Little is known of the natural history of thymic carcinoids in multiple endocrine neoplasia type 1 (MEN1). This is important because in 1993 they were identified as a frequent cause of death, yet only small retrospective studies and case reports exist. We report results of a prospective study of 85 patients with MEN1 evaluated for pancreatic endocrine tumors and followed over a mean of 8 yr with serial chest computed tomography, magnetic resonance imaging (MRI), chest x-ray, and, since 1994, octreoscans [somatostatin receptor scintigraphy (SRS)]. Seven patients (8%) developed thymic carcinoids. Patients with and without carcinoids did not differ in clinical, laboratory, or MEN1 tumor features, except for male gender and the presence of a gastric carcinoid. All thymic tumors were hormonally inactive. Four thymic carcinoids lacked 11q loss of heterozygosity, although it was found in three pancreatic endocrine tumors. Computed tomography and/or MRI were more sensitive than SRS or chest x-ray in detecting tumors initially or with recurrence. All patients underwent resection of the thymic carcinoid, and in all patients followed more than 1 yr, the tumor recurred. Bone metastases developed in two patients and were detected early only on MRI, not SRS. This study provides information on early thymic carcinoids and allows modifications of existing guidelines to be recommended for their diagnosis, surveillance, and treatment.

BACKGROUNDMalignant pancreatic endocrine tumors (PETs) have a poor prognosis and existing antitumor treatments are unsatisfactory. Recent studies have shown somatostatin analogues to have antitumor growth effects in patients with malignant PETs; however, to the authors' knowledge, little information exists regarding their efficacy or effect on survival in patients with progressive malignant gastrinoma, the most common symptomatic malignant PET. The purpose of the current study was to study prospectively the efficacy, safety, and effect on survival of long‐term treatment with octreotide in consecutive patients with progressive malignant gastrinoma.METHODSFifteen consecutive patients with malignant gastrinoma with progressive hepatic metastases were studied. All patients underwent conventional imaging studies (computed tomography scan, magnetic resonance imaging, ultrasound, and, if needed, selective angiography) and somatostatin receptor scintigraphy prior to treatment and at 3–6‐month intervals while receiving treatment. The patients all were treated initially with octreotide, 200 μg every 12 hours, and at last follow‐up were being maintained on long‐acting release octreotide, 20–30 mg every month. Tumor size and/or number were used to classify patient responses as either no tumor response or tumor response (stabilization or decrease in size). Treatment response was correlated with tumor and clinical characteristics.RESULTSTumors in 8 of the 15 patients studied (53%) responded at 3 months, with 47% (7 of 15 patients) demonstrating tumor stabilization and 6% (1 of 15 patients) demonstrating a decrease in tumor size. The mean duration of response was 25.0 ± 6.1 months (range, 5.5–54.1 months). Six of the eight responders were continuing to respond at the time of last follow‐up. Tumor response did not correlate with any clinical parameter (e.g., tumor extent, fasting gastrin, or acid secretory rates). However, slow‐growing tumors were more likely to respond prior to treatment (86% vs. 0%) (P < 0.0014). During follow‐up (range, 4–8 years), 25% of the responders died compared with 71% of the nonresponders, a difference that approached statistical significance (P = 0.10). Two patients (13%) developed serious side effects that required the withdrawal of octreotide.CONCLUSIONSOctreotide is an effective antitumor treatment in patients with progressive malignant gastrinoma. In approximately 50% of these patients octreotide has an antigrowth effect; treatment is associated with a low incidence of serious side effects compared with other antitumor treatments commonly used and, in contrast to many studies, the growth response is long‐lasting. The results of the current study suggest that octreotide treatment should replace chemotherapy as the standard treatment for these patients, especially those patients with slow‐growing tumors. Additional studies involving larger numbers of patients will be needed to determine a convincing effect on survival. Cancer 2002;94:331–43. © 2002 American Cancer Society.

Use of CAD led to a significant increase in sensitivity for detecting polyps in the 6 mm or larger and 6-9 mm groups at the expense of a similar significant reduction in specificity.

Background & Aims Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced, incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer. Methods We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases. Results Familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than 50 y were found to have occult tumors; the tumors were cleared surgically from 91% of these individuals (21/23). Linkage analysis and whole-exome sequencing identified a germline 4 bp deletion in the gene inositol polyphosphate multikinase (IPMK) that truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and 17/35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival. Conclusions We found that small intestinal carcinoids can occur as an inherited autosomal dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%–35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early-stage disease. IPMK haplo-insufficiency promotes carcinoid tumorigenesis.

OBJECTIVE Hydrogen-1 MR spectroscopy (1H-MRS) is gaining acceptance as a noninvasive technique for assessment of hepatic steatosis, and the findings have been found to correlate closely with histopathologic grade. The aims of this study were to validate 1H-MRS performed with a 3-T MRI system for quantifying hepatic steatosis and to determine threshold values of 1H-MRS proton density fat fraction corresponding to standard histopathologic grade in patients undergoing diagnostic liver biopsy. SUBJECTS AND METHODS We conducted a prospective cross-sectional liver MRS study with 52 subjects undergoing diagnostic liver biopsy. The diagnostic accuracy of 1HMRS was evaluated with receiver operating characteristic curves. RESULTS The diagnostic accuracy of 1H-MRS for hepatic steatosis was high with an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.88–1.0). Results were similar for three 1H-MRS measurements obtained at different locations in the liver, for two independent pathologists, and whether fibrosis was present or absent. One third of participants had elevated transaminase concentrations of unknown cause, and 1H-MRS estimates of steatosis had perfect agreement with histopathologic grade in this group. Calculated 1H-MRS proton density fat fraction thresholds for histologic grades were less than 17% for grade 0 or trace steatosis, 17–38.6% for grade 1, and greater than 38.6% for grade 2 or higher. CONCLUSION Hydrogen-1 MR spectroscopy is an effective, noninvasive technique that can be used to diagnose and quantify hepatic steatosis. Hydrogen-1 MR spectroscopy thresholds corresponded with histopathologic grades and may be useful in the workup of patients with elevated transaminase concentrations.