Prior Resection of the Primary Tumor Prolongs Survival After Peptide Receptor Radionuclide Therapy of Advanced Neuroendocrine Neoplasms.

OBJECTIVE: The aim of the study was to compare impact on survival after resection of primary tumors (PTs) after peptide receptor radionuclide therapy (PRRT). BACKGROUND: PRRT is a highly effective therapeutic option to treat locally advanced or metastatic neuroendocrine neoplasms (NENs). METHODS: We retrospectively analyzed the data of 889 patients with advanced NEN (G1-G3, stage IV) treated with at least 1 cycle of PRRT. In 486 of 889 patients (55%, group 1), PT had been removed before PRRT. Group 2 constituted 403 patients (45%) with no prior PT resection. Progression-free survival (PFS) and overall survival (OS) was determined by 68Ga SSTR-PET/CT in all patients applying RECIST and EORTC. RESULTS: Most patients had their PT in pancreas (n = 335; 38%) and small intestine (n = 284; 32%). Both groups received a mean of 4 cycles of PRRT (P = 0.835) with a mean cumulative administered radioactivity of 21.6 ±â€Š11.7 versus 22.2 ±â€Š11.2 GBq (P = 0.407). Median OS in group 1 was 134.0 months [confidence interval (CI): 118-147], whereas OS in group 2 was 67.0 months (CI: 60-80; hazard ratio 2.79); P < 0.001. Likewise, the median progression-free survival after first PRRT was longer in group 1 with 18.0 (CI: 15-20) months as compared to group 2 with 14.0 (CI: 15-18; hazard ratio 1.21) months; P = 0.012. CONCLUSIONS: A previous resection of the PT before PRRT provides a significant survival benefit in patients with NENs stage IV.

Laparoscopic versus open distal pancreatectomy-a propensity score-matched analysis from the German StuDoQ|Pancreas registry.

PURPOSE: The aim of this study was to assess intraoperative, postoperative, and oncologic outcome in patients undergoing laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) for benign and malignant lesions of the pancreas. METHODS: Data from patients undergoing distal pancreatic resection were extracted from the StuDoQ|Pancreas registry of the German Society for General and Visceral Surgery. After propensity score case matching, groups of LDP and ODP were compared regarding demography, comorbidities, operative details, histopathology, and perioperative outcome. RESULTS: At the time of data extraction, the StuDoQ|Pancreas registry included over 3000 pancreatic resections from over 50 surgical departments in Germany. Data from 353 patients undergoing ODP (n = 254) or LDP (n = 99) from September 2013 to February 2016 at 29 institutions were included in the analysis. Baseline data showed a strong selection bias in LDP patients, which disappeared after 1:1 propensity score matching. A comparison of the matched groups disclosed a significantly longer operation time, higher rate of spleen preservation, more grade A pancreatic fistula, shorter hospital stay, and increased readmissions for LDP. In the small group of patients operated for pancreatic cancer, a lower lymph node yield with a lower lymph node ratio was apparent in LDP. CONCLUSIONS: LDP needed more time but potential advantages include increased spleen preservation and shorter hospital stay, as well as a trend for less transfusion, ventilation, and mortality. LDP for pancreatic cancer was performed rarely and will need critical evaluation in the future. Data from a prospective randomized registry trial is needed to confirm these results.

High uptake of (68)Ga-DOTATOC in spleen as compared to splenosis: measurement by PET/CT.

AIM: The aim of this study is to ascertain the high somatostatin receptor (SSTR) uptake in spleen and to compare the uptake in spleen and splenosis using SSTR PET/CT using( 68)Ga-DOTATOC. MATERIALS AND METHODS: SUV(max) of spleen on (68)Ga-DOTATOC SSTR PET/CT (acquired for initial staging) in 10 patients with known neuroendocrine neoplasm of pancreatic tail was analyzed. All patients underwent left pancreatectomy and splenectomy. Diagnosis of splenosis was confirmed on CT, and SUV(max) was noted on follow-up SSTR PET/CT. RESULTS: SUV(max)was 28.8 ± 12.5 in normal spleen and 10.5 ± 4.3 in splenosis. CONCLUSION: The high uptake of( 68)Ga-DOTATOC (which has a high affinity to SSTR 2) in the spleen as compared to splenosis, which has a different histology, suggests white pulp as the probable site of high SSTR 2 expression.

Intraoperative somatostatin receptor detection after peptide receptor radionuclide therapy with (177)Lu- and (90)Y-DOTATOC (tandem PRRNT) in a patient with a metastatic neuroendocrine tumor.

AIM: The aim of this chapter is to present the results of the first intraoperative somatostatin receptor detection after peptide receptor radionuclide therapy (PRRNT) with (90)Y- and (177)Lu-DOTATOC using a handheld gamma probe and comparison with the findings of preoperative (68)Ga-DOTATOC PET/CT in a patient with a metastatic neuroendocrine tumor (NET) of the ileum. MATERIALS AND METHODS: A 56-year-old female patient, treated twice by PRRNT, was admitted for the third cycle and subsequent surgery. Before operation, the following studies were performed for restaging after the second cycle of PRRNT: (99m)Tc-MAG3 + TER, (99m)Tc-DTPA + GFR, abdominal ultrasonography, MRI of the abdomen, (68)Ga-DOTATOC PET/CT as well as (18)F-fluoride PET/CT. Serum tumor markers were measured before and after PRRNT. Tandem PRRNT was performed using 3000 MBq (90)Y-DOTATOC and 6000 MBq (177)Lu-DOTATOC. Whole-body scintigrams were obtained at 23 and 43 h. Five days after PRRNT, the patient was operated using a handheld gamma probe. Immunohistochemistry and histopathology of the resected tissue were performed. RESULTS: Tandem PRRNT was very well tolerated by the patient. Before PRRNT, (68)Ga-DOTATOC PET/CT revealed the primary tumor in the ileocoecal region as well as bilobular liver metastases and a right iliac bone lesion (osteoblastic on (18)F-fluoride PET/CT). Compared with the previous findings, there was good therapy response (partial remission of the tumor lesions). No nephrotoxicity was observed. Serum chromogranin A (836 µg/l, n < 100) and serotonin (852 µg/l, n < 200) were strongly elevated. Posttherapy scans showed intense uptake in metastases and the primary tumor. Intraoperative gamma probe detected-in addition to the known lesions-bilateral ovarian metastases not visualized by (68)Ga-DOTATOC PET/CT. Bilateral adnexectomy, right hemicolectomy, excision of hepatic metastases in S3, and partial resection of peritoneum were performed. Histopathology confirmed metastases in both ovaries. CONCLUSIONS: Gamma probe-guided surgery after (177)Lu PRRNT is feasible and appears to be more sensitive than (68)Ga-DOTATOC PET/CT. This technique might aid the surgeon in achieving more complete tumor resection through intraoperative detection of very small lesions (<5 mm) directly after PRRNT.

Role of PET/CT in the functional imaging of endocrine pancreatic tumors.

Endocrine pancreatic tumors (EPTs) are a heterogeneous group of neoplasms with variable clinical and biological features and prognosis, ranging from very slow-growing tumors to highly aggressive and very malignant ones. As other neuroendocrine tumors, EPTs are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy. The more widespread use of hybrid machines, i.e., positron emission tomography/computed tomography (PET/CT), allows to perform imaging with high resolution and high diagnostic accuracy especially for small lesions, and to correlate anatomic location with function. The recent WHO recommendations for classification and prognostic factors help the selection of tracers likely to show a positive image on PET; therefore, tracers exploiting specific metabolic patterns ((18)F-DOPA and (11)C-5-HTP) or specific receptor expression ((68)Ga-DOTA-peptides) are suited to well-differentiated tumors, while the use of (18)F-FDG is preferred for poorly-differentiated neoplasms with high proliferative activity and loss of neuroendocrine features. In differentiated EPTs, (11)C-5-HTP performs better than (18)F-DOPA even though its use is hampered by its complex production and limited availability and experience; (68)Ga-peptides are indicated for all type of gastroenteropancreatic (GEP) neuroendocrine tumors, regardless of their functional activity. In addition, (68)Ga-DOTA-peptides play a distinctive role in planning peptide receptor radionuclide therapy.

Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours.

PURPOSE: Somatostatin receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3-5. METHODS: Overall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative (68)Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUV(max) and SUV(mean)) were used for PET/CT. RESULTS: The IRS for SSTR2A and SSTR5 correlated highly significant with the SUV(max) on the PET/CT (p < 0.001; p < 0.05) and the IRS for SSTR2A with the SUV(mean) (p < 0.013). The level of SSTR2A score correlated significantly with chromogranin A staining and indirectly to the tumour grading. CONCLUSION: The highly significant correlation between SSTR2A and SSTR5 and the SUV(max) on the (68)Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of (68)Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using (68)Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy.

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

INTRODUCTION: Blunt 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 REPORT: We 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. DISCUSSION: We 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.

Primary Neuroendocrine Neoplasia of the Liver.

ABSTRACT: The presence of primary neuroendocrine tumors in the liver is still a matter of controversy. We present a case of a somatostatin-receptor-positive mass of the liver in the 68Ga-DOTATOC PET/CT. No other primary tumor was found after conventional imaging, endoscopically, and after liver-segment resection. Immunohistochemically, a constellation of findings was found to be compatible with a primary neuroendocrine neoplasm of the liver.

Detection of unknown primary neuroendocrine tumours (CUP-NET) using (68)Ga-DOTA-NOC receptor PET/CT.

PURPOSE: This bi-centric study aimed to determine the role of receptor PET/CT using (68)Ga-DOTA-NOC in the detection of undiagnosed primary sites of neuroendocrine tumours (NETs) and to understand the molecular behaviour of the primarily undiagnosed tumours. METHODS: Overall 59 patients (33 men and 26 women, age: 65 + or - 9 years) with documented NET and unknown primary were enrolled. PET/CT was performed after injection of approximately 100 MBq (46-260 MBq) of (68)Ga-DOTA-NOC. The maximum standardised uptake values (SUV(max)) were calculated and compared with SUV(max) in known pancreatic NET (pNET) and ileum/jejunum/duodenum (SI-NET). The results of PET/CT were also correlated with CT alone. RESULTS: In 35 of 59 patients (59%), (68)Ga-DOTA-NOC PET/CT localised the site of the primary: ileum/jejunum (14), pancreas (16), rectum/colon (2), lungs (2) and paraganglioma (1). CT alone (on retrospective analyses) confirmed the findings in 12 of 59 patients (20%). The mean SUV(max) of identified previously unknown pNET and SI-NET were 18.6 + or - 9.8 (range: 7.8-34.8) and 9.1 + or - 6.0 (range: 4.2-27.8), respectively. SUV(max) in patients with previously known pNET and SI-NET were 26.1 + or - 14.5 (range: 8.7-42.4) and 11.3 + or - 3.7 (range: 5.6-17.9). The SUV(max) of the unknown pNET and SI-NET were significantly lower (p < 0.05) as compared to the ones with known primary tumour sites; 19% of the patients had high-grade and 81% low-grade NET. Based on (68)Ga-DOTA-NOC receptor PET/CT, 6 of 59 patients were operated and the primary was removed (4 pancreatic, 1 ileal and 1 rectal tumour) resulting in a management change in approximately 10% of the patients. In the remaining 29 patients, because of the far advanced stage of the disease (due to distant metastases), the primary tumours were not operated. Additional histopathological sampling was available from one patient with bronchial carcinoid (through bronchoscopy). CONCLUSION: Our data indicate that (68)Ga-DOTA-NOC PET/CT is highly superior to (111)In-OctreoScan (39% detection rate for CUP according to the literature) and can play a major role in the management of patients with CUP-NET.

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, chi(2)). Ibandronate with calcium and vitamin D3 reduces the BMD-loss after LTX and decreases the rate of bone fractures significantly.

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms.

INTRODUCTION: Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. METHODS: In our center, 2294 patients were screened between 2004 and 2014 by 68Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90Yttrium or 177Lutetium-based PRRT. Progression free survival was determined by 68Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. RESULTS: Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. CONCLUSION: PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy.

A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

Introduction of MMF in conjunction with stepwise reduction of calcineurin inhibitor in stable liver transplant patients with renal dysfunction.

Mycophenolat mofetil (MMF) is a new imunosuppressant without nephrotoxic adverse effects. The aim of this study was to evaluate feasibility and effect of MMF introduction in conjunction with stepwise reduction of calcineurin inhibitors (CNI) in stable liver transplant patients with chronic CNI-induced renal dysfunction (RDF). In the MMF-group (n=27) but not in the controls (n=16), mean serum level of creatinine fell from a baseline of 227.4+/-67.9 micromol/l to 159.2+/-48.2 micromol/l (P<0,001), while mean urea level declined significantly from a baseline of 18.5+/-8.7 mmol/l to 11.4+/-4.2 mmol/l 6 months after initiation of MMF. Additionally, systolic and diastolic blood pressure values improved. In 52% of patients, dose reduction (n=11) or withdrawal (n=3) of MMF was necessary due to gastrointestinal or hematologic adverse effects. But also in patients on low dose MMF, there was a significant improvement of renal function without increased immunological risk.

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.

Analysis of somatostatin receptor 2A immunohistochemistry, RT-qPCR, and in vivo PET/CT data in patients with pancreatic neuroendocrine neoplasm.

OBJECTIVE: Gallium 68 somatostatin receptor (SSTR) positron emission tomography/computed tomography (PET/CT) is one of the most sensitive imaging methods for pancreatic neuroendocrine tumors. The aim of the study was to correlate the receptor density generated from the static PET/CT (maximum standard uptake values [SUVmax], mean standard uptake values [SUVmean]) with subtype 2A SSTR (SSTR2A) immunohistochemistry and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) gene-expression data. METHODS: Thirty-nine tumor specimens (17 primary pancreatic tumors [PTs], 22 metastases [MTS]) of 19 patients with PET/CT scans preoperatively were evaluated. Subtype 2A SSTR expression was quantified immunohistochemically (immunoreactive score [IRS]) and on messenger RNA (mRNA) level by RT-qPCR. RESULTS: The PT and MTS did not differ significantly in their SUVmax (P = 0.07) but displayed a dissimilarity with respect to their SSTR2A expression (mean [SD] IRS PT, 8.8 [3.6] vs mean [SD] IRS MTS, 5.1 [4.5]; P = 0.02).The SUVmean was highly significantly correlated to SSTR2A mRNA expression (C = 0.85, P < 0.001) and moderately to SSTR2A protein expression (C = 0.53, P = 0.05). Moreover, the SUVmax correlated moderately with SSTR2A protein expression (C = 0.44, P = 0.03) and mRNA expression (C = 0.64, P = 0.042). CONCLUSIONS: The SUVmax and SUVmean are reliable ex vivo parameters for in vivo quantification of SSTR expression in pancreatic neuroendocrine tumors. Both immunohistochemistry and RT-qPCR are comparable methods for SSTR2A quantification. The PT and MTS differ significantly in their SSTR2A expression. This fact should be taken into account when treating patients with somatostatin analogs or peptide receptor radionuclide therapy.

Proteomic profiling in microdissected hepatocellular carcinoma tissue using ProteinChip technology.

At present, the molecular mechanisms of hepatocellular carcinogenesis are not well understood. It is known, however, that cancer development and progression are accompanied by profound changes at the cellular and subcellular level, involving RNA/DNA and protein structure and function. Therefore, high-throughput, proteomic techniques targeting these biological molecules may provide novel insights into HCC genesis and prognosis. We characterized tissue protein profiles from 10 HCC patients using ProteinChip technology (SELDI) which is able to detect minute amounts of proteins and moreover to analyze complex protein pattern. Therefore, after histopathological examination, proteins from kryostat sections of non-tumorous hepatic tissue as well as from central and peripheral tumor areas were isolated from complete histological sections or from selected and microdissected tissue areas. Analysis on the SAX and WCX ProteinChip Arrays revealed 14-26, and 25-29 differentially expressed peaks respectively, which characterized non-tumorous and tumor tissue (p< or =0.05). One feature which allows differentiation between central tumor and peripheral tumor regions could only be detected in microdissected tissue. Using ProteinChip technology in combination with tissue microdissection it is possible to investigate complex changes at the protein level in hepatocellular cancer associated with tumor development and progression.

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.

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.

Somatostatin receptor immunohistochemistry in neuroendocrine tumors: comparison between manual and automated evaluation.

BACKGROUND: Manual evaluation of somatostatin receptor (SSTR) immunohistochemistry (IHC) is a time-consuming and cost-intensive procedure. Aim of the study was to compare manual evaluation of SSTR subtype IHC to an automated software-based analysis, and to in-vivo imaging by SSTR-based PET/CT. METHODS: We examined 25 gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients and correlated their in-vivo SSTR-PET/CT data (determined by the standardized uptake values SUVmax,-mean) with the corresponding ex-vivo IHC data of SSTR subtype (1, 2A, 4, 5) expression. Exactly the same lesions were imaged by PET/CT, resected and analyzed by IHC in each patient. After manual evaluation, the IHC slides were digitized and automatically evaluated for SSTR expression by Definiens XD software. A virtual IHC score "BB1" was created for comparing the manual and automated analysis of SSTR expression. RESULTS: BB1 showed a significant correlation with the corresponding conventionally determined Her2/neu score of the SSTR-subtypes 2A (rs: 0.57), 4 (rs: 0.44) and 5 (rs: 0.43). BB1 of SSTR2A also significantly correlated with the SUVmax (rs: 0.41) and the SUVmean (rs: 0.50). Likewise, a significant correlation was seen between the conventionally evaluated SSTR2A status and the SUVmax (rs: 0.42) and SUVmean (rs: 0.62). CONCLUSION: Our data demonstrate that the evaluation of the SSTR status by automated analysis (BB1 score), using digitized histopathology slides ("virtual microscopy"), corresponds well with the SSTR2A, 4 and 5 expression as determined by conventional manual histopathology. The BB1 score also exhibited a significant association to the SSTR-PET/CT data in accordance with the high affinity profile of the SSTR analogues used for imaging.