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Biomedical subjects

K N Syrigos

Publications and source records attributed to K N Syrigos.

At least 19 recordsLinked to original sources
PubMed2006

Gefitinib (ZD1839, Iressa) as palliative treatment in recurrent or metastatic head and neck cancer.

To assess the level of activity and toxicity of gefitinib (ZD1839, Iressatrade mark) in a population of patients with locally recurrent and/or metastatic head and neck cancer. Patients were recruited into an expanded access programme through the multidisciplinary head and neck clinics at the Royal Marsden and St George's Hospitals. Patients were required to have received at least one course of standard systemic chemotherapy or radiation therapy, or be medically unfit for chemotherapy. Patients were commenced on single-agent gefitinib at a dose of 500 mg day(-1). Clinical, symptomatic and radiological response, time to progression (TTP), survival and toxicity were recorded. A total of 47 patients were enrolled (35 male and 12 female) with a median age of 62 years (range 18-93 years). The observed clinical response rate was 8% with a disease control rate (complete response, partial response, stable disease) of 36%. In all, 34% of patients experienced an improvement in their symptoms. The median TTP and survival were 2.6 and 4.3 months, respectively. Acneiform folliculitis was the most frequent toxicity observed (76%) but the majority of cases were grade 1 or 2. Only four patients experienced grade 3 toxicity of any type (all cases of folliculitis). Gefitinib was well tolerated and yielded symptomatic improvement in one-third of patients. However, this agent appeared to possess limited antitumour activity in this group of patients with head and neck cancer in whom the objective response rate, median TTP and survival were all lower than has been reported in a previous study.

Administration, Oral↗
PubMed2005

Immune responses in advanced colorectal cancer following repeated intradermal vaccination with the anti-CEA murine monoclonal antibody, PR1A3: results of a phase I study.

BACKGROUND AND AIMS: The aim was to determine the toxicity, clinical and immune responses to the murine monoclonal anti-carcinoembryonic antigen (CEA) antibody, PR1A3, in patients with advanced colorectal cancer. MATERIALS AND METHODS: Fifteen patients with advanced colorectal cancer received either 0.5-, 1.0- or 5.0-mg doses of PR1A3 mixed with 10% w/v Alum adjuvant (Superfos Biosector, Denmark) intradermally at 4-week intervals for 3 months. Patient serum was assessed for anti-idiotypic (Ab2), anti-anti-idiotypic (Ab3) and human anti-mouse antibody (HAMA) reactivity. Peripheral blood mononuclear cell (PBMC) proliferation with phytohaemagglutinin (PHA), CEA and PR1A3, stimulated IL-2, IL-4 and IFN-gamma levels and PR1A3-stimulated IL-2 receptor expression during immunotherapy were determined. Comparisons were made with 16 age-matched controls without malignant disease. RESULTS: Hyperimmune sera from 12 of the 15 patients showed Ab2 reactivity with no detectable Ab3 responses. Strong HAMA reactivity was recorded in 7 of the 15 cases with no adverse clinical effect. Delayed-type hypersensitivity (DTH) responses developed in 12 of the 15 patients. Pre-treatment PBMC proliferation with PHA was subnormal in each patient compared with controls, becoming normal (or supranormal) in all patients during immunisation (P<0.001). PBMC proliferation with CEA and PR1A3 increased during immunotherapy (P<0.001) along with stimulated production of IL-2, IFN-gamma and IL-2 receptor expression. Progressive disease was observed in 14 of the 15 patients with minimal toxicity. CONCLUSION: PR1A3 generated limited idiotypic responses but robust DTH reactivity in most patients. In vitro PBMC proliferation with mitogens and recall antigens is greatly increased during the course of immunisation, with a shift in stimulated cytokine profile.

Aged↗
PubMed2005

Management of non-Hodgkin's lymphoma of the thyroid: the Royal Marsden Hospital experience.

A retrospective review was conducted of patients treated for thyroid non-Hodgkin's lymphoma (TNHL) at the Royal Marsden Hospital between 1936 and 1996 to determine the effect of radiotherapy (RT) on outcome. 91 patients were identified from the Thyroid Unit Database. There were 77 females and 14 males with a median age of 65 years (range 22-87 years). RT was delivered according to two separate policies: (1) involved field radiotherapy (IFRT) to the thyroid bed and cervical lymph nodes; (2) extended field radiotherapy (EFRT) covering the thyroid bed, cervical and mediastinal lymph nodes. 89 patients received RT as part of definitive treatment following surgery, to a dose of approximately 40 Gy. 25 patients received IFRT and 64 patients EFRT. 27 patients received cytotoxic chemotherapy. 18 patients (72%) treated with IFRT died of TNHL with a median relapse free survival (RFS) of 10 months and a median overall survival (OS) of 21 months. In contrast, only 29 patients (46%) treated with EFRT died of TNHL with a median RFS of 76 months (p = 0.01 for RFS with respect to IFRT and p = 0.04 for OS). Significantly more patients treated with IFRT relapsed locally (52% vs 27%). There was no difference in the rates of systemic relapse (20% vs 22%). EFRT alone for Stage I, but not for Stage II disease, yielded acceptable rates of local control and disease free survival with doses of at least 40 Gy. These historical data strongly support the addition of combination chemotherapy to the treatment regimen in all patients with Stage II disease. Indeed, in recent years this has become the standard of care for all cases of thyroid lymphoma unless the histology is of marginal zone type (mucosa associated lymphoma tissue (MALT) lymphoma).

Adult↗
PubMed2004

Targeted radiosensitisation by pegylated liposome-encapsulated 3', 5'-O-dipalmitoyl 5-iodo-2'-deoxyuridine in a head and neck cancer xenograft model.

5-Iodo-2'-deoxyuridine (IUdR) is an effective radiosensitiser but its clinical development has been limited by toxicity. Prolonged intravenous infusions of IUdR are necessary for optimal tumour uptake but cause dose-limiting myelosuppression. The lack of selective tumour uptake can lead to radiosensitisation of adjacent normal tissues and enhanced local radiation toxicity. Liposomal IUdR delivery offers selective targeting of tumour tissues and avoidance of local and systemic toxicity. In these studies, we report the development of a pegylated liposome containing a lipophilic IUdR derivative (3', 5'-O-dipalmitoyl-5-iodo-2'-deoxyuridine) for use in a head and neck cancer xenograft model. Initial studies confirmed the ability of IUdR to sensitise two head and neck cancer cell lines to single fractions of radiotherapy (SFRT) and this effect was seen to correlate with the thymidine replacement index in KB cells. In vivo delivery of single doses of either unencapsulated IUdR or pegylated liposomal IUdR (PLIUdR) to nude mice bearing KB xenograft tumours did not enhance the effect of SFRT delivered 16 h later. When PLIUdR was delivered by a protracted administration schedule to a dose of 48 mg kg(-1) over 7 days, it enhanced the effect of both 4.5 Gy SFRT and fractionated radiotherapy. PLIUdR was at least as effective as unencapsulated IUdR delivered by multiple intravenous injections or continuous subcutaneous infusion. Immunohistochemistry with a specific anti-IUdR monoclonal antibody confirmed greater levels of tumour staining in tumours from animals treated with PLIUdR compared with those treated with unencapsulated IUdR.

Animals↗
PubMed2002

Serum E-cadherin concentrations and their response during laparoscopic and open cholecystectomy.

BACKGROUND: Elevated serum levels of the cell adhesion molecule E-cadherin have been associated with the presence of tissue injury and inflammation. We compared soluble E-cadherin response during laparoscopic and open cholecystectomy. METHODS: The E-cadherin response to surgery was studied in 16 patients undergoing laparoscopic cholecystectomy and 12 patients undergoing open cholecystectomy. Serum E-cadherin levels were measured by an enzyme immunoassay (ELISA) preoperatively, 10 and 30 min after the commencement of surgery, and at 6 and 24 h following the operation. RESULTS: Serum E-cadherin levels decreased progressively during laparoscopic cholecystectomy; their concentrations at 24 h after surgery were significantly lower when compared with preoperative values. In the open cholecystectomy group, serum E-cadherin levels did not differ from preoperative values at any time point. Serum E-cadherin concentrations at 24 h after surgery and the cumulative E-cadherin response were significantly higher in the open cholecystectomy group than in the laparoscopic group. CONCLUSION: Compared with open cholecystectomy, the cumulative E-cadherin response is significantly reduced following laparoscopic cholecystectomy.

Cadherins↗
PubMed2002

Colonoscopy in asymptomatic individuals with a family history of colorectal cancer.

BACKGROUND: This study was performed to evaluate the use of total colonoscopy as the optimal screening test in asymptomatic individuals with a family history of colorectal cancer (CRC). METHODS: Colonoscopy was performed in 249 asymptomatic individuals who had one or two first-degree relatives (FDRs) with CRC; individuals with three or more FDRs with CRC were excluded. RESULTS: Eighty-six colonic lesions were found in 51 individuals (51 of 249; 20.5%). Among these 51 subjects, 27 had neoplastic polyps (n = 38) and 29 had metaplastic polyps (n = 44). Although no invasive cancer was detected, in 14 individuals the lesions had a high malignancy potential because of their size and histopathology. We did not confirm a statistically significant difference in the incidence of neoplastic polyps according to the number of affected FDRs. Finally, the presence of metaplastic polyps was a very strong indication for the concomitant presence of metaplastic polyps (P <.0001). CONCLUSIONS: Total colonoscopy is the optimal screening procedure for the examination of asymptomatic individuals with a family history of CRC.

Adult↗
PubMed2001

The effect of irradiation on the biodistribution of radiolabeled pegylated liposomes.

PURPOSE: The effect of total-body irradiation (TBI) on the biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) was evaluated in tumor-bearing nude mice as part of an ongoing effort to develop liposome-targeted radiosensitizers. METHODS AND MATERIALS: Mice received TBI (2 Gy or 5 Gy) according to two protocols: (1) to test the effect of radiation delivered 30 min before liposome injection on the time course of IDLPL biodistribution to tumor and normal tissues over 96 h; (2) to test the effect of radiation at times ranging from 72 h to 1 h before liposome injection on tumor and normal tissue uptake of IDLPL at 24 h. Tumor and tissue/organ levels of liposome uptake were measured by dissection and quantitation in a gamma counter. RESULTS: For most tissues (tumor, liver, kidney, lung, skin, heart, and central nervous system), irradiation did not alter IDLPL biodistribution. Splenic uptake appeared to be increased by TBI, but further analysis revealed that this effect was due to reduced splenic weight in irradiated mice. IDLPL uptake was increased in the small intestine, stomach, musculoskeletal system, female reproductive tract, and adrenal glands in irradiated mice. CONCLUSION: These findings suggest that concomitant administration of liposomal radiosensitizers during radical radiotherapy is likely to be safe. However, caution should be exercised in situations in which significant volumes of small intestine or hemopoietic tissue will be irradiated.

Animals↗
PubMed2001

Serum levels of E-selectin, ICAM-1 and VCAM-1 in colorectal cancer patients: correlations with clinicopathological features, patient survival and tumour surgery.

The serum concentrations of the cell adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were investigated in 63 patients with colorectal cancer and in 51 controls by an enzyme-linked immunosorbent assay (ELISA). Their relationship to clinicopathological variables and patient survival and changes in their levels after surgery were examined. Colorectal cancer patients showed significantly higher serum levels of E-selectin, ICAM-1 and VCAM-1 compared with healthy controls. There was a significant association between the serum levels of these molecules, disease stage and the presence of both lymph node and distant metastases. Both ICAM-1 and VCAM-1 levels correlated with serum E-selectin and carcinoembryonic antigen (CEA) levels. Serum levels of all three molecules decreased significantly after radical resection of the tumour. Elevated pre-operative E-selectin, ICAM-1 and VCAM-1 levels were significant prognostic factors, although not independent of stage, for patient survival. These findings suggest that serum concentrations of E-selectin, ICAM-1 and VCAM-1 may reflect tumour progression and metastasis. Since these markers are linked to CEA levels, it is uncertain whether their measurement will prove cost-effective in colorectal cancer management.

Aged↗
PubMed2001

The development of monoclonal antibody therapy in leukemias.

Conventional cytotoxic management of leukemia has less than optimal results, while it is associated with life-threatening toxic effects due to lack of specificity for hematopoietic cells. Therefore, novel therapeutic strategies with monoclonal antibodies (MAbs) are being explored for delivering chemotherapy or radiation directly to malignant cells. Recently, anti-CD33 antibodies have been engineered to target malignant myeloid and immature normal cells and have been used to deliver cytotoxic agents or radiation to leukemic cells. 131I-labeled anti-CD45 antibodies are used in combination with conventional chemotherapy in leukemic patients receiving marrow transplantation. Additionally, the emergence of Rituximab (against CD20) and Campath-1H (against CD52) for chronic lymphocytic leukemia (CLL) has provided encouraging clinical results for the prognosis of this disease. In conclusion, there has been ongoing research indicating that the approach of patients with leukemia through the application of MAbs might be safer and more effective than current treatment. Considering the preliminary data, MAb therapy appears to be a new, promising weapon in the oncologist's armentarium.

Antibodies, Monoclonal↗
PubMed2000

Epithelial mucin expression in bladder cancer: correlation with pathological and clinical parameters.

Recently, attention has been drawn to the role of polymorphic epithelial mucin (PEM) as a possible target for cancer immunotherapy. To investigate the expression of this molecule in bladder tissue, we used two mouse monoclonal antibodies (HMFGI and HMFG2) raised against the core protein of the PEM. The localization of these two anti-PEM antibodies was examined in normal (n = 10), inflammatory (n = 10) and malignant (n = 67) bladder tissue samples with the use of a three-step avidin-biotin method. For HMFG1 and HMFG2 localization was successful in 78% and 60% of the bladder cancer samples, respectively, where as they were localized only in 30% and 40% of normal bladder tissue samples, respectively. Staining of either antibodies did not correlate with the grade, stage, or survival of bladder cancer patients. We conclude that PEM is frequently overexpressed by bladder cancer cells and HMFG1 is the antibody of choice to be used as a carrier of a cytotoxic agent for application of intravesical targeted therapy of bladder cancer.

Aged↗
PubMed2000

The role of E-cadherin-catenin complex: more than an intercellular glue?

It is now widely recognized that alterations in the adhesion properties of neoplastic cells may play a pivotal role in the development and progression of the malignant phenotype in a range of tumor types. The cadherins and catenins, being the prime mediators of cell-cell adhesion, are intimately involved in the control of morphological differentiation and cellular proliferation; loss of their intercellular function allows malignant cells to escape from their site of origin, degrade the extracellular matrix, acquire a more motile and invasive phenotype, and, finally, invade and metastasize. In addition to participating in tumor invasiveness and metastasis, the E-cadherin-catenin complex is fundamental for the establishment and maintenance of multicellular organisms and regulates or significantly contributes to a variety of functions, including signal transduction, cell growth, differentiation, site-specific gene expression, morphogenesis, immunologic function, cell motility, wound healing, and inflammation. We reviewed the role of the E-cadherin-catenin complex in tumor development and presented the potential clinical applications of these molecules.

Animals↗
PubMed2000

Biodistribution and pharmacokinetics of 111In-DTPA-labelled pegylated liposomes in a human tumour xenograft model: implications for novel targeting strategies.

The biodistribution and pharmacokinetics of 111In-DTPA-labelled pegylated liposomes in tumour-bearing nude mice was studied to examine possible applications of pegylated liposome-targeted anti-cancer therapies. Nude mice received an intravenous injection of 100 microl of 111In-DTPA-labelled pegylated liposomes, containing 0.37-0.74 MBq of activity. The t1/2alpha and t1/2beta of 111In-DTPA-labelled pegylated liposomes were 1.1 and 10.3 h, respectively. Tumour uptake was maximal at 24 h at 5.5 +/- 3.0% ID g(-1). Significant reticuloendothelial system uptake was demonstrated with 19.3 +/- 2.8 and 18.8 +/- 4.2% ID g(-1) at 24 h in the liver and spleen, respectively. Other sites of appreciable deposition were the kidney, skin, female reproductive tract and to a lesser extent the gastrointestinal tract. There was no indication of cumulative deposition of pegylated liposomes in the lung, central nervous system, musculoskeletal system, heart or adrenal glands. In contrast, the t1/2alpha and t1/2beta of unencapsulated 111In-DTPA were 5 min and 1.1 h, respectively, with no evidence of accumulation in tumour or normal tissues. Incubation of 111In-DTPA-labelled pegylated liposomes in human serum for up to 10 days confirmed that they are very stable, with only minor leakage of their contents. The potential applications of pegylated liposomes in the arena of targeted therapy of solid cancers are discussed.

Animals↗
PubMed2000

Influence of tumour size on uptake of(111)ln-DTPA-labelled pegylated liposomes in a human tumour xenograft model.

The relationship between tumour size and uptake of(111)In-DTPA-labelled pegylated liposomes has been examined in a human head and neck cancer xenograft model in nude mice. The mean tumour uptake of(111)In-labelled pegylated liposomes at 24 hours was 7.2 +/- 6.6% ID/g. Liposome uptake for tumours < 0.1 g, 0.1-1.0 g and > 1.0 g was 15.1 +/- 10.8, 5.9 +/- 2.2 and 3.0 +/- 1.3% ID/g, respectively. An inverse correlation between tumour weight and liposome uptake was observed by both Spearman's rank correlation test (r(s)= - 0.573, P< 0.001) and Pearson's correlation coefficient (r(s)= - 0.555, P< 0.001). For 18 tumours with macroscopic central necrosis, the ratio of uptake in the tumour rim relative to the necrotic tumour core was 11.2 +/- 6.4. Measurement of tumour vascular volume for tumours of various sizes revealed an inverse correlation between tumour weight and tumour vascular volume (Spearman's rank correlation test, r(s)= - 0.598, P< 0.001), consistent with poor or heterogeneous vascularization of larger tumours. These data have important implications for the clinical application of pegylated liposome targeted strategies for solid cancers which are discussed in detail.

Animals↗
PubMed2000

Pegylated liposomes have potential as vehicles for intratumoral and subcutaneous drug delivery.

The potential value of intratumoral or s.c. injections of pegylated liposomes as locoregionally targeted therapy of tumors and their draining lymph nodes was assessed in nude mice as part of an ongoing program aimed at developing pegylated liposomal radiosensitizers for the treatment of head and neck cancers. Animals received (111)In-labeled diethylenetriaminepentaacetic acid (DTPA), either encapsulated in pegylated liposomes (IDLPL) or in the unencapsulated form ((111)In-DTPA), as intratumoral or s.c. injections, and the local retention, locoregional nodal drainage, and systemic biodistribution were measured. After intratumoral injections, IDLPL were effectively retained in the tumor with an area under the curve (AUC) between 1 and 96 h of 2,574.4% injected dose per gram hours (%ID/g x h). The corresponding value for (111)In-DTPA was 204.4%ID/g x h. Accumulation of IDLPL was seen in ipsilateral lymph nodes. The maximal ipsilateral:contralateral node ratios were 8:1 (2.2 versus 0.27%ID/g) for inguinal nodes at 24 h and 19:1 (2.5 versus 0.13%ID/g) for axillary nodes at 48 h. Unencapsulated (111)In-DTPA showed no evidence of accumulation in locoregional nodes. After s.c. injection, IDLPL were cleared slowly from the injection site with an AUC between 1 and 192 h of 24,051.1%ID/g x h. Unencapsulated (111)In-DTPA was cleared rapidly with an AUC between 1 and 192 h of 46.4%ID/g x h. Again, significant levels of IDLPL were detected in the ipsilateral locoregional nodes, with ipsilateral:contralateral ratios of 121:1 (57.9 versus 0.48%ID/g) at 24 h (inguinal nodes) and 17:1 (5.2 versus 0.3%ID/g) at 72 h (axillary nodes). There was no retention of unencapsulated (111)In-DTPA in the draining nodes. Locoregional administration of pegylated liposomal radiosensitizers may be a useful approach for targeted therapy of head and neck tumors and their nodal metastases.

Animals↗
PubMed2000

Pegylated liposome-encapsulated doxorubicin and cisplatin enhance the effect of radiotherapy in a tumor xenograft model.

Concomitant chemotherapy and radiotherapy (CCRT) has recently been shown to improve treatment outcome in a range of solid tumors. Pegylated liposomes have the potential to target drugs directly to tumors and may increase the efficacy and reduce the toxicity of CCRT by selectively delivering radiosensitizing agents to tumor, as opposed to normal, tissues. In these studies, we have assessed CCRT using pegylated liposome encapsulated doxorubicin (PLED) and pegylated liposome encapsulated cisplatin (PLEC) against KB head and neck cancer xenograft tumors in nude mice. The addition of low-dose (2 mg/kg) PLED (P < 0.001) and PLEC (P < 0.001) significantly increased the effect of 4.5 Gy, but not 9 Gy, single-fraction radiotherapy (SFRT). Both PLED and PLEC were significantly more effective than their unencapsulated counterparts in increasing the effect of SFRT. In addition, PLED (P < 0.001) and PLEC (P < 0.05) significantly increased the effect of fractionated radiotherapy (9 Gy in 3 fractions) in two different dosing schedules (2 mg/kg single dose or three sequential doses of 0.67 mg/kg). Unencapsulated diethylenetriaminepentaacetic acid and pegylated liposomal diethylenetriaminepentaacetic acid were used as controls to test the effect of the liposome vehicle and showed no interaction with 4.5 Gy or 9 Gy SFRT (P > 0.1). CCRT was well-tolerated, with no evidence of increased local or systemic toxicity, as compared with radiotherapy alone. This study is the first to demonstrate the value of pegylated liposomes as vehicles for the delivery of radiosensitizing drugs in CCRT strategies.

Animals↗
PubMed1999

Role of adhesion molecules in bladder cancer: an important part of the jigsaw.

There is a growing body of evidence suggesting that alterations in the adhesion properties of neoplastic cells may play a pivotal role in the development and progression of bladder cancer. Loss of intercellular adhesion and the desquamation of cells from the underlying lamina propria allows malignant cells to escape from their site of origin, degrade the extracellular matrix, acquire a more motile and invasive phenotype, and finally invade and metastasize. In addition to participating in tumor invasiveness and metastasis, adhesion molecules regulate or significantly contribute to a variety of functions, including signal transduction, cell growth, differentiation, site-specific gene expression, morphogenesis, immunologic function, cell motility, wound healing, and inflammation. To date, a diverse system of transmembrane glycoproteins have been identified that mediate the cell-cell and the cell-extracellular matrix adhesion. The main families of adhesion molecules are the cadherins, integrins, members of the immunoglobulin superfamily, and selectins. We review the recent data regarding the role of selected adhesion molecules in the pathogenesis of bladder cancer and their clinical exploitation as biomarkers of this malignant disease.

Cadherins↗
PubMed1999

Intravesical administration of radiolabelled tumour-associated monoclonal antibody in bladder cancer.

Considerable progress has been made over the past decade in the use of tumour-associated monoclonal antibodies (mAbs) as carriers of cytotoxic agents in the management of several malignancies. In the present study we investigated the tumour localization and biodistribution of the mAb HMFG1 to bladder cancer following intravesical administration. HMFG1, which has been raised against the polymorphic epithelial mucin (PEM), was labelled with 125I and administered intravesically 2 h and 24 h before cystoscopy. During cystoscopy, biopsies were taken from the normal bladder and the malignant lesion. Tissue samples were tested for HMFG1 immunostaining and for radioactivity with the use of a gamma-counter. The mean ratio of tumour to normal uptake for 125I-HMFG1 was 5.81 +/- 1.23, at 2 h and 2.17 +/- 0.42 at 24 h. No radioactivity was detected in the blood. We conclude that HMFG1 could be used intravesically for the successful delivery of a cytotoxic agent.

Administration, Intravesical↗