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Biomedical subjects

M A Forbes

Publications and source records attributed to M A Forbes.

At least 19 recordsLinked to original sources
PubMed2000

Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen.

The assessment of angiogenesis in breast cancer is of importance as a key indicator of survival and response to therapy. Circulating vascular endothelial growth factor (VEGF) measurements may provide a less subjective analysis than microvessel density (MVD) or immunohistochemical analysis of VEGF expression; however, most studies have used serum, which is now known to largely reflect platelet-derived VEGF concentrations. This study examined for the first time both plasma (VEGFp) and serum (VEGFs) VEGF concentrations in 201 blood samples from pre- and postmenopausal healthy controls and from patients with benign breast disease, localized breast cancer, breast cancer in remission, or metastatic breast cancer and related these to other clinicopathological markers. VEGFp but not VEGFs concentrations of patients with localized disease were significantly elevated compared with normal controls (P = 0.016). Patients with metastatic disease had higher VEGFp and VEGFs levels than normal controls (P < 0.001, P = 0.044 respectively), and higher VEGFp, but not VEGFs, than patients with benign disease (P = 0.009) and patients with localized disease (P = 0.004). However, the highest VEGFp and VEGFs concentrations were seen in patients in remission compared with normal controls (P < 0.001 and P = 0.008, respectively). VEGFp concentrations in patients in remission were also higher than in patients with benign disease (P = 0.01) or patients with localized disease (P = 0.005). Tamoxifen treatment was significantly associated with higher circulating and platelet-derived VEGF levels. Circulating VEGF did not correlate with any clinicopathological factor, including MVD or VEGF expression. VEGF expression was significantly correlated with estrogen receptor status and inversely correlated with tumor grade. MVD correlated with tumor size. Tamoxifen-induced increases in VEGF may be important in clinical prognosis or associated pathologies.

Adult↗
PubMed2000

Subcutaneous administration of recombinant glycosylated interleukin 6 in patients with cancer: pharmacokinetics, pharmacodynamics and immunomodulatory effects.

This is the first report of the serum profile of a glycosylated recombinant form of human IL-6 (rhIL-6) administered subcutaneously (1-10 microg/kg/day) in a phase I/II trial as a thrombopoietic agent in patients with advanced cancer. The pharmacodynamic effects of IL-6 were also examined. Detailed pharmacokinetic measurements were made in four patients. Peak concentrations at 5-8 h and a median t0.5 of ca. 5 h were similar to those previously reported for non-glycosylated IL-6. However, higher peak concentrations and apparent differences in effective dose levels to those previously reported with the non-glycosylated form were seen. Indications of an apparent attenuation in circulating IL-6 concentrations with continuing injections were seen in eight of 10 patients examined but anti-IL-6 antibody generation was seen in only two patients. Soluble interleukin 6 receptor concentrations generally decreased. No major changes in T cell subsets were seen but expression of CD25 and CD54 by T lymphocytes significantly increased, accompanied by marked increases in soluble CD25 (sIL-2R) and CD54 (sICAM-1). No consistent change in B cells, monocytes or NK cells were seen. No evidence for induction of TNF-alpha was found. This study demonstrates similar biological effects of glycosylated rhIL-6 to those reported for the non-glycosylated form but illustrates several apparent differences which are discussed further.

Adjuvants, Immunologic↗
PubMed1999

Hope in the older adult with chronic illness: a comparison of tow research methods in theory building.

When current theory about a concept of interest is insufficient, the researcher may desire to build or expand theory. Two research methods for building nursing theory are compared by asking the same question using each method. Phenomenology was used to analyze the interviews of six older adults with chronic illness regarding their experience of hope. Eight theme categories depicted the essential structure. Using concept mapping, eight older adults with chronic illness generated statements about hope. Nine clusters resulted. The methods are compared for procedure and outcome. Although differing with regard to time and participant involvement, the similarity of outcomes suggests that qualitative research is robust.

Adaptation, Psychological↗
PubMed1998

Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor with a key role in several pathological processes, including tumour vascularization. Our preliminary observations indicated higher VEGF concentrations in serum samples than in matched plasma samples. We have now demonstrated that this difference is due to the presence of VEGF within platelets and its release upon their activation during coagulation. In eight healthy volunteers, serum VEGF concentrations ranged from 76 to 854 pg ml(-1) and were significantly higher (P < 0.01) than the matched citrated plasma VEGF concentrations, which ranged from < 9 to 42 pg ml(-1). Using platelet-rich plasma, mean (s.d.) platelet VEGF contents of 0.56 (0.36) pg of VEGF 10(-6) platelets were found. Immunocytochemistry demonstrated the cytoplasmic presence of VEGF within megakaryocytes and other cell types within the bone marrow. From examination of the effects of blood sample processing on circulating VEGF concentrations, it is apparent that for accurate measurements, citrated plasma processed within 1 h of venepuncture should be used. Serum is completely unsuitable. The presence of VEGF within platelets has implications for processes involving platelet and endothelial cell interactions. e.g. wound healing, and in tumour metastasis, when platelets adhering to circulating tumour cells may release VEGF at points of adhesion to endothelium, leading to hyperpermeability and extravasation of cells.

Adult↗
PubMed1998

Serum concentrations of soluble adhesion molecules in patients with colorectal cancer.

The concentrations of the soluble adhesion molecules E-cadherin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were investigated in 48 patients with colorectal cancer before treatment, and their relation to clinical, histological and routine laboratory parameters was examined. Data were collected on tumour stage at presentation, presence and sites of metastatic disease, tumour pathology and results of routine laboratory tests. Serum concentrations of ICAM-1 and VCAM-1 were significantly elevated in the patients with colorectal cancer in comparison with a group of healthy subjects (P < 0.00001). Levels of circulating ICAM-1 and VCAM-1 were increased both in patients with local and those with metastatic disease. Although elevated in some patients soluble E-cadherin and E-selectin concentrations were not significantly elevated compared with the control group (P = 0.71 and P = 0.052 respectively). The levels of circulating ICAM-1 were significantly correlated with those of VCAM-1 and E-selectin. A correlation was also found between the serum concentrations of E-selectin and ICAM-1 and alkaline phosphatase, total white cell count and platelet count. VCAM-1 was positively correlated with age and negatively with degree of tumour differentiation and haemoglobin concentration. The biological implications and possible clinical relevance of these findings are discussed.

Adult↗
PubMed1998

Evidence for the existence of a novel pregnancy-associated soluble variant of the vascular endothelial growth factor receptor, Flt-1.

Angiogenesis is essential in physiological processes including ovulation, implantation and pregnancy. One of the most potent regulators is the cytokine vascular endothelial growth factor (VEGF). We provide evidence for a novel pregnancy-associated soluble variant of the VEGF receptor Flt-1. VEGF ranged from undetectable to 157.3 pg/ml (mean 49.9 pg/ml, SD 48.4 pg/ml) in plasma samples from normal volunteers (n = 10), but was undetectable in plasma from pregnant women (n = 12) and amniotic fluid (n = 10). Recoveries of spiked VEGF were poor in pregnancy-related samples, indicating the presence of VEGF-binding activity which was confirmed using biosensor and chromatographic techniques. Partial purification and protein sequencing indicated a novel soluble form of Flt-1 with a subunit size of 150 kDa. Normally present as a multimeric structure of approximately 400-550 kDa, complexes of 600-700 kDa were formed following binding of multiple VEGF molecules. Reverse transcriptase polymerase chain reaction of Flt-1 in placenta, amnion, chorion, human umbilical vein endothelial cells and cord blood samples produced bands of the predicted sizes but failed to identify any additional RNA species, and possible reasons for this are discussed. Soluble Flt-1 may be important in regulating the actions of VEGF in angiogenesis and trophoblast invasion and may have therapeutic implications in diseases with inappropriate angiogenesis such as proliferative retinopathies and cancer.

Amino Acid Sequence↗
PubMed1997

Treatment of metastatic renal cell carcinoma with subcutaneous interleukin 2: evidence for non-renal clearance of cytokines.

The circulating cytokine concentrations following administration of subcutaneous recombinant interleukin 2 (IL-2) in combination with interferon alpha and 5-fluorouracil used to treat advanced renal cancer were studied. One patient was anephric and on dialysis, and seven had normal biochemical renal function, although five had undergone single nephrectomy. The pharmacokinetics of IL-2 and changes in IL-6 and tumour necrosis factor (TNF)-alpha were essentially similar in all patients including the anephric patient, irrespective of the periods of dialysis, although at some time points, IL-2 concentrations were slightly higher in the anephric patient than in the others. These results show that for subcutaneous administration of low-dose IL-2, renal clearance of IL-2 is not important. This contrasts with high-dose, intravenous IL-2 where blood concentrations are higher and renal clearance seems to occur, perhaps because of saturation of the non-renal mechanisms of clearance. The subcutaneous route is certainly preferred if IL-2 is used in anephric patients and in those with impaired renal function, and it may be generally preferred for most purposes.

Adult↗
PubMed1997

Circulating soluble adhesion molecules E-cadherin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in patients with gastric cancer.

The concentrations of the soluble adhesion molecules E-cadherin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were investigated in 45 patients with gastric cancer before treatment and their correlation with clinical, histological and routine laboratory parameters was examined. Data were collected on tumour stage at presentation, presence and sites of metastatic disease, tumour pathology, survival and results of routine laboratory tests. Serum concentrations of ICAM-1 and VCAM-1 were significantly elevated in the patients with gastric cancer in comparison with the group of healthy subjects (P < 0.00001 and P < 0.0001 respectively). Increased serum concentrations of VCAM-1 were associated with locally advanced and metastatic disease whereas ICAM-1 was significantly elevated both in local and in advanced/metastatic disease. Soluble E-cadherin and E-selectin concentrations did not show any significant elevation in gastric cancer patients. Concentrations of soluble adhesion molecules showed significant correlation with each other (except E-selectin and VCAM-1) and with alkaline phosphatase. Soluble ICAM-1 and VCAM-1 were significantly associated with an elevated total white cell count. Patients with elevated VCAM-1 had significantly poorer survival in comparison with patients with normal serum levels (P = 0.0361).

Adult↗
PubMed1996

A phase II study of interferon-alpha, interleukin-2 and 5-fluorouracil in advanced renal carcinoma: clinical data and laboratory evidence of protease activation.

OBJECTIVE: To confirm the activity and evaluate the toxicity of the combination of subcutaneous interferon-alpha (IFN-alpha) and interleukin-2 (IL-2) with intravenous 5-fluorouracil (5-FU) in patients with advanced and recurrent renal carcinoma and of performance status 0-2. Additionally, to examine protease, complement and neutrophil activation as potential mediators of IL-2 toxicity. PATIENTS AND METHODS: Fifty-five patients were treated in an 8-week cycle with IFN-alpha (6 MU/m2 on day 1 in weeks 1 and 4 and thrice weekly in weeks 2-3, and 9 MU/m2 thrice weekly in weeks 5-8) IL-2 (20 MU/m2 on days 3-5 in weeks 1 and 4 and 5 MU/m2 thrice weekly in weeks 2-3) and 5-FU (750 mg/m2 on day 1 of weeks 5-8). Patients responding to the first cycle were eligible to continue with further cycles. Toxicity and effects on quality of life were assessed using World Health Organization criteria and the Rotterdam Symptom Checklist and Hospital Anxiety and Depression Scale. Serum levels of C3a, prekallikrein and elastase-alpha 1 proteinase inhibitor (elastase-alpha 1-antitrypsin) were assayed in a subset of patients before, during and after the administration of high-dose IL-2 in week 1. RESULTS: There were partial remissions in nine patients, with responses in 24% (95% CI 10-38%) of evaluable patients and 16% of all patients. Amongst 25 evaluable patients who had undergone nephrectomy, the response rate was 32% (95% CI 14-50%), whereas there was only one response amongst 22 patients who had not undergone nephrectomy. The median survival for patients with stable disease or partial remission exceeded 22 months. Outcome and survival were related to performance status, number of sites of metastases and nephrectomy. This group of patients was of relatively poor performance status and 18 patients (36%) failed to complete one 8-week treatment cycle. Cardiovascular and renal toxicities were less than those seen with intravenous IL-2 schedules but 44% of patients experienced at least one grade III toxicity and only 14% reported less than two grade II toxicities. Plasma levels of elastase-alpha 1 proteinase inhibitor exceeded the normal range in three of seven patients tested before treatment and increased in all seven patients after treatment with IL-2. The same three patients had raised levels of C3a before treatment and in all patients examined, C3a increased after treatment with IL-2. In contrast, plasma prekallikrein concentrations were below normal before treatment and decreased further afterwards. CONCLUSIONS: This study confirms the activity of this regimen in patients of good performance status, with limited sites of disease and in those who are fit for nephrectomy, but also showed that treatment was associated with considerable toxicity. The administration of IL-2 is associated with protease activation which may be a suitable target for pharmacological intervention in attempts to ameliorate toxicity.

Adult↗
PubMed1996

Bone alkaline phosphatase in rheumatoid arthritis: a longitudinal study.

OBJECTIVE: To determine whether the raised total alkaline phosphatase (TAP) found in patients with active rheumatoid arthritis (RA) is derived primarily from an increase of the bone or liver isoenzyme, and to evaluate the treatment effect of steroids and disease modifying antirheumatic drugs (DMARD) on bone alkaline phosphatase (BAP) in serial analyses. METHODS: 58 patients with RA were treated with the DMARD gold sodium thiomalate (n = 22), D-penicillamine (n = 18), or sulfasalazine (n = 18) over a 24 week period with regular assessment of disease activity and measurement of BAP using a newly developed specific double monoclonal radioimmunometric assay. RESULTS: In the RA group as a whole, BAP correlated with TAP at all time points (e.g., Week 0 rs = 0.50, p < 0.0001). In contrast, no correlation was found between the intraindividual change of BAP and TAP between Weeks 4 and 24. TAP was correlated with disease activity (assessed by plasma viscosity rs = 0.33, p < 0.02 for the whole RA group and rs = 0.48, p < 0.0002 for intraindividual change from Weeks 4 to 24). Similarly, gamma-glutamyltranspeptidase was correlated with disease activity (rs = 0.56, p < 0.0001, and rs = 0.50, p < 0.0001, respectively). In contrast, BAP was not correlated with disease activity. Low dose steroids and the 3 DMARD studied had no significant effect on the time course of BAP. CONCLUSION: In the majority of patients with active RA, any increase of TAP is not mirrored by an increase of BAP. This supports the hypothesis that inflammatory reactions result in an increase in the plasma concentration of the membrane bound enzymes of the hepatobiliary system, including gamma-glutamyltranspeptidase and the liver isoenzyme of alkaline phosphatase, which is likely to be responsible, at least in part, for the increase of TAP. Since BAP is not correlated with disease activity, BAP measurements are not useful in monitoring response to treatment.

Aged↗
PubMed1995

The acute phase protein response in patients receiving subcutaneous IL-6.

IL-6, tumour necrosis factor-alpha (TNF-alpha) and IL-1 are thought to be the key mediators of the acute phase response although much of the evidence is based on in vitro studies. It is not clear to what extent each of the acute phase proteins are regulated in vivo by each of these cytokines. The aim of this study was to examine the effects of IL-6 treatment in eight patients with cancer on the concentrations of an extensive range of positive and negative acute phase proteins. It was part of a larger investigation to assess the value of IL-6 in the management of chemotherapy-induced thrombocytopenia. IL-6 was administered by a daily subcutaneous injection for 7 days at a dose level of 1, 3, or 10 micrograms/kg/day. Increases in the positive acute phase proteins, serum amyloid A, C-reactive protein, alpha 1-acid glycoprotein, alpha 1-antichymotrypsin, haptoglobin, alpha 1-antitrypsin, fibrinogen, complement component C3, and caeruloplasmin, were observed, with the greatest incremental changes and fastest responses being seen for C-reactive protein and serum amyloid A protein. The negative acute phase proteins transferrin, transthyretin and retinol binding protein all fell to a nadir within 48-96 h after the first IL-6 injection. Increases in complement component C4 were only found in two patients, which may be related to the increase in circulating TNF-alpha concentrations found only in these patients. This study has therefore shown that IL-6 is capable of causing changes in the majority of acute phase proteins in vivo. Although secondary induction of TNF-alpha was not observed in the majority of patients examined, it is still possible however that other cytokines involved in regulation of the acute phase response, such as IL-1, may have been induced and contributed to the overall response.

Acute-Phase Proteins↗
PubMed1995

Bone alkaline phosphatase in rheumatic diseases.

A double monoclonal immunoradiometric assay specific for bone alkaline phosphatase (BAP) was used to determine whether the raised total alkaline phosphatase (TAP) often found in patients with active rheumatoid arthritis (RA) and ankylosing spondylitis (AS) is derived from bone or liver. Fifty-eight patients with RA were compared to 14 with AS and 14 with non-inflammatory rheumatic diseases (NI). None had clinical liver disease and only one had a slightly elevated aspartate transaminase activity. Elevated BAP concentrations were found in seven patients (5 RA, 1 AS, 1 NI), only two of whom also had abnormal TAP. Abnormal TAP activities were found in only three patients (all RA). BAP did not correlate with disease activity in RA or AS. In contrast, TAP correlated with disease activity (assessed by plasma viscosity) in RA (P < 0.002) and gamma-glutamyl transferase (GGT) also correlated with plasma viscosity in RA (P < 0.01). Both TAP and BAP were significantly correlated with GGT in RA (P < 0.001 and P < 0.02, respectively). These findings are discussed, together with possible reasons for the conflicting nature of some of the observations.

Adult↗
PubMed1993

Hyaluronic acid metabolism and its clinical significance in patients treated by continuous ambulatory peritoneal dialysis.

Musculoskeletal syndromes are common in patients treated by dialysis for end-stage renal failure and abnormal connective tissue metabolism has been implicated. Hyaluronic acid is a major component of connective tissue ground substance. Serum, dialysate, and 24-h urine hyaluronic acid was therefore measured in 43 patients treated by CAPD to determine hyaluronic acid metabolism and to relate these variables to morbidity and mortality over an 18-month period. Serum hyaluronic acid was elevated in 71% patients, being correlated with patient age, length of time on dialysis, and weight loss over the preceding 6 months. Small quantities of predominantly low-molecular-weight hyaluronic acid were lost in the urine, whereas much larger amounts of mixed-molecular-weight hyaluronic acid were excreted in peritoneal dialysate. Dialysate hyaluronic acid exceeded serum hyaluronic acid. Baseline serum hyaluronic acid was closely correlated with morbidity and mortality over the following 18 months. Serum hyaluronic acid is an accurate predictor of mortality and morbidity over an 18-month period in patients treated by CAPD. Large quantities of hyaluronic acid are excreted in peritoneal dialysate, which in part represents local hyaluronic acid production.

Adult↗
PubMed1992

Serum bone alkaline phosphatase and CA 549 in breast cancer with bone metastases.

A monoclonal radioimmunometric assay for bone alkaline phosphatase (BAP) developed by Hybritech, USA, with an upper limit of normal of 40 U/l, was examined in 125 patients with breast cancer. Eleven patients who remained tumour free for 5-6 years had small intra-individual variations of BAP. The median value in 33 patients with multiple bone metastases of 60 U/l was elevated when compared with that in 40 patients with no evidence of metastases (22 U/l) and 34 U/l in 16 with limited bone disease (1-2 hot spots). By contrast, only 2 out of 25 patients with extensive local recurrence, lung, or hepatic metastases, without bone involvement showed an increase of BAP (< 200 U/l). The BAP levels were compared to total alkaline phosphatase (TAP), the breast cancer marker CA 549 (HybriBREScan). Longitudinal studies of 15 patients with bony metastases showed that TAP and BAP were well correlated only when the TAP was elevated; CA 549 and BAP could vary independently. The main use of BAP in patients with bone metastases appears to be an aid to the monitoring of treatment; however, it is not significantly raised in limited bone metastases.

Alkaline Phosphatase↗
PubMed1991

Serum hyaluronate as a marker of hepatic derangement in acute liver damage.

Twenty patients with paracetamol(acetaminophen)-induced acute liver damage of varying severity were studied longitudinally with assessment of clinical state, standard liver function tests and radiometric hyaluronate (HYA) assay (Pharmacia). In patients (n = 6) who developed coma, HYA rose rapidly with clinical deterioration to reach a median value of 27,510 micrograms/l, 7 days post-ingestion, which was significantly higher (p less than 0.005) than in patients (n = 7) who exhibited only marked derangement of liver function tests without evidence of encephalopathy, HYA median value of 3240 micrograms/l. These peak values showed no correlation to the peak values of serum alanine aminotransferase (ALT). A third group of patients (n = 7) who were treated with N-acetyl cysteine, did not exhibit any evidence of liver failure and showed no significant rise in levels of HYA or ALT. The data demonstrate that HYA is a rapidly changing marker of liver derangement which appears to follow the clinical course of the patient. The increase to extremely high levels in patients with hepatic encephalopathy, suggests that there is a reversible defect in the hepatic endothelial cell HYA receptor, possibly due to endothelial cell damage or release of toxins from the necrotic liver.

Acetaminophen↗
PubMed1991

Use of mucin like cancer associated antigen (MCA) in the management of breast cancer.

A study of the epithelial mucin marker MCA was made in 233 patients with breast cancer. Only 6% of 72 patients with Stage I-III disease had a raised MCA (greater than 15 U ml-1) when assessed following surgical treatment of the primary tumour. Raised levels of MCA occurred in one out of 20 (10%) patients with stable local recurrence, and six out of ten (60%) patients with progressive local recurrence. In 115 patients with metastases 89 (77%) had a raised MCA, tumour extent and disease activity both influenced the MCA level. The change of MCA level during the treatment of 11 cases of local recurrence and 55 cases of metastatic disease showed a 64 and 84% concordance respectively with the change in clinical status. Coincidental measurement of MCA and bone scans showed a raised MCA in one out of 63 (1.5%) patients with negative or equivocal scans, and 26 out of 35 (74%) with positive scans. MCA provides a useful marker for the monitoring of the treatment of local recurrence and metastatic disease, and an independent indicator of the effects of changes in treatment.

Antigens, Neoplasm↗
PubMed1991

Hyaluronic acid in end-stage renal failure treated by haemodialysis: clinical correlates and implications.

Serum hyaluronic acid was measured in 176 adults and 15 children receiving regular dialysis therapy. Hyaluronic acid was elevated to greater than 80 micrograms/l in more than 90%, with median value 182 micrograms/l (range 39-898 micrograms/l). Concentrations did not correlate with serum creatinine, but showed a significant correlation with duration of dialysis and serum beta 2-microglobulin. Values greater than 400 micrograms/l were frequent in patients whose clinical condition deteriorated, but in others, hyaluronic acid remained stable over 4-15 months. Serum hyaluronic acid is mainly in a high-molecular-weight form, which in the presence of normal hepatic function suggests that there is a metabolic disorder involving connective tissue and/or vascular endothelium that increases with progressive loss of renal function. Hyaluronic acid may also be a biochemical marker of patients whose condition deteriorates despite renal replacement therapy.

Adult↗