The prognostic impact of primary tumor resection in pancreatic neuroendocrine tumors with synchronous multifocal liver metastases
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Primary tumor
Univariate analysis
Pancreatic tumor
Liver tumor
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Chromogranin A
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Despite recent progress in cancer treatment, the prognosis of patients with pancreatic cancer still remains poor. Pancreatic tumors are reported to display high molecular heterogeneity. Elucidating the molecular mechanisms underlying pancreatic cancer progression is essential for improving patient treatment and survival. The overexpression of E3 ubiquitin ligase mind bomb 1 (MIB1) was previously described in pancreatic cancer cells, where it enhanced tumor cell proliferation. However, the role of MIB1 in pancreatic cancer progression remains elusive. In the present study, we confirmed that MIB1 expression is elevated in pancreatic cancer tissues and that high levels of MIB associate with unfavorable prognosis. Overexpression of MIB1 enhanced proliferation and invasion of pancreatic cancer cells both in vitro and in vivo. We further investigated the molecular mechanisms downstream of MIB1 and observed for the first time that MIB1 targets suppressor of tumorigenicity 7 protein (ST7), previously described as suppressor of tumorigenicity, for proteasomal degradation. Furthermore, we found that ST7 suppressed tumor growth by downregulating IQ motif containing GTPase activating protein 1 (IQGAP1) in pancreatic tumor cells. Thus, these data show that MIB1 promotes pancreatic cancer progression by inducing ST7 degradation followed by downregulation of IQGAP1 in pancreatic cancer cells. In conclusion, our research shows that the MIB1/ST7/IQGAP1 axis is essential for pancreatic cancer progression, and MIB1 inhibition may serve as a novel therapeutic strategy in patients with pancreatic cancer.
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1259 Objectives In patients with neuroendocrine tumors (NET) 68Ga-DOTA-Tyr-octreotide (DOTATOC)-PET/CT is a tool of growing importance for tumor-detection, therapy planning and control. Even though the somatostatin receptor expression can be relatively quantified using standard uptake values (SUV), just few trials have so far aimed to determine characteristic ranges for SUV in primary and metastatic NET-lesions of specific localisations. We present a descriptive analysis of SUV ranges in NET and their metastases. Methods Ga68-DOTATOC-PET/CT-Scans of 80 Patients with metastasised NET of the small bowel (38%), pancreas (20%), lung (11%) or other/unknown primary (31%) were analysed retrospectively. SUVmax in metastatic lesions was compared to SUVmax of the primary tumor site. We furthermore correlated SUVmax of the primary tumor lesions to SUVmax in the organ-specific metastatic lesions. Results SUVmax of metastatic lesions was significantly higher in pancreatic NET (20.9; n=11) than in NET of the small bowel (16.7; n=54). Mean SUVmax in liver-metastasis was 20.5 (SD 19.1; range 5.1 - 64.4) and 18.7 (SD 18.1; range 3.2 - 59.9) in the corresponding primary tumor site. In lymph node metastases we observed a mean SUVmax of 13.0 (SD 10.2; range 1.9 - 28.1) and 14.3 (SD 6.8; range 6 - 25.4) in the corresponding primary tumor site. A significant correlation between SUVmax in organ-specific metastases and in primary NET was found in patients with liver-metastases and in lymph node metastases. Conclusions In this retrospective study metastatic NET lesions showed higher SUV values in pancreatic NET than in bowel NET with the SUV in metastatic lesions closely correlated to the primary tumor SUV. Since SUV values represent the somatostatin receptor expression on NET-cells, these findings might be used in the future for response prediction of radiopeptide therapy in metastasised NET. Further prospective studies should be carried out to confirm our findings
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Renal cell carcinoma (Grawitz tumor) is an epithelial tumor able, to develop, in some cases, very late metastases. The most frequent localization are: lung, bones and liver. Pancreatic metastasis are rare and appear late, sometime even after 12 years from primary renal tumor. In this cases the differential diagnosis must be made with primary pancreatic tumors. We present a case report of pancreatic metastatic tumor developed 5 years after right nephrectomy for renal cell carcinoma. We decide to perform cephalic duodenopancreatectomy (Wipple type).
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3033 Objectives: Pheochromocytomas and paragangliomas (PPG) are rare neuroendocrine tumors which may be amenable to surgical excision or systemic therapy. Metastatic or unresectable PPG may be imaged and treated with targeted neuroendocrine transporter 1 (NET1) radionuclide therapy using meta-iodobenzylguanidine (MIBG). MIBG tumor imaging and therapy, however, may be suboptimal to due low NET1 expression or tumor heterogeneity. An alternative theranostic target is the somatostatin receptor 2 (SSR2) via DOTATATE. If DOTATATE tumor uptake in PPG is high, DOTATATE could be tested as an additional or complimentary theranostic strategy. The purpose of this study is to compare 68Ga DOTATATE uptake in PPG compared to the established indications of small bowel and pancreatic neuroendocrine (GEPNET) tumors.
Methods: We retrospectively reviewed 50 consecutive patients referred for 68Ga DOTATATE PET/ CT imaging. A single outlier PPG subject with extremely high tumor uptake (SUVmax > 300) was excluded. Of the remaining subjects with identifiable tumor, we quantified the tumor uptake and target to background ratios (T/B) in subjects with PPG (n=5 subjects; 14 lesions) compared to small bowel neuroendocrine and pancreatic (GEPNET) tumors (n=20 subjects; 44 lesions). Tumors were contoured using a semi-automated program based on a modified PERCIST criteria. SUVmax and SUVmean were measured and tumor/background was calculated as the ratio of SUVmax in the tumor to SUVmean in the aortic blood pool. Mean values and standard deviations were calculated for SUVmax, SUVmean, and T/B.
Results: High tumor uptake in PPG (SUVmax = 36.7 + 21.4) was comparable to GEPNETS (SUVmax = 37.8 + 23.5), and not found to be significantly different via t-test (p=0.90). High T/B in PPG (T/B = 40.2 + 28.6) were also comparable to GEPNET (T/B = 42.2 + 41.1), and again not significantly different (p=0.90). The PPG tumor uptake ranged from 6.3 to 66.7. Using a modified PERCIST threshold to define the tumor boundaries, the average SUVmean of the PPG tumors was 8.4 + 4.2.
Conclusions: PPG may show high tumor uptake and T/B in 68Ga DOTATATE PET / CT imaging. This data supports further investigations of DOTATATE as an alternative or complimentary theranostic for imaging and therapy of metastatic or unresectable PPG.
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Radionuclide therapy
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Neuroendocrine tumor originates from several sites. This study was conducted to reveal the differences in clinical course of neuroendocrine tumors by the origin.We reviewed data of patients diagnosed with neuroendocrine tumor between January 1996 and July 2007.A total of 371 patients were enrolled [pancreas 60, gastrointestinal (GI) tract 210, lung 35, other sites 46, unknown primary sites 20]. The primary tumor site correlated with the stage (P=0.000) and grade (P=0.000). At diagnosis, metastasis was observed in 28.3%, 6.7%, and 2.9% of the cases in pancreatic, GI, and pulmonary neuroendocrine tumors, respectively. Grade 3 neuroendocrine tumor was observed in 7.7%, 0.5%, and 0.0% in pancreatic, GI, and pulmonary neuroendocrine tumors. Overall survival was 116.0 months (95% confidence interval, 86.9-145.1). Overall survival was 116.0 months in pancreatic neuroendocrine tumor, not reached in GI neuroendocrine tumor and 120.0 months in pulmonary neuroendocrine tumor (P=0.024). The recurrence rate was 18.0%. It was 20.9%, 11.9%, and 2.9% in pancreatic, GI, and pulmonary neuroendocrine tumors (P=0.062). In multivariate analysis, stage, grade, and age were prognostic for overall survival (OS). Stage, grade, and sex were prognostic for disease-free survival.Neuroendocrine tumors from the pancreas, GI tract, and lung showed different clinical characteristics.
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Pancreatic neuroendocrine tumor (P-NET) is a rare and slow-growing tumor. Unfortunately, there is no clear consensus on the role and timing of surgery for primary tumor and liver metastases, although current reports refer to liver surgery including LT for unresectable liver metastases.A thirty-nine-year-old man was diagnosed with nonfunctioning pancreatic neuroendocrine tumor (P-NET) in the pancreatic head, with multiple liver metastases. The tumor was 2.5 cm in diameter and he was asymptomatic. Small but multiple metastases were detected in the liver, and no extrahepatic metastases were observed. We initially intended to control the liver metastases before resection of the primary tumor. To begin with, transarterial chemoembolization (TACE) and transcatheter arterial infusion (TAI) were repeated. Thereafter, systemic chemotherapy and biotherapy were introduced according to follow-up assessments. Unfortunately, imaging assessment at about 10 months later revealed that liver metastases were partially enlarged, although some were successfully treated. Therefore, these therapies were switched to other regimens, and TACE/TAI, systemic chemotherapies and biotherapies were repeated. Although liver metastases seemed to be stable for a while, the primary tumor was enlarged even after therapy. At 3.5 years after initial diagnosis, the primary tumor became symptomatic (pain and jaundice). Liver metastases enlarged and massive swelling of the para-aortic lymph nodes was observed. Thereafter, palliative therapy was the main course of action. He died at 4.3 years after initial diagnosis.Our young patient could have been a candidate for initial surgery for primary tumor and might have had a chance of subsequent liver transplantation for unresectable metastases. Surgeons still face questions in deciding the best surgical scenario in patients with P-NET with liver metastases.
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Pancreatic neuroendocrine tumors (pancreatic NET) are relatively rare, slowly growing tumors, although their incidence is increasing, and patients may survive for several years with metastatic disease. Apart from symptomatic relief, there have been few treatment options for these tumors in the past. More recently, investigators have explored the potential of molecularly targeted agents in treating pancreatic NET, with some success. In this review, we consider the data supporting exploitation of different targets in pancreatic NET, including peptide receptors, receptor tyrosine kinases (involved in tumor angiogenesis and more directly supporting tumor growth), and intracellular targets, such as the mammalian target of rapamycin (mTOR), which has a central role in regulating cell growth, metabolism, and apoptosis. Probably due to the paucity of pancreatic NET, many clinical trials to date have included heterogeneous NET populations, and there are few randomized studies of this specific patient population. Very recently, promising results have been achieved in placebo-controlled, phase III trials with the multitargeted tyrosine kinase inhibitor, sunitinib, and the mTOR inhibitor, everolimus. These agents have been approved or are currently being reviewed by authorities for use in patients with pancreatic NET. Here we review potential molecular targets in pancreatic NET and summarize the available data for targeted agents from phase II and III trials open to patients with this tumor.
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