Significance of CA72.4 in patients with colorectal cancer. Comparison with CEA and CA19.9.

CA72.4 is a new tumor-associated antigen identified by monoclonal antibodies cc49 and B72.3. Serum levels of CA72.4 were measured in patients with benign and malignant diseases. The cut-off used was 4 U/mL. CA72.4 is a highly specific marker since only 3% of 162 patients with benign diseases had elevated levels of antigen. Forty-four percent of 89 patients with colorectal cancer had elevated CA72.4 levels. Compared with CEA and CA19.9, we have found that CEA (75%) is the most sensitive marker (p less than 0.001). The simultaneous use of two or three markers did not further contribute to the evaluation of patients with colorectal cancer.     

Relationship of CA 125 and CA 19.9 with lung carcinoma histological subtype: preliminary study

The aim of this work was to study the possible utility of simultaneous determination of CA 125 and CA 19.9 in patients with lung cancer. Serum levels of both markers were studied in 87 patients without metastases (Mo), 72 patients with distant metastases (MT) and 15 cases without clinical evidence of disease after primary treatment (NED). Sixty-five tumors were epidermoid, 34 were adenocarcinomas, 24 were cell undifferentiated carcinomas and 51 were small-cell carcinomas. Sera from 75 healthy subjects and 20 patients with benign lung disease were used as controls. The cut-off values used were 35 and 37 U/ml for CA 125 and CA 19.9, respectively. CA 125 and CA 19.9 serum levels were within normal limits in all control patients. In NED patients these markers were not elevated, except in one with chronic liver disease who showed elevated CA 19.9 (76 U/ml). Twenty-five percent of Mo lung cancer patients and 40.3% of MT cases had CA 19.9 over 37 U/ml. Abnormally high levels of CA 125 were found in 18.7% and 22.9% of Mo and MT patients, respectively. Sixty percent of patients with large cell undifferentiated carcinoma had elevated CA 125 (mean 176 U/ml) compared to 15.4% of patients with all other histological types of tumors combined (54.3 U/ml, p less than 0.01). CA 19.9 serum levels were also more often elevated in patients with large cell undifferentiated carcinomas (50%, 7/14 cases) than in other histological types (30%, 36/120 patients), but the difference was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diagnostic and Prognostic Impact of Circulating YKL-40, IL-6, and CA 19.9 in Patients with Pancreatic Cancer

Purpose

We tested the hypothesis that high plasma YKL-40 and IL-6 associate with pancreatic cancer and short overall survival.

Patients and Methods

In all, 559 patients with pancreatic cancer from prospective biomarker studies from Denmark (n = 448) and Germany (n = 111) were studied. Plasma YKL-40 and IL-6 were determined by ELISAs and serum CA 19.9 by chemiluminescent immunometric assay.

Results

Odds ratios (ORs) for prediction of pancreatic cancer were significant for all biomarkers, with CA 19.9 having the highest AUC (CA 19.9: OR = 2.28, 95% CI 1.97 to 2.68, p<0.0001, AUC = 0.94; YKL-40: OR = 4.50, 3.99 to 5.08, p<0.0001, AUC = 0.87; IL-6: OR = 3.68, 3.08 to 4.44, p<0.0001, AUC = 0.87). Multivariate Cox analysis (YKL-40, IL-6, CA 19.9, age, stage, gender) in patients operated on showed that high preoperative IL-6 and CA 19.9 (dichotomized according to normal values) were independently associated with short overall survival (CA 19.9: HR = 2.51, 1.22–5.15, p = 0.013; IL-6: HR = 2.03, 1.11 to 3.70, p = 0.021). Multivariate Cox analysis of non-operable patients (Stage IIB-IV) showed that high pre-treatment levels of each biomarker were independently associated with short overall survival (YKL-40: HR = 1.30, 1.03 to 1.64, p = 0.029; IL-6: HR = 1.71, 1.33 to 2.20, p<0.0001; CA 19.9: HR = 1.54, 1.06 to 2.24, p = 0.022). Patients with preoperative elevation of both IL-6 and CA 19.9 had shorter overall survival (p<0.005) compared to patients with normal levels of both biomarkers (45% vs. 92% alive after 12 months).

Conclusions

Plasma YKL-40 and IL-6 had less diagnostic impact than CA 19.9. Combination of pretreatment YKL-40, IL-6, and CA 19.9 may have clinical value to identify pancreatic cancer patients with the poorest prognosis.     

Significance of CA 72.4 serum levels in gastrointestinal diseases

In order to evaluate the usefulness of Ca 72.4 tumor associated antigen assay in gastrointestinal diseases, we have studied 751 patients suffering from benign (376) and neoplastic (375) digestive diseases and 305 normal controls. The cut-off point was fixed at 6 U/ml. The Ca 72.4 assay, with the proposed method, provides additional information only in gastric cancers; the positivity of the marker in gastric neoplasms is 38.4% and the specificity vs gastric ulcers and atrophic gastritis is 99%. In six patients with gastric cancer, the Ca 72.4 is the only positive test. The most striking observation to be made from the current study is a no good sensitivity of the marker for gastrointestinal cancers (29.6% vs 35.7 and 37.6% for CEA and Ca 19-9 respectively), but rather the excellent specificity of the Ca 72.4 immunoassay with respect to being gastrointestinal diseases (98.7%), vs values of specificity for CEA and Ca 19-9 of 94 and 92%. In conclusion, the high specificity of this marker for gastrointestinal neoplasms may be very interesting in follow-up studies. In fact, an elevation of serum levels of Ca 72.4 should always be taken seriously.     

High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects

Objective: Our objective was to test the effect of biliopancreatic diversion (BDP) in adiponectin multimerization. Adiponectin, the major protein secreted by adipose tissue, circulates in plasma in different isoforms. The most clinically relevant oligomers are high‐molecular weight (HMW) multimers and low‐molecular weight (LMW) trimers. Contrasting data on the effect of weight loss on adiponectin isoforms have been reported. Research Methods and Procedures: We measured total plasma adiponectin and HMW and LMW adiponectin oligomers (by Western blot analysis) before and 1 month after BPD, in 18 severely obese subjects. Results: One month after BPD, body weight decreased ～11%. Total adiponectin showed significant increase after BPD. In addition, we found a significant increase in HMW (percentage) adiponectin oligomers. We found a significant inverse correlation between HMW (percentage) and BMI before and after BPD. Homeostasis model of assessment‐insulin resistance decreased significantly after the BPD, without any significant correlation with total serum adiponectin and adiponectin oligomers. Discussion: A moderate weight loss after BPD increases total and HMW adiponectin oligomers. The significant correlation between BMI and HMW (percentage) adiponectin oligomers but not between BMI and total adiponectin might indicate a role of body fat mass in regulation of adiponectin multimerization. These data suggest that HMW oligomers represent a very sensitive parameter to short‐term BMI changes after BPD.     

Behavior of plasma insulin and GIP in obese patients subjected to biliopancreatic bypass

Biliopancreatic bypass for obesity entails a 2/3 distal gastrectomy with Roux-en-Y reconstruction, being the small bowel transected at its midpoint and the enteroenteroanastomosis placed 50 cm proximal to the ileocecal valve. Insulin and GIP fasting and meal-stimulated plasma concentrations were determined in 13 nonobese healthy volunteers, in 13 nonoperated obese patients, in 11 subjects within two months, in 12 subjects four to twelve months, and in 7 subjects fifteen to twenty months after operation. Insulin in the obese patients was significantly higher than in the control group. Postoperatively these patients showed a sharp reduction in basal and postprandial values. Plasma insulin levels, both basally and following the test meal, were very similar in the 15-20 month and the control group. Plasma GIP fasting level, meal-stimulated peak and integrated response in the obese group were higher than in control group. Due to the extreme variability among subjects in the obese group, the difference was significant only for the mean peak response. All values were greatly reduced after surgery. The mean fasting level in the 15-20 month group was very similar to that in the control group, and both peak and integrated responses were significantly lower than in the preoperative and control groups.     

Identification of blood-protein carriers of the CA 19-9 antigen and characterization of prevalence in pancreatic diseases

The current best serum marker for pancreatic cancer, CA 19-9, detects a carbohydrate antigen on multiple protein carriers. Better knowledge of the protein carriers of the CA 19-9 antigen in various disease states may lead to improved diagnostic tests. To identify proteins that carry the CA 19-9 antigen, we immunoprecipitated the CA 19-9 antigen from pooled sera and identified the associated proteins using MS. Among the high-confidence identifications, we confirmed the presence of the CA 19-9 antigen on Apolipoprotein B-100 by antibody arrays and Western blot and on kininogen, ARVCF, and Apolipoprotein E by antibody arrays. We characterized the frequency and levels of the CA 19-9 antigen on the four proteins across various patient groups (pancreatic cancer, pancreatitis, and healthy controls) using antibody arrays. Nearly, 10-25% of the subjects showed elevations of the antigen on each protein, but the elevations were not associated with disease state or total CA 19-9 levels. These results contribute to our knowledge of the carrier proteins of an important functional glycan and the rate at which the glycan is displayed. This work also demonstrates a strategy for using the complementary methods of MS and antibody microarrays to identify protein carriers of glycans and assess the diagnostic value of measuring glycans on individual proteins.     

Structural Properties of Silkworm Small Heat-Shock Proteins: sHSP19.9 and sHSP20.8

sHSP20.8 and sHSP19.9 are silkworm small-heat shock proteins (sHSPs) comprising a number of polypeptides of molecular sizes of several tens of kilodaltons as subunits. The structural properties of sHSPs were investigated. sHSP19.9 was found to be aggregated by itself during incubation at 60 °C. Aggregation was suppressed in the presence of dithiothreitol and at high ionic strength. In contrast, sHSP20.8 was not aggregated. Aggregation of sHSP19.9 was partially suppressed by sHSP20.8 and in the presence of catalase as a target protein. Based on changes in small-angle X-ray scattering, it is possible that the molecular size of sHSP19.9 is larger than that of sHSP20.8, and that their molecular sizes increase with increasing temperature in a reversible, biphasic manner. sHSPs did not protect catalase from thermal inactivation, but protected it from precipitation by forming a soluble complex. sHSP20.8 and sHSP19.9 with dithiothreitol were stable against lyophilization, autoclaving at 120 °C, and boiling.     

Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion

Objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes. Methods and Procedures: Twenty‐one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA‐IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([ΔI5/ΔG5]/HOMA‐IR). Results: Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 ± 29.5 vs. 644.9 ± 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 ± 0.5 vs. 17.6 ± 3.9 1/mmol², P < 0.001). One month following BPD, in both groups BW was reduced (by ～11%), but all subjects were still severely obese; HOMA‐IR and leptin decreased significanlty, while high‐molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non‐diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 ± 29.5 to 273.8 ± 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia. Discussion: BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations.     

Tumour associated antigens CA 15.3 and CA 125 in ovarian cancer

CA 125 and CA 15.3 antigens were determined by enzyme immunoassay in 78 patients with ovarian cancer for a total of 540 determinations. The antigens were also investigated in sera from 100 women with other gynaecological diseases, 82 lung cancer patients and in 39 pleural fluids of varying origin. CA 15.3 reference values were evaluated in 91 healthy women (cut-off: 25 U/ml). CA 15.3 sensitivity at diagnosis (60%) and for detecting relapse (44%) was lower than that of CA 125 (90% and 64.7%, respectively). However, CA 15.3 does not increase with aspecific mesothelial cell reaction and thus it is more specific than CA 125. Combined use of the markers during follow-up improves early detection of relapse (at least one of the two was positive in 79% of cases). Therefore both CA 15.3 and CA 125 should be routinely determined for the detection and monitoring of ovarian cancer.     

Upregulation of plasma insulin-like growth factor binding protein 2 levels after biliopancreatic diversion in humans

The biliopancreatic diversion surgery with duodenal switch (BPD-DS) is a surgical procedure that not only induces significant weight loss, but also promotes remission of diabetes. However, the mechanism responsible for this insulin-potentiating effect (both on sensitivity and production) is not yet clearly understood. The insulin-like growth factor (IGF) binding protein 2 (IGFBP-2) is a 36 kDa circulating protein that has been recently suggested to modulate insulin sensitization and fat accumulation. In humans, a low-circulating concentration of IGFBP-2 has been associated with obesity and insulin resistance. We thus tested the hypothesis that BPD-DS would trigger an increase in IGFBP-2 levels. Plasma IGFBP-2 was quantified by enzyme-linked immunosorbent assay in 77 severely obese men and women before and up to 1 year after BPD-DS surgery. Baseline IGFBP-2 levels were 159 ± 17 ng/ml. Plasma IGFBP-2 levels increased significantly as soon as 24 h after BPD-DS surgery and were further augmented at both 6 months and 1 year after the surgery, reaching 748 ± 65 ng/ml. Changes in IGFBP-2 concentrations were significantly and negatively associated with blood glucose, insulin, triglycerides, and total cholesterol levels. The present findings suggest that the rise in IGFBP-2 levels is associated with the improvements in glucose and lipid metabolism in the short- and long-term after BPD-DS. The mechanisms for the augmentation in IGFBP-2 after BPD-DS and its contribution to insulin sensitization remain to be elucidated.     

Optogenetics reveals paradoxical network stabilizations in hippocampal CA1 and CA3

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CA 125 in biological fluids

CA 125 is not a specific tumor marker, and is synthesized by normal and malignant cells of different origin (mainly in tissues derived from the müllerian epithelia) in a similar proportion. Abnormal CA 125 levels may be found in fluids of different origin (ascites, pleura, pericardium, amniotic fluid, cyst fluid, bronchoalveolar fluid, etc.) and in serum from patients with these fluids. Differences in serum CA 125 found in malignant or benign diseases may be related to the number of cells that synthesize the marker, and are highly dependent on the access to serum, where the marker is normally determined. Moreover, CA 125 is a very good tumor marker in ovarian and lung cancer. The sensitivity of CA 125 in ovarian cancer is related to stage (40-95%), histological type (lower levels in mucinous adenocarcinoma), and the marker is useful in the early detection of recurrence (sensitivity 80%) and in therapy monitoring. It's sensitivity in lung cancer is lower than in ovarian cancer, 39% in locoregional malignancies and 69% in metastatic disease, but clearly related to stage and histology (mainly in adenocarcinomas and large cell lung cancer) and it is useful in prognosis and disease monitoring.