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Malignant pancreatic tumors in children are rare. The major problem for the clinician is a lack of experience and of accepted therapeutic strategies. Malignant pancreatic tumors in children show a pattern different from that in adults. In infants, especially pancreatoblastomas, solid cystic tumors of females, and endocrine carcinomas of the pancreas must be expected. We report our experience in three patients with malignant pancreatic tumors (one pancreatoblastoma and two malignant endocrine pancreatic carcinomas) and review the present literature with a focus on the typical clinical and biologic features and the presently recommended therapeutic strategies. Pancreatoblastomas and solid cystic tumors are mainly found in the head of the pancreas. Fibrotic capsules with rare, late metastases are characteristics of these tumors, indicating total resection to be an important therapeutic procedure. Pancreatoblastomas should additionally be treated with chemotherapy (ADM, IFO, cis-PL, VP16). Endocrine carcinomas of the pancreas (malignant gastrinomas and malignant insulinomas) should also primarily be treated with radical surgery, including extensive lymph node dissection. In case of distant metastases, local resection (liver) or somatostatin in combination with chemotherapy (streptozocin in the case of malignant insulinomas) may be used.

The efficacy of tivozanib/mFOLFOX6 was comparable with but not superior to bevacizumab/mFOLFOX6 in patients with previously untreated mCRC. Since data from the prespecified interim analysis did not demonstrate superiority, this resulted in discontinuation of the study. The safety and tolerability profile of tivozanib/mFOLFOX6 was consistent with other tivozanib trials. NRP-1 is a potential predictive biomarker for tivozanib activity, but these results require further validation. Clin Cancer Res; 22(20); 5058-67. ©2016 AACR.

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1 Using methylation-specific real-time PCR, we determined the prevalence of aberrant methylation in the mismatch repair gene hMLH1 and in the recently described HPP1 gene among 50 esophageal, 50 cardiac and 50 gastric ADCs. Additionally, expression of hMLH1 protein was detected immunohistochemically and correlated with DNA MSI. Hypermethylation of hMLH1 was found in 14% of esophageal, 28% of cardiac and 32% of gastric ADCs, whereas HPP1 hypermethylation was found more frequently in the 3 tumor types (64% vs. 38% vs. 54%). In gastric ADC, HPP1 hypermethylation was found more frequently in tumors with concomitant hMLH1 hypermethylation (81%) than in those without hMLH1 hypermethylation (41%, p ‫؍‬ 0.008). Complete loss of hMLH1 protein expression, which was present in 10 carcinomas (5 cardiac and 5 gastric), was invariably correlated with hMLH1 hypermethylation and MSI. In conclusion, our data indicate that MSI and loss of the mismatch repair protein hMLH1, which is mainly caused by hMLH1 gene hypermethylation, are more prevalent in stomach and cardia carcinogenesis than in that of the esophagus. Moreover, in gastric cancer, hMLH1 hypermethylation is correlated with hypermethylation of the HPP1 ADCs of the esophagus and stomach are characterized by important differences concerning etiologic and clinical background. Chronic gastroesophageal reflux disease and subsequent intestinal metaplasia of the esophagus (Barrett's esophagus), on the one side, and Helicobacter pylori infection with subsequent atrophic gastritis, on the other side, are among the most important risk factors for esophageal or gastric ADC, respectively. 1,2 Moreover, the incidence of esophageal ADC has been rising rapidly over the last 3 decades, whereas the incidence of gastric ADC has been declining. 3 Although traditionally considered a gastric carcinoma, cardiac ADC shares a number of features with esophageal ADC, e.g., profound male predominance, rising incidence and etiologic association with chronic gastroesophageal reflux. 4,5 Hypermethylation of CpG islands represents an important epigenetic mechanism for silencing tumor-suppressor genes during carcinogenesis. 6 For example, loss of function of the DNA mismatch repair gene hMLH1 by hypermethylation of its promoter has been described in different cancer types, such as colorectal and endometrial cancers. 6,7 Lack of hMLH1 protein expression strongly decreases the fidelity of DNA replication and has been correlated with MSI, a surrogate marker for the so-called RER phenotype. 8,9 Thus, hypermethylation of hMLH1 has been detected in about 95% of RER-positive gastric ADCs but in only 5% of RER-negative cases. 8 Shibata et al. 10 found an as yet unexplained association between hypermethylation of hMLH1 and HPP1 in a series of 32 gastric ADCs. Currently, only limited data exist about the structural and functional properties of HPP1. It is thought to encode for a cell membrane receptor. The HPP1 protein shares a high grade of structural homology to regulatory proteins of the CNS (i.e., tomoregulin...