Merten Hommann

Receptor PET/CT Imaging of Neuroendocrine Tumors

This chapter is dedicated to Gustav Hor, Professor Emeritus and former Director of the Department of Nuclear Medicine, University of Frankfurt/Main, on the occasion of his 75th birthday.

Thrombin-mediated hepatocellular carcinoma cell migration: Cooperative action via proteinase-activated receptors 1 and 4

Proteinase‐activated receptor‐1 (PAR1), a thrombin receptor and the prototype of a newly discovered G‐protein‐coupled receptor subfamily, plays an important role in tumor development and progression. In this study, we documented the expression of the thrombin receptors PAR1, PAR3, and PAR4 in permanent hepatocellular carcinoma (HCC) cell lines and primary HCC cell cultures. Stimulation of HCC cells with thrombin and the PAR1‐selective activating peptide, TFLLRN‐NH2, increased transmembrane migration across a collagen barrier. This effect was blocked by the PAR1 antagonist SCH 79797, confirming that the PAR1 thrombin receptor subtype is involved in regulating hepatoma cell migration. In addition, the PAR4‐selective agonist, AYPGKF‐NH2, also stimulated HCC cell migration whilst the PAR4 antagonist, trans‐cinnamoyl‐YPGKF‐NH2, attenuated the effect of thrombin on HCC cell migration. PAR1‐ and PAR4‐triggered HCC cell migration was blocked by inhibiting a number of key mediators of signal transduction, including G proteins of the Gi/Go family, matrix metalloproteinases, ERK/MAPKinase, cyclic AMP‐dependent protein kinase, Src tyrosine kinase, and the EGF receptor kinase. Our data point to a cooperative PAR1/PAR4 signaling network that contributes to thrombin‐mediated tumor cell migration. We suggest that a combined inhibition of coagulation cascade serine proteinases, the two PARs and their complex signaling pathways may provide a new strategy for treating hepatocellular carcinoma. J. Cell. Physiol. 211: 699–707, 2007.

Treatment of osteoporosis after liver transplantation with ibandronate.

Osteoporosis is a major side‐effect after liver transplantation (LTX). Therefore, the objective of the study was to evaluate the efficacy of ibandronate to reduce fractures after LTX.  Seventy‐four patients after LTX were included in the study and measurements of bone mineral density (BMD) of lumbar spine and proximal femur using dual energy X‐ray absorptiometry (DEXA) were performed prior to and 3, 6, 12 and 24 months after surgery. The study group (IBA) consisted of 34 patients who received calcium (1 g/day), vitamin D3 (800–1000 IE/day) and ibandronate 2 mg every 3 months intravenously for 1 year. The control group consisted of 40 patients (CON) who received calcium and vitamin D3 at the same dosages. Prevalence of new fractures was predefined as primary endpoint. Changes of BMD and biochemical markers of bone metabolism were also investigated. In all patients, we found a reduction of BMD in the first few months after LTX. In the lumbar spine and the proximal femur the maximum reduction occurred 3 and 6 months post‐LTX. One and 2 years after transplantation, the group receiving ibandronate demonstrated a better recovery from loss of BMD and a significantly lower prevalence of fractures (IBA 2 vs. CON 10 P < 0.04, χ2). Ibandronate with calcium and vitamin D3 reduces the BMD‐loss after LTX and decreases the rate of bone fractures significantly.

Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases

A characteristic of human gastroenteropancreatic neuroendocrine tumors (GEP-NET) is a minute unobtrusive primary tumor which often cannot be detected by common physical examinations. It therefore remains unidentified until the tumor has spread and space-occupying metastases cause clinical symptoms leading to diagnosis. Cases in which the primary cannot be located are referred to as NET with CUP-syndrome (cancer of unknown primary syndrome). With the help of array-CGH (comparative genomic hybridization, Agilent 105K) and gene expression analysis (Agilent 44K), microdissected primaries and their metastases were compared to identify up- and down-regulated genes which can be used as a marker for tumor progression. In a next analysis step, a hierarchical clustering of 41.078 genes revealed three genes [C-type lectin domain family 13 member A (CD302), peptidylprolyl isomerase containing WD40 repeat (PPWD1) and abhydrolase domain containing 14B (ABHD14B)] which expression levels can categorize the metastases into three groups depending on the localization of their primary. Because cancer therapy is dependent on the localization of the primary, the gene expression level of these three genes are promising markers to unravel the CUP syndrome in NET.

Radioguided surgery in neuroendocrine tumors using Ga-68-labeled somatostatin analogs: a pilot study.

Background: Previous studies of the intraoperative use of a hand-held gamma probe to localize metastases and primary tumors have shown improved assessment of tumor spread and changes in surgical management based on additional information gained by radioguided surgery (RGS). Purpose: The aim was to test the feasibility and advantages of doing RGS using a gallium-68 labeled with somatostatin receptor analogs in the intraoperative detection of neuroendocrine tumors. Methods: Ga-68 somatostatin receptor PET/CT imaging was performed preoperatively in 9 patients with gastroenteropancreatic neuroendocrine tumors. Statistical analyses were performed to find out the correlation between the pathologic size of the tumor lesions and the maximum standardized uptake value on PET/CT as well as the target/nontarget ratio (T/NT) of gamma probe counts. Thereafter, the impact of the planned operation procedure and the lesion-based sensitivity of tumor detection (surgical palpation vs. PET/CT vs. gamma probe) had been observed. Results: Overall, 72 locations in 9 patients were examined intraoperatively using gamma probes. The gamma probe detected 94% of the whole histologically quantified lesions, whereas the PET/CT allocated 69% and surgical palpation, 50%. RGS resulted in change in the operative procedure in 56%. There was a significant correlation between the maximum standardized uptake value and tumor size (0.74; P < 0.005). Conclusion: Hand-held gamma probe surgery using gallium-68-labeled somatostatin analogs is a feasible and an attractive option for real-time detection of small metastases and primaries of neuroendocrine tumors.

Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy.

Introduction Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC). Methods SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 (n = 31), G2 (n = 47), and low (G3a; Ki-67: 21–49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data. Results Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors. Conclusion We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies.

Molecular imaging of late somatostatin receptor-positive metastases of renal cell carcinoma in the pancreas by 68Ga DOTATOC PET/CT: a rare differential diagnosis to multiple primary pancreatic neuroendocrine tumors.

Ga somatostatin receptor PET/CT, currently the most sensitive imaging modality for well-differentiated neuroendocrine tumors, is based on the molecular imaging of somatostatin receptors (SSTRs) that are expressed in different tumor entities such as neuroendocrine neoplasms, lymphomas, meningiomas, or renal cell cancer (RCC). Most neuroendocrine neoplasms show a high expression of SSTR subtypes 2A and 5, whereas the overexpression of SSTR2A in RCC is mainly seen in peritumoral vessels. Here we report a case with strongly SSTR-positive pancreatic lesions detected by Ga DOTATOC PET/CT, which histologically turned out to be ultralate metastases of a RCC.

Treatment of bone loss in patients with chronic liver disease awaiting liver transplantation

BackgroundMost of the patients awaiting liver transplantation already have osteopenia or even osteoporosis by end-stage liver disease.In a retrospective study, we investigated the effect of pre-treatment with oral monthly ibandronate (150 mg), vitamin D3 (800 IU/day) and calcium (1 g/day) for osteopenia and osteoporosis caused by end-stage liver disease in patients before and after liver transplantation (LT).MethodsThe bone mineral density (BMD) of the lumbar spine (LS) and the femoral neck was measured prospectively pre- and post-LT in 31 patients with existing pre-transplant osteopenia. Patients had osteopenia of the LS prior to LT (T-score −1.8 ± 1.5) so that the treatment medication was initiated immediately after the diagnosis.ResultsThe study group showed a permanently increased BMD with significant differences (g/cm²) from baseline up to 12 months post LT at the lumbar spine (LS: pre-LT 0.80 ± 0.11 g/cm², three months: 0.90 ± 0.08 (P <0.005); six months: 0.95 ± 0.11 (P < 0.008); 12 months: 1.00 ± 0.09 -0.85 (P <0.012).ConclusionThe combined pre- and post-operative treatment with oral ibandronate had significantly improved bone mineral density of the lumbar spine at 3, 6 and 12 months post LT. The immediate post-operative bone loss after LT can be significantly avoided by pre-treatment of liver transplant candidates affected by osteopenia.

Reconstruction of a total avulsion of the hepatic veins and the suprahepatic inferior vena cava secondary to blunt thoracoabdominal trauma

IntroductionBlunt injury to the inferior vena cava is a rare but dramatic event having a high mortality up to 80%. The mortality increases after total avulsion especially in combination with secondary intra-abdominal injuries.Case reportWe report on a 15-year-old boy who sustained a blunt trauma with a total, partially covered avulsion of the hepatic veins and the suprahepatic inferior vena cava.DiscussionWe treated the patient under internal bypassing of the retrohepatic vena cava by using the heart–lung machine and reconstructed the hepatic veins and suprahepatic vena cava with a conduit made of pericard.

Rationale for clinical trials of coagulation: reactive drugs in hepatocellular carcinoma.

Evidence for the regulation of cancer growth by components of the blood coagulation mechanism provides abundant opportunity for the development of novel hypotheses for the experimental treatment of malignancy. Information available on the heterogeneity in mechanisms of interaction between various cancer cell types, and procoagulant and fibrinolytic pathways, platelets, glycosaminoglycan-regulated growth factors and cell-adhesion molecules indicates that insightful clinical trial design may allow targeting of individual cancer cell types with agents capable of intercepting mechanisms of growth control that are relevant to specific tumor types. This paper reviews the evidence that the common anticoagulant, heparin, inhibits hepatocellular carcinoma cell proliferation and hepatocellular carcinoma tumor dissemination in experimental animals. Clinical trials of heparin performed to date have shown increased tumor response rates and survival in other tumor types. Expression of urokinase-type plasminogen activator by hepatocellular carcinoma cells enhances tumor cell proliferation, motility, invasiveness and metastatic dissemination. Inhibition of the urokinase-type plasminogen activator/plasmin system by protease inhibitors such as aprotinin (Trasylol®, Bayer) have shown improvement in the clinical course of certain tumor types. These data suggest that drugs that are well-known in the field of vascular medicine may find a role in the treatment of hepatocellular carcinoma, a common tumor type that has resisted containment by other means.