Candidate microRNA biomarkers of pancreatic ductal adenocarcinoma: meta-analysis,experimental validation and clinical significance

Background

The diagnostic and prognostic value of microRNA (miRNA) expression aberrations in pancreatic ductal adenocarcinoma (PDAC) has been studied extensively in recent years. However, differences in measurement platforms and lab protocols as well as small sample sizes can render gene expression levels incomparable.

Methods

A comprehensive meta-review of published studies in PDAC that compared the miRNA expression profiles of PDAC tissues and paired neighbouring noncancerous pancreatic tissues was performed to determine candidate miRNA biomarkers for PDAC. Both a miRNA vote-counting strategy and a recently published Robust Rank Aggregation method were employed. In this review, a total of 538 tumour and 206 noncancerous control samples were included.

Results

We identified a statistically significant miRNA meta-signature of seven up- and three down-regulated miRNAs. The experimental validation results showed that the miRNA expression levels were in accordance with the meta-signature. The results from the vote-counting strategy were consistent with those from the Robust Rank Aggregation method. The experimental validation confirmed that the statistically unique profiles identified by the meta-review approach could discriminate PDAC tissues from paired nonmalignant pancreatic tissues. In a cohort of 70 patients, the high expression of miR-21 (p=0.018, HR=2.610; 95% CI=1.179-5.777) and miR-31 (p=0.039, HR=2.735; 95% CI=1.317-6.426), the low expression of miR-375 (p=0.022, HR=2.337; 95% CI=1.431-5.066) were associated with poor overall survival following resection, independent of clinical covariates.

Conclusions

The identified miRNAs may be used to develop a panel of diagnostic and prognostic biomarkers for PDAC with sufficient sensitivity and specificity for use in a clinical setting.     

Brain metastasis in renal cancer patients: metastatic pattern,tumour-associated macrophages and chemokine/chemoreceptor expression

Background:

The mechanisms of brain metastasis in renal cell cancer (RCC) patients are poorly understood. Chemokine and chemokine receptor expression may contribute to the predilection of RCC for brain metastasis by recruitment of monocytes/macrophages and by control or induction of vascular permeability of the blood–brain barrier.

Methods:

Frequency and patterns of brain metastasis were determined in 246 patients with metastatic RCC at autopsy. Expression of CXCR4, CCL7 (MCP-3), CCR2 and CD68⁺ tumour-associated macrophages (TAMs) were analysed in a separate series of 333 primary RCC and in 48 brain metastases using immunohistochemistry.

Results:

Fifteen percent of 246 patients with metastasising RCC had brain metastasis. High CXCR4 expression levels were found in primary RCC and brain metastases (85.7% and 91.7%, respectively). CCR2 (52.1%) and CCL7 expression (75%) in cancer cells of brain metastases was more frequent compared with primary tumours (15.5% and 16.7%, respectively; P<0.0001 each). The density of CD68⁺ TAMs was similar in primary RCC and brain metastases. However, TAMs were more frequently CCR2-positive in brain metastases than in primary RCC (P<0.001).

Conclusion:

Our data demonstrate that the monocyte-specific chemokine CCL7 and its receptor CCR2 are expressed in tumour cells of RCC. We conclude that monocyte recruitment by CCR2 contributes to brain metastasis of RCC.     

直肠良恶性肿瘤中肿瘤相关巨噬细胞和微血管及淋巴管生成的关系

目的:探讨直肠良恶性肿瘤组织中微血管密度(MVD)及淋巴管密度(LVD)与肿瘤相关巨噬细胞(TAMs)数量的相关性。方法:采用免疫组化的方法,用CD68标记TAMs,分别用CD31和D2-40标记微血管和淋巴管,光镜下对TAMs,MVD及LVD进行计数,分析。结果:直肠腺癌组织中的TAMs,MVD及LVD计数明显高于直肠腺瘤型息肉组织(P<0.01);在直肠腺癌组中,TAMs与MVD和LVD有明显相关性(TAMs与MVD:P<0.01;TAMs与LVD:P<0.01),且MVD与直肠癌淋巴结转移(P<0.01)和分化程度(P<0.05)密切相关;而TAMs和LVD仅与淋巴结转移有显著相关性(P<0.01,P<0.05)。结论:TAMs,MVD及LVD可能是反映直肠腺癌发生、发展、转移及侵袭能力的生物学指标,TAMs在肿瘤中的浸润可能与肿瘤血管及淋巴管的生成有关。     

直肠良恶性肿瘤中肿瘤相关巨噬细胞和微血管及淋巴管生成的关系

目的：探讨直肠良恶性肿瘤组织中微血管密度（MVD）及淋巴管密度（LVD）与肿瘤相关巨噬细胞（TAMs）数量的相关性。方法：采用免疫组化的方法,用CD68标记TAMs,分别用CD31和D2-40标记微血管和淋巴管,光镜下对TAMs,MVD及LVD进行计数,分析。结果：直肠腺癌组织中的TAMs,MVD及LVD计数明显高于直肠腺瘤型息肉组织（P〈0.01）;在直肠腺癌组中,TAMs与MVD和LVD有明显相关性（TAMs与MVD：P〈0.01;TAMs与LVD：P〈0.01）,且MVD与直肠癌淋巴结转移（P〈0.01）和分化程度（P〈0.05）密切相关;而TAMs和LVD仅与淋巴结转移有显著相关性（P〈0.01,P〈0.05）。结论：TAMs,MVD及LVD可能是反映直肠腺癌发生、发展、转移及侵袭能力的生物学指标,TAMs在肿瘤中的浸润可能与肿瘤血管及淋巴管的生成有关。     

microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis

BackgroundReports have described the prognostic relevance of microRNAs (miRNAs) in patients treated for pancreatic ductal adenocarcinoma (PDAC). However, many of these include small numbers of patients. To increase statistical power and improve translation, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of miRNAs on overall survival (OS) and disease-free survival (DFS) in PDAC.MethodsEligible studies were identified and quality assessed using multiple search strategies (last search December 2014). Data were collected from studies correlating clinical outcomes with dysregulated tumoural or blood miRNAs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations.ResultsTwenty studies involving 1525 patients treated for PDAC were included. After correcting for publication bias, OS was significantly shortened in patients with high tumoural miR-21 (adjusted HR = 2.48; 1.96–3.14). This result persisted when only studies adjusting for adjuvant chemotherapy were combined (adjusted HR = 2.72; 1.91–3.89). High miR-21 also predicted reduced DFS (adjusted HR = 3.08; 1.78–5.33). Similarly, we found significant adjusted HRs for poor OS for high miR-155, high miR-203, and low miR-34a; and unadjusted HRs for high miR-222 and high miR-10b. The small number of studies, limited number of miRNAs and paucity of multivariate analyses are the limitations of our study.ConclusionsThis is the first rigorous pooled analysis assessing miRNAs as prognostic biomarkers in PDAC. Tumoural miR-21 overexpression emerged as an important predictor of poor prognosis after PDAC resection independent of other clinicopathologic factors, including adjuvant chemotherapy use.     

Targeting the tumor microenvironment in pancreatic ductal adenocarcinoma

Introduction: The dismally slow improvement in patient survival over the years for pancreatic cancer patients is mainly due to two factors: the late diagnosis, at which point the disease is spread to distant organs; and the fact that tumor cells are surrounded by a dense, highly immunosuppressive microenvironment. The tumor microenvironment not only shields pancreatic cancer cells from chemotherapy but also leaves it unsusceptible to various immunotherapeutic strategies that have been proven successful in other types of cancer.

Areas covered: This review highlights the main components of the pancreatic tumor microenvironment, how they cross-talk with each other to generate stroma and promote tumor growth. Additionally, we discuss the most promising treatment targets in the microenvironment whose modulation can be robustly tested in combination with standard of care chemotherapy. Currently, active clinical trials for pancreatic cancer involving components of the microenvironment are also listed.

Expert opinion: Although immunotherapeutic approaches involving checkpoint inhibition are being pursued enthusiastically, there is still more work to be done with several other emerging immune targets that could provide therapeutic benefit.     

Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach

Tumour-associated macrophages, TAMs, play a pivotal role in tumour growth and metastasis by promoting tumour angiogenesis. Treatment with clodronate encapsulated in liposomes (clodrolip) efficiently depleted these phagocytic cells in the murine F9 teratocarcinoma and human A673 rhabdomyosarcoma mouse tumour models resulting in significant inhibition of tumour growth ranging from 75 to >92%, depending on therapy and schedule. Tumour inhibition was accompanied by a drastic reduction in blood vessel density in the tumour tissue. Vascular endothelial growth factor (VEGF) is one of the major inducers of tumour angiogenesis and is also required for macrophage recruitment. The strongest effects were observed with the combination therapy of clodrolip and a VEGF-neutralising antibody, whereas free clodronate was not significantly active. Immunohistologic evaluation of the tumours showed significant depletion of F4/80+ and MOMA-1+ and a less pronounced depletion of CD11b+ TAMs. Blood vessel staining (CD31) and quantification of the vessels as well as TAMs and tumour-associated dendritic cells (TADCs) in the A673 model showed reduction rates of 85 to >94%, even 9 days after the end of therapy. In addition, CD11c+ TADCs, which have been shown to potentially differentiate into endothelial-like cells upon stimulation by tumour released growth and differentiation factors, were similarly reduced by clodrolip or antibody treatment. These results validate clodrolip therapy in combination with angiogenesis inhibitors as a promising novel strategy for an indirect cancer therapy aimed at the haematopoietic precursor cells that stimulate tumour growth and dissemination and as a tool to study the role of macrophages and dendritic cells in tumorigenesis.     

E-cadherin在乳腺浸润性导管癌中的表达及临床意义

目的 探讨E-钙黏蛋白（E-cad）在乳腺浸润性导管癌中的表达及其与乳腺癌临床病理特征、淋巴结转移及预后的关系。方法 采用免疫组织化学 SP 法检测30例乳腺纤维腺瘤、450例乳腺浸润性导管癌组织中E-cad的表达,分析其表达与临床病理特征的关系, Kaplan-Meier法绘制生存曲线。结果E-cad在无淋巴结转移乳腺癌组织中阳性表达率为49.04％（77／157）,在有淋巴结转移的乳腺癌组织中阳性表达率为29.69％（87／293）,差异有统计学意义（P＜0.05）。E-cad表达与年龄、淋巴结转移、肿块大小、ER表达、分子分型及组织学分级有关（P＜0.05）,而与肿瘤分期、是否绝经、HER-2及Ki-67表达情况无关。乳腺癌淋巴结转移组、三阴性乳腺癌组中E-cad阳性表达者5年生存率优于E-cad阴性表达者,差异有统计学意义（P＜0.05）。结论 E-cad表达与乳腺癌淋巴结转移关系密切,其亦可成为乳腺癌伴淋巴结转移者或三阴性乳腺癌预后的判断指标。     

Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation

BACKGROUND:

Neoadjuvant chemoradiation before surgery is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC). However, analysis of prognostic factors is limited for patients with PDAC treated with neoadjuvant chemoradiation and pancreaticoduodenectomy (PD).

METHODS:

The study population was comprised of 240 consecutive patients with PDAC who received neoadjuvant chemoradiation and PD and was compared with 60 patients who had no neoadjuvant therapy between 1999 and 2007. Clinicopathologic features were correlated with disease‐free survival (DFS) and overall survival (OS).

RESULTS:

Among the 240 treated patients, the 1‐year and 3‐year DFS rates were 52% and 32%, with a median DFS of 15.1 months. The 1‐year and 3‐year OS rates were 95% and 47%, with a median OS of 33.5 months. By univariate analysis, DFS was associated with age, post‐therapy tumor stage (ypT), lymph node status (ypN), number of positive lymph nodes, and American Joint Committee on Cancer (AJCC) stage, whereas OS was associated with intraoperative blood loss, margin status, ypT, ypN, number of positive lymph nodes, and AJCC stage. By multivariate analysis, DFS was independently associated with age, number of positive lymph nodes, and AJCC stage, and OS was independently associated with differentiation, margin status, number of positive lymph nodes, and AJCC stage. In addition, the treated patients had better OS and lower frequency of lymph node metastasis than those who had no neoadjuvant therapy.

CONCLUSIONS:

In patients with PDAC who received neoadjuvant chemoradiation and subsequent PD, post‐therapy pathologic AJCC stage and number of positive lymph nodes are independent prognostic factors. Cancer 2012. © 2011 American Cancer Society.     

淋巴结切除术对子宫内膜癌的临床意义

手术治疗是子宫内膜癌的主要治疗方式,通过手术治疗可以明确诊断、病理分级、临床分期,并为术后的辅助治疗提供充分的临床资料。对于子宫内膜癌患者是否常规进行淋巴结切除仍存在较大争议,特别是对于低危的子宫内膜癌患者而言,因为低危患者淋巴结转移发生率非常低,且不影响患者的预后,但目前没有全面的划分淋巴结转移危险因素及其危险程度的统一标准。本文就子宫内膜癌的淋巴结转移特点,影响淋巴结转移的因素,淋巴结切除的并发症,淋巴结切除术对预后的影响,淋巴结切除的临床意义及淋巴结切除的发展方向等方面加以综述,我们认为对于内膜癌患者应选择个体化的治疗方案,注重术前的全面评估,对于G3,透明细胞,浸润肌层≥1/2,病灶>2cm,宫颈受累等应进行包括腹主动脉旁淋巴结在内的系统淋巴结切除术。     

MicroRNA in pancreatic ductal adenocarcinoma and its precursor lesions

Pancreatic ductal adenocarcinoma (PDAC) is the 4^th deadliest cancer in the United States, due to its aggressive nature, late detection, and resistance to chemotherapy. The majority of PDAC develops from 3 precursor lesions, pancreatic intraepithelial lesions (PanIN), intraductual papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm. Early detection and surgical resection can increase PDAC 5-year survival rate from 6% for Stage IV to 50% for Stage I. To date, there are no reliable biomarkers that can detect PDAC. MicroRNAs (miRNA) are small noncoding RNAs (18-25 nucleotides) that regulate gene expression by affecting translation of messenger RNA (mRNA). A large body of evidence suggests that miRNAs are dysregulated in various types of cancers. MiRNA has been profiled as a potential biomarker in pancreatic tumor tissue, blood, cyst fluid, stool, and saliva. Four miRNA biomarkers (miR-21, miR-155, miR-196, and miR-210) have been consistently dysregulated in PDAC. MiR-21, miR-155, and miR-196 have also been dysregulated in IPMN and PanIN lesions suggesting their use as early biomarkers of this disease. In this review, we explore current knowledge of miRNA sampling, miRNA dysregulation in PDAC and its precursor lesions, and advances that have been made in using miRNA as a biomarker for PDAC and its precursor lesions.     

Analysis of liver metastasis after resection for pancreatic ductal adenocarcinoma

AIM:To investigate the risk factors affecting the liver metastasis(LM) of pancreatic ductal adenocarcinoma(PDAC) after resection.METHODS:We retrospectively analyzed 101 PDAC patients who underwent surgical resection at the Samsung Medical Center between January 2000 and December 2004.Forty one patients with LM were analyzed for the time of metastasis,prognostic factors affecting LM,and survival.RESULTS:LM was found in 40.6%.The median time of the LM(n = 41) was 6.0 ± 4.6 mo and most LM occurred within 1 year.In univariate analysis,tumor size,preoperative carbohydrate antigen 19-9,and perineural invasion were factors affecting LM after resection.In multivariate analysis,tumor size was the most important factor for LM.In univariate analysis,tumor cell differentiation was significant to LM in low-risk groups.CONCLUSION:LM after resection of PDAC occurs early and shows poor survival.Tumor size is the key indicator for LM after resection.     

乳腺浸润性导管癌中Maspin、uPA的表达及其临床意义

目的：探讨乳腺浸润性导管癌组织中Maspin蛋白和尿激酶型纤溶酶原激活物（uPA）蛋白的表达及其临床意义。方法：应用免疫组织化学法检测60例乳腺浸润性导管癌组织中Maspin、uPA蛋白的表达情况,并对其与乳腺癌临床病理特征的关系进行统计学分析。结果：乳腺浸润性导管癌组织中Maspin蛋白的阳性表达率为46．7％,uPA蛋白的阳性表达率为61．7％,Maspin、uPA蛋白的表达存在显著负相关,r=-0．362,P〈0．01。结论：乳腺癌的发生、浸润和转移可能和Maspin蛋白表达下调及uPA表达上调相关,Maspin表达的下调或缺失使得uPA对肿瘤细胞介导的纤溶酶原激活抑制作用丧失,uPA表达上调,成为促进乳腺癌细胞的侵袭和转移的途径之一。     

Immunohistochemical analysis of p53 in colorectal cancer regarding clinicopathological correlation and prognostic significance

The overexpression of the tumor suppressor gene p53 was investigated immunohistochemically in 144 cases of primary colorectal cancer and in 8 cases with cancer in the corresponding metastatic lymph nodes. Abnormalities in p53 expression were found in 36 cases (25%) of the 144 primary cancer cases. In addition, p53-positive tumors were found to metastasize frequently to the lymph nodes, as compared to p53-negative tumors (61.1% vs. 41.7%, P=0.0428). p53 staining was identical in 7 of 8 (87.5%) cases in primary and metastatic lesions. When the DNA content of the tumor was determined by flow cytometry, the DNA index (mean ± SD) was significantly higher in p53-positive tumors than in p53-negative tumors (1.57 ± 0.38 vs. 1.39 ± 0.37, P=0.012). Therefore, the immunohistochemical data of p53 in colorectal cancer may help in potentially predicting metastatic spread to the lymph nodes. © 1995 Wiley-Liss, Inc.     

胃中部癌前哨淋巴结邻近、横向和跳跃性转移的临床分析

Objective: To investigate the distribution pathway of sentinel lymph nodes (SLN) in middle third gastric carci-noma, as the foundation for rational lymphadenectomy. Methods: 52 cases of middle third tumors with solitary lymph nodes from 1852 gastric carcinomas were selected. The locations and histological types of metastatic lymph nodes were analyzed retrospectively. Results: Of 52 solitary node metastases cases, 37 were limited to perigastric nodes (N1), while 15 with skipping metastasis. In the 35 cases with tumor of lesser curvature, there were 17 cases found lymph nodes of the lesser curvature side (No. 3), 5 cases involved lymph nodes of the greater curvature (No. 4), and 8 cases with lymph nodes of the left gastric artery (No. 7). In the 17 cases with tumor of greater curvature, 7 cases spread to No. 4, while 3 metastasized to lymph nodes of the spleen hilum (No. 10). The difference of the histological types in groups N1 and over N1, were not statistically significant (P > 0.05). Conclusion: Adjacent metastasis formed the primary distribution pattern of SLN in middle third gastric carcinoma, transversal and skipping metastases being also notable.     

Lymph node size and metastatic infiltration in adenocarcinoma of the pancreatic head

Background

Preoperative lymph node staging of pancreatic cancer by CT relies on the premise that malignant lymph nodes are larger than benign nodes. In imaging procedures lymph nodes >1 cm in size are regarded as metastatic nodes. The extend of lymphadenectomy and potential application of neoadjuvant therapy regimens could be dependent on this evaluation.

Patients and methods

In a morphometric study regional lymph nodes from 52 patients with pancreatic cancer were analyzed. The lymph nodes were counted, the largest diameter of each node was measured, and each node was analyzed for metastatic involvement by histopathological examination. The frequency of metastatic involvement was calculated and correlated with lymph node size.

Results

A total of 636 lymph nodes were present in the 52 specimens examined for this study (12.2 lymph nodes per patient). Eleven patients had a pN0 status, whereas 41 patients had lymph nodes that were positive for cancer. Five-hundred-twenty (82%) lymph nodes were tumor-free, while 116 (18%) showed metastatic involvement on histopathologic examination. The mean (±SD) diameter of the nonmetastatic nodes was 4.3 mm, whereas infiltrated nodes had a diameter of 5.7 mm (p = 0.001). Seventy-eight (67%) of the infiltrated lymph nodes and 433 (83%) of the nonmetastatic nodes were ≤5 mm in diameter. Of 11 pN0 patients, 5 (45%) patients had at least one lymph node ≥10 mm, in contrast only 12 (29%) out of 41 pN1 patients had one lymph node ≥10 mm.

Conclusion

Lymph node size is not a reliable parameter for the evaluation of metastatic involvement in patients with pancreatic cancer.     

Clinicopathological characteristics and treatment strategies in early gastric cancer: a retrospective cohort study

Background

Both endoscopic and surgical approaches are employed in the treatment of early gastric cancer (EGC). The aim of this study was to establish appropriate treatment strategies for early gastric cancer.

Methods

We retrospectively examined clinicopathological data of EGC patients who had undergone surgery.

Results

A total of 327 patients (204 males and 123 females, mean age 63.2 years) were eligible for inclusion in the study. The median follow-up period was 31 months. Of 161 mucosal (pT1a) tumors, 87 were mainly undifferentiated and 110 had an undifferentiated component. Four patients with pT1a tumors had lymph node metastases; all these tumors were signet-ring cell carcinomas and were macroscopic type 0-IIc with ulceration, and only one of them had lymphatic invasion. Among patients with submucosal tumors, four of 43 patients with pT1b1 tumors and 37 of 123 patients with pT1b2 tumors had nodal metastases. Lymph node metastases were significantly higher in mixed undifferentiated type group than differentiated type group for both groups, pT1a-pT1b1 (p = 0.0251) and pT1b2 (p = 0.0430) subgroups. Only four of 45 patients with nodal metastases were diagnosed preoperatively by computed tomography (sensitivity 8.9%, specificity 96.2%). Nine patients with pT1b tumors had recurrence after surgery, and died. The sites of initial recurrence were liver, bone, peritoneum, distant nodes, and the surgical anastomosis.

Conclusions

The incidence of nodal metastases was approximately 5% in undifferentiated type mucosal (pT1a) tumors, and higher in submucosal (pT1b) tumors. The sensitivity of preoperative diagnosis of nodal metastases in EGC using computed tomography was relatively low in this study. Therefore at present surgery with adequate lymphadenectomy should be performed as curative treatment for undifferentiated type EGC.     

Radiofrequency ablation of pancreatic ductal adenocarcinoma:The past,the present and the future

Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive cancers with a grim overall 5-year survival rate of 5%.Advances in surgical techniques,critical care,molecular diagnosis,diagnostic imaging,endosonology and adjuvant therapy have improved outcomes;but still more needs to be achieved.There is an urgent need to discover new avenues that may impact survival.Radiofrequency ablation(RFA)has attracted attention as an adjunctive treatment in PDAC.A review of English literature in Pub Med was done using the MESH terms for PDAC and RFA.All the articles were reviewed and core information was tabulated for reference.After a comprehensive review of all articles the data was evaluated to discover the role of RFA in PDAC management.Indications,contraindications,feasibility,success rate,safety,complications and impact on survival were reviewed and are discussed further.RFA appears to be an attractive option for nonmetastatic locally advanced PDAC.RFA is feasible but has a significant morbidity.At the present time the integration of RFA into the management of pancreatic ductal adenocarcinoma is evolving.It should be considered as having a complimentary role to current standard therapy in the multimodal management care model.It is likely that indications and patient selection for pancreatic RFA will expand.     

1 585 例甲状腺癌的临床病理特点及总结分析

目的:研究甲状腺乳头状癌（pnpillary thyroid cancer,PTC ）的发病趋势及临床病理特点。方法:回顾性分析湖北省人民医院2001年1 月至2013年7 月甲状腺疾病和湖北省肿瘤医院2006年1 月至2013年7 月甲状腺癌的临床病理资料。结果:湖北省人民医院自2008年以来,甲状腺癌发病明显升高,由14.94% 上升至18.10% ,其中甲状腺乳头状癌所占比例明显上升,由2008年的15.23%（46/302）上升至2012年的19.32%（166/859）。 两家医院中,甲状腺乳头状癌所占比例明显上升,由85.33%（378/443）上升至90.89%（1 038/1 142）;微小乳头状癌比例由9.26%（35/378）上升至22.83%（237/1 038）;确诊甲状腺乳头状癌患者1 416 例,男女比例为1:3.75;颈部淋巴结阳性检出率在性别、年龄方面相比均有显著性差异（P<0.05）,多病灶甲状腺乳头状癌患者颈部淋巴结阳性检出率为77.94% ,与单病灶甲状腺乳头状癌患者相比有显著性差异（P<0.05）。 单纯甲状腺乳头状癌患者颈部淋巴结阳性检出率为72.29% ,与合并结节性甲状腺肿者及合并桥本氏甲状腺炎者相比有显著性差异（P<0.05）。 结论:甲状腺乳头状癌的发病呈增长趋势,男性、年龄<45岁肿瘤直径>1 cm、多病灶肿瘤、单纯PTC 更易并发颈部淋巴结转移。      

Lack of CCR7 expression is rate limiting for lymphatic spread of pancreatic ductal adenocarcinoma

CCR7 expression on tumor cells promotes lymphatic spread in several malignant tumors. However, a comprehensive characterization of the CCL19/CCL21-CCR7 axis in pancreatic ductal adenocarcinoma (PDAC), which is known for its high rates of lymph-node metastases, is still lacking. CCR7 mRNA and CCR7 protein were found to be expressed in spheroid cultures of all six examined PDAC cell lines. In migration assays, CCR7 expressing PDAC cells showed enhanced migration toward CCL19 and CCL21, the two ligands of CCR7. In an orthotopic nude mouse model, CCR7-transfected PT45P1 cells gave rise to significantly larger tumors and showed a higher frequency of lymph vessel invasion and lymph-node metastases than mock-transfected cells. In an analysis using quantitative real-time PCR, CCR7 showed fourfold overexpression in microdissected PDAC cells compared to normal duct cells. Moderate-to-strong immunohistochemical CCR7 expression, found in 58 of 121 well-characterized human PDACs, correlated with high rates of lymph vessel invasion. Conversely, PDACs completely lacking CCR7 expression showed only low rates of lymph vessel invasion and lymph-node metastases. The evaluation of CCL21 expression by immunofluorescence staining revealed a significant upregulation of CCL21 in peritumoral and intratumoral lymph vessels compared to lymph vessels in disease-free pancreata. In conclusion, our study revealed strong evidence that lack of CCR7 impairs the metastatic potential of PDAC. Lymph vessel invasion by CCR7 expressing PDAC cells may be additionally enhanced by upregulation of CCL21 in tumor-associated lymph vessels, representing a previously unknown factor of lymphatic spread.