恶性上皮来源肿瘤骨转移生物标志物的研究进展

恶性上皮来源的肿瘤常伴有骨转移,影响到患者的生存率、生活质量及心理状态。肿瘤的骨转移是一个复杂的过程,包括上皮间质转化、肿瘤细胞的定植、骨髓微环境的改变以及细胞间的相互作用等。因此在肿瘤发生的早期,通过各类相关细胞分泌或携带的蛋白、RNA作为特异的检测指标来预测和评估骨转移的发生,将预防和治疗骨转移的窗口明显前移,将会成为恶性上皮来源肿瘤研究的新热点。本文综述了肿瘤骨转移的生物标志物的研究现状,期望能为早期预防和评估肿瘤骨转移的发生提供理论基础。

Hilar Cholangiocarcinoma with Synchronous Metastases to Breast and Skeletal Muscle: A Case Report and Literature Review

Hilar cholangiocarcinoma has been reputed as a slow growth tumor in the past. Skeletal muscle is one of the most unusual sites of metastasis from any malignancy. We report herein a case of hilar cholangiocarcinoma with synchronous metastases to skeletal muscle and breast, and review the literature. The patient was a 48-year-old woman who presented with jaundice and weight loss. An inoperable hilar cholangiocarcinoma was diagnosed. She was treated with a combination of endoscopic plastic stent biloiary drainage and three-dimensional conformal radiotherapy （3DCRT）. Good response was achieved. Ten months later, she exhibited with a painful metastatic mass in the muscle rectus femoris of left thigh and a painless mass in the left breast. She underwent operation to relieve the pain, but died from liver failure after 8 months. The literature only offers isolated cases of cholangiocarcinoma with distant metastases, of which the common sites were cervical lymph node, bone, and portal venous system. Most patients were presented with multiple metastases with extensive local disease.

Mechanisms of cancer metastasis to the bone

Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. What is the basis for their preferential growth within the bone microenvironment? Bidirectional interactions between tumor cells and cells that make up bone result in a selective advantage for tumor growth and can lead to bone destruction or new bone matrix deposition. This review discusses our current understanding of the molecu- lar components and mechanisms that are responsible for those interactions.

肿瘤免疫中的NF-κB受体激活剂及其配体

NF-κB受体激活剂配体(RANKL)/NF-κB受体激活剂(RANK)最早在免疫系统中发现,是一种多功能细胞因子,在肿瘤发生、进展尤其是骨转移中发挥重要作用。原发恶性肿瘤一旦发生骨转移则预后极差。地诺单抗是目前应用最为广泛的RANKL抑制剂,更多研究者试图以RANKL为靶点,寻求新型抗RANKL药物的同时实行RANKL特异性精准成像,推动原发肿瘤的早期诊疗进程。

CD44v6 in peripheral blood and bone marrow of patients with gastric cancer as micro-metastasis

AIM： To detect the expression of CD44 correlated with the ability of micro-metastasis in peripheral blood and bone marrow of patients with gastric cancer and to deduce its clinical significance. METHODS： Preoperative peripheral blood and bone marrow specimens from 46 patients with gastric cancer and 6 controls were studied by semi-quantitative RTPCR amplification of CD44v6mRNA. Preoperative and postoperative peripheral blood specimens from 40 patients with gastric cancer and 14 controls were studied by quantitative RT-PCR amplification of CD44v6mRNA in the corresponding period. RESULTS： Semi-quantitative RT-PCR amplification showed that CD44v6mRNA expression of peripheral blood and bone marrow was positive in 39 （84.8%） and 40 （86.9%） of 46 patients with gastric cancer, respectively. In peripheral blood, CD44v6mRNA expression was positive for diffuse type in 30 （93.8%） of 32 patients and for intestinal type in 9 （64.3%） of 14 patients. On the other hand, in bone marrow, CD44v6mRNA expression was positive for diffuse type in 31 （96.9%） of 32 patients and for intestinal type in 10 （71.4%） of 14 patients. There was a significant difference between the diffuse type and intestinal type. Quantitative RTopCR amplification demonstrated that CD44v6mRNA was not expressed in the peripheral blood of controls and CD44v6mRNA expression was positive for preoperative peripheral blood in 40 patients with gastric cancer, the expression levels being from 4.9 × 10^2 to 3.2× 10^5 copies/g RNA. The average expression level of CD44v6mRNA in peripheral blood was 3.9 × 10^10 copies/g RNA. The expression levels of CD44v6mRNA in peripheral blood in gastric cancer patients after curative operation increased from 5.5 × 100 to 7.6 × 10 copies/g RNA （P = 0.00496）. After curative operation, the expression level decreased markedly. CONCLUSION： Semi-quantitative and quantitative RTPCR amplification for CD44v6mRNA is a sensitive and specific method for the detection of micro-metastasis in peripheral blood and bone marrow, which might be used as an indicator of tumor burden and therapeutic effect.

FEASIBILITY OF WHOLE BODY DIFFUSION WEIGHTED IMAGING IN DETECTING BONE METASTASIS ON 3.0T MR SCANNER

Objective To evaluate the feasibility of whole body diffusion weighted imaging (DWI) in bone metastasis detection using bone scintigraphy as comparison. Methods Forty-five patients with malignancy history were enrolled in our study. All the patients received the whole body DWI and bone scintigraphy scan within 1 week. The magnetic resonance (MR) examination was performed on 3.0T MR scanner using embedded body coil. The images were reviewed separately by two radiologists and two nuclear medicine physicians, who were blinded to the results of the other imaging modality. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the two techniques for detecting bone metastasis were analyzed. Results A total of 181 metastatic lesions in 77 regions of 34 patients were detected by whole body DWI, and 167 metastatic lesions in 76 regions of 31 patients were identified by bone scintigraphy. The patient-based sensitivity and PPV of whole body DWI and bone scintigraphy were similar (89.5% vs. 81.6%, 97.1% vs. 91.2%), whereas, the patient-based specificity and NPV of whole body DWI were obviously higher than those of bone scintigraphy (85.7% vs. 57.1%, 60.0% vs. 36.4%). Ten regions negative in scintigraphy but positive in whole body DWI, mainly located in spine, pelvis, and femur; nine regions only detected by scintigraphy, mainly located in skull, sternum, clavicle, and scapula. The region-based sensitivity and specificity of whole body DWI were slightly higher than those of bone scintigraphy (89.5% vs. 88.4%, 95.6% vs. 87.6%). Conclusion Whole body DWI reveals excellent concordance with bone scintigraphy regarding detection of bone metastasis, and the two techniques are complementary for each other.

Altered cytoskeletal structures in transformed cells exhibiting obviously metastatic capabilities

Oytoskeletal changes in transformed cells (LM-51) exhibiting obviously metastatie eapabilities were investigated by utilization of double-fluorescent labelling through combinations of:(1) tubulin indirect immunofluoresoenoe plus Khodamine-phalloidin staining of F-artins;(2) indirect immunofluorescent staining with α-aotinin polyolonal- and vinoulin monoclonal antibodies. The LM-51 cells which showed metastatic index of >50% were derived from lung metastasis in nude mice after subcutaneous inoculation of human highly metastatic tumor DNA transfected NIH3T3 cell transformants. The parent NIH3T3 cells exhibited well-organized miorotubu-les, prominent stress fibers and adhesion plaques while their transformants showed remarkable oytoskeletal alterations: (1) reduced microtubules but increased MTOC fluorescence; (2) disrupted stress fibers and fewer adhesion plaques with their protein components redistributed in the cytoplasm; (3) F-aotin-and α-actinin/vinculin aggregates appeared in the cytoplasm. These aggregates were dot-like, varied in size (0.1-0.4u,m) and number, located near the ventral surface of the cells. TPA-induced aotin/vinoulin bodies were studied too. Indications that aotin and α-actinin/vinoulin redistribution might be important alterations involved in the expression of metastatio capabilities of LM-51 transformed cells were discussed.

Preliminary Observation on the Influence of Tumor Osseous Metastasis on Autologous Peripheral Blood Stem Cell Collection

OBJECTIVE To examine the influence of tumor osseous metastasis on the patients undergoing autoiogous peripheral blood stem ceil collection. METHODS A total of 36 patients with malignant diseases who received an autoiogous peripheral blood stem ceil transplantation, during a period from April 2004 to June 2006, were chosen. The patients were divided into two groups, i.e. group A were patients with a complication of tumor osseous metastasis, and group B were without metastasis. Both groups were treated with Taxotere 120 mg/m^2 plus granuiocyte colony-stimulating factor （G-CSF） 5 μg/kg/d, for a mobilization regimen. A blood ceil separator was used to collect the mononuciear ceils. The proportion of harvested CD34＋ ceils in the peripheral blood and the collected mononuciear ceils were detected by flow cytometry. The number of CD34＋ ceils was used to determine the difference in the nature of the collections between the two groups. RESULTS After mobilization in groups A and B, the number of the peripheral blood mononuciear ceils （PBMC） was 39.3±14.7% and 41.1±12.4 % and the proportion of CD34＋ ceils was 0.16±0.07% and 0.17±0.10%, respectively. Following administration of the drugs, there was no significant difference between the number of harvested PBMC and CD34＋ cells of the two groups, i.e., 3.47±1.16×10^8/Kg and 2.52±1.43×10^6/Kg in group A and 4.02±1.31×10^8/Kg and 2.73±1.87×10^6/Kg in group B, respectively. CONCLUSION Osseous metastasis, as a single factor, may have no impact on mobilization and harvesting of hematopoietic stem ceils and their engraftment after autotransplantation.

Clinical research on zoledronic acid in treatment of pain caused by bone metastasis of malignant tumors

Objective:To evaluate the efficacy and safety of zoledronic acid for the pain caused by metastatic tumor of bone.Methods:52 patients with metastatic tumor of bone were randomly divided into two groups.The zoledronic acid group received 4 mg zoledronic acid infusion for 30 minutes and the control group received 90 mg pamidronate infusion for 6 hours. Results:The effective rates in zoledronic acid group and control group were 73.08%and 69.23%respectively.No significant difference was observed between the two groups.The median pain relief onset at days 5 and 7,respectively,and no significant difference was observed.The ECOG scores on the 7th day after medication:the differences in the zoledronic acid group before and after medication and between the two groups were both significant(P<0.001 and P=0.0448).The adverse reac- tion was no significant difference between the two groups.Conclusion:Zoledronic acid is efficient and safe in the treatment of pain caused by metastatic tumor of bone and it has low adverse reaction rate and convenient shorter using time.