全自动DNA图像分析系统在胰腺恶性肿瘤诊断中的价值

目的： 评估全自动DNA图像分析（DNA-ICM）系统在诊断胰腺恶性肿瘤中的价值。方法： 108例可疑胰腺恶性肿瘤患者行超声内镜引导下细针穿刺,所获标本分别行常规细胞学检测及DNA-ICM检测,以组织病理学诊断结果为标准,参考临床随访资料,分析细胞学、DNA-ICM及两者联合的诊断价值。结果： 常规细胞学诊断的敏感性（93.1%）、特异性（95.2%）、阳性预测值（98.8%）、阴性预测值（76.9%）及准确率（93.5%）均高于DNA-ICM（分别为90.8%、90.5%、97.5%、70.4%、90.7%）,但两者之间的差异均无统计学意义（P>0.05）。两种方法联合诊断的各项指标分别为敏感性（95.4%）、特异性（90.5%）、阳性预测值（97.6%）、阴性预测值（82.6%）及准确率（94.4%）。两者联合诊断的敏感性、阴性预测值、准确率均高于单独诊断,但其差异均无统计学意义（P>0.05）。结论： DNA-ICM联合细胞学诊断有很好的临床应用价值,DNA-ICM是胰腺细胞学诊断的一种较好的辅助诊断手段。     

Sunitinib for advanced pancreatic neuroendocrine tumors

Recent recognition of the high prevalence of neuroendocrine tumors in combination with a sustained failure to improve outcomes for patients with advanced disease has elevated their priority for research and drug development. Sunitinib (SU11248, Sutent; Pfizer Inc. NY, USA) potently inhibits multiple-receptor tyrosine kinases, resulting in antiangiogenic effects. A growing body of evidence indicates angiogenesis is a clinically relevant therapeutic target in pancreatic neuroendocrine tumors, culminating in a Phase III randomized study of sunitinib in patients with advanced progressive pancreatic neuroendocrine tumors. Sunitinib has recently gained regulatory approval as a single agent in this setting, and future studies will investigate most appropriate patient selection, and sequencing and combination with other targeted and cytotoxic agents. Here, we discuss in detail the molecular properties, clinical efficacy and safety of sunitinib in the context of pancreatic neuroendocrine tumors.     

Treatment of endocrine pancreatic tumors

Endocrine pancreatic tumors are rare with an incidence of 4 per million inhabitants. Most tumors are malignant except for insulinomas that usually are benign. They are slowly growing in the majority of cases but there are exceptions with rapidly progressing malignant carcinomas. Because of the rarity of these tumors large randomized trials are difficult to accomplish. However, most physicians treating these patients agree that surgery should be considered in all cases and that medical treatment with chemotherapy and biotherapy is well established for this group of patients.     

Endocrine pancreatic tumors: factors correlated with survival.

BACKGROUND: The aim of this study was to evaluate the survival rate of patients with endocrine tumors of the pancreas, functioning or non-functioning, associated or not with MEN 1 syndrome. PATIENTS AND METHODS: Eighty-three patients with pancreatic endocrine tumors diagnosed in our department from 1978 to 2003 were studied. RESULTS: The study included 37 men (44.6%) and 46 women (55.4%). The median age of patients at diagnosis was 55 years (range 19-81 years). Fifty-two patients (62.7%) had non-functioning endocrine tumors, 16 (19.3%) had functioning endocrine tumors and 15 (18.1%) had MEN 1 disease with pancreatic involvement. Twenty-seven patients (32.5%) had liver metastases at the time of diagnosis, involvement of the lymph nodes was found in 47 out of 79 patients (59.5%). Forty patients (48.2%) had radical surgery, 20 (24.1%) had palliative surgery and 53 were treated medically. The survival rate was significantly related to the presence of metastases, lymph node involvement, and the type of tumor and treatment. CONCLUSIONS: Tumor resection, the absence of liver and lymph node metastases, and the presence of MEN 1 syndrome are related to a better survival rate. Radical surgery continues to have a central role in the therapeutic approach to endocrine tumors of the pancreas.     

Middle-segment preserving pancreatectomy for multifocal neuroendocrine pancreatic tumors

BackgroundMultifocal neuroendocrine tumors (NET) usually occur in the context of a multiple neuroendocrine neoplasia type 1 (MEN1). When the proximal part of the pancreatic body is spared by NET, Miura et al. have proposed a “middle-segment preserving” pancreatectomy (MSP) as alternative to total pancreatectomy [[1], [2], [3]].VideoA 28-year-old woman with MEN1 was referred for surgical resection of a multifocal pancreatic tumor with single metastasis located and a single liver metastasis in close contact with the left hepatic duct. The preoperative work-up by DOTATOC-PETSCAN revealed multifocal tumors sparing only the proximal part of the pancreatic body. Hormonal dosages were normal but Chromogranine A was elevated at 700 μg/l. At surgery pancreatic intraoperative ultrasonography confirmed the absence of tumor at the proximal part of the pancreas. A pancreaticoduodenectomy was performed first followed by a left pancreatectomy with partial splenectomy. A 3 × 5 cm remnant of the pancreatic body vascularized by a dorsal pancreatic artery was preserved (Fig. 1). A left hepatectomy was then performed (Fig. 2). Digestive reconstruction is performed by a pancreatojejunostomy with an externalized pancreatic stent (Fig. 3), hepaticojejunostomy and a gastrojejunal anastomosis.ResultsSurgery lasted 660 minutes. Postoperative course was uneventful but a late readmission was necessary because of pyelonephritis due to nephrolithiasis treated by ureteral stent insertion. At 11 months postoperative follow-up the patient was disease-free with no endocrine dysfunction under oral pancreatic enzyme supplementation. Total weight loss since surgery was 8 Kilograms.ConclusionsA middle-segment-preserving pancreatectomy could be a valid surgical alternative to total pancreatectomy for multifocal pancreatic tumors sparing the proximal pancreatic body. This operation can achieve acceptable functional outcomes but large series with long-term follow up are needed to evaluate the advantages and results of MSP.     

Serum biomarkers for the differentiation of autoimmune pancreatitis from pancreatic ductal adenocarcinoma

Autoimmune pancreatitis(AIP), a chronic inflammation caused by the immune system attacking the pancreas, usually presents imaging and clinical features that overlap with those of pancreatic ductal adenocarcinoma(PDAC). Serum biomarkers, substances that quantitatively change in sera during disease development, are a promising non-invasive tool with high utility for differentiating between these diseases. In this way, the presence of AIP is currently suspected when serum concentrations of immunogl...     

Microsatellite DNA alterations of gastrointestinal stromal tumors are predictive for outcome.

PURPOSE: In gastrointestinal stromal tumors (GIST), loss of heterozygosity (LOH) on chromosome 22 and its presumptive biological function has been described. The prognostic value of these and other DNA regions for patient survival remains unclear. EXPERIMENTAL DESIGN: Sixty patients who underwent surgery at our institution between 1992 and 2003 for GIST were histopathologically reclassified by immunohistochemistry and the GIST consensus group criteria 2001. Twenty-one microsatellite loci on chromosomes 3, 9, 13, 17, 18, and 22 were screened for alterations in tumor and healthy DNA. Survival was calculated by Kaplan-Meier plots. RESULTS: Eleven (18.3%) of 60 patients showed metastases at presentation. Thirteen (21.7%) of 60 were high-risk GISTs. LOH was found in all tumors. Twenty-eight (46.7%) of 60 showed more than two LOH in 21 microsatellite marker sites. The frequency of single marker LOH varied from 1.7% to 28.3% among tumors. Frequent LOH was found on chromosomes 22 and 17. The correlation of LOH positivity and the consensus scoring was significant (P=0.005, chi2 test). After a median observation time of 33.3 months (95% confidence interval, 23.9-42.6), overall survival was best for patients with tumors of very low, low, and intermediate risks with only 6 of 36 death events, whereas 14 of 24 high-risk and metastasized patients had died (P<0.001, log-rank test). Likewise, LOH significantly predicted survival (P=0.013) and the effect was particularly detrimental for LOH on chromosome 17 (P<0.001). CONCLUSIONS: LOH is a useful phenomenon for the prognosis of GIST. Rather than chromosome 22 markers, chromosome 17 markers independently predict survival.     

Molecular pathology of pancreatic neuroendocrine tumors

Pancreatic endocrine tumors (PETs) are rare neoplasms which account for 1% to 2% of all pancreatic malignancies. The diagnostic, grading and prognostic criteria for PETs have been controversial in surgical pathology and clinical medicine. The newly updated 2010 WHO classification introduced in clinical practice will give more insight into genetic and molecular changes related to PET subtypes. These neoplasms can be graded into 1 of 3 tiers, based on histologic characteristics in likeness to epithelial neuroendocrine tumors in other anatomic sites. Most PETs are sporadic, however, some of them, may occur as part of familial tumors (inherited syndromes) such as multiple endocrine neoplasia type 1 (MEN1 syndrome), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF-1), and tuberous sclerosis (TSC). In sporadic endocrine pancreatic tumors, losses of chromosome 1 and 11q as well as gain on 9q appear to be early events in the development of pancreatic tumors. Multiple genetic defects may accumulate with time and result in pancreatic neuroendocrine tumor progression and malignancy. Although PETs may be similar or identical in histologic appearance to neuroendocrine tumors of the gastrointestinal tract, differences in their underlying biology and likely differences in response to therapeutic agents suggest that they should be treated and investigated as a distinct entity. The correlation of PI3K/Akt/mTOR pathway in the pathogenesis of PETs has been reported, and clinical trials data of mTOR inhibitors is promising.Key Words: Pancreatic neuroendocrine tumors (PNET), tumorigenesis, molecular pathology and diagnosis     

A shining light in the darkness for the treatment of pancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors are rare neoplasms; past decades have seen limited research channeled into this area. Recently, 2 placebo-controlled phase III trials using 2 drugs--everolimus and sunitinib--with distinct molecular rationales achieved their principal objective of increasing survival in patients with advanced pancreatic neuroendocrine tumors (PNET). Nonetheless, several questions remain unanswered, notably defining the optimal schedule for integrating these targeted agents with conventional cytotoxics and other treatment options, and identifying appropriate biomarkers for patients with the potential to derive greater benefit. In this article, we analyze the results of the 2 largest studies ever completed in patients with PNETs and discuss the challenges for future drug development in this setting. SUMMARY: Sunitinib and everolimus will become new treatment options for patients with PNETs and will be integrated into the complex therapeutic management of this disease. In this review, we summarize the evidence-based data of these drugs as well as the molecular-based science in this setting that will lay the groundwork for future studies.     

Tubedown expression correlates with the differentiation status and aggressiveness of neuroblastic tumors.

PURPOSE: The discovery and validation of new prognostic factors and further refinement of risk group stratification are needed to improve clinical interpretation of neuroblastoma. Our laboratory isolated and characterized a developmentally regulated gene named TUBEDOWN against which we have raised a monoclonal antibody (OE5). Tubedown becomes down-regulated postnatally yet remains strongly expressed in some neuroblastomas. The purpose of this study is to define the utility of Tubedown expression as a new measure of the differentiation status and aggressiveness of neuroblastic tumors. EXPERIMENTAL DESIGN: Tubedown protein expression was quantitatively assessed in neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) and normal adrenal tissues using Western blot and OE5 immunohistochemistry. Regulation of Tubedown expression during retinoic acid-induced neuronal differentiation in neuroblastoma cell lines was assessed by Western blotting. RESULTS: High levels of Tubedown expression are observed in tumors with significant neuroblastic component, unfavorable histopathology, advanced stage, high-risk group, and poor outcome. In contrast, more differentiated subsets of neuroblastic tumors, ganglioneuroblastomas with favorable histopathology and ganglioneuromas, express low levels of Tubedown. In vitro, marked retinoic acid-induced neuronal differentiation responses of neuroblastoma cells are associated with a significant decrease in Tubedown expression, whereas limited neuronal differentiation responses to retinoic acid were associated with little or no decrease in Tubedown expression. CONCLUSIONS: Our results indicate that the levels of Tubedown expression are linked to the differentiation status and aggressiveness of neuroblastic tumors and represent an independent prognostic factor for neuroblastoma. Tubedown expression may be useful to more accurately define different neuroblastic tumor subsets and ultimately provide more adequate assessment and treatment for neuroblastoma patients.     

Cytophotometric studies of the nuclear DNA content in cartilaginous tumors.

The histopathological differentiation between chondromas and low-grade malignant chondrosarcomas can be difficult. For this reason we studied in 37 different cartilaginous tumors the mitotic index and the Feulgen DNA content using a scanning-integration cytophotometric technique. In 23 chondromas the Feulgen DNA content was diploid and showed a unimodal normal distribution. The number of mitoses was 0--0, 5%. The nuclei of a chondroblastoma were also diploid and the Feulgen DNA content was normally distributed. The mitotic index was 1% and few tetraploid nuclei, which were probably G2 nuclei, were observed. In two chondromyxoid fibromas, the average Feulgen DNA content was diploid and normally distributed. Several tetraploid nuclei were noted. The mitotic index was respectively 0.25% and 1.75%. Recurrence was noted in the first case. The Feulgen DNA content and mitotic index were clearly different in the chondrosarcomas. The distribution of the DNA content was bimodal or unimodal in low-grade chondrosarcomas. The mitotic index was less than 3%. In high-grade malignant chondrosarcomas, the histograms were broad unimodal or aneuploid. The mitotic index was above 5%.     

Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors.

PURPOSE: Molecular targeting with monoclonal antibodies and tyrosine kinase inhibitors is a novel approach to cancer treatment. We have examined the expression of molecular targets in patients with malignant endocrine pancreatic tumors, which is necessary to justify additional studies investigating the potential benefit from such treatment. EXPERIMENTAL DESIGN: Thirty-eight tumor tissues from malignant endocrine pancreatic tumors were examined with immunohistochemistry using specific polyclonal antibodies with regard to the expression pattern of platelet-derived growth factor receptors (PDGFRs) alpha and beta, c-kit, and epidermal growth factor receptor (EGFR). RESULTS: All 38 tissue specimens expressed PDGFRalpha on tumor cells, and 21 of 37 specimens (57%) expressed PDGFRalpha in tumor stroma (1 specimen was nonevaluable). Twenty-eight samples (74%) stained positive for PDGFRbeta on tumor cells, and 36 of 37 samples (97%) stained positive for PDGFRbeta in the stroma (1 specimen was nonevaluable). Thirty-five tumor tissues (92%) stained positive for c-kit, and 21 (55%) stained positive for EGFR on tumor cells. No differences were seen between syndromes or between poorly differentiated or well-differentiated tumors. Previous treatment did not influence expression pattern. Receptor expression pattern varied considerably between individuals. CONCLUSIONS: We have found that tyrosine kinase receptors PDGFRs alpha and beta, EGFR, and c-kit are expressed in more than half of the patients with endocrine pancreatic tumors. Because these receptors represent molecular targets for STI571 and ZD1839 (tyrosine kinase inhibitors) and IMC-C225 (a monoclonal antibody), we propose that patients suffering from EPTs might benefit from this new treatment strategy. However, because of great variability in receptor expression pattern, all patients' individual receptor expression should be examined.     

Cytomegalovirus strain differentiation by DNA restriction analysis.

The heterogeneity of CMV DNA obtained from standard strains and new isolates, including a vaccination strain (Towne 125), was investigated. The cleavage patterns produced by the restriction endonucleases Eco RI and Bam 1 revealed stable strain specificities of CMV. On the other hand, a remarkable homology of sequence-specific CMV DNA fragmentation was demonstrated. A CMV subtyping relevant to clinical questions seems to be improbable.     

Cell surface differentiation antigens of normal urothelium and bladder tumors.

Bladder cancer ranks as the third most common malignancy among men and tenth among women. Superficial transitional cell carcinomas (stage Ta, Tis, and T1) account for approximately 70-80% of these tumors, while the remaining 20-30% are invasive (T2, T3, and T4). Approximately 70% of superficial tumors will have one or more recurrences, with 25% of these expressing a higher histologic grade and 10-15% subsequently developing invasive and/or metastatic disease. The detection and prediction of tumor recurrence and/or tumor progression is crucially important if timely and appropriate therapy is to be instituted. Conventional histopathologic evaluation usually provides definitive diagnosis upon which therapeutic planning is based. However, at present there are no more reliable morphologic indicator to identify which individuals will have recurrent disease or who will progress to invasive and/or metastatic cancer. Recent advances in tumor biology have identified markers that are good candidates for clinical applications in early tumor detection, as well as for the stratification of patients with like-appearing morphological lesions with different biological and clinical behavior. The ultimate goal is to develop predictive assays that would segregate patients with high probability of failures versus patients who would be cured by localized modes of therapy.