实验性肝癌癌组织的发生和甲胎蛋白表达

目的：研究实验性肝癌的组织发生过程中甲胎蛋白的表达,旨在为肝癌诊断奠定形态学基础。方法：Ｗｉｓｔａｒ大白鼠喂０．０４％３‘－Ｍｅ－ＤＡＢ不同日程处死,３６周处互完,观察动力形态变化和免疫组化ＡＦＰ表达。结果：实验早期卵圆细胞增生,该细胞是多向分化的干细胞。它进一步分化成过渡细胞,胚胎性小肝细胞,后者可呈不典型增生,它们散在或群集,这些细胞ＡＦＰ强阳性,群集不典型增生的小肝细胞形态上不同于肝细胞增生     

Ovarian Sertoli-Leydig cell tumour with raised serum alpha fetoprotein

Summary A case of ovarian Sertoli-Leydig cell tumour with a raised serum alpha fetoprotein in reported. The patient first presented at the age of 27 years with a history of 6 years' amenorrhoea followed by 3 months irregular vaginal bleeding. A ovarian tumour was found and excised and shown microscopically to be a spindle cell malignant tumour. The patient was treated with chemotherapy and had a complete response. Thirty months after first presentation there was a recurrence in the pelvis which microscopically showed the typical features of a Sertoli-Leydig cell tumour. Six months later a second recurrence had the microscopic appearance of a lipid cell tumour. A raised serum alpha fetoprotein was found at the time of the second recurrence and immunohistochemistry showed this protein in the Leydig and luteinized cells of the recurrent tumours but not in the spindle cells of the original ovarian neoplasm.     

Diagnostic value of glypican-3 in alpha fetoprotein negative hepatocellular carcinoma patients

Background

The prognosis of patients with hepatocellular carcinoma(HCC) is generally very poor with a 5-year survival rate of less than 15% since most of them are diagnosed clinically at their late stage. However, the differential diagnosis between alpha fetoprotein(AFP) negative HCC and cirrhotic nodules is still difficult.

Objectives

To evaluate the diagnostic value of glypican-3(GPC3) in patients with AFP negative hepatitis B related HCC.

Methods

The liver tissue GPC3 (GPC3L) expression was tested from 426 for surgery and 179 of needle biopsies of hepatitis B related HCC patients using immunohistochemistry staining. Serum GPC3 (GPC3S) and AFP were also measured.

Results

Among surgical HCC samples, 80.0% of GPC3L expression was positive, however, in paracarcinomatous and cirrhotic nodules were negative. In needle biopsy tissues, GPC3L positively expression was in 74.9%. The sensitivity of AFP>400µg/L was 25.4%. The GPC3S >3.5µg/L was determined as a positive. The area of ROC curve of GPC3S was 0.68(95% CI 0.56–0.79,P<0.05) in all HCC patients,0.81 (95% CI 0.62 –0. 98, P<0.05) in AFP greater or equal to 400µg/L and 0.64 (95% CI 0.51–0.77, P=0.051) in AFP negative patients. The GPC3S was positive in 48.8% of patients with AFP negative. No difference was observed between GPC3L/GPC3S and serum AFP.

Conclusions

GPC3 may be helpful in improving diagnosis of HCC and in differentiating diagnosis between AFP negative HCC and cirrhotic nodules.     

ANGPTL6-mediated angiogenesis promotes alpha fetoprotein-producing gastric cancer progression

Alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC) is regarded as a rare but highly malignant gastric adenocarcinoma subtype and its clinic pathological presentation mimics hepatocellular carcinoma. However, the underlying mechanism of this disease remains elusive. The level of ANGPTL6 in AFPGC cell lines is much higher than that of common types of gastric cancer cells. A high level of ANGPTL6 confers a poor prognosis and is correlated with the expression of CD34 (an endothelial cell marker). ANGPTL6 promotes endothelial cell migration and tube formation, Moreover, ANGPTL6 knockdown inhibits cancer cell apoptosis and invasiveness. Mechanistically, ANGPTL6 activates the ERK1/2 and AKT pathways. Treatment of ERK1/2 or AKT inhibitor can attenuated cell migration and tube formation. ANGPTL6 loss results in tumor growth in vivo. Our study revealed that ANGPTL6 is an important driver gene of angiogenesis in AFPGC development. These findings provide not only an effective biomarker for diagnosis but also an attractive therapeutic target for use in AFPGC patients.     

高通量酶免系统定量检测甲胎蛋白的临床应用评估

目的 对高通量酶免系统定量检测血清甲胎蛋白(alpha fetoprotein,AFP)进行临床应用评估.方法 收集肝癌、肝炎、肝硬化患者血清共184份,健康查体者血清200份.验证高通量酶免系统测定AFP的重复性和正确度,与电化学发光法(electrochemiluminescence immunoassay,ECLIA)结果进行比对,评价其临床应用价值.结果 高通量酶免系统测定4种浓度AFP的总变异系数(coefficient of variation,CV)分别为13.1％、13.7％、11.4％、10.3％,正确度能力比对试验(proficiency testing,PT)结果为100％,线性范围是(0.0 ～200.0)μg/L.高通量酶免系统和ECLIA检测结果呈直线相关(Y=1.14X+0.83,R2 =0.92),两方法检测标本的阳性率分别为67.39％和69.02％,差异无统计学意义(P =0.453).检测血清AFP诊断原发性肝癌的最佳临界值为195.7 μg/L.原发性肝癌与转移性肝癌患者的诊断界值为99.44μg/L,与肝炎肝硬化患者的诊断界值为379.15 μg/L.结论 高通量酶免系统测定血清AFP结果可靠、稳定,可用于筛查和诊断原发性肝癌.     

Genetic alterations of the Cdx2 gene in gastric cancer

Gastric atrophy and intestinal metaplasia are generally considered precancerous lesions of the stomach; Cdx2 plays an important role in intestinal metaplasia and gastric carcinogenesis. To elucidate the potential etiological role of the Cdx2 gene in gastric carcinogenesis, we analyzed genetic mutations and allelic loss in the Cdx2 gene of 95 sporadic gastric cancers. We found two somatic missense mutations in the Cdx2 gene, P63L in exon 1 and E204K in exon 2, encoding the caudal-like protein activation region (codon 13-180) and the homeobox domain (codon 188-243) of the gene, in the gastric cancers. In addition, 9 (25.0%) of 36 informative cases showed allelic loss at D13S220 and/or D13S260. In 11 cases with a genetic alteration, Cdx2 nuclear staining was observed only in 8 cases of gastric mucosa with intestinal metaplasia. Loss or reduced expression of the Cdx2 gene in cancer cells was found in two cases with a somatic mutation and in three cases with LOH. Interestingly, all of the cases were intestinal-type gastric cancers. Thus, these results suggest that genetic alterations of the Cdx2 gene may contribute to the loss of Cdx2 expression and to the development of gastric cancer, especially in the intestinal-type.     

Sounding board: Antenatal diagnosis, alpha fetoprotein and the FDA.

Elevated amniotic fluid alpha fetoprotein (AFP) levels have been associated with neural tube defects and may be associated with fetal death, omphalocele, and congenital nephrosis. AFP levels determined in 2694 cases where amniotic fluid samples were obtained for routine antenatal genetic studies resulted in the detection of 9 cases (1 in 300) of open neural tube defects. Thus AFP determination is important in every second trimester amniotic fluid sample obtained. However, the U.S. Food and Drug Administration (FDA) banned the commercial distribution of serologic reagents for AFP testing in 1973, thereby limiting availability of AFP assays to a few large centers. The FDA should establish criteria to license AFP reagents immediately so that they may be available for routine use.     

Biamnial alpha fetoprotein concentration in twins, one with multiple malformations.

In the 18th week of pregnancy in a 22 year old patient, twins were diagnosed by ultrasound. It was found that one twin had an abnormal skull outline and an echo-free area covered by a thin membrane in the region of the abdomen. The second embryo showed no sign of malformation. Amniocentesis was performed and the AFP in both samples of amniotic fluid were in the pathological range. Our own observations with indirect immunofluorescence confirmed that one twin with defects leading to abnormally high AFP levels can cause pathological AFP levels in the amniotic sac of a healthy twin.     

A population of human cord blood mononuclear cells with surface alpha fetoprotein.

Suspensions of mononuclear cells from adult peripheral blood (PBL) and mononuclear cells from cord blood (CBL) were examined for the presence of surface alpha-fetoprotein (AFP) using a fluoresceinated F(ab')2 fragment of rabbit IgG anti-human AFP. The mean proportion of CBL with AFP was increased (10%) when compared with PBL (1%) although some CBL specimens did not demonstrate such an increase (range 0--15%). The presence of AFP on CBL could be either due to cytophilic AFP attached to a unique surface receptor or intrinsic AFP synthesis. The following observations could not distinguish between these two possibilities: (1) After treatment with trypsin, only minor reappearance of surface AFP could be observed in AFP-free medium in contrast to the larger numbers observed in medium containing AFP. Such selective reappearance depending on the media could be related to either cytophilic attachment of heterologous or homologous AFP or preferential stimulation of intrinsic AFP synthesis. (2) The reappearance of AFP positive CBL following trypsin treatment and incubation in media with or without AFP containing sera was inhibited by cyclohexamide. Such inhibition could be due to inhibition of synthesis of an AFP surface receptor or intrinsic AFP. (3) The shedding of surface AFP observed at 2--4 degrees C could be due to release of exogenous cytophilic AFP or the continued "turnover" of intrinsic AFP without concomitant AFP synthesis due to the cold temperature. Finally, the removal of AFP positive cells via selective depletion of B cells using bead columns coated with IgG-anti-IgG and the absence of depletion of AFP positive cells after successive gradient centrifugation of E-rosettes and cells with IgG-Fc receptors are consistent with the identity of AFP positive CBL as cells without IgG-Fc receptors or lymphocytes without conventional T-cell markers as defined by E-rosettes.     

Alpha fetoprotein and carcinoembryonic antigen producing hepatocellular carcinoma. A case report studied by immunohistochemistry

Hepatocellular carcinoma (HCC) showing marked elevation of serum alpha fetoprotein (AFP) (maximum; 70942.0 ng/ml at the end stage) and serum carcinoembryonic antigen (CEA)(maximum; 7368.4 ng/ml at the end stage) was surgically resected. In the resected liver, there were two different tumor nodules which were adjacent to each other but clearly separated by a thin connective tissue. One of the nodules was a well differentiated and the other was poorly differentiated HCC. Immunoperoxidase study revealed that both CEA and AFP were localized in the tumor cells of the poorly differentiated HCC. This is the first report which clearly proved CEA synthesis in the cells of HCC. Serial staining showed that there was simultaneous synthesis of CEA and AFP in some of the tumor cells.     

Bioclinical study of the electro-immunodiffusion technic for the assay of serum alpha fetoprotein]

The author discusses the result that may be expected in clinical medicine from an electro-immunodiffusion method for the detection of alpha-foetoprotein. The samples studied were obtained from pregnant women, patients with liver cell carcinoma or severe digestive diseases, whether malignant or not, and a few amniotic fluids and sera obtained from the umbilical cord. This simple, rapid method is characterized by a sensitivity threshold of about 300 ng/ml and permits one to detect about 75% of cases of liver cell carcinoma.     

Genetic variability of DNA repair mechanisms influences chemotherapy outcome of gastric cancer

Genetic variability of DNA repair mechanisms influences chemotherapy treatment outcome of gastric cancer. We conducted a cohort study to investigate the role of ERCC1-ERCC2 gene polymorphisms in the chemotherapy response and clinic outcome of gastric cancer. Between March 2011 and March 2013, 228 gastric patients who were newly diagnosed with histopathology were enrolled in our study. Genotypes of ERCC1 rs11615, rs3212986, rs2298881 and ERCC2 rs3212986 were conducted by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. We found that individuals carrying TT genotype of ERCC1 rs11615 and CC genotype of ERCC1 rs2298881 were associated with better response to chemotherapy and longer survival time of gastric cancer. Moreover, individuals with AA genotype of ERCC2 rs1799793 were correlated with shorter survival of gastric cancer. In conclusion, ERCC1 rs11615, rs2298881 and ERCC2 rs1799793 polymorphism play an important role in the treatment outcome of gastric cancer.     

Genetic analyses supporting colorectal,gastric, and prostate cancer syndromes

Colorectal cancer (CRC), prostate cancer (PrC), and gastric cancer (GC) are common worldwide, and the incidence is to a certain extent dependent on genetics. We have recently shown that in families with more than one case of CRC, the risk of other malignancies is increased. We therefore suggested the presence of not yet described CRC syndromes. In this study, we have searched for genetic susceptibility loci for potential cancer syndromes involving CRC combined with PrC and/or GC. We have performed SNP (single‐nucleotide polymorphism)‐based linkage analyses in 45 families with CRC, PrC, and GC. In the regions with suggested linkage, we performed exome and association haplotype analyses. Five loci generated a high logarithm of odds (HLOD) score >2, suggestive of linkage, in chromosome bands 1q31‐32, 1q24‐25, 6q25‐26, 18p11‐q11, and Xp11. Exome analysis detected no potential pathogenic sequence variants. The haplotype association study showed that one of the top five haplotypes with the lowest P value in the chromosome band 6q25 interestingly was found in the family which contributed the most to the increased HLOD at that locus. This study supports a suggested hereditary cancer syndrome involving CRC and PrC and indicates a location at 6q25. The impact of this locus needs to be confirmed in additional studies.