Summary Cellular adhesion molecules have been implicated in tumour progression and metastasis. This study examines for the first time the serum concentrations of circulating VCAM-1 and E-selectin in a consecutive series of 110 cancer patients seen in a general medical oncology clinic, and confirms and extends previous studies reporting measurement of circulating ICAM-1. Soluble ICAM-1 and VCAM-1 levels were significantly higher in all the patient groups compared with the controls whereas soluble E-selectin was significantly higher in the ovarian, breast and GI cancer groups and lower in the myeloma group. The significance of these results together with the possible sources and stimuli for release of these adhesion molecules are discussed. Sera and patientsBlood samples were obtained from a consecutive series of all patients being seen in a general medical oncology clinic, including those with both localised or advanced disease and those on active therapy or during follow-up. The following malignancies were represented: bladder (n = 6), breast (n = 13), gastrointestinal (n = 18), ovarian (n = 15), renal (n = 12), Hodgkin's disease (n = 15), non-Hodgkin's lymphoma (n = 13), and myeloma (n = 18). Approximately 85% of those with epithelial cancers had clinical evidence of metastases. Samples were allowed to clot, and the serum stored at -70'C until assayed. Samples were also obtained from 89 healthy laboratory and clinical personnel and blood donors (age range 18-60 years) and assayed for E-selectin and VCAM-1. In the case of ICAM-1, a sub-group of 27 of the control samples (age range 24-54 years) were assayed.Assay of soluble adhesion molecules Levels of circulating ICAM-1 were measured with a commercial ELISA kit (British Bio-technology Products, Oxford, UK). Concentrations of circulating E-selectin and VCAM-1 were measured using dual monoclonal antibody two-site ELISAs Pigott et al., 1992). Briefly, microtitre ELISA plates (Nunc Immunoplates, Life Technologies, Paisley, Scotland) were coated overnight with a specific capture antibody (BBIG-E2 for E-selectin, BBIG-V4 for VCAM-1) at a final concentration of 10 tg ml-' in 0.1 M bicarbonate buffer pH 8.9. Standards and samples were added to the plate, incubated for 2 h at room temperature and the bound soluble adhesin of interest was detected by sequential incubation with a specific biotin-labelled antibody (BBIG-E5 for E-selectin, BBIG-V3 for VCAM-1) followed by horseradish peroxidase-conjugated streptavidin (Amersham International, Amersham, UK) and finally tetramethylbenzidine (Universal Biologicals, Kingston-upon-Thames, UK). The reaction was stopped by the addition of 1 M HCI to each well and the O.D. 450 nm measured using a Titertek MS-2 reader (ICN Flow, Rickmansworth, UK). The assays were standardised using a recombinant soluble form of Eselectin or VCAM-1 (Pigott et al., 1991) lacking their transmembrane and cytoplasmic domains and given an arbitrary unitage against which all samples were measured.Statistical analysis Data was analysed using SPSS/PC + . Res...

Summary Although the need for a method of measuring the quality of life of patients undergoing therapy for cancer has been widely recognised, no adequately evaluated or feasible method has been established. We describe a method in which 31 items were assessed by patient self report using linear analogue scales. Eighteen items inquiring about general health problems were derived from the Sickness Impact Profile, an established method of assessing the effect of health upon behaviour and function. Thirteen items inquiring about major problems associated with breast cancer were derived from clinical experience and the opinions of patients with this disease.Each item of the measurement method (instrument) has been evaluated for content, feasability, reliability and validity by methods that are widely used in psychometry but less familiar in medicine. It appeared easy to use, acceptable and reliable in these assessment. Validity was evaluated indirectly since no standard measurements of quality of life exist for comparison. Most items appeared valid when compared to alternative measurement methods including the Sickness Impact Profile and evaluation by a physician in a structured interview. The correlations between items in the instrument were analysed by factor analysis and seemed to fit with the clinical features of breast cancer. The method distinguished between clinically distinct groups of patients and detected changes with time.The study illustrates the possible approaches to the scientific evaluation of methods for measuring subjective features of patients lives. This method appears suitable for some purposes to measure quality of life in breast cancer and is intended to be flexible enough to be modified for other diseases. However, further evaluation, development and refinement will be needed before routine clinical application can be recommended.

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Summary 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 wiare 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.Keywords: E-cadherin; E-selectin; intercellular adhesion molecule-1 (ICAM-1); vascular cell adhesion molecule-1 (VCAM-1); adhesion molecule; colorectal cancer Cellular adhesion molecules play an important role in the process of metastasis. Positive and negative regulation of cell adhesion will influence the process as metastatic cells break away from the primary tumour, travel in the circulation and then adhere to cellular and extracellular matrix elements in particular secondary sites. Several families of cell adhesion molecules have been identified together with specific aberrations in malignant diseases (Zetter, 1993). The cadherins, Ca++-dependent homotypic cell-cell adhesion molecules, are essential for establishing and maintaining intercellular connections. Epithelial cadherin (E-cadherin) plays a crucial role in maintaining the integrity of epithelial tissues and has been positively correlated with tumour differentiation and negatively with infiltrative tumour growth and metastatic potential in a range of cancer types (Takeichi, 1993;Shino et al, 1995). Selectins are transmembrane glycoproteins that mediate heterotypic cell-cell contact through Ca+-dependent interactions with cell surface carbohydrates. In addition to mediating leucocyte adhesion to activated vascular endothelium, endothelial selectin (E-selectin) has been shown to be involved in the adhesion of cancer cells to the vasculature. Stronger adhesion to the endothelium is mediated through other classes of adhesion molecules, namely the integrins and cytokine-inducible endothelial cell adhesion molecules of the immunoglobuli...

Summary Eighty-two patients were randomly allocated to receive intravenous acyclovir 5 mg kg 1t.d.s. for 23 days followed by oral acyclovir 800mg 6-hourly for 6 months or matching placebos after allogeneic bone marrow transplantation. Herpes simplex and varicella zoster virus infections were significantly reduced during the period of administration of acyclovir. No reduction in cytomegalovirus infection was demonstrated. The drug was not toxic.The introduction of acyclovir into clinical practice was a useful development in the management of herpesvirus infections (Selby et al., 1979). The drug has been proved to be a highly effective treatment for herpes simplex (HSV) and varicella zoster virus (VZV) infections both in immune compromised and immune competent patients (Meyers et al., 1982;Balfour et al., 1983;Prober et al., 1982; reviewed by Fiddian & Grant, 1985;Prentice & Hann, 1985;Strauss, 1985;Gore & Selby, 1987). The efficacy and lack of toxicity of acyclovir has led to its use to prevent reactivation of herpesvirus infections. It is effective in the prophylaxis of HSV reactivation both in the immune competent patient with, for instance, recurrent genital herpes simplex and in the immune compromised patient, after, for instance, allogeneic bone marrow transplantation (Saral et al., 1981;Gluckman et al., 1983;Wade, 1984; Fiddian & Grant, 1985;Prentice & Hann, 1985; Straus, 1985;Gore & Selby, 1987). However, information about the prophylaxis of VZV infection is much less complete.The concentrations of acyclovir that are required to inhibit VZV in vitro are much higher than those required to inhibit HSV. This observation, together with the limited absorption of acyclovir when given by the oral route (Brigden & Whiteman, 1985), led to doubt about the effectiveness of acyclovir for the oral treatment or prophylaxis of VZV. However, it has been shown that oral acyclovir in high doses is effective in shortening the duration of VZV infections in immune competent patients (Peterslund, 1985;McKendrick et al., 1986).Reactivation of both HSV and VZV after bone marrow transplantation are a common source of morbidity. Up to 70% of patients who are seropositive for HSV infection develop reactivations and 40% of patients get herpes zoster or varicella (Saral et al., 1981;Locksley et al., 1985). However, evidence that long-term oral acyclovir will prevent the development of VZV was inconclusive. We have therefore carried out a prospective randomised double blind trial of intravenous acyclovir given for 23 days followed by oral acyclovir for 6 months in patients following allogeneic bone marrow transplantation. (Freedman & White, 1976).Acyclovir or placebo was administered to adults at a dose of 5mg kg-1 in 100 ml of normal saline infused over 1 h, given 8-hourly starting on the day before transplantation and continuing for 23 days. At that point adults received 800mg tablets 6-hourly for 6 months. Children less than 12 years of age received 250 mg m-2 acyclovir intravenously followed by 400mg orally 6-hourly. Patients wer...

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Although approximately 50% of patients with non-invasive (Ta) papillary transitional cell carcinoma show no recurrence of their disease, current histopathological approaches cannot distinguish this sub-group from those patients in whom the disease will recur. In this 5 year retrospective study, we have shown that cytokeratin 20 (CK20) was expressed in 19 of 29 (65.5%) of non-invasive papillary tumours of grades 1 or 2. CK20 expression patterns were predictive of disease non-recurrence in a sub-group of eight patients, representing 51.7% of patients with non-recurrent disease. In normal bladder mucosa, CK20 expression was restricted to the terminally-differentiated superficial cell. In eight CK20-positive tumours which showed no recurrence at 5 years, CK20 expression was either restricted to, or most intense in, the luminal cells of the papillae. This pattern of expression was not seen in any of the 15 tumours from the recurrent group. Disruption of normal CK20 expression was highly significantly correlated with recurrent tumours. These results suggest that changes in the expression of differentiation-associated antigens, such as CK20, may be useful in predicting benign versus malignant behaviour and may, therefore, be useful in defining treatment strategies.

Summary Tumour markers CEA, were measured in 33 patients undergoing chemotherapy for advanced colorectal cancer. The aim was to determine whether they could be used to accurately monitor the course of the disease, and reduce the need for imaging. Treatment with a 5-fluorouracil based regimen resulted in a partial response in nine patients (27%), whereas the remainder either had disease stabilisation or suffered from progression. Before treatment the CEA was elevated in 85% of patients and the and CA-242 in 78%. All three markers were elevated in 70% and at least one elevated in 93%. (Hammarstrom, 1985;Gupta et al., 1987;Safi et al., 1987;Sagar et al., 1991;Nilsson et al., 1992). Although none of these markers has proved to be of any particular value in screening for the disease, CEA is commonly used to assess the progress of patients following surgical treatment (Minton et al., 1985) and remains the 'gold standard'. Other markers appear less useful in isolation, but when combined as a panel with CEA may be of greater value than any one marker on its own (Safi et al., 1987;Persson et al., 1989). The aim of this study was to assess whether three tumour markers CEA, are of value in monitoring the progress of patients being treated with systemic chemotherapy for advanced colorectal cancer. Patients and methods PatientsThirty-three patients were studied; 24 were male and nine female, mean ages 58 (range 27-76) and 60 (42-78) respectively. All patients had histologically proven colorectal cancer with metastases. Twenty-six had liver metastases, ten locoregional disease, eight lung metastases, and two with disease at other sites. Several of these patients had disease at more than one site. The patients were a consecutive series in chemotherapy studies which required that the disease was measurable on CT scan. The time interval between presentation with the primary tumour and recurrent disease averaged at 16 months with a range of 0-91 months. Performance status was assessed by means of the Karnofsky scale (Karnofsky et al., 1948), the average being 80 with a range of 70-90.The study was approved by Leeds Eastern District Clinical Research (Ethics) Committee.Treatment schedule All patients received chemotherapy with a 5-fluorouracil (5-FU) based regimen as detailed below. Some of these patients were being treated in a multi-centre study comparing 5-FU and interferon alpha with 5-FU and leucovorin. The results of this study will be published separately. In the 5-FU/ interferon based regimen 5-FU was administered as a continuous intravenous infusion over a period of 5 days at a daily dose of 750 mg m2 followed by weekly intravenous bolus doses also of 750 mg m-2 commencing on day fifteen. Interferon alpha-2a 9 MU, was administered as a subcutaneous injection three times weekly. In the 5-FU/ leucovorin based regimen I-leucovorin 200 mg m-2 was infused over 10 min and followed within 5 min by a bolus of 5-FU at 370 mg m-2 for 5 consecutive days. This cycle was repeated every 4 weeks. Tumour markersA 10 ml sample of ...