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Biomedical subjects

Michael Jefford

Publications and source records attributed to Michael Jefford.

18 recordsLinked to original sources
PubMed2006

Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination.

PURPOSE: The marked variability of irinotecan (Ir) clearance warrants individualized dosing based on hepatic drug handling. The aims of this trial were to identify parameters from functional hepatic nuclear imaging (HNI) that correlate with (1) Ir pharmacology, and (2) single-nucleotide polymorphisms (SNPs) for the ABCB1 (P-glycoprotein) and UGT-1A1 genes, known to influence Ir handling. METHODS: Patients underwent genotyping for ABCB1 SNPs and UTUGT-1A1*28 carriage and HNI with 99mTc-DIDA (acetanilidoiminodiacetic acid)/99mTc-DISIDA (disofenin) and MIBI (99mTc-sestamibi) scans, probes for biliary transport proteins ABCC1 and -2, and ABCB1 function. HNI data were analyzed by noncompartmental and deconvolutional analysis to provide hepatic extraction and biliary excretion parameters. Patients received Ir, fluorouracil, and folinic acid using a weekly x2, every-3-weeks schedule. Plasma was taken for Ir and SN-38 analysis on day 1, cycle 1. RESULTS: Of the 21 patients accrued, Ir pharmacokinetics data were obtained from 16 patients. 99mTc-DIDA/DISIDA percent retention at 1 hour (1-hour RET) correlated to baseline serum bilirubin (P = .008). Both 99mTc-DIDA/DISIDA and MIBI 1-hour RET correlated with SN-38 area under the curve (AUC; P < .01). On multiple regression analysis, SN-38 AUC = -215 + 18.68 x bilirubin + 4.27 x MIBI 1-hour RET (P = .009, R2 = 44.2%). HNI parameters did not correlate with Ir toxicity or UGT1A1*28 carriage. MIBI excretion was prolonged in patients with the ABCB1 exon 26 TT variant allele relative to wild-type (P = .015). CONCLUSION: Functional imaging of hepatic uptake and excretory pathways may have potential to predict Ir pharmacokinetics. Evaluation of a larger cohort as well as polymorphisms in other biliary transporters and UGT1A1 alleles is warranted.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Development and evaluation of an audiovisual information resource to promote self-management of chemotherapy side-effects.

Based on a theoretical framework, we developed an audiovisual resource to promote self-management of eight common chemotherapy side-effects. A patient needs analysis identified content domains, best evidence for preparing patients for threatening medical procedures and a systematic review of effective self-care strategies informed script content. Patients and health professionals were invited to complete a written evaluation of the video. A 25-min video was produced. Fifty health professionals and 37 patients completed the evaluation. All considered the video informative and easy to understand. The majority believed the video would reduce anxiety and help patients prepare for chemotherapy. Underpinned by a robust theoretical framework, we have developed an evidence-based resource that is perceived by both patients and health professionals as likely to enhance preparedness for chemotherapy.

Adult↗
PubMed2006

Recent developments in the systemic therapy of advanced gastroesophageal malignancies.

Cancers of the upper gastrointestinal tract are a common cause of worldwide morbidity and mortality. The prognosis for patients with these cancers remains poor and only a minority of patients are cured. Systemic therapy has been used to treat patients with advanced disease but outcomes have not improved dramatically in the past few decades. Newer, more effective agents are desperately needed, and agents such as the taxanes (docetaxel and paclitaxel), irinotecan, oxaliplatin and capecitabine have recently shown some promise. In addition, molecularly targeted, non-cytotoxic therapies are being evaluated with the hope of improving the available therapeutic options. This article reviews the current clinical data regarding systemic therapy for patients with advanced upper gastrointestinal malignancies.

Animals↗
PubMed2005

Beyond 5-fluorouracil: new horizons in systemic therapy for advanced colorectal cancer.

Worldwide, colorectal cancer is a common cancer and a major cause of morbidity and mortality. Patients frequently present with, or later develop, metastatic disease. Median survival with supportive care alone is approximately 6 - 8 months. However, a number of recent developments have greatly increased the range of therapeutic options, improving median survival to > 20 months. Cytotoxic agents such as capecitabine, irinotecan and oxaliplatin are now established treatment strategies. In parallel, an improved understanding of tumour biology has led to the development of non-cytotoxic targeted therapies. Examples include bevacizumab (targeting tumour angiogenesis) and cetuximab (targeting the epidermal growth factor receptor). These agents have recently been incorporated into standard management. This paper reviews these and other advances in the care of patients with advanced colorectal cancer and discusses a number of agents that are currently under development.

Animals↗
PubMed2005

Peer support for cancer patients.

People directly affected by cancer report significant psychological distress. Peer support programs are based on the premise that shared experience is a valuable resource that assists individuals to adjust to, and cope effectively with, stressful events. This article considers two types of peer support service available to cancer patients--telephone peer support (the 'Cancer Connect' program) and cancer support groups.

Australia↗
PubMed2004

The impact of imiquimod, a Toll-like receptor-7 ligand (TLR7L), on the immunogenicity of melanoma peptide vaccination with adjuvant Flt3 ligand.

Dendritic cells (DCs) show promise as adjuvants in anticancer immunotherapeutic strategies. Flt3 ligand (FL) is a hematopoietic growth factor that increases the number of immature DCs in the blood and other tissues. We treated 27 patients with metastatic or high-risk resected melanoma with s.c. FL daily for 14 d in three 28 d cycles. Eighteen of these patients also received vaccination with influenza (Flu), Melan-A (Mel), tyrosinase (Tyr), and NY-ESO-1 peptides. To induce local DC maturation, 8 of the vaccinated patients had imiquimod, a Toll-like receptor-7 ligand (TLR7L), applied topically to their vaccine sites. Patients were monitored for clinical and hematological effects. Immune responses were assessed by cutaneous reactivity to vaccination and by the induction of peptide-specific CD8+ T-cells. Eight patients did not complete the protocol due to adverse events related to their cancer. The treatment was generally safe and well tolerated, although some patients developed clinically significant toxicities related to FL. FL induced increases in immature CD11c+ and CD123+ peripheral blood (PB) DCs. Other hematological effects included monocytosis, granulocytosis, and thrombocytosis, which were marked in some patients. Cutaneous reactions to peptide vaccination and circulating peptide-specific CD8+ T-cells were more frequent in imiquimod-treated patients. FL treatment of melanoma patients has pleiotropic clinical and hematological effects. In vivo maturation of FL-generated DCs using imiquimod may increase immune responses to tumor antigens.

Adjuvants, Immunologic↗
PubMed2004

A novel combination of cisplatin, irinotecan, and capecitabine in patients with advanced cancer.

BACKGROUND: We conducted a dose escalation study combining cisplatin, irinotecan, and capecitabine (CIC), aiming to establish the maximum tolerated doses (MTD), side effect profile, and dose-limiting toxicity (DLT) of this novel regimen. PATIENTS AND METHODS: Intravenous cisplatin and irinotecan were to be administered on days 1 and 8, and oral capecitabine on days 1-14 of a 3-week cycle. The study was conducted in three parts. Part A: escalating doses of irinotecan (40 --> 80 mg/m2) and capecitabine (1000 --> 3300 mg/d) combined with a fixed dose of cisplatin (30 mg/m2). Part B: escalating doses of irinotecan (MTD-A --> MTD-A + 40 mg/m2) with fixed doses of cisplatin (20 mg/m2) and capecitabine (MTD-A level). Part C: escalating doses of capecitabine (1300 mg/d-->2600 mg/d) with fixed doses of cisplatin (20 mg/m2) and irinotecan (60 mg/m2). RESULTS: Of 51 eligible patients 27 (53%) were male, median age was 58 years and 88% had PS 0-1. Major primary disease sites were colorectal (24%), unknown (14%), stomach (14%), and pancreas (12%). MTD-A was cisplatin 30 mg/m2, irinotecan 60 mg/m2, capecitabine 1000 mg/d and MTD-B was cisplatin 20 mg/m2, irinotecan 90 mg/m2, capecitabine 1000 mg/d. An MTD was not formally established for part C. DLTs consisted of infection with neutropenia (1), diarrhea and fatigue (1), hypokalemia (1), diarrhea and febrile neutropenia (1) and C2 delay of > or = 2 weeks or 25% dose reduction in C1 due to neutropenia or thrombocytopenia (6). Seven patients had a partial response to treatment (four colorectal, one SCLC, one NSCLC, one unknown primary), twenty seven SD (53%), twelve PD (24%) and five NE (10%). CONCLUSION: CIC was associated with moderate toxicity and only modest antitumor activity. We conclude that this regimen has insufficient activity to justify further study in the phase II setting.

Adult↗
PubMed2004

Metastatic basal cell carcinoma: rapid symptomatic response to cisplatin and paclitaxel.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in the community, although it rarely metastasizes. The literature reports less than 100 patients who have received chemotherapy for metastatic BCC. A further case of this rare disease is reported here. The pattern of disease in the reported patient was similar to that described in the literature, but the patient experienced a long period with untreated metastatic disease compared with that in the literature. METHOD: The patient was treated with cisplatin in combination with paclitaxel. Literature review suggests this to be the first report of this combination. RESULTS: Rapid symptomatic response was achieved though late neurotoxicity occurred. CONCLUSION: This regimen is an active combination for the rare patient with metastatic BCC. The combination of carboplatin and paclitaxel causes less neurotoxicity and may therefore be a superior regimen.

Antineoplastic Agents↗
PubMed2003

Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli.

Dendritic cells (DCs) are a family of leukocytes that initiate T- and B-cell immunity against pathogens. Migration of antigen-loaded DCs from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. In humans, the major peripheral blood DC (PBDC) types, CD1c+ DCs and interleukin 3 receptor-positive (IL-3R+) plasmacytoid DCs, are significantly expanded in vivo with the use of Flt3 ligand (FL). DC-like cells can also be generated from monocyte precursors (MoDCs). A detailed comparison of the functional potential of these types of DCs (in an autologous setting) has yet to be reported. Here, we compared the functional capacity of FL-expanded CD1c+ PBDCs with autologous MoDCs in response to 3 different classes of stimuli: (1) proinflammatory mediators, (2) soluble CD40 ligand trimer (CD40L), and (3) intact bacteria (Escherichia coli). Significant differences in functional capacities were found with respect to changes in phenotype, migratory capacity, cytokine secretion, and T-cell stimulation. MoDCs required specific stimuli for the expression of functions. They responded vigorously to CD40L or E coli, expressing cytokines known to regulate interferon-gamma (IFN-gamma) in T cells (IL-12p70, IL-18, and IL-23), but required prostaglandin E2 (PGE2) during stimulation to migrate to chemokines. In contrast, PBDCs matured in response to minimal stimulation, rapidly acquired migratory function in the absence of PGE2-containing stimuli, and were low cytokine producers. Interestingly, both types of DCs were equivalent with respect to stimulation of allogeneic T-cell proliferation and presentation of peptides to cytotoxic T lymphocyte (CTL) lines. These distinct differences are of particular importance when considering the choice of DC types for clinical applications.

Antigens, CD1↗
PubMed2003

Rational approaches to human cancer immunotherapy.

Over most of the 20th century, immunotherapy for cancer was based on empiricism. Interesting phenomena were observed in the areas of cancer, infectious diseases, or transplantation. Inferences were made and extrapolated into new approaches for the treatment of cancer. If tumors regressed, the treatment approaches could be refined further. However, until the appropriate tools and reagents were available, investigators were unable to understand the biology underlying these observations. In the early 1990s, the first human tumor T cell antigens were defined and dendritic cells were discovered to play a pivotal role in antigen presentation. The current era of cancer immunotherapy is one of translational research based on known biology and rationally designed interventions and has led to a rapid expansion of the field. The beginning of the 21st century brings the possibility of a new era of effective cancer immunotherapy, combining rational, immunological treatments with conventional therapies to improve the outcome for patients with cancer.

Animals↗
PubMed2002

Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets.

Migration of antigen (Ag)-loaded dendritic cells (DCs) from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. We evaluated monocyte-derived DCs (MoDCs) and peripheral blood DCs (PBDCs) to respond to proinflammatory mediators, CD40L, and intact bacteria. All classes of stimuli induced DC phenotypic maturation. However, for MoDCs, only prostaglandin E(2) (PGE(2))-containing stimuli induced migratory-type DCs. Thus, immature MoDCs that encountered proinflammatory cytokines or CD40L or intact bacteria in the presence of PGE(2) acquired migratory capacity but secreted low levels of cytokines. Conversely, MoDCs that encountered pathogens or CD40L alone become nonmigratory cytokine-secreting cells (proinflammatory type). Interestingly, both migratory- and proinflammatory-type DCs expressed equivalent levels of chemokine receptors, suggesting that the role of PGE(2) was to switch on migratory function. We demonstrate that PGE(2) induces migration via the E-prostanoid 2/E-prostanoid 4 (EP(2)/EP(4)) receptors and the cAMP pathway. Finally, migratory-type MoDCs stimulated T-cell proliferation and predominantly IL-2 secretion, whereas proinflammatory-type MoDCs induced IFN-gamma production. In contrast, CD1b/c(+) PBDC rapidly acquired migratory capacity irrespective of the class of stimulus encountered and secreted low levels of cytokines. This suggests that not all mature stages of DCs are destined to migrate to lymphoid organs and that the sequence in which stimuli are encountered significantly affects which functions are expressed. Thus, certain immature DC subsets recruited from the resting precursor pool may have multiple functional fates that play distinct roles during the induction and effector phases of the immune response. These findings have important implications for the clinical utility of DCs in immunotherapy.

CD40 Ligand↗
PubMed2002

IL-1 beta enhances CD40 ligand-mediated cytokine secretion by human dendritic cells (DC): a mechanism for T cell-independent DC activation.

CD40 ligand (CD40L) is a membrane-bound molecule expressed by activated T cells. CD40L potently induces dendritic cell (DC) maturation and IL-12p70 secretion and plays a critical role during T cell priming in the lymph nodes. IFN-gamma and IL-4 are required for CD40L-mediated cytokine secretion, suggesting that T cells are required for optimal CD40L activity. Because CD40L is rapidly up-regulated by non-T cells during inflammation, CD40 stimulation may also be important at the primary infection site. However, a role for T cells at the earliest stages of infection is unclear. The present study demonstrates that the innate immune cell-derived cytokine, IL-1beta, can increase CD40L-induced cytokine secretion by monocyte-derived DC, CD34(+)-derived DC, and peripheral blood DC independently of T cell-derived cytokines. Furthermore, IL-1beta is constitutively produced by monocyte-derived DC and monocytes, and is increased in response to intact Escherichia coli or CD40L, whereas neither CD34(+)-derived DC nor peripheral blood DC produce IL-1beta. Finally, DC activated with CD40L and IL-1beta induce higher levels of IFN-gamma secretion by T cells compared with DC activated with CD40L alone. Therefore, IL-1beta is the first non-T cell-derived cytokine identified that enhances CD40L-mediated activation of DC. The synergy between CD40L and IL-1beta highlights a potent, T cell-independent mechanism for DC activation during the earliest stages of inflammatory responses.

Adjuvants, Immunologic↗
PubMed2002

Informing and involving cancer patients in their own care.

Doctors have long feared that disclosure of a cancer diagnosis may harm the patient. However, the vast majority of cancer patients in more developed countries prefer to have as much information as possible, regardless of whether it is good or bad. Moreover, these patients are often dissatisfied with the amount and quality of information they receive. Additionally, many patients are unable to participate to the extent that they wish in decisions about their own care, and doctors frequently fail to recognise or appreciate the role that their patients prefer in decision-making. Various information resources have been developed to meet the needs of patients and their families. This paper discusses the information needs and participation preferences of patients with cancer and the consequences of not meeting these expectations. The paper then reviews the types of information resources that have been developed focusing on their reported effectiveness. The review concludes with suggestions for future research.

Decision Making↗
PubMed2002

Phase II trial of continuous infusion carboplatin, 5-fluorouracil, and radiotherapy for localized cancer of the esophagus.

The aim of this study was to determine the toxicity, response rate, failure-free survival, and overall survival in a treatment program comprising continuous infusion carboplatin, short in-fusion 5-fluorouracil (5-FU) and radiotherapy for localized carcinoma of the thoracic esophagus. To be eligible, patients were required to have Karnofsky performance status greater than or equal to 60, adequate organ function, and have received no prior therapy. Planned radiation dose was 50 Gy in 25 fractions over 5 weeks. 5-FU was to be administered commencing days 1 and 29 of radiotherapy, and given at a dose of 1 g/m2/d for 4 days as a continuous infusion. Carboplatin was to commence on day 1 of radiotherapy and be given throughout the period of radiation as a continuous infusion. The starting dose of carboplatin was 28 mg/m2/d. The protocol specified a 25% dose reduction of carboplatin if more than two of the first six patients experienced dose-limiting toxicity (DLT). DLT was defined as grade IV neutropenia lasting more than 7 days, grade IV thrombocytopenia, or any grade IV nonhematologic toxicity. All 23 patients in the study received protocol radio-therapy, except one who was given an extra 10 Gy. Seven patients received carboplatin at 28 mg/m2/d and 16 received 21 mg/m2/d. Hematologic DLTs were experienced by all of the seven patients receiving the higher dose. No patients in the low-dose group experienced hematologic DLTs, and only 2 of 16 ceased chemotherapy early because of myelosuppression. Three patients in the low-dose group experienced grade IV esophagitis but were able to complete protocol radiotherapy. Apart from esophagitis, nonhematologic toxicity was generally moderate or mild. Six patients had thrombosis complicating the central venous catheters. Endoscopy was performed in 21 patients (91%), with an overall complete response rate of 65% (CI: 43-84%) for the whole group or 71% (CI: 48-89%) for the endoscopically evaluated group. Estimated median failure-free survival time was 8.9 months (CI: 7.1-12.9), and estimated median overall survival time was 21.4 months (CI: 9.6 -35.4). Carboplatin at 21 mg/m2/d as a continuous infusion may be given safely in combination with short infusional 5-FU and radiotherapy for localized carcinoma of the esophagus. This combination has resulted in response data comparable to that of larger studies of cisplatin-containing regimens and warrants further study, ideally in a phase III randomized controlled trial.

Adult↗