良性前列腺增生及前列腺癌的ADC值与PAP、P504S、PSA表达的相关性研究

目的：探讨良性前列腺增生和前列腺癌的ADC值与前列腺相关标志物PAP、P504S、PSA表达的关系。方法收集经病理证实的65例前列腺疾病患者,其中良性前列腺增生30例,前列腺癌35例。病理检查前3个月内均行前列腺MRI、DWI检查,采用单次激发EPI序列,b值为0 s/mm2和800 s/mm2,并采用免疫组化检测组织标本中PAP、P504S、PSA的表达,分析ADC值与PAP、P504S、PSA表达的关系。结果良性前列腺增生和前列腺癌的ADC值分别为（1.73±0.21）×10-3 mm2/s和（1.34±0.15）×10-3 mm2/s,差异具有统计学意义（t=8.545,P=0.000）。PAP和PSA在良性前列腺增生和前列腺癌中均表达,差异无统计学意义（P均＞0.05）,P504S在前列腺癌中的表达显著高于良性增生（Z=-7.055,P=0.000）,双变量相关分析显示ADC值与P504S的表达呈显著负相（Spearman's相关系数r=-0.654,P=0.000）;结论 PAP和PSA不能区别前列腺良恶性病变;P504S可以作为前列腺癌标志物;ADC值可以定量评价良性前列腺增生和前列腺癌,且与P504S存在负相关,可以作为前列腺良恶性病变MRI诊断的参考指标。     

Detection of chromosomal anomalies in endometrial atypical hyperplasia and carcinoma by using fluorescence in situ hybridization

BACKGROUND:

Endometrial cancer is the most common pelvic gynecological malignancy. The diagnosis of well‐differentiated endometrial adenocarcinoma, atypical hyperplasia, and hyperplasia is often challenging. The authors sought to investigate the utility of chromosomal anomalies for the detection of endometrial hyperplasia and carcinoma using multitarget fluorescence in situ hybridization (FISH).

METHODS:

Samples were collected by endometrial Tao brush and processed by liquid‐based cytological preparation protocol from consecutive cases to include 50 benign, 50 hyperplasia without atypia, 47 atypical hyperplasia, and 53 endometrial cancers. Each was hybridized using fluorescence‐labeled DNA probes to chromosomes 1, 8, and 10. The FISH signals were enumerated in 100 cells per case, and the chromosomal anomalies were correlated with pathologic findings, including histologic diagnoses on matched endometrial tissue samples.

RESULTS:

Numeric chromosomal anomalies were found in 0% (0 of 50) of benign, 20% (10 of 50) of hyperplasia, 74% (35 of 47) of atypical hyperplasia, and 87% (46 of 53) of carcinoma specimens. The mean percentage of cells with chromosomal changes was 55% in cancer specimens, which was significantly higher than that in hyperplasia without atypia (13%, P < .0001) and atypical hyperplasia (32%, P = .003). The most frequent chromosomal anomaly was gain of chromosome 1. FISH anomalies had an overall sensitivity of 81% and specificity of 90% for the detection of atypical hyperplasia and/or endometrial carcinoma. There was no association with grade of endometrial carcinoma.

CONCLUSIONS:

Multitarget FISH appears to be useful for the differential diagnosis of hyperplasia, atypical hyperplasia, and endometrial adenocarcinoma, with a high level of sensitivity and specificity. It is also a potential tool for the early detection of neoplastic cells in endometrial cytology specimens. Endometrial hyperplasia with FISH‐detected chromosomal anomalies may represent a clinically significant subset of cases that warrant close clinical follow‐up. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.     

In situ hybridization for gastrin-releasing peptide receptor (GRP receptor) expression in prostatic carcinoma

Bombesin-like peptides (BLPs), which have been implicated in the regulation of growth of prostatic carcinoma cells, are a product of neuroendocrine cells frequently found in prostate tissue and are postulated to play a role in the initiation or progression of prostatic carcinoma. In this report, we examined the expression, in human prostate tissue, of mRNA encoding the 3 known receptors that respond to BLPs in humans, i.e., gastrin-releasing peptide (GRP) receptor, neuromedin B (NMB) receptor and bombesin receptor subtype 3 (BRS-3). Competitive rt-PCR experiments demonstrated the widespread but variable expression of GRP receptor mRNA in fresh-frozen specimens of prostatic carcinoma (12 cases) and benign prostatic hypertrophy (6 cases). NMB receptor mRNA expression was also widespread, but its level was less variable than GRP receptor message. In contrast, we could not detect BRS-3 mRNA in most tissue samples by rt-PCR. To address which cells in the prostate express the GRP receptor, we used in situ hybridization methods to stain selectively GRP receptor mRNA. GRP receptor mRNA was expressed predominantly in the luminal and basal epithelial cells in both histologically normal and cancerous glands within sections of normal (3 cases) and diseased (37 cases) tissue. GRP receptor mRNA staining in cancerous tissue ranged widely from very intense to not detectable (about 30% of the cases), while normal tissue consistently displayed a low level of message staining. Taken together, our results demonstrate expression of the GRP receptor in a high percentage of basal and/or luminal epithelial cells of normal and diseased prostate tissues. Int. J. Cancer (Pred. Oncol.) 79:82–90, 1998. © 1998 Wiley-Liss, Inc.     

Spindle-cell ameloblastic carcinoma: A case report with immunohistochemical,ultrastructural, and comparative genomic hybridization analyses

Spindle-cell ameloblastic carcinoma is a classification proposed for a group of rare odontogenic carcinomas with sarcomatoid components and is distinguished from odontogenic carcinosarcoma. We report a case of spindle-cell ameloblastic carcinoma of the right mandible that occurred in a 67-year-old Japanese man. Growth of the tumor was destructive, there was extensive lung metastasis, and the outcome was unfavorable. Ultrastructural and immunohistochemical examination showed the spindle-cell component of the tumor to be epithelial in character. A gain of 5q with amplification of 5q13 was detected in the tumor by comparative genomic hybridization.     

Two-step radio-immunotargeting of renal-cell carcinoma xenografts in nude mice with anti-renal-cell-carcinoma X anti-DTPA bispecific monoclonal antibodies

The specificity of antibodies offers unique opportunities to target tumors with radionuclides. However, due to the slow clearance of radiolabeled antibody, relatively high background is observed in non-target organs. Pre-targeting protocols using bispecific monoclonal antibodies (bsMAbs) and radiolabeled chelates may overcome this problem. We have evaluated the anti-renal-cell-carcinoma (RCC) × anti-DTPA bsMAb G250 x DTIn1 for 2-step targeting of RCC tumors in nude mice. Tumor uptake of ¹¹¹In-DTPA was similar up to a 3-day interval between bsMAb and ¹¹¹In-DTPA injections and decreased thereafter. The effect of G250 x DTIn1 protein dose was studied. High tumor uptake was seen at 1 to 4 μg, whereas at higher doses uptake decreased. Tumor was saturated with 15 μg bsMAb. At the saturating bsMAb dose the ¹¹¹In-DTPA amount was varied. High tumor uptake was observed at a 10-fold molar excess ¹¹¹In-DTPA, whereas at higher excess uptake decreased. After priming with 15 μg bsMAb and targeting with a 10-fold molar excess ¹¹¹In-DTPA, the biodistribution of ¹¹¹In-DTPA was studied for 1 to 48 hr after injection. Good tumor retention of ¹¹¹In-DTPA was observed, while the radiolabel cleared rapidly from the blood. Consequently, tumor-to-blood ratios increased with time to 500 at 24 hr after injection. In conclusion, RCC xenografts can be targeted efficiently using G250 x DTIn1 and ¹¹¹In-DTPA. However, this requires careful tuning of bsMAb protein dose and ¹¹¹In-DTPA dose. Using the optimal protein dose and ¹¹¹In-DTPA dose, high ¹¹¹In-DTPA tumor uptake and tumor-to-blood ratios can be obtained, thus providing good perspectives for diagnostic and therapeutic use in humans. Int. J. Cancer 75:74–80, 1998.© 1998 Wiley-Liss, Inc.     

Analysis of alpha-fetoprotein gene expression in hepatocellular carcinoma and liver cirrhosis by in situ hybridization

The expression of the alpha-fetoprotein (AFP) gene in hepatocellular carcinoma (HCC) and liver cirrhosis by in situ hybridization analysis of AFP mRNA in cryostat and paraffin-embedded tissue sections was studied. In HCC sections the majority of tumor cells showed positive hybridization with a 3H-labeled AFP complementary DNA probe. The number of radioactive hybrid grains detected in HCC sections generally paralleled the level of serum AFP in the patient. In liver cirrhosis sections a small number of cells showed positive hybridization. These cells were dispersed in the tissue and morphologically indistinguishable from surrounding hepatocytes. Each of these cells contained a high level of hybridization signals to permit easy identification. In situ hybridization analysis of AFP mRNA may be of use in detecting preneoplastic cells in liver cirrhosis that cannot be defined on the morphologic and immunohistochemical basis.     

Arginase activity in prostatic tissue of patients with benign prostatic hyperplasia and prostatic carcinoma

We studied arginase activity in human prostatic tissue in 15 patients with benign hyperplasia and 27 patients with prostatic carcinoma. Arginase specific activity is greater (p less than 0.0001) in prostatic carcinomas than in hyperplastic prostates. Arginase specific activity is correlated inversely (p less than 0.0001) with the histological grade of the tumor.     

Prostatic hexosaminidase activity in patients with benign prostatic hyperplasia and prostatic carcinoma

Hexosaminidase activity in prostatic tissue has been compared in 15 patients with benign prostatic hyperplasia and 15 patients with prostatic carcinoma. The ratio of enzymatic activity for the two substrates tested (p-nitrophenyl-2-acetamido-2-deoxy-beta-D-glucopyranoside and p-nitrophenyl-2-acetamido-2-deoxy-beta-D-galactopyranoside) was not significantly different in the two groups of patients. The proportion of hexosaminidase represented by the B isozyme was not significantly different for the two groups of patients. Prostatic tissue hexosaminidase was greater (p = 0.0141) in carcinomatous prostates than in hyperplastic prostates.     

Enhanced tumor binding using immunohistochemical analyses by second generation anti-tumor-associated glycoprotein 72 monoclonal antibodies versus monoclonal antibody B72.3 in human tissue

Monoclonal antibody (MAb) B72.3 was generated using a membrane-enriched fraction of a human mammary carcinoma biopsy. It has demonstrated reactivity to the majority of human adenocarcinomas including colorectal, gastric, pancreatic, ovarian, endometrial, mammary, and nonsmall cell lung cancer as well as weak or nondetectable reactivity to the majority of normal adult tissues, with the exception of secretory endometrium. Radiolabeled B72.3 has demonstrated MAb localization of carcinoma in approximately 70% of several hundred colorectal and ovarian carcinoma patients. The B72.3-reactive antigen, tumor-associated glycoprotein 72, has been purified from a human colon cancer xenograft and used as an immunogen to generate second generation MAbs. Twenty-eight of these MAbs, designated CC (colon cancer), were shown to be reactive with tumor-associated glycoprotein 72; direct-binding radioimmunoassays, Western blotting, live cell surface binding assays, liquid competition radioimmunoassays, and affinity constant measurements distinguished CC MAbs from each other and from B72.3. Two of these MAbs, CC49 and CC112, were selected for further immunohistochemical characterization. These MAbs were tested here against a spectrum of normal, benign, and malignant human adult tissues using the avidin-biotin-peroxidase technique, and their reactivity was compared with B72.3. Both CC MAbs were more reactive than B72.3 against a range of tumors. Extensive testing with MAbs CC49 and B72.3 using serial tissue sections demonstrated that both MAbs reacted similarly to most normal adult tissues with MAb CC49 reacting stronger to inflammatory colonic tissue. In 35 of 48 (72%) carcinoma biopsies of the gastrointestinal tract, ovary, breast, and lung in which one of the MAbs reacted to at least 20% of the cells, CC49 reacted to a greater percentage of carcinoma cells and/or tumor-associated mucin than B72.3. The reciprocal was observed in only 2% of the carcinomas. This study thus provides evidence that these second generation anti-tumor-associated glycoprotein MAbs may be more efficient than B72.3 in the further study of human carcinoma cell populations and in the diagnostic and therapeutic procedures presently being pursued with MAb B72.3.     

双特异性单克隆抗体在肿瘤治疗中的应用

双特异性单克隆抗体(BsMAb)是含有两个不同配体结合位点的免疫球蛋白分子,在疾病的诊断治疗上具有较大临床应用潜力,特别在肿瘤治疗方面,有其不容忽视的优越性.现综述近年来BsMAb在肿瘤治疗中的研究及应用进展.同时,对其人源化进程也进行了概述.     

Preparation of anti-ras Mr 21,000 protein monoclonal antibodies and immunohistochemical analyses on expression of ras genes in human stomach and thyroid cancers

Sixteen clones (RASK-1 to -16) of murine monoclonal antibodies were raised against ras Mr 21,000 protein (p21). The p21 produced by Escherichia coli with inserted v-Ki-ras genes was used as immunogen. RASK-1 was found to be specific for Ki-ras p21, whereas RASK-2 to -16 reacted with the p21s of Ki-, N-, and Ha-ras genes in both enzyme-linked immunosorbent and immunoblotting assays. Binding inhibition assays with biotinylated monoclonal antibodies by enzyme-linked immunosorbent assay showed that the monoclonal antibodies of the 16 clones included those binding to several mutually distinct sites on p21. The expressions of ras p21 in human stomach and thyroid tissues were examined with RASK-3, which reacted with all the Ki-, N-, and Ha-ras p21s immunohistochemically by the avidin-biotin peroxidase complex method. Formalin-fixed, paraffin-embedded tissues of 101 cases of stomach cancer, 53 cases of noncancerous stomach, 74 cases of cancer of the thyroid, and 59 cases of noncancerous thyroid were analyzed. In both the stomach and thyroid, cancer cells expressed p21 predominantly. Cells of cases with various noncancerous disorders as well as certain types of normal cells were also p21 positive. These findings suggest that precaution is required in use of p21 as a cancer marker. Expression of p21 was noted in moderately to well-differentiated stomach cancer, intestinal metaplasia, and atypical hyperplasia. This finding suggests that the appearance of p21 in stomach cancer may be initiated before cytological transformation.     

Acid phosphatase in prostatic tissue homogenates from patients with benign prostatic hyperplasia and prostatic carcinoma

Acid phosphatase activity biochemically in the primary tumor of 20 patients with prostatic carcinoma, was studied in an attempt to understand the basis for a correlation or lack of correlation between serum and/or bone marrow acid phosphatase levels and the presence and/or clinical behavior of prostatic carcinoma. The enzyme activity was similarly measured in 19 patients with benign prostatic hyperplasia as controls. On the average, enzyme activities were lower (P less than 0.002) in the tissues from patients with carcinoma. There was no correlation of enzyme activity in tumor with the age of the patient, stage of disease, degree of differentiation of the tumor, or serum acid phosphatase activity.     

前列腺癌与前列腺增生患者血清游离PSA和总PSA的改变

背景与目的:血清总前列腺特异性抗原(totalprostate-specificantigen,TPSA)被认为是目前诊断前列腺癌(carcinomaofprostate,PCa)的最佳肿瘤标记物,游离前列腺特异性抗原(freeprostatespecificantigen,FPSA)与TPSA的比值(FPSA/TPSA)可以提高其诊断PCa的特异性。本研究比较PCa与前列腺增生(benignprostatehyperplasia,BPH)患者血清TPSA及FPSA/TPSA比值水平,为临床诊断PCa提供参考。方法:用酶联免疫法检测66例BPH患者、29例BPH合并急性尿潴留(acuteurinaryretention,AUR)患者及22例PCa患者的血清TPSA、FPSA值,并对三组患者的血清TPSA及FPSA/TPSA的差异进行比较分析。结果:BPH患者血清TPSA(4.10±1.39)μg/L、BPH合并AUR患者血清TPSA(15.50±3.34)μg/L与PCa患者血清TPSA(55.00±13.50)μg/L之间均有显著性差异(P<0.05)。但三组患者血清TPSA在<4.0μg/L、4.0～10.0μg/L、>10.0μg/L区间存在重叠,BPH合并AUR患者与PCa患者重叠更为明显;BPH患者和BPH合并AUR者的FPSA/TPSA值无显著性差别(P>0.05),但与PCa患者比较均有显著性差异(P<0.05);三组患者FPSA/TPSA水平在<0.15、0.15～0.25、>0.25区间均存在重叠。结论:TPSA、FPSA/TPSA在BPH患者、BPH合并AUR患者和PCa患者中均存在重叠。血清TPSA、FPSA/TPSA水平临床上     

荧光原位杂交技术检测c-erbB-2和p53基因在胃癌中的表达

目的：探讨胃癌组织中ｃ－ｅｒｂＢ－２和Ｐ５３基因的表达及其意义。方法：应用荧光原位杂交技术对５５例有癌及移行区、正常区组织的常规石蜡包埋标本进行检测。结果：ｃ－ｅｒｂＢ－２和Ｐ５３基石 阳性率分别为３６．３６％和４５．４５％,移行芡为１０．９１％和３．６４％,正常粘膜区为３．６５％和０,三区间差异无有极显著意义（Ｐ值均〈０．０１）。在肠型和弥温型胃癌中,ｃ－ｅｒｂＢ阳性率分别为５１．６１％和１６．     

Management of atypical lobular hyperplasia,atypical ductal hyperplasia,and lobular carcinoma in situ

Atypical hyperplasia and lobular carcinoma in situ are rare proliferative breast lesions, growing inside ducts and terminal ducto-lobular units. They represent a marker of increased risk for breast cancer and a non-obligate precursor of malignancy. Evidence available on diagnosis and management is scarce. They are frequently found incidentally associated with other lesions, but can be visible through mammography, ultrasound or magnetic resonance. Due to the risk of underestimation, surgical excision is often performed. The analysis of imaging and histopathological characteristics could help identifying low-risk cases, for which surgery is not necessary. Chemopreventive agents can be used for risk reduction. Careful imaging follow up is mandatory; the role of breast MRI as screening modality is under discussion.     

Heterogeneous distribution of acidic TA-4 in cervical squamous cell carcinoma: immunohistochemical demonstration with monoclonal antibodies

Tumor antigen TA-4 is divided into two subgroups; acidic and neutral TA-4. The tissue localizations of these TA-4 subgroups were examined by using monoclonal antibodies, i.e., Mab-21 which reacts with both acidic and neutral TA-4, and Mab-317 which is specific to acidic TA-4. Immunohistochemical staining with Mab-21 showed positive cells in most parts of the cancer nest and in the intermediate layer of the non-cancerous squamous epithelium of the uterine cervix, whereas positive staining with Mab-317 was observed only in the cells at the peripheral parts of the cancer nest adjacent to the surrounding stromal tissue. Thus, examination of the subgroups of TA-4 may be a useful aid for investigating the biologic behavior of squamous cells.     

Pepsinogens I and II in gastric cancer: an immunohistochemical study using monoclonal antibodies

Monoclonal antibodies were used to examine the immunohistochemical expression of pepsinogens I and II in 31 early and 76 advanced gastric cancers. Of the 107 carcinomas studied, 19 contained pepsinogen II and only 3, found exclusively in pepsinogen II-positive cases, contained pepsinogen I. Gastric cancer produces pepsinogen II more frequently than pepsinogen I, and production of the latter is significantly associated with the former. Histologically, there were 54 intestinal-type and 53 diffuse-type cancers. The former produced pepsinogen II more frequently than the latter. In the diffuse type, the four pepsinogen II-positive cases were found exclusively in females. Although the pepsinogen expression was independent of the macroscopic features in advanced gastric cancer, it was found that the protruded-type early gastric cancer produced pepsinogen II more frequently than the depressed type. Incidences of pepsinogen positivity were not different between early and advanced gastric cancers or between cancers with or without lymph node metastasis, suggesting that production of pepsinogen is independent of tumor growth.     

Correlation of cyclooxygenase-2 and aromatase immunohistochemical expression in invasive ductal carcinoma, ductal carcinoma in situ, and adjacent normal epithelium

Summary The purpose of our study was to evaluate the correlation between cyclooxygenase-2 (COX-2) and aromatase immunohistochemical expression in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) present in the same breast, as well as in adjacent stroma and normal epithelium, we still correlated with nuclear grade, histologic grade, presence or absence of comedonecrosis, tumor size, and age at diagnosis. Forty-seven cases were evaluated through the use of anti-aromatase and anti-COX-2 polyclonal antibodies. Making the correlation of COX-2 and aromatase expression, we observed that COX-2 expression in IDC was correlated with aromatase expression in IDC (p<0.001), DCIS (p<0.001), normal epithelium (p=0.024), and stroma tumor (p<0.001). When the correlation was made between COX-2 expression in DCIS with aromatase, we observed positive correlation in IDC (p<0.001), DCIS (p<0.001), normal epithelium (p=0.013), and stroma tumor (p<0.001). In the correlative analysis of COX-2 expression in normal epithelium with aromatase in different evaluated tissues, we observed the following statistical results: IDC (p<0.001), DCIS (p<0.001), normal epithelium (p=0.005), and stroma tumor (p=0.047). Our results demonstrate the high correlation between COX-2 and aromatase expression in IDC, DCIS and normal epithelium, showing the importance of these two enzymes in the induction, promotion and progression of breast cancer.