Carsten Palnæs Hansen

Functional Imaging of Neuroendocrine Tumors: A Head-to-Head Comparison of Somatostatin Receptor Scintigraphy, 123I-MIBG Scintigraphy, and 18F-FDG PET

Functional techniques are playing a pivotal role in the imaging of cancer today. Our aim was to compare, on a head-to-head basis, 3 functional imaging techniques in patients with histologically verified neuroendocrine tumors: somatostatin receptor scintigraphy (SRS) with 111In-diethylenetriaminepentaacetic acid-octreotide, scintigraphy with 123I-metaiodobenzylguanidine (MIBG), and 18F-FDG PET. Methods: Ninety-six prospectively enrolled patients with neuroendocrine tumors underwent SRS, 123I-MIBG scintigraphy, and 18F-FDG PET on average within 40 d. The functional images were fused with low-dose CT scans for anatomic localization, and the imaging results were compared with the proliferation index as determined by Ki67. Results: The overall sensitivity of SRS, 123I-MIBG scintigraphy, and 18F-FDG PET was 89%, 52%, and 58%, respectively. Of the 11 SRS-negative patients, 7 were 18F-FDG PET-positive, of which 3 were also 123I-MIBG scintigraphy–positive, giving a combined overall sensitivity of 96%. SRS also exceeded 123I-MIBG scintigraphy and 18F-FDG PET based on the number of lesions detected (393, 185, and 225, respectively) and tumor subtypes. 123I-MIBG scintigraphy was superior to 18F-FDG PET for ileal neuroendocrine tumors, and 18F-FDG PET was superior to 123I-MIBG scintigraphy for pancreaticoduodenal neuroendocrine tumors. The sensitivity of 18F-FDG PET (92%) exceeded that of both SRS (69%) and 123I-MIBG scintigraphy (46%) for tumors with a proliferation index above 15%. Conclusion: The overall sensitivity of 123I-MIBG scintigraphy and 18F-FDG PET was low compared with SRS. However, for tumors with a high proliferation rate, 18F-FDG PET had the highest sensitivity. The results indicate that, although SRS should still be the routine method, 18F-FDG PET provides complementary diagnostic information and is of value for neuroendocrine tumor patients with negative SRS findings or a high proliferation index.

Peptide Receptor Radionuclide Therapy with 90Y-DOTATOC and 177Lu-DOTATOC in Advanced Neuroendocrine Tumors: Results from a Danish Cohort Treated in Switzerland

Aim: Limited therapeutic options have highlighted the demand for new treatment modalities for patients with advanced neuroendocrine tumors (NET). Promising results of initial studies have warranted the implementation of peptide receptor radionuclide therapy (PRRT) in clinical practice. However, this treatment option still needs clinical evaluation. Methods: In this study, we evaluated the PRRT treatment response of 69 Danish patients with NET mainly originating from the gastroenteropancreatic system. Fifty-six patients (81%) were referred for PRRT to the Department of Nuclear Medicine, University Hospital Basel, Switzerland, between 2004 and 2008 due to progression assessed by the referring physicians. However, when retrospectively evaluated, only 42 of the 69 patients (61%) had progression according to RECIST (Response Evaluation Criteria in Solid Tumors). Most patients were treated with 90Y-DOTATOC. Results: Based on RECIST, a complete response was observed in 5 patients (7.4%), a partial response in 11 patients (16.2%) and stable disease in 42 patients (61.8%). Progressive disease after completed therapy was observed in 10 patients (14.7%). The median progression-free survival was 29 months (95% CI: 22–36 months). Pancreatic NET seemed to respond better to PRRT than small intestinal carcinoid tumors (p = 0.03). The overall frequency of serious adverse events was low. Conclusion: Implementation of PRRT in clinical routine has provided a valuable new therapeutic option for the treatment of advanced NET. We suggest that PRRT may advance from second- or third-line to first- or second-line therapy in inoperable/unresectable NET patients.

Evidence of Extrapancreatic Glucagon Secretion in Man.

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry–based proteomics) and show that 29–amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.

Temozolomide as Second or Third Line Treatment of Patients with Neuroendocrine Carcinomas

Background. Knowledge of the clinical efficacy in recurrent neuroendocrine carcinomas is sparse. Treatment with temozolomide alone or in combination with capecitabine and bevacizumab has recently shown promising results. Patients and Methods. Analysis of consecutive patients with neuroendocrine carcinomas (Ki-67 proliferation index >20%) and performance status 0–2 treated with temozolomide 200 mg/sqm orally days 1–5 every 28 days after at least one previous platin-containing chemotherapy regimen. Results. Twenty-eight eligible patients received a median of 3 courses. Sixteen patients were evaluable for response: Six achieved stable disease and ten progressed. The median survival for the 28 patients was 3.5 months. Survival in patients with tumors of pancreatic origin (n = 7) was 7.0 months versus 2.9 months in non-pancreatic origin (n = 21). Patients in PS 0-1 (n = 22) had a median survival of 4.5 months versus 1.1 months in patients in PS 2 (n = 6). Ki-67 index ≥50% was associated with a significantly shorter median survival than Ki-67 index <50% (2.7 months versus 10.9 months). The treatment was well tolerated. Conclusion. Temozolomide monotherapy has limited effect in treatment of recurrent neuroendocrine carcinomas. Second line treatment with temozolomide in combination with other compounds should be further investigated in patients in good performance with Ki-67 index <50%.

Quantitative Gene Expression of Somatostatin Receptors and Noradrenaline Transporter Underlying Scintigraphic Results in Patients with Neuroendocrine Tumors

Aim: To measure, by a quantitative approach, the gene expression underlying the results of somatostatin receptor (sst) scintigraphy (111In-DTPA-octreotide) and noradrenaline transporter (NAT) scintigraphy (123I-MIBG) in patients with neuroendocrine (NE) tumors. Methods: The gene expression of somatostatin receptors 1–5 (sst) and NAT was measured quantitatively by real-time PCR in a group of patients with NE tumors (n = 14) and compared to a group of patients with colorectal adenocarcinomas (n = 15). If available, scintigraphic results were compared with gene expression results (9 octreotide and 3 MIBG scintigraphies). Results: The sst2 was upregulated in 13 of 14 patients (93%) with NE tumors, and the absolute level of gene expression was highest for sst2. Gene expression alterations of NAT and the other sst subtypes were more variable. Gene expression of sst2 was in all cases in agreement with positive octreotide scintigraphies. In 2 of 3 cases where MIBG scintigraphy was positive, NAT was also upregulated. Sst2 was generally downregulated in the colorectal tumor group with the gene expression of the other receptors being more heterogeneous. Conclusions: In general, changes in gene expression of sst2 corresponded with scintigraphic results. Our data support that sst2 is the best target for visualization of NE tumors, whereas NAT is only a useful target in a subpopulation of NE tumors. Comparison of scintigraphic results with quantitative gene expression may be used to achieve a better understanding of the link between them, which in turn could aid in planning and development of noninvasive molecular imaging of key molecular processes.

Surgery for GEP-NETs

Surgery is the only treatment that may cure the patient with gastroentero-pancreatic (GEP) neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC) and should always be considered as first line treatment if R0/R1 resection can be achieved. The surgical and interventional procedures for GEP-NET are accordingly described below. Life-long follow-up should be performed in almost all patients at a specialized NET center.

Usefulness of contrast-enhanced transabdominal ultrasound for tumor classification and tumor staging in the pancreatic head.

Abstract Objective. To evaluate contrast-enhanced ultrasound (CEUS) and compare it to ultrasound (US) and 64-slice-CT (64-CT) for diagnosing, staging and evaluation of resectability of pancreatic cancer. Material and methods. US, CEUS and 64-CT were performed in 49 consecutive patients with pancreatic head tumors and with suspected cancer. After evaluation 44 patients had pancreatic head adenocarcinoma and 5 had chronic pancreatitis, all confirmed by histology. Results. The sensitivity of US, CEUS and 64-CT for diagnosing malignant pancreatic head tumors was 89%, 86% and 93%, respectively, and the overall accuracy was 82%, 86% and 88% respectively. There was no significant difference in the malignant tumor size measurement between US and CEUS (p = 0.3619) or between US and 64-CT (p = 0.2129), but a significant difference was seen in the size measured by CEUS and 64-CT (p = 0.0197). The CEUS measurements on the tumor size were smaller. The overall accuracy for M staging of the patients who had surgery for adenocarcinoma was 86% and 90% for US + CEUS and 64-CT, respectively. By performing the CEUS and 64-CT we additionally found, respectively, 35% and 45% non-resectable patients of a group of patients, who were considered resectable on the primary radiological image material. Conclusions. CEUS may be a useful diagnostic tool in the diagnosis and staging of pancreatic head tumors. For the assessment of resectability CEUS did not prove useful. However, CEUS seemed very useful as an additional instrument in the detection of non-resectable patients already considered resectable on primary radiological image material.

First-line treatment of patients with disseminated poorly differentiated neuroendocrine carcinomas with carboplatin, etoposide, and vincristine: A single institution experience

Abstract Poorly differentiated neuroendocrine carcinomas (PDECs) represent highly malignant tumors with an immense tendency to metastasize and with a poor prognosis. The treatment consists of palliative chemotherapy and corresponds to the treatment of extensive stage small cell lung cancer. Material and methods. We present the patient characteristics and treatment results of 31 consecutive, chemonaïve patients with PDECs treated with carboplatin, etoposide, and vincristine. Results. The response rate was 52%, the disease control rate 77%, and the median overall survival 15.3 months. The one-year survival rate was 55%, and the two-year survival rate was 19%. The median progression free survival (PFS) time was 6.6 months. Survival rates did not correlate with the Ki-67 proliferation index. The treatment was well tolerated. Conclusion. Treatment results with carboplatin, etoposide, and vincristine in chemonaïve patients with PDECs are comparable to those in patients with SCLC. The prognosis is however poor.

Use of Contrast-Enhanced Ultrasound Imaging to Detect the First Draining Lymph Node (FDLN) in a Swine Model Correlation of Imaging Findings With the Distance From the Injection Site to the FDLN

Objective. The purpose of this study was to investigate the use of contrast‐enhanced ultrasound imaging (CEUS) to detect the first draining lymph node (FDLN) in a swine model and to determine whether the distance from the contrast agent injection site to the FDLN has any affect on the ability to detect contrast‐enhanced FDLNs. Methods. Thirteen swine (25–32 kg) were anesthetized during examinations and euthanized afterward. In every swine, 1 mL of a sulfur hexafluoride microbubble ultrasound contrast agent was bilaterally injected subcutaneously below a mammilla. The examined distances varied from 6 to 36 cm. The contrast‐enhanced lymphatic channels were visualized with low–mechanical index CEUS and mapped from the injection site to the FDLN. After CEUS was performed, blue dye was injected in the same locations as the contrast agent, and dye‐guided surgery was used to localize the FDLNs. To ensure the lymph node detected with the blue dye technique was the same found with CEUS, it was scanned again to confirm contrast enhancement. Results. After 26 injections, 22 inguinal FDLNs were detected with CEUS and the blue dye technique. After 4 injections in 2 swine, contrast‐filled lymphatic channels were identified with a course running toward the neck. In all cases but 1, the FDLNs received the contrast agent within 5 minutes. Conclusions. In this swine model, it was possible to use CEUS to locate the FDLNs. In these preliminary experiments, the distances from the contrast agent injection site to the FDLN did not affect the ability to detect the contrast‐enhanced FDLNs.

Characteristics of the Danish families with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is caused by autosomal dominantly inherited mutations in the MEN1 gene. Here, we report 25 MEN1 mutations - of which 12 are novel - found in 36 Danish families with MEN1 or variant MEN1 disease. Furthermore, one FIHP family was found to have an earlier reported mutation. The mutations were predominantly found in exons 9 and 10 encoding the C-terminal part of menin. Seven of the mutations were missense mutations, changing conserved residues. Furthermore screening of 93 out of 153 consecutive patients with primary hyperparathyroidism (pHPT) identified five mutation carriers. Two of these belonged to known MEN1 families, whereas the only MEN1-related disease in the other three was pHPT. Screening of 96 consecutive patients with fore-/midgut endocrine tumours revealed five mutation carries out of 28 patients with sporadic gastrinomas, whereas no mutations were found in 68 patients with other fore-/midgut endocrine tumours. Moreover, screening of 60 consecutive patients with primary prolactinoma did not identify any mutation carriers. Our data indicate that MEN1 mutation screening is efficient in patients with familial MEN1. Screening should also be offered to patients with pHPT or gastrinomas after thorough investigation into the family history. In contrast, sporadic carcinoid tumours or primary prolactinomas are rarely associated with germ-line MEN1 mutations.