patients who underwent peritonectomy, to assess the morbidity and mortality associated with the procedure and to review the published reports on the survival of patients with peritoneal spread of colorectal cancer (CRC). Peritonectomy involves resection of all visible peritoneal tumour and is followed by heated intraperitoneal chemotherapy. Peritonectomy with heated intraperitoneal chemotherapy is associated with a 3-year survival of 30-50% in patients with low peritoneal cancer index (PCI) with peritoneal carcinomatosis from CRC. There are approximately 1000 patients in phase 2 studies and a large survival advantage was shown in a randomized control trial. We have carried out over 100 peritonectomy procedures. This study describes 22 patients with peritoneal spread of gastrointestinal cancer treated with peritonectomy between 1996 and March 2005. Twenty of these patients had primary colorectal cancer and two patients had primary small bowel cancer. Of the 22 patients who underwent peritonectomy, 8 patients are now deceased. The median follow up is now 16.1 months. At 12 months, the survival was 61.5% and at 24 months the survival was 46.1%, which are creditable results comparable with the world published reports. We found that those patients with all macroscopic residual tumour removed at the end of the procedure (completeness of cancer resection, CCR O) had improved 24-month survival compared with patients in whom there was incomplete tumour resection (53.3% survival vs 22.2%, respectively, P = 0.024). Patients with a PCI score less than 13 had better survival (P = 0.0003). Peritonectomy for peritoneal carcinomatosis from CRC offers patients improved survival. Our results are consistent with the published data with respect to improved survival in patients with low PCI and complete cytoreduction.
Publisher: Informa UK Limited
Date: 2009
Publisher: BMJ
Date: 16-11-2006
Publisher: Bond University
Date: 17-10-2023
DOI: 10.53300/001C.89083
Publisher: Oxford University Press (OUP)
Date: 07-08-2009
DOI: 10.1093/JNCI/DJP232
Abstract: The National Cancer Institute of Canada Clinical Trials Group CO.17 study showed that patients with advanced colorectal cancer had improved overall survival when cetuximab, an epidermal growth factor receptor-targeting antibody, was given in addition to best supportive care. We conducted a cost-effectiveness analysis using prospectively collected resource utilization and health utility data for patients in the CO.17 study who received cetuximab plus best supportive care (N = 283) or best supportive care alone (N = 274). Direct medical resource utilization data were collected, including medications, physician visits, toxicity management, blood products, emergency department visits, and hospitalizations. Mean survival times for the study arms were calculated for the entire population and for the subset of patients with wild-type KRAS tumors over an 18- to 19-month period. All costs were presented in 2007 Canadian dollars. One-way and probabilistic sensitivity analysis was used to determine the robustness of the results. Cost-effectiveness acceptability curves were determined. The 95% confidence intervals (CIs) for the incremental cost-effectiveness ratios and the incremental cost-utility ratios were estimated by use of a nonparametric bootstrapping method (with 1000 iterations). For the entire study population, the mean improvement in overall and quality-adjusted survival with cetuximab was 0.12 years and 0.08 quality-adjusted life-years (QALYs), respectively. The incremental cost with cetuximab compared with best supportive care was $23,969. The incremental cost-effectiveness ratio was $199,742 per life-year gained (95% CI = $125,973 to $652,492 per life-year gained) and the incremental cost-utility ratio was $299,613 per QALY gained (95% CI = $187,440 to $898,201 per QALY gained). For patients with wild-type KRAS tumors, the incremental cost with cetuximab was $33,617 and mean gains in overall and quality-adjusted survival were 0.28 years and 0.18 QALYs, respectively. The incremental cost-effectiveness ratio was $120,061 per life-year gained (95% CI = $88,679 to $207,075 per life-year gained) and the incremental cost-utility ratio was $186,761 per QALY gained (95% CI = $130,326 to $334,940 per QALY gained). In a sensitivity analysis, cetuximab cost and patient survival were the only variables that influenced cost-effectiveness. The incremental cost-effectiveness ratio of cetuximab over best supportive care alone in unselected advanced colorectal cancer patients is high and sensitive to drug cost. Incremental cost-effectiveness ratios were lower when the analysis was limited to patients with wild-type KRAS tumors.
Publisher: Informa UK Limited
Date: 2009
DOI: 10.1080/07357900802210752
Abstract: Vascular endothelial growth factor (VEGF) is the key molecule mediating tumor growth and malignant ascites formation. We recently reported that, in an end stage OVCAR-3 xenograft model, albendazole (ABZ) suppresses ascites formation, but not tumor growth. Hence, in the present study, we assessed the effect of ABZ on in vitro OVCAR-3 cell proliferation plus in vivo tumor growth, however, initiating ABZ treatment at mid stage (3 weeks post cell inoculation) rather than end stage disease. Here, ABZ treatment led to potent inhibition of cell proliferation, VEGF suppression, complete inhibition of ascites formation and most strikingly arrest of tumor growth.
Publisher: Springer Science and Business Media LLC
Date: 25-08-2012
DOI: 10.1007/S13187-011-0261-8
Abstract: There is an urgent need for efficient cancer education programmes to promote safe practice in a comprehensive cancer centre. Educational practice has developed historically in an unplanned and inefficient way. Developments in educational theory and information technology provide an opportunity to develop systems with better educational methodology, better efficiency and potential for better impact on safety outcomes. We have developed such a programme at St. George Comprehensive Cancer Centre in Sydney, Australia, and describe here our experience in the first 2 years of implementing such a programme. In this article, we describe the programme, the obstacles and solutions we encountered and our reflections on the journey so far.
Publisher: Wiley
Date: 09-2017
DOI: 10.1111/IMJ.13512
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-12-2007
Abstract: Controversy exists over the optimal dose rate for administration of gemcitabine. There is a strong pharmacologic rationale for increased intracellular accumulation with prolonged infusions, but this failed to translate into a significant benefit in a large randomized study. The purpose of this study was to compare the intracellular pharmacokinetics of gemcitabine given for 30 minutes or for 100 minutes in a crossover design. We randomly assigned 33 patients to a standard dose of 1,000 mg/m 2 over either 30 minutes or 100 minutes. At the second week, they were transferred to the alternate schedule. Blood s les were collected at various times after the gemcitabine infusion. Gemcitabine and difluorodeoxyuridine were measured in plasma by high-performance liquid chromatography (HPLC), and gemcitabine-triphosphate was measured by HPLC in leukocytes. Intracellular accumulation was greater during the 100-minute infusion, which was consistent with previous data. This effect was confounded by an increase in gemcitabine-triphosphate accumulation between weeks 1 and 2, which was consistent with self-induction of gemcitabine accumulation. There was significant heterogeneity: 27% of patients had greater WBC accumulation during the 30-minute infusion (regardless of treatment order). Patients with relatively greater levels of gemcitabine-triphosphate in WBCs tended to have less under-dosing and a greater reduction in midcycle neutrophils. However, this observation did not correlate with plasma gemcitabine levels. This work identifies significant variations in intracellular gemcitabine-triphosphate accumulation between and within in iduals, and it provides evidence that this variation has potential clinical significance. The observed self-induction of gemcitabine metabolism has broad implications for the dosing of nucleoside analogs.
Publisher: Wiley
Date: 15-11-2016
DOI: 10.1111/HIS.13076
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-07-2001
Abstract: Abstract —Tissue factor (TF) is a low-molecular-weight glycoprotein that initiates the extrinsic clotting cascade and is considered a major regulator of arterial thrombogenicity. TF pathway inhibitor (TFPI) is a major physiological inhibitor of TF-initiated coagulation. The aim of this study was to define the complex interplay between TF and TFPI and the regulation of vascular thrombogenicity in a model of vascular remodeling. To determine the levels and pattern of vascular expression of TF and TFPI associated with vascular remodeling, a murine model of flow cessation was studied. TF activity of the arteries increased after ligation ( P .05). Quantitative analysis of homogenates of remodeled carotid arteries revealed increased TF expression but unchanged TFPI expression compared with normal carotid arteries, resulting in enhanced TF activity. To determine the potential therapeutic role of TFPI in this thrombogenic state, mice were treated with intravascular adenoviral delivery of either murine TFPI (Ad-mTFPImyc) or a control adenovirus (Ad-ΔE1). Overexpression of TFPI decreased vascular TF activity compared with viral control ( P .01). Overexpression of TFPI inhibited neointimal formation ( P =0.038), resulting in enhanced luminal area ( P =0.001) 4 weeks after flow cessation. In this murine model of vascular remodeling, an imbalance between TF and TFPI expression is generated, resulting in increased TF activity. Overexpression of TFPI in this model inhibits vascular TF activity and results in attenuation of vascular remodeling associated with flow interruption.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2020
DOI: 10.1186/S12909-019-1922-2
Abstract: Effective communication between patients-clinicians, supervisors-learners and facilitators-participants within a simulation is a key priority in health profession education. There is a plethora of frameworks and recommendations to guide communication in each of these contexts, and they represent separate discourses with separate communities of practice and literature. Finding common ground within these frameworks has the potential to minimise cognitive load and maximise efficiency, which presents an opportunity to consolidate messages, strategies and skills throughout a communication curriculum and the possibility of expanding the research agenda regarding communication, feedback and debriefing in productive ways. A meta-synthesis of the feedback, debriefing and clinical communication literature was conducted to achieve these objectives. Our analysis revealed that the concepts underlying the framework can be usefully categorised as stages, goals, strategies, micro-skills and meta-skills. Guidelines for conversations typically shared a common structure, and strategies aligned with a stage. Core transferrable communication skills (i.e., micro-skills) were identified across various types of conversation, and the major differences between frameworks were related to the way that power was distributed in the conversation and the evolution of conversations along the along the path of redistributing power. As part of the synthesis, an overarching framework “prepare-EMPOWER enact” was developed to capture these shared principles across discourses . Adopting frameworks for work-based communication that promote dialogue and empower in iduals to contribute may represent an important step towards learner-centred education and person-centred care for patients.
Publisher: Wiley
Date: 24-02-2009
Publisher: American Medical Association (AMA)
Date: 02-2018
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JTHO.2016.10.007
Abstract: We performed a meta-analysis to assess the role of immune checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC. Randomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation-defined subgroups. We used the fixed-effects inverse variance-weighted method to pool estimates of treatment efficacy. Statistical tests were two sided. In the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81 treatment-mutation interaction p = 0.03). In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first-line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second-line treatment for these patients.
Publisher: Oxford University Press (OUP)
Date: 13-07-2006
DOI: 10.1002/BJS.5427
Abstract: Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) has been used to treat pseudomyxoma peritonei. The aim of this prospective study was to evaluate survival outcome and treatment-related prognostic markers in patients who underwent CRS and PIC for pseudomyxoma peritonei from appendiceal mucinous neoplasms. Survival data and 12 clinicopathological and treatment-related prognostic variables for survival were obtained prospectively in 50 consecutive patients (23 men). Univariate analysis was used to determine their prognostic significance for overall survival, determined from the time of CRS. The mean(s.d.) age was 52(12) years. Eighteen patients had moderate complications, and six patients had severe complications that required operation or intensive care support. Two patients died after surgery. The actuarial 5-year survival rate was 69 per cent. Univariate analysis demonstrated that the extent of previous surgery (P = 0·045) and Ronnett's histopathological classification (P & 0·001) were significantly related to overall survival. CRS combined with PIC was associated with improved survival in patients with less extensive previous surgery and diffuse peritoneal adenomucinosis histopathological type.
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.EJSO.2006.06.007
Abstract: Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy has been reported as a treatment option for patients with peritoneal carcinomatosis from colorectal carcinoma. Thirty patients with colorectal peritoneal carcinomatosis underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy. All appendiceal cancers were excluded. All patients were followed until January 2006 or death. Univariate analysis was performed to evaluate significant prognostic factors for overall survival, defined from the time of surgery. There were 13 male patients. The mean age at the time of surgery was 54years. There was no hospital mortality. The mean duration of hospital stay was 27days. The overall median survival was 29months, with 1- and 2-year survival of 72% and 64%, respectively. Twenty-one patients had complete cytoreduction and their 1- and 2-year survival rates were 85% and 71%, respectively. Univariate analysis demonstrated that patients with non-mucinous colorectal adenocarcinoma, Peritoneal Cancer Index (PCI) < or =13, and complete cytoreduction were associated with an improved survival. This study reported on 30 patients who underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis. Patients with mucinous tumour had relatively more extensive intraperitoneal disease. Non-mucinous colorectal adenocarcinoma, PCI < or =13, and complete cytoreduction were associated with an improved survival.
Publisher: American Association for Cancer Research (AACR)
Date: 2007
DOI: 10.1158/1535-7163.MCT-06-0264
Abstract: Tumor-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, has strong prognostic relevance, and is thus a potential therapeutic target. Experimental data published to date has established the proof-of-principle of uPA targeting by 213Bi-labeled plasminogen activator inhibitor type 2 (α-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of α-PAI-2 in mice, using both single and multiple-dose schedules, administered by an i.p. route. We also present novel data showing that human PAI-2 inhibited murine uPA and was specifically endocytosed by murine fibroblast cells. This diminishes potential problems associated with species specificity of the targeting reagent in toxicologic assessments as human α-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg α-PAI-2 did not reach the maximum tolerated dose (MTD). The MTD for a multiple fractionated (once daily for 5 days) administration schedule was determined to lie between 4.8 and 6.0 mCi/kg/d × 5. Comparison of the tumor growth rates and survival using sub-MTD single and multiple-dose schedules in an orthotopic human breast carcinoma xenograft murine model indicated that 4.8 mCi/kg/d × 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of α-PAI-2 administration in mice, thus confirming that it is an efficacious therapeutic modality against tumor growth. This will allow detailed safety evaluation in a second species and for the initiation of human studies. [Mol Cancer Ther 2007 (1):203–11]
Publisher: Springer Science and Business Media LLC
Date: 04-02-2006
DOI: 10.1007/S00280-006-0189-6
Abstract: We wished to define the maximum tolerated dose (MTD), toxicity, and pharmacokinetics of the novel isoflav-3-ene, NV06 (Phenoxodioltrade mark), a compound with a diphenolic structure related chemically and biologically to genistein and flavopiridol. Twenty-one patients with advanced cancers were treated with weekly intravenous administration of NV06 at escalating dose levels with 1-4 patients at each dose cohort. Plasma s ling was undertaken to characterize the pharmacokinetic (PK) profile of the compound. Toxicity was minimal, with asymptomatic Grade 3 lymphocytopenia occurring in nine patients. Nine patients developed Grade 1 nausea, six patients developed Grade 1 increases in alkaline phosphatase, and six patients developed Grade 1 increases in transaminases. Two patients experienced hypersensitivity reactions. The MTD was not reached. Most patients had progressive disease on treatment but eight completed 12 weeks and two completed 24 weeks of treatment. The best response was stable disease of 6 months duration. The plasma half-life (T1/2), clearance (Cl), and volume of distribution (VD) were 304 (+/-91) min, 82 (+/-19) ml/min and 32,663 (+/-7,199) ml, respectively, for total NV06. NV06 is well tolerated and can be given safely as an intravenous infusion over 1-2 h at a dose of at least 30 mg/kg.
Publisher: Springer Science and Business Media LLC
Date: 28-07-2005
Abstract: Bisphosphonate therapy has been readily accepted as standard of care for in iduals with bone metastases from breast cancer. In this study we determined whether the proportion of patients experiencing a skeletal related event (SRE) in a clinical practice population was similar to that observed in phase III randomized controlled studies. A retrospective chart review was conducted of 110 patients receiving intravenous bisphosphonates for advanced breast cancer. The proportion of patients experiencing at least one SRE after 12 months of therapy was determined. SRE included vertebral or non-vertebral fracture, cord compression, surgery and/or radiotherapy to bone. The proportion of patients who had an SRE was 30% (28 in iduals) and the median time to first event was greater than 350 days. Non-vertebral events and radiotherapy were the most frequent type of SRE, while cord compression and hypercalcaemia were rare (1%). Most patients in the study had bone-only disease (58.2%) and most had multiple bone lesions. In the first 12 months the mean duration of exposure to intravenous bisphosphonates was 261 days and most patients remained on treatment until just before death (median 27 days). This study suggests that the rate of clinically relevant SREs is substantially lower than the event rate observed in phase III clinical trials. We attribute this lower rate to observational bias. In the clinical trial setting it is possible that over-detection of skeletal events occurs due to the utilisation of regular skeletal survey or radionucleotide bone scan, whereas these procedures are not routine in clinical practice. Phase IV observational studies need to be conducted to determine the true benefits of bisphosphonate therapy in order to implement rationale use of bisphosphonates.
Publisher: Elsevier BV
Date: 08-2005
Publisher: Wiley
Date: 20-07-2006
DOI: 10.1111/J.1440-1673.2006.01597.X
Abstract: The aim of this study was to audit the results of a high-dose, combined-modality prospective protocol for non-small-cell lung cancer in terms of survival, disease-specific survival and toxicity. One hundred and twenty-one patients with non-small-cell lung cancer were treated with a concurrent, end-phase, boost, high-dose radiotherapy protocol with 65 Gy in 35 fractions for more than 5 weeks. Sixty-six patients received radiotherapy alone (group 1), 29 received concurrent chemoradiation (group 2) and 26 received neoadjuvant and concurrent chemotherapy (group 3). Thirty-four patients had stage I disease, six had stage II and 81 had stage III. Overall median survival was 23 months: 75% at 1 year and 23% at 5 years. Median survivals for patients with stage I and stages II and III disease were 43 and 19 months, respectively. For stages II and III patients by groups 1-3, median survivals were 18, 25 and 18 months, respectively, and 2-year survivals were 36, 52 and 38%, respectively. Toxicity was acceptable. Overall, 9% had symptomatic pneumonitis and 7% had grades 3 and 4 oesophagitis. For those who had the mediastinum included in the volume, grade > or = 3 oesophagitis occurred in 0, 11 and 22% (n = 110, P = 0.001), respectively, for treatment groups 1-3. Overall treatment-related mortality was 3%, consisting of two septic deaths, one pneumonitis and possibly one late cardiac event, all occurring in patients who had chemotherapy (7% of 55 patients). Treatment-related mortality declined over the study period. Accelerated radiotherapy was well tolerated, with only moderate increased acute toxicity when combined with concurrent platinum chemotherapy. Toxicity was enhanced by induction chemotherapy. Overall survival outcomes were excellent for this condition. Continued use of this radiotherapy schedule is recommended as the platform for assessment of other chemotherapy schedules.
Publisher: Cambridge University Press (CUP)
Date: 06-02-2015
DOI: 10.1017/S1478951514001333
Abstract: Psychosocial interventions directed to couples where one has advanced cancer can reduce distress, enhance communication, and provide an opportunity for relational growth. The present study aimed to develop an intervention to facilitate communication about living with advanced cancer using the Patient Dignity Inventory (PDI) as the focus of a clinical interview with couples toward the end of life. Couples were recruited from oncology and palliative care services at a Sydney hospital. After the PDI was developed and manualized as an intervention for couples, the PDI–Couple Interview (PDI–CI) was delivered by a clinical psychologist and comprised the following: (1) the patient completed the PDI (2) the patient's identified partner completed the PDI about how they thought the patient was feeling and (3) the clinician reviewed the results with the couple, summarizing areas of concurrence and discordance and facilitating discussion. Some 34 couples were referred, of which 12 consented, 9 of whom completed the clinical interview. Reported benefits included enabling couples to express their concerns together, identifying differences in understanding, and giving “permission to speak” with each other. The focus of the interview around the PDI provided a structure that was particularly acceptable for men. Most couples confirmed that they were “on the same page,” and where differences were identified, it provided a forum for discussion and a mutual understanding of the challenges in managing advanced cancer within a supportive context. Participant couples' experiences of the PDI–CI provide valuable insight into the benefits of this intervention. This preliminary study indicates that the intervention is a relatively simple means of enhancing closer communication and connection between couples where one has advanced cancer and may be an important adjunct in helping prepare couples for the challenges inherent toward the end of life. Further investigation of feasibility with a larger s le is recommended.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2005
DOI: 10.1007/S00280-005-0152-Y
Abstract: This dose escalation study aimed to determine the recommended doses, toxicity and pharmacokinetics of oxaliplatin and gemcitabine given on days 1 and 8 every 21 days. This schedule may maximize dose intensity of both drugs with acceptable or reduced toxicity. Eligible patients had solid malignancies, no more than two prior courses of chemotherapy, ECOG performance status 0-2, neurotoxicity < or = NCI-CTC grade 1 and adequate organ function. Dose escalation commenced at oxaliplatin 40 mg/m(2) and gemcitabine 750 mg/m(2), both given on days 1 and 8 every 21 days, and reached oxaliplatin 80 mg/m(2) and gemcitabine 1,500 mg/m(2). The two highest dose levels were each expanded to six patients to gain additional toxicity data. There were no dose limiting toxicities related to treatment and an MTD was not reached. Five patients (24%) had grade 3 neutropenia, without associated infection, and seven patients (33%) had grade 3/4 thrombocytopenia. Neurotoxicity was mild and no worse than grade 1. Two patients with mesothelioma (10%) had partial responses and 11 patients (52%) had disease stabilization. No pharmacokinetic interaction between oxaliplatin and gemcitabine was detected. Dose intensity was maximal at level 4 (oxaliplatin 70 mg/m(2) and gemcitabine 1,250 mg/m(2)). This schedule allows oxaliplatin and gemcitabine to be delivered at the full dose intensity of each drug with excellent tolerability and predictable pharmacokinetics. The recommended doses for phase II studies are oxaliplatin 70 mg/m(2) and gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days.
Publisher: Informa UK Limited
Date: 2009
Publisher: Informa UK Limited
Date: 11-12-2018
Publisher: Springer Science and Business Media LLC
Date: 11-11-2009
DOI: 10.1007/S00280-009-1157-8
Abstract: Albendazole is a potential anticancer agent that is currently under development for the treatment of cancer. We carried out a dose-finding phase I study of oral albendazole in patients with advanced malignancies. Thirty-six patients with refractory solid tumors were enrolled. Albendazole was given orally on a day 1-14 of a 3 weekly cycle, starting at 400 mg BD with dose escalation until 1,200 mg BD. Serial blood s les were collected up to 96 h and also on day 8 of cycles 1 and 4. The maximum tolerated dose was 2,400 mg per day (1,200 BD). Myelosuppression was the main dose limiting toxicity. Fatigue and mild gastrointestinal upset were the other major adverse effects. 4 out of 24 assessable patients (16%) had a tumor marker response with a fall of at least 50% from baseline values and another patient had a prolonged period of stable marker response. A decline in plasma vascular endothelial growth factor levels was observed. Albendazole was well tolerated on the schedule tested in this trial. The results of this study suggest that the recommended dose for further study is 1,200 mg twice daily for 14 days in a 21-day cycle.
Publisher: Informa UK Limited
Date: 26-03-2018
Publisher: Springer Science and Business Media LLC
Date: 03-1994
DOI: 10.1007/BF00572089
No related grants have been discovered for Matthew Links.