Stephan U. Goebel

Prospective Study of the Clinical Course, Prognostic Factors, Causes of Death, and Survival in Patients With Long-Standing Zollinger-Ellison Syndrome

PURPOSE The long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors (PETs) in whom the excess-hormone state is controlled is largely unknown. To address this issue, patients with gastrinomas were assessed. PATIENTS AND METHODS Two hundred twelve patients with Zollinger-Ellison syndrome (ZES) were prospectively studied. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up period of 13.8+/-0.6 years (range, 0.1 to 31 years). Annual assessments of possible factors that might affect prognosis or treatment approaches were performed, such as those for tumor size and location; the presence, location, and extent of metastases; and the occurrence of ectopic Cushings syndrome or another PET syndrome. Deaths were categorized as ZES-related or non-ZES-related and classified into different causes. RESULTS Thirty-one percent of patients died, all of non-acid-related causes. One half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushings syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. The presence of liver metastases alone only moderately decreased survival time; however, the additional development of bone metastases or ectopic Cushings syndrome markedly decreased survival rate. CONCLUSIONS In ZES, gastrinoma growth is now the main single determinant of long-term survival, with one half of patients dying a gastrinoma-related death and none an acid-related death. Large primary tumors that are pancreatic in location, the development of liver metastases, (especially if associated with bone metastases or Cushings syndrome), and the extent of liver metastases are all important prognostic factors. The identification of these factors allows the recognition of subgroups that can be used to tailor antitumor treatment approaches.

Gluten sensitivity in sporadic and hereditary cerebellar ataxia

Gluten sensitivity, with or without classical celiac disease symptoms and intestinal pathology, has been suggested as a potentially treatable cause of sporadic cerebellar ataxia. Here, we investigated the prevalence of abnormally high serum immunoglobulin A (IgA) and IgG anti‐gliadin antibody titers and typical human lymphocyte antigen (HLA) genotypes in 50 patients presenting with cerebellar ataxia who were tested for molecularly characterized hereditary ataxias. A high prevalence of gluten sensitivity was found in patients with sporadic (7/26; 27%) and autosomal dominant (9/24; 37%) ataxias, including patients with known ataxia genotypes indicating a hitherto unrecognized association between hereditary ataxias and gluten sensitivity. Further studies are needed to determine whether gluten sensitivity contributes to cerebellar degeneration in patients with hereditary cerebellar ataxia. Patients with hereditary ataxia (including asymptomatic patients with known ataxia genotype) should be considered for screening for gluten sensitivity and gluten‐free diet trials. Ann Neurol 2001;49:540–543

Is the epidermal growth factor receptor (EGFR) overexpressed in gastrinomas

The EGFR is overexpressed in many tumors including pancreatic exocrine cancers. Whether it is overexpressed in pancreatic endocrine tumors (PETs) such as gastrinomas is unclear. In one report all gastrinomas expressed EGFR, whereas with other PETs EGFR was only rarely expressed. Because overexpression of EGFR is associated with poor prognosis in many tumors, and a proportion of gastrinomas are aggressive, the expression of EGFR may have prognostic significance. To address this question the following study was performed. Gastrinomas from 16 patients with Zollinger-Ellison syndrome were examined for EGFR expression and the expression was compared to the tumor growth. Competitive RT-PCR and immunohistochemistry were performed on 10 gastrinomas each. Paraffin-embedded sections were stained using 3 different monoclonal antibodies. Breast cancer specimens served as positive controls. mRNA levels were assessed by competitive RT-PCR with mRNA-specific primers. EGFR mRNA levels were normalized for b-actin mRNA levels and expressed as the ratio between the two. Pooled mRNA fractions from normal human pancreatic tissue were used as normal controls. Sixteen gastrinomas (6M, 10F), 14 sporadic tumors and 2 MEN-l associated gastrinomas were analyzed. The mean age of the patients was 43.6±0.4 yr [15.5-65.3). The mean fasting serum gastrin level was 5934±2018 pglml [404-26667]. The mean follow-up was 5.3±0.7 yr [0.9-11.2). Five patients had aggressive disease. All tumors expressed EGFR mRNA. The mean EGFRIb-actin ratio of the gastrinomas was lower than that of normal pancreatic tissue (0.0085±0.OO24 vs. 0.055±0.025). In none of the 10 gastrinomas did the ratio exceed that found in normal pancreas. The mean EGFRIb-actin ratio did not differ between aggressive (n=5) and benign (n=5) gastrinomas (0.040±0.035 vs. 0.0115±0.004). The EGFRIb-actin ratio did not differ between duodenal gastrinomas (n=5) and primary tumors in another location (n=4), (0.011±0.004 vs. 0.OO6±0.OO2). Immunostaining for EGFR was negative in each of the 10 tumors tested. The results show that the EGFR is expressed in all gastrinomas, however it is not overexpressed compared to normal pancreatic tissue. Furthermore its level of expression does not correlate with the aggressiveness of the tumor or with the primary location of the tumor, which has been shown to be an important determinant of metastatic potential. These results suggest that in contrast to exocrine pancreatic tumors, in PETs overexpression of EGFR is unlikely to be an important pathogenic process.