Steen Sørensen

High Serum YKL-40 Level after Surgery for Colorectal Carcinoma Is Related to Short Survival

YKL‐40 is a member of family 18 glycosyl hydrolases. YKL‐40 is a growth factor and may stimulate migration of endothelial cells. YKL‐40 may also play a role in inflammation and degradation of connective tissue. Elevated preoperative serum YKL‐40 levels in patients with colorectal carcinoma are associated with a significantly poorer prognosis compared to patients with normal serum YKL‐40. In the current study the authors evaluated the value of serum YKL‐40 in monitoring patients with colorectal carcinoma.

Preoperative plasma plasminogen activator inhibitor type-1 and serum C-reactive protein levels in patients with colorectal cancer

Background: Preoperative plasma plasminogen activator inhibitor-1 (PAI-1) is a prognostic variable in patients with colorectal cancer. It has been suggested, however, that plasma PAI-1 is a nonspecific prognostic parameter similar to the acute-phase reactant C-reactive protein (CRP). In the present study we analyzed the association between plasma PAI-1 and serum CRP in patients scheduled for elective resection of colorectal cancer. In addition, the prognostic value of PAI-1 and CRP was studied in this patient cohort. Methods: PAI-1 and CRP were analyzed in citrated plasma and serum, respectively, obtained preoperatively from 594 patients. Patients who required preoperative blood transfusion received SAGM blood, in which soluble PAI-1 is not present. None of the patients received pre- or postoperative adjuvant chemotherapy, and all were followed in the outpatient clinic for at least 5 years or until death. The association of PAI-1 and CRP, respectively, with survival was tested using the median value of PAI-1 and the upper normal limit for CRP. Analyses were performed by inclusion of all patients, and in the subgroup of patients, who underwent curative resection. Results: The median follow-up period was 6.8 (5.4–7.9) years. The median value of plasma PAI-1 was 35.8 ng/ml, and values greater than 94 nmol/L identified patients with increased CRP levels. Comparison of the molecules showed that PAI-1 was weakly correlated with CRP (r=.26;P<.0001). Both molecules showed a Dukes independent distribution. In univariate survival analyses high levels of PAI-1 were found associated with poor prognosis and low levels with good prognosis (P=.02, HR: 1.3). Similarly, high levels of CRP were found associated with poor prognosis and low levels with good prognosis (P<.0001, HR: 1.9). In a multivariate statistical analysis including Dukes classification, gender, age, tumor location, perioperative blood transfusion, PAI-1 and CRP, plasma PAI-1 was a dependent prognostic variable, while serum CRP (P<.0001; HR: 1.4; 95% CI: 1.3–1.5) was found to be a Dukes independent prognostic variable. Similar analyses, excluding patients with Dukes’ D disease showed serum CRP to be an independent prognostic variable (P<.0001; HR: 1.3: 95% CI: 1.2–1.5). Conclusions: This study did not show a strong correlation between plasma PAI-1 and serum CRP in patients with colorectal cancer. Serum CRP was found to be a Dukes independent prognostic variable in this patient cohort, and was found to identify a subgroup of curatively resected patients at risk for short survival.Background: Preoperative plasma plasminogen activator inhibitor-1 (PAI-1) is a prognostic variable in patients with colorectal cancer. It has been suggested, however, that plasma PAI-1 is a nonspecific prognostic parameter similar to the acute-phase reactant C-reactive protein (CRP). In the present study we analyzed the association between plasma PAI-1 and serum CRP in patients scheduled for elective resection of colorectal cancer. In addition, the prognostic value of PAI-1 and CRP was studied in this patient cohort.Methods: PAI-1 and CRP were analyzed in citrated plasma and serum, respectively, obtained preoperatively from 594 patients. Patients who required preoperative blood transfusion received SAGM blood, in which soluble PAI-1 is not present. None of the patients received pre- or postoperative adjuvant chemotherapy, and all were followed in the outpatient clinic for at least 5 years or until death. The association of PAI-1 and CRP, respectively, with survival was tested using the median value of PAI-1 and the upper normal limit for CRP. Analyses were performed by inclusion of all patients, and in the subgroup of patients, who underwent curative resection.Results: The median follow-up period was 6.8 (5.4–7.9) years. The median value of plasma PAI-1 was 35.8 ng/ml, and values greater than 94 nmol/L identified patients with increased CRP levels. Comparison of the molecules showed that PAI-1 was weakly correlated with CRP (r=.26;P<.0001). Both molecules showed a Dukes independent distribution. In univariate survival analyses high levels of PAI-1 were found associated with poor prognosis and low levels with good prognosis (P=.02, HR: 1.3). Similarly, high levels of CRP were found associated with poor prognosis and low levels with good prognosis (P<.0001, HR: 1.9). In a multivariate statistical analysis including Dukes classification, gender, age, tumor location, perioperative blood transfusion, PAI-1 and CRP, plasma PAI-1 was a dependent prognostic variable, while serum CRP (P<.0001; HR: 1.4; 95% CI: 1.3–1.5) was found to be a Dukes independent prognostic variable. Similar analyses, excluding patients with Dukes’ D disease showed serum CRP to be an independent prognostic variable (P<.0001; HR: 1.3: 95% CI: 1.2–1.5).Conclusions: This study did not show a strong correlation between plasma PAI-1 and serum CRP in patients with colorectal cancer. Serum CRP was found to be a Dukes independent prognostic variable in this patient cohort, and was found to identify a subgroup of curatively resected patients at risk for short survival.

Adoptive transfer of allogeneic cytotoxic T lymphocytes equipped with a HLA-A2 restricted MART-1 T-cell receptor: a phase I trial in metastatic melanoma.

PURPOSE: We did a phase I dose-escalation trial to evaluate the feasibility and safety of intratumoral injections of C Cure 709, an allogeneic, continuous CTL cell line that, restricted by HLA-A2, recognizes MART-1-positive tumor cells through transduction with a T-cell receptor encoding gene. EXPERIMENTAL DESIGN: Cells were administered intratumorally in four dose levels ranging from 10(8) to 10(9) cells/d on days 1, 4, 7, 10, 14, and 28 of each treatment cycle to patients with metastatic melanoma. Main inclusion criteria were HLA-A2 tissue type, MART-1-positive tumor cells, and metastases suitable for ultrasound-guided injections. Patients were assessed for toxicity and response. Three to six patients were treated per dose level. Patients without progressive disease were offered up to three treatment cycles. RESULTS: Fifteen patients received a total of 24 treatment cycles with a total of 266 injections of C Cure 709. Toxicity was minor to moderate and most common injection site reactions were fever, fatigue, nausea/vomiting, and arthralgia/myalgia. Side effects disappeared in general within 24 hours. Toxicity was not dose dependent. One patient obtained a partial response, encompassing both metastases used and not used for intratumoral injections. Remaining patients did not achieve an overall response. In addition, we observed local regression of metastases used for injection in two patients and of metastases not used for injection in one patient. CONCLUSION: Intratumoral injections of C Cure 709 are feasible, safe, and capable of inducing tumor regression. Further investigation in a phase II setting is warranted.

Human placental lactogen and pregnancy-associated plasma protein A in first trimester and subsequent fetal growth

Objective. To study in an optimized design the possible relation between serum levels in weeks 8‐14 of human placental lactogen and pregnancy‐associated plasma protein A and fetal size at delivery.

The role of anti‐Müllerian hormone in female fertility and infertility – an overview

Anti‐Müllerian hormone (AMH) plasma levels reflect the continuous non‐cyclic growth of small follicles, thereby mirroring the size of the resting primordial follicle pool and thus acting as a useful marker of ovarian reserve. Anti‐Müllerian hormone seems to be the best endocrine marker for assessing the age‐related decline of the ovarian pool in healthy women; thus, it has a potential ability to predict future reproductive lifespan. The most established role for AMH measurements is before in vitro fertilization is initiated, because AMH can be predictive of the ovarian response, namely poor and hyper‐responses. However, recent research has also highlighted the use of AMH in a variety of ovarian pathological conditions, including polycystic ovary syndrome, granulosa cell tumors and premature ovarian failure. A new commercial enzyme‐linked immunosorbent assay for measuring AMH levels has been developed, making results from different studies more comparable. Nevertheless, widespread clinical application awaits an international standard for AMH, so that results using future assays can be reliably compared.

Purification and characterization of osteopontin from human milk

Osteopontin (OPN) is expressed in many organs and tissues and has different biological properties related to different molecular forms in respect to size and posttranslational modifications. However, a purification procedure for authentic intact OPN as well as fragments of OPN from an accessible biological source is missing. A four-step procedure was used to purify OPN from human milk, based on its crystal growth inhibitory activity, including anion exchange chromatography, the elimination of casein, hydroxyapatite chromatography, and negative affinity chromatography. Purified OPN was further separated into its different molecular forms by means of a two-step procedure, involving size exclusion chromatography and reverse phase chromatography. A rabbit polyclonal antibody was raised to purified intact OPN and high M(r) OPN components; the immunoreactivity of both forms was almost equal when investigated by enzyme immunoassay (EIA). The procedures facilitate the purification of intact OPN and OPN fragments for purposes of standardization, preparation of monospecific antibodies, and functional studies.

SCHWANGERSCHAFTSPROTEIN 1 (SP1) AS A MATERNAL SERUM MARKER FOR DOWN SYNDROME IN THE FIRST AND SECOND TRIMESTERS

The potential of the maternal serum concentration of schwangerschaftsprotein 1 (MSSP1) as a marker for Down syndrome (DS) pregnancies was evaluated in the fifth to the 20th gestational week using 156 DS pregnancies and 546 unaffected control pregnancies. In DS pregnancies, the median of the multiple of the median (MOM) of MSSP1 was 0·27 [95 per cent confidence interval (CI) 0·11–0·59] in weeks 5–9 (n=25) and 1·28 (CI 1·11–1·49) in weeks 14–20 (n=117), significantly different from controls (P<10−6). In weeks 10–12, the median MSSP1 MOM was 0·89 (CI 0·20–2·09) (n=14), not different from controls (P=0·42). Using MSSP1 alone as a marker for DS gave—in empirical receiver‐operator‐characteristics (ROC) analysis—a detection rate of about 44 per cent for a false‐positive rate of about 5 per cent in weeks 5–9 (using MSSP1 MOM≤cut‐off), whereas a sensitivity of about 20 per cent was found for a false‐positive rate of 5 per cent in weeks 14–20 (using MSSP1 MOM≥cut‐off). In parameterized ROC analysis, the detection rates were 38 and 18 per cent for a false‐positive rate of 5 per cent in weeks 5–9 and 14–20, respectively.

Characterisation of non-maternal serum proteins in amniotic fluid at weeks 16 to 18 of gestation

Proteins found in amniotic fluid are mainly serum proteins, probably of maternal origin. About 5% of the total protein concentration has the potential of being fetal or decidual in origin. Only a few of these proteins have been isolated and characterised. In order to describe the foetal and decidual components in amniotic fluid more extensively, a polyspecific antiserum to amniotic fluid at weeks 16-18 of gestation was raised. Specificities in the antiserum to serum proteins were removed by adsorption. Several proteins of non-serum protein origin reacted with the antiserum. Three of these proteins were chosen for isolation and further characterisation. With the use of immunological methods, SDS-PAGE and N-terminal sequencing we identified two of the proteins as C-terminal propeptides of procollagen Type I and Type III, which have not hitherto been described in amniotic fluid. The third protein, called here protein-4, showed up as homologous to fetal antigen-1 (FA-1) and human dlk, containing EGF-like domains and associated with growth in neuroendocrine tissues and tumours.

Serum tetranectin is an independent prognostic marker in colorectal cancer and weakly correlated with plasma suPAR, plasma PAI‐1 and serum CEA

Soluble tetranectin (TN) was measured preoperatively in serum from 567 patients with primary colorectal cancer and levels were tested for association with prognosis. The prognostic significance of TN was also compared to that of plasminogen‐activator inhibitor‐1 (PAI‐1), urokinase plasminogen activator (uPAR) and carcinoembryonic antigen (CEA). Significantly shorter survival was found for patients with TN levels below a cut‐off point of 7.5 mg/l compared to patients with levels above, as illustrated by Kaplan‐Meier curves. By Cox analyses, log TN, log soluble uPAR as well as log CEA were found to have an independent prognostic value for survival (log TN: HR=0.47, 95% CI: 0.29–0.76); log soluble uPAR: HR=1.65, 95% CI: 1.18–2.31; log CEA: HR=1.11, 95% CI: 1.03–1.20). Based on the multivariate model, a patient with a combination of low levels of TN and PAI‐1 and elevated levels of soluble uPAR and CEA had a 2.43 increased risk as compared to a patient with median levels of these biochemical markers. Significant correlations were found with Dukes stages for all the biochemical markers and between the respective biochemical markers. The findings confirm that TN is a strong prognostic factor in patients with colorectal cancer. TN may be valuable as a prognostic variable in future studies evaluating new treatment strategies for colorectal cancer.

Serial measurements of serum human placental lactogen (hPL) and serial ultrasound examinations in the evaluation of fetal growth

Serial serum hPL measurements and serial ultrasound fetometry were compared in the evaluation of fetal growth by relating these two parameters to size at birth and to clinical factors known to influence size at birth. The data were from a prospective study of 1000 consecutive pregnant women considered to be at risk for fetal growth retardation with retrospective analysis. Serum hPL was measured by radioimmunoassay and fetal weight estimated by ultrasound every 3 weeks during the last trimester. hPL values were expressed as multiples of the median (MoM) and linear regression analysis of the hPL MoM values was carried out for each pregnancy to find the slope of the line (hPL-slope); at least 3 serum hPL values were required. The estimated fetal weight and weight-for-age at birth was expressed in Z-scores. The individual intrauterine growth velocity was calculated by regression analysis and expressed as change in Z-score for 12 weeks. At least two ultrasound measurements over an interval of at least 42 days were used to estimate the fetal growth velocity. In 588 women the file was complete. The main outcome measures were the individual mean hPL, hPL-slope, fetal growth velocity, birth weight deviation, smoking in pregnancy and diagnosis of preeclampsia. A significant correlation was found between the hPL-slope and the intrauterine fetal growth velocity (r=0.34), and between hPL-slope and birth weight deviation (r=0.32). Mean hPL was correlated to birth weight deviation (r=0.27), but only very weakly to intrauterine growth velocity (r=0.08). hPL-slope and intrauterine growth velocity independently predicted birth weight deviation. Heavy smoking which was stopped before the third trimester was not associated with low intrauterine growth velocity, but with a low hPL-slope. Preeclampsia was associated with a trend towards low and decreasing hPL and with an increasing intrauterine growth velocity and birth weight deviation. In conclusion the rate of change of serial hPL measurements correlated well to intrauterine fetal growth velocity in the third trimester as estimated by ultrasound and to the deviation in birth weight, but hPL seems to have a separate physiological significance, since it did not pick up when smoking was stopped and growth velocity was normalised and it did not at all detect the increased growth associated with preeclampsia.