Progressive increase of SCCA-IgM immune complexes in cirrhotic patients is associated with development of hepatocellular carcinoma

About 3-4% of cirrhotic patients develop primary liver cancer every year. Specific serologic markers have not yet been identified for screening of high risk patients. The serpin squamous cell carcinoma antigen (SCCA) is overexpressed in liver cancer and circulating SCCA-IgM complexes have been described in patients with hepatocellular carcinoma (HCC). The aim of the present study was to assess the behavior of SCCA-IgM in relation to HCC development in patients with cirrhosis. A retrospective, longitudinal study was conducted in a cohort of prospectively followed cirrhotic patients. Two groups with similar clinical profile at presentation were studied : group A included 16 patients who developed HCC during a median follow up of 4 years; group B included 17 patients who did not develop HCC during the same time interval. Circulating SCCA-IgM immune complexes were determined using a recently standardized ELISA assay. At presentation similar levels of SCCA-IgM complexes [mean +/- SD: 267.40 +/- 382.25 U/ml vs. 249.10 +/- 446.90 U/ml, p = 0.9006] and of alpha-fetoprotein [AFP; 24.11 +/- 59.04 IU/ml vs. 10.91 +/- 23.34 IU/ml, p = 0.3995] were detected in group A and in group B. The increase over time (phi) of SCCA-IgM, assessed within at least one year before clinical diagnosis of HCC, was remarkably higher in group A than in group B (mean +/- SD = 280.05 +/- 606.71 (U/ml)/year vs. -37.92 +/- 95.94 (U/ml)/year, p = 0.0408), while AFP increase was not significantly different (11.89 +/- 23.27 (IU/ml)/year vs. 3.67 +/- 11.46 (IU/ml)/year, p = 0.2179). Receiver operating characteristic (ROC) curves were plotted for the rate of change in the levels of both markers and the diagnostic accuracy measured as AUROC was higher for SCCA-IgM phi (0.821) than for AFP phi (0.654). In conclusion, the progressive increase of SCCA-IgM over time was associated with liver tumor development, suggesting that monitoring the behavior of SCCA-IgM might become useful to identify cirrhotic patients at higher risk of HCC development.     

Expression of human Kallikrein 14 (KLK14) in breast cancer is associated with higher tumour grades and positive nodal status

Human kallikrein 14 (KLK14) is a steroid hormone-regulated member of the tissue kallikrein family of serine proteases, for which a prognostic and diagnostic value in breast cancer has been suggested. To further characterise the value of KLK14 as a breast tumour marker, we have carefully analysed KLK14 expression in normal breast tissue and breast cancer both on the RNA level by real-time RT-PCR (n = 39), and on the protein level (n = 127) using a KLK14-specific antibody for immunohistochemistry. We correlated KLK14 protein expression data with available clinico-pathological parameters (mean follow-up time was 55 months) including patient prognosis. KLK14 RNA expression as quantified by real-time RT-PCR was significantly more abundant in breast tumours compared to normal breast tissue (P = 0.027), an issue that had not been clarified recently. Concordantly with the RNA data, cytoplasmic KLK14 protein expression was significantly higher in invasive breast carcinomas compared to normal breast tissues (P = 0.003). Furthermore, KLK14 protein expression was associated with higher tumour grade (P = 0.041) and positive nodal status (P = 0.045) but was not significantly associated with shortened disease-free or overall patient survival time in univariate analyses. We conclude that KLK14 is clearly overexpressed in breast cancer in comparison to normal breast tissues and is positively associated with conventional parameters of tumour aggressiveness, but due to a missing association with survival times, the use of KLK14 immunohistochemistry as a prognostic marker in breast cancer is questionable.     

Prognostic significance of changes in CA 15-3 serum levels during chemotherapy in metastatic breast cancer patients

Summary Tumor response to first-line chemotherapy in advanced breast cancer offers prognostic information and may be used as a surrogate marker for evaluating treatment efficacy. With this study we wanted to determine whether changes in circulating serum CA 15-3 levels during chemotherapy provided additional information for prognostic prediction. Serum CA 15-3 was measured at baseline and after 3 and 6 months during anthracycline-based first-line chemotherapy in 526 patients with advanced breast cancer prospectively enrolled in five phase II-III trials. Changes in marker levels were correlated with disease response, time to progression and overall survival. In all, 336 patients attained a disease response. A significant relationship was found between disease response and CA 15-3 variations, although many individual discrepancies were also observed. At the 6-month time point, the median time to progression was 15.3 months in patients with normal marker levels throughout the study, 11.7 months in those with a CA15-3 reduction >25%, 9.6 months in those with elevated baseline CA 15-3 levels which did not change during therapy and 8.6 months in those with increased marker levels (p < 0.001). The median survival was 42.3, 29.7, 28.5, and 24.8 months, respectively (p < 0.002). The prognostic role of changes in CA 15-3 levels was maintained in the patient subset attaining disease response or stabilization to treatment (p < 0.001) and after adjusting for clinical response and major prognostic parameters in the multivariate analysis (p < 0.001). In conclusion, monitoring serum CA 15-3 levels during first-line chemotherapy in advanced breast cancer patients provides prognostic information independently from tumor response.     

胆囊结石病致病基因的定位研究

目的 寻找中国人群胆囊结石病的致病基因。方法 采用荧光标记微卫星位点,对12个胆囊结石病家系进行全基因组扫描;采用非参数分析软件GENEHUNTER和参数分析软件BATCHLINK进行连锁分析,寻找染色体上与胆囊结石病发病有关的位点。按患者发病年龄、体重指数、胆固醇和甘油三酯水平等指标,对家系进行分组分析。结果 染色体上D3S1266、D4S406、D9S1682和D1IS902位点,提示与胆囊结石病发病有关。其中D4s406和D9S1682的非参数分析优势对数值（NPL）分别为1．77（P=0．05）和1．92（P=0．04）,参数分析优势对数值（LOD）分别为1．84和2．07。D3S1266位点的LOD值为1．35。D11S902位点传递不平衡检验,P值为0．0027。高发病年龄组D3S1266位点的LOD值由1．35上升到2．71,高甘油三酯组D9S1682位点的LOD值由2．07上升到2．40。结论 3号、4号、9号和11号染色体上,可能有胆囊结石病致病的基因位点;3号染色体上的致病基因位点可能与发病年龄较大患者发生胆囊结石病有关;9号染色体上致病基因位点可能与伴有高甘油三酯患者发生胆囊结石病有关。     

Utilizing Quantitative Polymerase Chain Reaction to Evaluate Prostate Stem Cell Antigen as a Tumor Marker in Pancreatic Cancer

Background Real-time quantitative polymerase chain reaction (qPCR) may prove to be a sensitive technique by which to evaluate potential tumor markers in pancreatic cancer.Methods The prostate stem cell antigen (PSCA) gene was identified as a marker highly expressed in pancreatic adenocarcinoma and not normal pancreas. RNA from pancreatic and nonpancreatic cancer cell lines as well as tissue and blood from pancreatic cancer and control patients was reverse-transcribed and PSCA quantified by qPCR.Results Individual operator experience affects the results of qPCR, with significantly different copy numbers at experiment numbers 5, 15, and 40. Five of six pancreatic cell lines had PSCA/actin ratios 10-fold greater than nonpancreatic cancer lines. Mean PSCA expression in pancreatic tumor tissue was significantly higher (P < 0.05, Student’s t-test) than in the tissue of benign pancreatic processes. The close correlation of PSCA/actin copy number with number of tumor cells in the blood was demonstrated by regression analysis (r = 0.768, P = 0.0001). PSCA copy number was significantly higher in the blood of patients with metastatic pancreatic cancer than in that of normal patients (P < 0.05, Student’s t-test).Conclusions Such trends suggest that PSCA may prove to be a valuable pancreatic cancer tumor marker. More generally, the technique of qPCR is shown to provide a sensitive method of evaluating markers in cancer patients.This work was presented at the Society of Surgical Oncology Annual Meeting, Los Angeles, CA, March 2003.     

Changes in the serum sex steroids, IL-7 and RANKL-OPG system after bone marrow transplantation: influences on bone and mineral metabolism

This study prospectively investigated the changes of the serum levels of the sex steroids, IL-7, soluble receptor activator of nuclear factor κB ligand (sRANKL) and osteoprotegerin (OPG) in bone marrow transplantation (BMT) recipients. This study also examined whether the changes of these cytokine levels and sex steroids actually influence bone turnover and post-BMT bone loss by correlation analysis. Data were analyzed from 39 patients (33.6 ± 6.4 years, 19 men and 20 women) who had DXA performed before BMT and at 1 year after BMT. The bone turnover markers, sex steroids and the cytokine levels were measured before BMT and serially after BMT.

The mean bone loss in the lumbar spine and the total proximal femur was 5.9% (P < 0.01) and 11.3% (P < 0.01), respectively. During the immediate post-BMT period, bone formation decreased, whereas the bone resorption increased. For the female recipients, the estradiol levels declined at 1 week after BMT, and they did not recover to the basal levels. For the male recipients, the testosterone levels decreased at 1 week and then it increased to its baseline level. The IL-7 levels reached their maximum at 1 week and then declined to baseline level by 3 months. The serum sRANKL, OPG levels and the sRANKL/OPG ratio showed their peak at post-BMT 3 weeks.

The mean daily dose of steroid was associated with suppressed bone formation, enhanced bone resorption and increased sRANKL levels. The IL-7 levels were also noted to be either positively correlated with the levels of ICTP or they were negatively correlated with the levels of osteocalcin at 1 and 3 weeks after BMT. Bone loss at the lumbar spine and the proximal femur was influenced by the decreased sex steroids and increased IL-7 levels. During the observation period, the IL-7 levels showed positive correlations with the sRANKL levels and the sRANKL/OPG ratio. For the female patients, the serum IL-7 levels were negatively associated with the estradiol levels at 1 and 3 weeks after BMT.

All these findings suggest that IL-7 plays an important role for post-BMT bone loss, and this possibly happens via the RANKL pathway. These data also suggest that the up-regulation of IL-7 during the early post-BMT period may result from a deficiency of estrogen.     

Raloxifene increases serum leptin levels in postmenopausal women: a prospective study

OBJECTIVE: The purpose of this study was to investigate the effect of raloxifene on leptin and insulin-like growth factor-I levels and their relation with the biochemical markers of bone metabolism in postmenopausal women. STUDY DESIGN: Sixty-four women were given 60 mg/d raloxifene for 6 months. Serum leptin, insulin-like growth factor-I, alkaline phosphatase, calcium, osteocalcin, and collagen type I cross-link C-telopeptide levels were measured before and after the treatment. The patients were grouped as obese (body mass index, > or =25 kg/m2) or non-obese (body mass index, <25 kg/m2). RESULTS: The mean basal leptin level was significantly higher (P < .001), and the mean cross-link C-telopeptide level was significantly lower (P = .001) in obese patients. Raloxifene therapy increased leptin levels (P < .001) and decreased insulin-like growth factor-I, alkaline phosphatase, and cross-link C-telopeptide levels significantly (P < .001). There was a strong negative correlation between leptin and cross-link C-telopeptide (r = -0.703; P < .001). Insulin-like growth factor-I was not correlated with any parameter. CONCLUSION: Raloxifene increases serum leptin levels while decreasing bone resorption in postmenopausal women.     

Hyperprolinemia type II: evidence of the excretion of 3-hydroxy delta 1-pyrroline 5-carboxylic acid.

We report the identification of delta 1-pyrroline 3-hydroxy 5-carboxylic acid (hydroxy PCA) in a previously reported patient with hyperprolinemia Type II. This compound had been called pseudo PCA in a previous report.