Laminin and type IV collagen in different histological stages of Kaposi's sarcoma and other vascular lesions of blood vessel or lymphatic vessel origin

Immunohistochemical staining was used to demonstrate basement membrane (BM) laminin and type IV collagen in eight cases of Kaposi's sarcoma (KS). These KS were not associated with AIDS and represented different histological stages of the disease: patch (three cases), plaque (one case), and nodule (four cases). Nine cases of benign angiogenic lesions, five of blood vessel origin, and four of lymphatic vessel origin were also studied. An early event in vascular proliferation at the patch stage of KS was an intersection of dermal collagen bundles and the appearance of granular BM material around this space. With the increase of amount and linear arrangement of BM material, well-defined capillaries were formed. Two types of capillary were found in KS lesions. One showed morphological features of blood capillaries, with a round lumen; thick, continuous BM, and occasional pericytes in the wall. The other included irregularly shaped vessels with thin, often disrupted BMs; thus these capillaries morphologically resembled lymphatic capillaries. BM staining also clearly revealed the vascular nature of the nodular lesions of KS, which were composed of a network of slit-like spaces surrounded by BMs. The solid tumor cell areas were sparse; they were composed of spindle-shaped cells surrounded by thin, interrupted basal laminae. By using antibodies against human laminin and human type IV collagen, it was also possible to demonstrate thin, widely disrupted BMs subendothelially in normal dermal lymphatic capillaries. Typically, the BMs in lymphangiomas and lymphangiectasias were continuous and more clearly defined.     

Pimecrolimus cream 1% in the treatment of lichen sclerosus

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory skin condition, which most commonly causes dysuria, pruritus and soreness of the vulval and perianal areas. Potent topical corticosteroids are used for the treatment of LS, but it is well known that they inhibit collagen synthesis and cause skin atrophy as a side effect. METHODS: The present pilot study evaluated the efficacy and safety of pimecrolimus cream 1% applied twice daily for up to 6 months in 29 women with severe LS. RESULTS: Of the 26 subjects who completed the follow-up period, 42% (11/26) were in complete remission with relief from itchiness, pain and inflammation. A 3.5-fold increase in type I collagen synthesis and a 7.5-fold increase in type III collagen synthesis of the affected areas was detected after 2 months of pimecrolimus treatment. There were no systemic adverse reactions, although mild local skin reactions were reported by 50% of the patients. Blood concentrations of pimecrolimus were checked in 10/26 patients (39%) and were undetectable in all cases. CONCLUSIONS: Patient-applied 1% pimecrolimus cream is safe and effective for the treatment of LS.     

Impact of chemotherapy on collagen metabolism: a study of serum PIIINP (aminoterminal propeptide of type III procollagen) in advanced sarcomas

We have previously shown that the serum aminoterminal propeptide of type III procollagen (PIIINP) is a prognostic factor for survival in localised soft-tissue sarcomas, and that elevated values are frequent in metastatic discase. In the present study PIIINP is analysed during chemotherapy in 26 patients with advanced sarcomas. Non-responders had a significantly higher pretreatment level of PIIINP than responders (P=0.05), when only patients with no recent therapeutic interventions were studied. However, during chemotherapy PIIINP followed the clinical course of the malignant disease in only a minority of patients. Patients with recent surgery or recently completed chemotherapy had an increased pretreatment PIIINP value (P=0.03). In these patients PIIINP declined during chemotherapy irrespective of tumour response. A pretreatment PIIINP level within the reference range tended to increase with time irrespective of response. Moreover, the values taken during a chemotherapy infusion were significantly higher than those immediately preceding the corresponding cycle (P=0.001). Our results suggest that pretreatment PIIINP is of value as a prognostic factor for chemotherapy response in patients with advanced sarcomas. During chemotherapy PIINP is of minor importance in monitoring response because of the influence of chemotherapy and other therapeutic interventions on the level of PIIINP.This study was supported in part by grants from the Finnish Cancer Foundations, the Medical Research Council of the Academy of Finland and Finska Läkaresällskapet (Finnish Medical Society)     

Growth velocity, growth hormone therapy, and serum concentrations of the amino-terminal propeptide of type III procollagen

The relationship between serum concentrations of the amino-terminal propeptide of type III procollagen (PIIINP) and growth was assessed in 307 healthy subjects and 82 children with disorders of growth (41 with insufficient growth hormone, 23 with short stature and normal endocrinologic studies, 18 with tall stature) by means of a recently developed, simplified PIIINP radioimmunoassay. The PIIINP value appeared to be related to height velocity; in healthy children of each sex, the pattern of change with age mirrored the shape of the standard height velocity curve; in children with disorders of growth, there was a statistical correlation (p less than 0.001) between PIIINP concentration and height velocity. However, measurement of serum PIIINP alone had no diagnostic value because there was considerable overlap of PIIINP values in children with growth hormone insufficiency, short stature, normal stature, and tall stature. The most appropriate application of PIIINP may be in the monitoring of prepubertal children receiving exogenous growth hormone therapy; in these patients, increases in height velocity were reflected by increases in PIIINP, and early increases in PIIINP may have predictive value.     

Type I collagen degradation product (ICTP) gives information about the nature of bone metastases and has prognostic value in prostate cancer.

Although osteosclerotic bone metastases are characteristic of prostate cancer, mixed metastases with a lytic component are not uncommon. Type I collagen is synthesised by osteoblasts and accounts for about 90% of the organic matrix of bone. We have used new specific immunoassays for PICP (carboxy-terminal propeptide of type I procollagen) and ICTP (cross-linked carboxy-terminal telopeptide of type I collagen) which allow simultaneous assessment of the synthesis and degradation of type I collagen respectively. Forty patients with bone metastases due to prostate cancer at the time of diagnosis were investigated with these methods. Twenty-three of them had sclerotic (S) and 17 had mixed metastases with sclerotic and lytic components (S + L) as assessed by radiographs. The concentrations of PICP and ICTP in serum as well as the activity of alkaline phosphatase (AP) were increased in all patients of the S + L group, who had more aggressive bone disease and a shorter survival than the S group (P < 0.017). The ICTP level was above the reference range in half of the patients in the S group, whereas the PICP and AP levels were elevated in 35%. Of the bone markers, only ICTP was of prognostic significance (P < .05). We conclude that ICTP and PICP give information about the type and activity of the skeletal metastases. In addition, ICTP predicts prognosis.     

Increased postoperative concentrations of tenascin-C in wound fluid

BACKGROUND: Tenascin-C (Tn-C) is the most studied member of a family comprising large oligomeric glycoproteins in the extracellular matrix. The function of Tn-C still is unclear, and the levels of Tn-C in human wound fluid have not been studied. METHODS: The participants in this study were 24 patients referred for elective major gastrointestinal surgery. Concentrations of Tn-C and procollagen propeptides type 1 and type 3 in serum and wound fluid were measured after surgery. RESULTS: In wound fluid, Tn-C was present on postoperative day 1, and the concentration increased from day 5 up to day 7. CONCLUSIONS: The concentration of Tn-C increases postoperatively in wound fluid. The concentration of Tn-C in wound fluid is markedly higher than that of serum. The differences in expression between Tn-C and the procollagen propeptides may reflect different tasks of these extracellular matrix proteins.     

Cross-linked telopeptides of type I and III collagens in malignant ovarian tumours in vivo

Malignant tumours often induce a fibroproliferative response in the adjacent stroma, characterized by increased expression of type I and type III procollagens. In normal tissues, fibrillar collagens normally undergo extensive intermolecular cross-linking that provides tensile strength to the tissue. Here we set out to characterize collagen cross-linking in human ovarian carcinoma tissue in vivo. Biochemical and immunochemical methods were used for cross-linked telopeptides of type I and III collagens in samples of benign and malignant serous tumours. The locations and staining patterns of these proteins were visualized immunohistochemically. The contents of both total collagen and the cross-linked type I and type III collagens in the malignant samples were only about 20% of those in the benign tumours. The cross-linked telopeptide antigens derived from the collagens were smaller and more heterogeneous in size in the malignant than in the benign tumours, indicating a defective cross-linking process scarcely leading to the formation of mature cross-links in the collagen fibres in malignancy. Immunostaining revealed disorganized type I and type III collagen bundles in carcinomas. These findings suggest that the collagen cross-linking process is aberrant in malignant tumours, possibly resulting in increased susceptibility of tumour collagens for the proteolysis often associated with tumour invasion.     

Serum concentrations of CA 125 and aminoterminal propeptide of type III procollagen (PIIINP) in patients with endometrial carcinoma

Serum CA 125 (a marker of coelomic epithelial cells) and aminoterminal propeptide of type III procollagen (PIIINP; an indicator of collagen metabolism) concentrations were measured in 148 patients with endometrial carcinoma. An initial serum concentration of CA 125 was pathologic in 17% of the patients, the frequency of abnormal values being higher (P = 0.0001) in advanced (63%) than in early disease (10%). The serum PIIINP concentration was increased in 35% of the patients and more often (P less than 0.05) so in advanced (63%) than in early disease (31%). Among all the patients, at least one of the tumor markers was increased in 43% of the cases. In early disease 12 of 108 patients contracted recurrent cancer. The accuracy of the pathologic CA 125 (9%) and PIIINP (18%) concentrations in their prediction was poor. In the total material, pathologic CA 125 and PIIINP concentrations appeared simultaneously in 11 patients, of whom eight had poor prognoses. In monitoring of treatment response of 24 patients, regression was accompanied by normal or decreasing CA 125 and PIIINP values. The persistence of pathologic CA 125 and/or PIIINP concentration predicted relapse of the malignancy. In progressive disease, CA 125 and PIIINP concentrations together or separately remained at a pathologic level or increased continuously. In clinically stable endometrial carcinoma, CA 125 gave false-negative results in 71% of the determinations and PIIINP only in 12%. The current results suggest the use of CA 125 and PIIINP, simultaneously, in monitoring the clinical course of advanced endometrial carcinoma.     

Combination drug strategy in recent-onset rheumatoid arthritis suppresses collagen I degradation and is associated with retardation of radiological progression.

OBJECTIVE: To assess whether serum C-terminal cross-linking telopeptide of type I collagen (ICTP), a marker of type I collagen degradation, has any additional value in the assessment of treatment effect in patients with early rheumatoid arthritis (RA). METHODS: A total of 182 patients were randomized to treatment either with three disease-modifying anti-rheumatic drugs (DMARDs) and low-dose prednisolone (COMBI) or with a single DMARD with or without low-dose prednisolone (SINGLE). We investigated the prognostic value of serum ICTP level for the progression of joint destruction in X-rays (Larsen's score) from baseline to 2 years. RESULTS: There was a statistically significant decrease in serum ICTP levels from baseline to 1 year. At 6 months, the serum ICTP level was lower in the COMBI patients compared to that of the SINGLE cases (p = 0.008, after adjustment for baseline ICTP). When grouping the patients according to serum ICTP tertiles at 6 months, there was a statistically significant trend for increasing median change in Larsen score from baseline to 2 years from lowest to highest ICTP tertile in the SINGLE patients [p = 0.008, after adjustment for 28-joint Disease Activity Score (DAS28) score and RF status at baseline], while in the COMBI, the change remained low in all ICTP tertiles. CONCLUSIONS: The COMBI strategy for recent-onset RA results in early suppression of type I collagen degradation, which is reflected in radiological joint damage at 2 years. Serum ICTP at 6 months may be useful for identifying those RA patients whose treatment should be intensified to prevent further joint damage.     

Serum type III procollagen and basement membrane proteins as noninvasive markers of hepatic pathology in Indian childhood cirrhosis

While serum concentrations of antigens of the aminopropeptide of type III procollagen have been considered as indicators of hepatic pathology in adults, the high concentrations normally found in children during growth may preclude their use in pediatric liver disease. To clarify this and to determine the role of other circulating connective tissue-related substances in children, we have measured serum concentrations of antigens related to aminopropeptide of type III procollagen, the 7S domain of type IV collagen and the P1 fragment of laminin in healthy subjects aged 1 month to 4 years and in children with Indian childhood cirrhosis, a particularly aggressive form of liver disease. In healthy subjects, there was a considerable age variation in serum aminopropeptide of type III procollagen but not in 7S collagen or laminin P1. In Indian childhood cirrhosis, all three serum antigens were increased (p less than 0.001) above the upper limit of normal for age. Both the serum 7S collagen and laminin P1 concentrations showed a significant correlation with the degree of intralobular fibrosis and also with the severity of necrosis and cellular infiltration, suggesting that these serum antigens may be a noninvasive means of assessing and monitoring events associated with hepatic fibrosis in Indian childhood cirrhosis. The raised serum aminopropeptide of type III procollagen in Indian childhood cirrhosis did not correlate with any histological parameter assessed. Gel filtration of serum showed that, in healthy subjects, the predominant antigenic form of aminopropeptide of type III procollagen was a degradation peptide smaller than authentic aminopropeptide of type III procollagen; while in Indian childhood cirrhosis the authentic peptide and a larger degradation peptide predominated.(ABSTRACT TRUNCATED AT 250 WORDS)