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The IGF pathway has been implicated in the regulation of neuroendocrine tumor (NET) growth, and preliminary studies suggested that ganitumab (AMG 479), a human MAB against IGF1R, may have antitumor activity in this setting. We performed a two-cohort phase II study of ganitumab in patients with metastatic progressive carcinoid or pancreatic NETs (pNETs). This open-label study enrolled patients (≥18 years) with metastatic low- and intermediate-grade carcinoid or pNETs. Inclusion criteria included evidence of progressive disease (by Response Evaluation Criteria in Solid Tumors (RECIST)) within 12 months of enrollment, ECOG PS 0–2, and fasting blood sugar

Purpose The American Joint Committee on Cancer (AJCC) staging manual has introduced a TNM staging classification for jejunal-ileal (midgut) neuroendocrine tumors (NETs). This classification has not been validated in a population consisting solely of midgut NETs. The purpose of this study was to test the prognostic validity of the classification in such a population. Methods Patients with jejunal and ileocecal NETs who were treated at the Moffitt Cancer Center between 2000 and 2010 were assigned stages (I through IV). Kaplan-Meier analyses for overall survival (OS) were performed on the basis of TNM stage and pathologic grade. Multivariate modeling was performed using Cox proportional hazards regression. Results We identified 691 patients with jejunal-ileocecal NETs. The AJCC classification in aggregate was highly prognostic for OS (P < .001). Five-year OS rates for stages I through IV were 100%, 100%, 91%, and 72%, respectively. The survival difference between stages III and IV was significant (P < .001); the difference between stages I/II versus III was not statistically significant (P = .1). Among patients with stage IIIB tumors, 5-year survival rates were 95% for resectable tumors versus 78% for unresectable mesenteric tumors (P = .02). A proliferative threshold of five mitoses per 10 high-power fields (HPF) was of greater prognostic value than a threshold of two mitoses per 10 HPF for discriminating between low- and intermediate-grade tumors. Conclusion Stage I and II midgut NETs are associated with identical survival rates. Stage IIIB tumors are heterogeneous, with significant differences in survival observed between resectable mesenteric lymph nodes versus unresectable masses in the root of the mesentery. A higher mitotic cutoff of five per 10 HPF may lead to improved prognostic differentiation between low- and intermediate-grade tumors. Revisions to the current AJCC staging and grading classification may be warranted.

Background: Metastatic neuroendocrine tumors of the thymus are exceedingly rare with an annual incidence of approximately 0.2 per 1,000,000. They are highly resistant to therapy and there have been no reports of an objective radiographic response to treatment. Materials and Methods: The authors retrospectively evaluated 3 patients with progressive, metastatic neuroendocrine tumors of the thymus who were treated with a combination of capecitabine and temozolomide. Radiographic scans were evaluated and response assessed using RECIST criteria. Results: One patient experienced a partial radiographic response, another patient experienced a minor response and the third patient experienced stable disease as the best response to treatment. Conclusion: The combination of capecitabine and temozolomide appears to be active in a rare neuroendocrine malignancy that is generally refractory to systemic therapy. Prospective multicenter trials are needed to validate this strategy.

Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst1,2,3) and sst5. Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150 μg twice daily (bid), escalated to a maximum dose of 1200 μg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600–900 μg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600–900 μg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy.

Pancreatic endocrine tumors (PETs) are clinically challenging neoplasms. The incidence of these tumors in the United States is estimated to be 4 cases per million persons per year, with a 5-year survival of 44% to 71%.1–3 Based on the presence or absence of metastases and/or gross invasion of adjacent organs, they are classified as pancreatic endocrine carcinomas (PECAs) or tumors PETs (World Health Organization, 2004).4 Clinical behavior of these neoplasms ranges from benign to highly aggressive. In the presence of negative metastatic workup at the time of first tissue diagnosis, it is difficult to predict which of these tumors will become metastatic (“malignant”) or remain localized to the pancreas (“benign”). Conventional prognostic criteria include the presence of a functional tumor, larger tumor size, presence of metastases, higher mitotic rate, tumor necrosis, vascular invasion, perineural invasion, and higher proliferation rate, conventionally assessed as Ki-67 index.4–6 To further refine prognostic evaluation of these neoplasms, a number of histological grading and staging schemes have been proposed.5,7–8 However, it has been difficult to establish reliable prognostic models for these neoplasms, due mainly to their rarity and complex biology. From a practical standpoint, histological tumor characteristics such as cytological atypia and angiovascular and perineural invasion are either not evident or, if present, fail to distinguish between indolent and aggressive tumors. Other frequently evaluated pathological criteria, including tumor size, mitotic count/histological grade, and Ki-67 index, often fail to predict malignant behavior.9 Because patients who develop distant metastases from pancreatic endocrine neoplasms are rarely cured and 5-year survival rates diminish significantly,10 identification of molecular markers of prognosis is vitally important to quantify the risk of (1) future metastases in patients with clinically localized pancreatic endocrine neoplasms and (2) metastatic recurrence in patients with resected pancreatic endocrine primaries. Such molecular markers may therefore identify patients who could benefit from adjuvant therapies and also provide objective criteria to determine the need for postoperative surveillance. Recently, we and others11–17 have carried out gene expression profiling in PETs. To identify candidate progression genes in pancreatic endocrine neoplasms, we used Affymetrix 2.0 gene chip on fresh-frozen metastatic primary PECAs (MP PECAs) that already had metastasized to the liver at the time of resection of the pancreatic primary and a set of frozen non-MP PETs that remained free of clinically detectable metastases until the last patient follow-up. All of the pancreatic endocrine primaries used in this experiment were nonfunctional. We applied rigorous criteria, taking into consideration the P values and fold changes in the differentially expressed genes, including gene function/class and pathway analysis using Metacore from GeneGo, to select our leading “candidate progression genes” that were differentially expressed between the 2 sets of pancreatic primaries (metastatic and nonmetastatic). Among these, CD24 antigen, insulin receptor, TMPRSS6, SERPINA1, SMURF1, RNF43, and AKR1C2 were notably up-regulated, whereas RUNX1T1, protocadherin 9, RASSF5, RERG, ST14, glucagon, and PDGFRL were notably down-regulated. The down-regulation of RUNX1T1, represented by 2 different probe sets, is shown in metastatic as compared with nonmetastatic pancreatic endocrine primaries from our original Affymetrix 2.0 gene chip analysis on RNA extracted from frozen tumor tissues (Fig. 1). From our “candidate progression gene list,” we validated underexpression of several leading candidate progression genes including RUNX1T1 and overexpression of TMPRSS6, SERPINA1, and others on an independent test set of archival PECAs (with liver metastases) using quantitative real-time polymerase chain reaction. FIGURE 1 Box plots showing down-regulation of 2 of the probe sets for RUNX1T1 gene in the primary PECAs that had already metastasized to the liver (MP1 group) as compared with those that were nonmetastatic (clinically localized) at the time of their resection ... In this study, we have further validated the differential expression of RUNX1T1 in pancreatic endocrine neoplasms with and without synchronous liver metastases at the protein level. Furthermore, we found RUNX1T1 protein expression in the primary tumor tissue to be more informative than other conventional pathological criteria as predictors of liver metastases. This is an important finding with potential clinical and therapeutic implications that merits further evaluation in larger-scale clinical validation studies.

Purpose No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. Patients and Methods This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. Conclusion Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

Background: Gastrointestinal neuroendocrine tumors (NETs) are heterogeneous neoplasms that vary in mortality according to location of primary tumor and stage of disease. Past analyses of survival suggest a trend towards improving longevity among patients with metastatic mid-gut NETs. Methods: We evaluated all cases of metastatic NETs of the mid-gut seen in our institution between 1999 and 2003, measuring survival from time of diagnosis of distant metastatic disease. Median and 5-year survival rates were estimated using Kaplan-Meier methodology. We assessed the impact of various prognostic factors including age, gender, hepatic cytoreductive surgery, and operative resection of the primary tumor. Results: 146 cases of metastatic mid-gut NETs were identified. The median overall survival was 103 months and the 5-year survival rate was 75%. Most patients (91%) received octreotide therapy. Other medical treatments included hepatic artery embolization, chemotherapy, and peptide receptor radiotherapy. Primary tumor resection was performed in 69% of cases, and hepatic cytoreductive surgery in 22% of cases. A median survival of 95 months was observed among patients who did not undergo cytoreductive surgery. Operative resection of the primary tumor was not associated with a significant survival advantage. Conclusions: Median overall survival is 103 months (8.5 years) in patients with metastatic mid-gut NETs. Among patients who are not candidates for hepatic cytoreductive surgery, median survival is 95 months (7.9 years). Resection of the primary tumor does not appear to be associated with a survival benefit in the metastatic setting.

Background: Pancreatic neuroendocrine tumors (PNETs) comprise a heterogeneous group of neoplasms for which treatment is variable, depending on the clinical stage. Despite this diversity, surgery remains the gold standard in the management of PNETs. This paper discusses whether aggressive surgical intervention is indicated for PNETs and investigates what prognostic factors may assist in predicting which patients with invasive disease will benefit most from surgical intervention. Methods: A review was conducted of large surgical series reported in the English literature over the last 10 years as they pertain to current surgical intervention in PNETs and of prognostic factors related to surgical outcome and survival. Results: Improved survival can be achieved with aggressive surgical management of PNETs. The presence of hepatic metastases is not a contraindication to surgical resection of the primary PNET. Results of series that reported prognostic factors are heterogeneous. Conclusions: Aggressive surgical resection for selected individuals with PNETs can be performed safely and may improve both symptomatic disease and overall survival. Consideration for resection of primary PNETs should be given to patients with treatable hepatic metastases. Prognostic indices such as tumor differentiation and ability to achieve R0/R1 resection have been linked to survival outcome in PNETs and should be considered when planning aggressive surgical management for this disease. Aggressive surgical resection of pancreatic neuroendocrine tumors may improve symptomatic disease and overall survival in selected patients.

We present an unusual case of a 52-year-old woman with severe, uncontrollable, refractory diarrhea attributable to pancreatic endocrine carcinoma (ECA) with markedly elevated serum vasoactive intestinal polypeptide (VIP) and calcitonin levels. After initial correction of fluid and electrolyte abnormalities, the patient was treated with high-dose octreotide. Shortly thereafter, due to the intractable nature of her diarrhea, she underwent cytoreductive hepatic surgery. The pancreatosplenectomy specimen showed a poorly differentiated ECA of the distal pancreas, immunoreactive for synaptophysin, CD56, and S100 protein, with morphologically similar hepatic and lymph node metastases. Postoperatively, her diarrhea improved, along with decline in serum VIP and calcitonin levels. Systemic chemotherapy with etoposide and cisplatin did not result in any radiographic and biochemical improvement. Having radiologically stable disease with depot-octreotide and short-acting octreotide (Sandostatin), she was subjected to peptide receptor radiotherapy with [Lu-177-DOTA(0), Tyr(3)] octreotate (LuTate) that resulted in marked clinical and biochemical improvement, along with dramatic reduction in the number and size of hepatic metastases. In summary, this is a unique case of metastatic VIP- and calcitonin-secreting pancreatic ECA with dramatic sustained clinical, biochemical, and objective tumor response to peptide receptor radionuclide therapy.

Objective We estimated the absorbed doses for In-111-DTPA-D-Phe(1)-octreotide and Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide in the same patients in order to compare the potential effectiveness (tumour dose) and safety (kidney and red marrow dose) of these drugs for peptide-targeted radiotherapy of somatostatin receptor positive tumours. Methods Six patients with neuroendocrine tumours underwent quantitative In-111-DTPA-D-Phe(1)-octreotide SPECT and Y-86-DOTA-D-Phe(1)-Tyr(3)-octreotide PET scan at intervals of 1 week. All studies were performed with a co-infusion of amino acids for renal protection. PET and SPECT were reconstructed using iterative algorithms, incorporating attenuation and scatter corrections. Tissue uptakes (IA%) were measured and used to calculate residence times. Absorbed doses to tissues were estimated and the maximal allowed activity, defined as either the activity delivering 23 Gy to the kidneys (MAA(K)) or 2 Gy to the red marrow (MAA(RM)), was calculated and the resulting tumour absorbed doses were computed. Results For the MAA(K) the mean absorbed dose to the red marrow was lower for Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide than for In-111-DTPA-D-Phe(1)-octreotide (1.8 +/- 0.9 Gy vs. 6.4 +/- 1.6 Gy; P < 0.001). The median absorbed dose to tumours for the MAA(K) was two-fold higher for Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide as compared to In-111-DTPA-D-Phe(1)-octreotide (30.1 vs. 12.6 Gy; P < 0.05). The median absorbed dose to tumours estimated for the MAA(RM) was 10-fold higher for Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide than for In-111-DTPA-D-Phe(1)-octreotide (35.1 Gy vs. 3.9 Gy; P < 0.05). Conclusions This direct intra-patient comparison confirms that the use of Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide is more appropriate for therapy of somatostatin receptor bearing tumours. When using In-111-DTPA-D-Phe(1)-octreotide, the red marrow represents the major critical organ; this can result in significant toxicity if high activities have to be administered to obtain efficient tumour irradiation.

Background/Aims: The use of chemoradiation in the management of locally advanced pancreatic endocrine tumors has not been reported in the medical literature. Patients with unresectable tumors are often included in trials of systemic chemotherapy, and use of external beam radiation has been only described in few case reports. Given the sensitivity of pancreatic endocrine tumors to cytotoxic agents including streptozocin, doxorubicin and 5-FU, we have hypothesized that the combination of concurrent and sequential chemotherapy and radiation will yield higher response rates than acheivable with chemotherapy alone. Methods: Six patients with locally advanced pancreatic endocrine tumors were treated with a protocol consisting of radiation concurrent with infusional 5-FU (or capecitabine) along with induction and consolidation chemotherapy (streptozocin and doxorubicin). We retrospectively determined the objective radiographic response rate. Results: The objective response rate was 80%. With a median follow-up of 29 months, all six patients in the study have had continued reduction in tumor size from the time of the first posttreatment scan to the most recent scan. None of the patients have experienced local or metastatic disease progression. Treatment was well tolerated with minimal toxicity. Conclusion: The combination of concurrent and sequential chemoradiotherapy appears to be a highly effective treatment for locally advanced pancreatic endocrine tumors.

Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors (GEPNETs) patients. Most studies report objective response rates in 15–35% of patients. Also, outcome in terms of progression free survival (PFS) and overall survival compares very favorably with that for somatostatin analogs, chemotherapy, or new, ‘targeted’ therapies. They also compare favorably to PFS data for liver-directed therapies. Two decades after the introduction of PRRT, there is a growing need for randomized controlled trials comparing PRRT to ‘standard’ treatment, that is treatment with agents that have proven benefit when tested in randomized trials. Combining PRRT with liver-directed therapies or with targeted therapies could improve treatment results. The question to be answered, however, is whether a combination of therapies performed within a limited time-span from one another results in a better PFS than a strategy in which other therapies are reserved until after (renewed) tumor progression. Randomized clinical trials comparing PRRT with other treatment modalities should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs.

The somatostatin analogs octreotide, lanreotide and RC-160 (vapreotide) are known to have direct and indirect antitumor effects. Direct effects include the arrest of tumor growth and stimulation of apoptosis, resulting in tumor shrinkage. Indirect antiproliferative effects may occur through antiangiogenesis, immunomodulatory effects and the suppression of tumor-stimulating growth factors. With a safety profile of somatostatin analogs established over 20 years of clinical use in the treatment of neuroendocrine tumors, somatostatin analogs are attractive therapeutic options for patients with non-neuroendocrine tumors. In early clinical trials of somatostatin analogs, however, some cancer patients responded well, while others showed a lack of benefit. This variability in clinical response may reflect the selective binding affinities of octreotide, lanreotide and RC-160, which bind with high affinity to just two of the five different somatostatin receptor subtypes. Treatment response may therefore depend on the specific receptor subtype(s) present in the tumor, the relative proportion of receptor(s) expressed on the tumor cell surface and the absolute quantity of each receptor subtype. Greater understanding of the role of somatostatin receptors, their binding affinities and modes of action has led to increased research into the use of somatostatin analogs, particularly octreotide, in cancer treatment as monotherapies, in combination with hormonal treatments and cytotoxic therapies, and in both adjuvant and neoadjuvant settings. A review of the literature suggests that the antitumor potential of somatostatin analogs should be investigated further and additional studies might determine how these analogs can best be used to improve the treatment of patients with non-neuroendocrine tumors.

Few data exist regarding outcomes after resection versus embolic treatment of symptomatic metastatic carcinoid and neuroendocrine tumors. The purpose of this study was to determine whether cytoreduction provides any benefit over embolic management of diffuse neuroendocrine tumors. A prospective database of 734 patients treated at our institution was retrospectively queried for symptomatic metastatic tumors treated with embolization or cytoreduction. Patients were compared with regard to pretreatment performance status, relief of symptoms, and survival. A total of 120 patients were identified: 59 undergoing embolization and 61 undergoing cytoreduction. Twenty-three patients had palliative cytoreduction (gross residual disease). Pretreatment performance status (Eastern Cooperative Oncology Group) was similar for both groups: .7 ± .70 (embolization) versus .8 ± .72 (cytoreduction; P = .27). Complete symptomatic relief was observed in 59% and partial relief in 32% of patients who underwent embolization, with a mean symptom-free interval of 22 ± 13.6 months. A total of 69% of patients who underwent cytoreduction had complete symptomatic relief, and 23% had partial relief (P = .08 vs. embolization). The mean duration of relief was 35 ± 22.0 months (P < .001 vs. embolization). The mean survival for the patients who underwent embolization was 24 ± 15.8 months versus 43 ± 26.1 months for those who underwent cytoreduction (P < .001). Survival in patients who underwent palliative cytoreduction was 32 ± 18.9 months (P < .001 vs. embolization), whereas it was 50 ± 27.6 months in patients who underwent curative resection (P < .001 vs. embolization; P < .001 vs. palliative). Cytoreduction for metastatic neuroendocrine tumors resulted in improved symptomatic relief and survival when compared with embolic therapy in this nonrandomized study. Cytoreduction should be pursued whenever possible even if complete resection may not be achievable.

Purpose: The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) β-emitters, such as 177Lu or 90Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET α-emitter, 213Bi, was evaluated. Experimental Design: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of 213Bi-DOTATOC (specific activity 7.4 MBq/μg) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq 213Bi-DOTATOC was determined in a rat pancreatic carcinoma model. Results: Radiolabeling of the 213Bi-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield ≥99.9%. Biodistribution data showed specific binding to somatostatin receptor–expressing tissues. Administration of free 213Bi, compared with 213Bi-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 ± 1.40% injected dose/g (ID/g) tissue versus 11.15 ± 0.46%, P < 0.0001] and bone marrow (0.31 ± 0.01% ID/g versus 0.06 ± 0.02%, P < 0.0324). A significant decrease in tumor growth rate was observed in rats treated with >11 MBq of 213Bi-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of 213Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving Conclusions: 213Bi-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.

Background: Patients with metastatic neuroendocrine cancers to the liver often present with disabling endocrinopathies and pain associated with bulky disease. Quality of life for these patients is poor and can require long-term therapy with somatostatin analogs for control of their symptoms. Alternative therapies to decrease tumor burden and subsequent hormone release have been investigated. Of these, cytoreductive surgery was found to have the most consistent and profound impact on symptom regression and overall survival. Methods: Several cases are reported that illustrate an aggressive multimodality approach in the treatment of metastatic neuroendocrine cancers to the liver. The literature is reviewed and the role of cytoreductive surgery in the management of hepatic neuroendocrine metastases is discussed. Results: Cytoreductive surgery can be performed safely with minimal morbidity and mortality. Regression of symptoms occurs in the majority of patients and survival is prolonged. Conclusions: Surgical intervention as part of an aggressive multimodality treatment plan results in improved outcomes for patients with advanced hepatic metastases of neuroendocrine origin. Future directions may include earlier surgical intervention with adjuvant therapies reserved for aggressive recurrent disease. Aggressive surgical resection is an important component of the multimodality treatment plan for neuroendocrine hepatic metastases in selected patients.

Background: Prognosis in patients with carcinoid and pancreatic endocrine tumors with diffuse, unresectable liver metastases is poor. Palliation is often difficult despite the use of somatostatin analogs, interferon alpha, or systemic chemotherapy. Several reviews have suggested that hepatic artery embolization, with or without intraarterial chemotherapy, can be used for control of symptoms and for cytoreduction in patients with liverdominant metastases. Methods: Between 2000 and 2002, 161 embolizations using polyvinyl alcohol or microspheres were performed on 84 patients with carcinoid or pancreatic endocrine tumors metastatic to the liver. A retrospective review was performed to evaluate symptomatic response, biochemical response, adverse effects, and duration of survival. Baseline and follow-up computed tomography scans were also assessed to determine radiographic response rates. Further analysis of survival was performed to assess the possible impact of various postembolization therapies. Results: Eighty-four patients underwent bland hepatic artery embolizations during the study period. Among 55 symptomatic patients, 44 patients had fewer symptoms, and among 35 patients whose tumor markers were followed, 28 had a major biochemical response. Objective radiographic responses were observed in 11 of 23 patients. No deaths occurred during therapy, and major toxicities were rare. Median overall survival was 36 months from time of initial embolization. Conclusions: Hepatic artery embolization frequently results in clinical and radiographic responses in patients with unresectable liver metastases from carcinoid or pancreatic endocrine tumors. Morbidity is low when appropriate supportive care is provided. Hepatic artery embolization often results in regressions in patients with unresectable liver metastases from carcinoid or pancreatic endocrine tumors.

On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Changes in the density of these receptors during disease, for example, overexpression in many tumors, provide the basis for new imaging methods. The first peptide analogues successfully applied for visualization of receptor-positive tumors were radiolabeled somatostatin analogues. The next step was to label these analogues with therapeutic radionuclides for peptide receptor radionuclide therapy (PRRT). Results from preclinical and clinical multicenter studies already have shown an effective therapeutic response when using radiolabeled somatostatin analogues to treat receptor-positive tumors. Infusion of positively charged amino acids reduces kidney uptake, enlarging the therapeutic window. For PRRT of CCK-B receptor-positive tumors, such as medullary thyroid carcinoma, radiolabeled minigastrin analogues currently are being successfully applied. The combination of different therapy modalities holds interest as a means of improving the clinical therapeutic effects of radiolabeled peptides. The combination of different radionuclides, such as (177)Lu- and (90)Y-labeled somatostatin analogues, to reach a wider tumor region of high curability, has been described. A variety of other peptide-based radioligands, such as bombesin and NPY(Y(1)) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation. Multireceptor tumor targeting using the combination of bombesin and NPY(Y(1)) analogues is promising for scintigraphy and PRRT of breast carcinomas and their lymph node metastases.

This consensus report gives a detailed description of the use of somatostatin analogs in the management of neuroendocrine tumors of the gastroenteropancreatic system. As background information we have outlined critical aspects of the pathology, the use of tumor markers, a definition of functional and non-functional digestive neuroendocrine tumors, different imaging modalities, surgical considerations, liver embolization and the use of cytotoxic drugs as well as interferon. Included in the report is an overview of somatostatin, somatostatin analogs and its receptor expression in different neuroendocrine tumors. It will also define the binding affinities of different somatostatin analogs to the five different subtypes of somatostatin receptor. We compare the efficacy of octreotide and lanreotide in reducing diarrhea and flushing. Side-effects are described and we provide practical information on somatostatin analog treatment.

Background: Pancreatic neuroendocrine tumors (PanNETs) constitute approximately 3% of pancreatic neoplasms. Like patients with pancreatic ductal adenocarcinoma (PDAC), some of these patients present with “borderline resectable disease.” For these patients, an optimal treatment approach is lacking. We report our institution’s experience with borderline resectable PanNETs using multimodality treatment. Methods: We identified patients with borderline resectable PanNETs who had received neoadjuvant therapy at our institution between 2000 and 2013. The definition of borderline resectability was based on National Comprehensive Cancer Network criteria for PDAC. Neoadjuvant regimen, radiographic response, pathologic response, surgical margins, nodal retrieval, number of positive nodes, and recurrence were documented. Statistics were descriptive. Results: Of 112 patients who underwent surgical resection for PanNETs during the study period, 23 received neoadjuvant therapy, 6 of whom met all inclusion criteria and had borderline resectable disease. These 6 patients received at least 1 cycle of temozolomide and capecitabine, with 3 also receiving radiation. All had radiographic evidence of treatment response. Four (67%) had negative-margin resections. Four patients had histologic evidence of a moderate response. Follow-up (3.0-4.3 years) indicated that all patients were alive, with 5/6 free of disease (1 patient with metastatic disease still on treatment without progression). Conclusions: A multimodality treatment strategy (neoadjuvant temozolomide and capecitabine ± radiation) can be successfully applied to patients with PanNETs who meet NCCN borderline resectable criteria for PDAC. To our knowledge, this is the first report of the use of a multimodality protocol in the treatment of patients with borderline resectable PanNETs.

Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs is a novel method of treatment in patients with metastatic neuroendocrine tumors (NETs). For the first time in the United States, we present preliminary results of the treatment with Lutetium (177)(Lu) DOTATATE in patients with progressive NETs.Thirty-seven patients with grade 1 and grade 2 disseminated and progressive gastroenteropancreatic NET were enrolled in a nonrandomized, phase 2 clinical trial. Repeated cycles of 200 mCi (7.4 GBq; ±10%) were administered up to the cumulative dose of 800 mCi (29.6 GBq; ±10%).Among 32 evaluable patients, partial response and minimal response to treatment were seen in 28% and 3%, respectively, and stable disease was seen in 41% of patients. A total of 28% had progressive disease. A response to treatment was significantly associated with lower burden of disease in the liver. No significant acute or delayed hematologic or kidney toxicity was observed. An impressive improvement of performance status and quality of life were seen after Lu-DOTATATE therapy.Treatment with multiple cycles of (177)Lu-DOTATATE peptide receptor radionuclide therapy is well tolerated. This treatment results in control of the disease in most patients, whereas systemic toxicities are limited and reversible. Quality of life is also improved.

BACKGROUND New agents with antitumor activity in patients with neuroendocrine tumors are sorely needed. A Phase II study of high-dose paclitaxel in patients with metastatic carcinoid and islet cell tumors was performed at the Mayo Clinic. Granulocyte–colony-stimulating factor (GCSF) also was administered to ameliorate neutropenia. METHODS Twenty-four patients (14 with carcinoid tumors, 9 with islet cell tumors, and 1 with an anaplastic tumor) were enrolled on this Phase II study of paclitaxel given as a 24-hour continuous infusion at a dose of 250 mg/m2 every 3 weeks plus GCSF at a dose of 5 μg/kg/day subcutaneously, beginning 24 hours after the completion of the paclitaxel dose and continuing until the absolute neutrophil count was > 10,000/μL. RESULTS All 24 patients were evaluable for analysis. The overall response rate was 8% (95% confidence interval [95% CI], 0–0.11). At last follow-up all patients except 1 had developed disease progression, with an estimated median time to disease progression of 3.2 months (95% CI, 1.6–6.0 months). The estimated median survival was 1.5 years (95% CI, 1.0–1.8 years). Hematologic toxicity was significant with 12 of 24 patients developing Grade 4 (according to the National Cancer Institute Common Toxicity Criteria scale) neutropenia; however, there were no septic deaths reported. There were 17 episodes of Grade 4 neutropenia in these 12 patients and the duration of these events ranged from 2–5 days. More common nonhematologic toxicities included arthralgia (21 patients), anorexia (15 patients), nausea (15 patients), diarrhea (12 patients), and allergic reactions (2 patients). CONCLUSIONS Given the lack of antitumor activity of paclitaxel and the significant hematologic toxicity observed despite the use of GCSF support in the current study cohort of patients with neuroendocrine tumors, further studies of this combination in this particular patient population are not recommended. Cancer 2001;91:1543–8. © 2001 American Cancer Society.

Staging for pancreatic neuroendocrine tumors (PNET) considers tumor size and lymph node (LN) status; however, correlation with survival remains unclear.A single-institution database of patients with resected PNET was analyzed.Of the 150 patients, incidentally discovered PNET was the most common presentation (42%). One hundred thirteen patients (75%) had LN data, 32 (28%) with positive LN (LN+). Procedure and tumor size did not predict LN+. Perineural invasion (P = .016) and lymphovascular (P.001) invasion, however, were more common in LN+. Multivariate analysis showed poor/moderate differentiation predicted LN+. Median follow-up was 52 months and median overall survival was 225 months. Fifty-two patients (35%) developed recurrence and median disease-free survival (DFS) was 74 months. Only poor/moderate differentiation affected DFS.PNET has an unclear prognosis based on variables factored into stage. In this study, tumor size did not predict LN+; furthermore, LN+ did not impact overall survival or DFS. Tumor differentiation appears to be more important in determining prognosis.

Quite simply, the 1983 article by Moertel on the treatment of the carcinoid tumor and the malignant carcinoid syndrome in the first volume of Journal of Clinical Oncology is brilliant. It is full of clinical pearls that ring as true today as when the article was written. I had the privilege and the pleasure of working with Dr Moertel for 18 years at the Mayo Clinic. This editorial will review the continuing evolution of oncology research in the field and highlight how the science has changed in the “land of small tumors” over the last 25 years.

A 43-year-old man with a history of metastatic carcinoid disease is presented. The patient had symptoms of chronic intermittent abdominal pain two years after undergoing a wireless capsule endoscopy procedure. Radiological examinations revealed a retained capsule endoscope, and the patient underwent exploratory laparotomy with capsule retrieval. To the authors’ knowledge, this is the first case presentation of chronic, partial small bowel obstruction caused by unrecognized retention of a capsule endoscope.

This paper employs classical concepts of diminishing marginal utility to demonstrate that risk-aversion can increase the perceived value of diagnostic procedures and thus raise optimum diagnostic expenditures. The theory is applied to a model in the spirit of Phelps and Mushlin's initial technology assessments. The specific evaluation is the cost-effectiveness of somatostatin receptor scintigraphy used to detect distant metastases of carcinoid liver tumours in a patient otherwise eligible for surgical resection of the liver. Data for the model are taken from published sources and financial databases, when available, and otherwise from a senior clinician's experience (LKK). The quantitative results indicate that receptor scintigraphy may have two beneficial impacts to risk-neutral individuals. First, it may reduce the combined costs of therapy and treatment because the diagnostic procedure costs less than the expected savings generated by avoiding inappropriate surgeries. Second, it may improve the patient's expected health-status-adjusted life years (HSALY) because the information allows physicians to better match treatment to the cancer's stage. Finally the paper demonstrates that risk aversion, as embodied in classical diminishing marginal utility applied to health status, can increase the value of the diagnostic tests and can lead the patient to choose a less beneficial treatment. An illustrative risk-averse utility function changed the optimum treatment from surgery to chemotherapy and increased scintigraphy's benefit by 500%. © 1998 John Wiley & Sons, Ltd.

To report the high prevalence of increased parathyroid hormone-related peptide (PTHrP) in patients with islet cell carcinoma and associated hypercalcemia.We conducted a retrospective study of PTHrP levels in patients with hypercalcemia and eucalcemia associated with islet cell carcinoma and compared these findings with those in healthy subjects.Using a sensitive PTHrP immunochemiluminometric assay, we measured PTHrP levels in 17 patients with islet cell carcinoma and 110 healthy subjects. The differences between PTHrP levels in patients with normal and those with high serum calcium concentrations were analyzed statistically.PTHrP levels were significantly higher (P0.01) in 10 patients with hypercalcemia and islet cell carcinoma (median, 14.0 pmol/L; range, undetectable to 40.1) than in 7 patients with eucalcemia and islet cell carcinoma (median, undetectable; range, undetectable to 1.3 pmol/L) or in the 110 healthy subjects (median, undetectable; range, undetectable to 4.2 pmol/L). The range of increased PTHrP levels in hypercalcemic islet cell carcinoma was 2 to 20 times the upper normal limit (2.0 pmol/L). Decreased PTHrP and serum calcium and increased parathyroid hormone levels were demonstrated in two patients after effective therapy. For all seven eucalcemic patients with islet cell carcinoma, PTHrP levels did not differ significantly from those in healthy subjects.PTHrP levels are increased in a substantial proportion of patients with hypercalcemia and islet cell carcinoma and seem to decrease after treatment of the underlying tumor. Measurement of PTHrP levels may be useful for confirming the diagnosis of hypercalcemia associated with malignant disease and for monitoring of therapy.

BACKGROUND The carcinoid syndrome is a common sequela in patients with carcinoid tumor metastatic to the liver. Cardiac involvement occurs in 19-56% of patients with symptomatic carcinoid syndrome and, in some patients, leads to valvular surgery to relieve symptoms due to progressive right-sided heart failure. Reports of these patients have emphasized amelioration of cardiac symptoms, but postoperative tumor status rarely has been discussed. METHODS This report describes four patients who underwent valvular heart surgery for severe carcinoid heart disease and had regression of their metastatic carcinoid tumor postoperatively. RESULTS All four patients had definite clinical improvement in cardiac function and relief of symptoms related to congestive heart failure postoperatively. Unexpectedly, they also had regression of their metastatic disease, as reflected in decreased levels of urinary 5-hydroxyindoleacetic acid, and objective evidence of a reduction in the size of hepatic metastases. CONCLUSIONS To the authors' knowledge, these four patients represent the first reported cases of metastatic disease regression after valvular surgery for carcinoid heart disease. Further descriptions of tumor status in patients having undergone a heart operation for this disease would be valuable in determining the clinical significance of this finding. Cancer 1997; 79:605-11. © 1997 American Cancer Society.

Neuroendocrine neoplasms of the pancreas are rare, accounting for 1% to 2% of all pancreatic neoplasms.1 They all have malignant potential, although the rate of progression may be slow. Currently, the extent of tumor spread and the grade of the tumor, based on proliferative rate and presence of necrosis, are features that reportedly correlate best with prognosis.2–7 Frequently, the disease course is variable, and additional prognostic criteria are needed. Clusterin gene (CLU) is a single-copy gene, organized into 9 exons (8 introns) and a 5′-untranslated region, located on chromosome 8 (8p21).8 In humans, CLU gene encodes for a nuclear (nCLU) and secreted (Clusterin) protein isoform that reportedly may have a role in proapoptotic and antiapoptotic functions, respectively.9 Clusterin is a multifunctional, stress-induced, ATP-independent molecular chaperone, previously known as testosterone-repressed prostate message 2, apolipoprotein J, sulfated glycoprotein 2, and complement lysis inhibitor.8,10 Recent data have demonstrated a significant role for Clusterin in carcinogenesis and progression of several human malignancies. The overexpression of Clusterin has been reported in prostate, breast, kidney, ovarian, and colorectal cancer as well as hematopoietic neoplasms such as anaplastic large cell lymphoma.11–16 Clusterin expression also positively correlates with increasing malignancy and pathological grading of tumors in breast and prostate cancer.17,18 Only 1 study, to our knowledge, has reported clusterin expression in pancreatic neuroendocrine tumors (PNETs) and solid pseudopapillary tumor of the pancreas but only included 30 PNETs.19 Based on the accumulated reported data, we sought to investigate the expression pattern of Clusterin in a larger set of pancreatic neuroendocrine neoplasms by immunohistochemistry (IHC) and to assess its role as a prognostic biomarker of pancreatic neuroendocrine neoplasm behavior.

Background/Aims: The phase III placebo-controlled RADIANT-2 trial investigated the efficacy of everolimus plus octreotide long-acting repeatable (LAR) in patients with advanced neuroendocrine tumors (NET) associated with carcinoid syndrome. Here we report a secondary analysis based on the previous somatostatin analogue (SSA) exposure status of patients enrolled in RADIANT-2. Methods: Patients were randomly assigned to receive oral everolimus 10 mg/day plus octreotide LAR 30 mg intramuscularly (i.m.) or to receive matching placebo plus octreotide LAR 30 mg i.m. every 28 days. SSA treatment before study enrollment was permitted. Patient characteristics and progression-free survival (PFS) were analyzed by treatment arm and previous SSA exposure status. Results: Of the 429 patients enrolled in RADIANT-2, 339 were previously exposed to SSA (95% received octreotide); 173 of 339 patients were in the everolimus plus octreotide LAR arm. All patients had a protocol-specified history of secretory symptoms, but analysis by type showed that more patients who previously received SSA therapy had a history of flushing symptoms (77%), diarrhea (86%), or both (63%) compared with SSA-naive patients (62, 62, and 24%, respectively). Patients who received everolimus plus octreotide LAR had longer median PFS regardless of previous SSA exposure (with: PFS 14.3 months, 95% confidence interval, CI, 12.0-20.1; without: 25.2 months, 95% CI, 12.0-not reached) compared with patients who received placebo plus octreotide LAR (with: 11.1 months, 95% CI, 8.4-14.6; without: 13.6 months, 95% CI, 8.2-22.7). Conclusion: Everolimus in combination with octreotide improves PFS in patients with advanced NET associated with carcinoid syndrome, regardless of previous SSA exposure.

Receptors for the regulatory peptide somatostatin are expressed in high density in the majority of neuroendocrine gastroenteropancreatic tumors, i.e. in carcinoids and islet cell carcinomas. These fin

The presence of transcripts for somatostatin receptor (SSTR) subtypes 1, 2, 3, and 4 was probed by reverse transcription and polymerase chain reaction in ribonucleic acid isolated from 46 malignant and 9 nonmalignant breast tissues, 15 carcinoid tumor tissues, and 13 renal cell carcinoma tissues. The transcripts for SSTR2 were amplified in all but 2 tissue samples, whereas transcripts for SSTR1, SSTR3, and SSTR4 were detected sporadically. In renal cell tumors, SSTR3 transcripts were completely absent. In breast cancer tissue, SSTR subtypes were transcribed independently of patient age, menstrual status, diagnosis, histological grade, and levels of estrogen receptor and progesterone receptor. The probability of finding transcripts for SSTR subtypes, P, was ranked differently for the three types of tumor tissues. For breast cancer, P2 > P3 = P1 > P4; for carcinoid tumors, P2 > P1 > P3 = P4; and for renal cell tumors, P2 > P1 > P4 > P3.

Objectives. The hypothesis was that cardiac surgery for symptomatic carcinoid heart disease in conjunction with adjunctive therapy could improve the long-term outlook of patients with carcinoid heart disease. Background. Patients with carcinoid heart disease have a dismal prognosis; most die of progressive right heart failure within 1 year after onset of symptoms. Improved therapies for the systemic manifestations of the carcinoid syndrome have resulted in symptomatic improvement and prolonged survival in patients without heart disease. Methods. Twenty-six patients with symptomatic carcinoid heart disease underwent valvular surgery. Preoperative clinical, laboratory, Doppler echocardiographic and hemodynamic factors were evaluated. The survival of the surgical group was compared with that of a control group of 40 medically treated patients. Results. There were nine perioperative deaths (35%), primarily from postoperative bleeding and right ventricular failure. Of the 17 surgical survivors, 8 were alive at a mean of 28 months of follow-up. The postoperative functional class of the eight surviving patients was substantially improved. Late deaths were primarily due to hepatic dysfunction caused by metastatic disease. The only predictor of operative mortality (p = 0.03) was low voltage on preoperative electrocardiography (limb lead voltage ≤ 5 mm). Predictors of late survival included a lower preoperative somatostatin requirement and a lower preoperative urinary 5-hydroxy-indoleacetic acid level. There was a trend toward increased survival for the surgical group compared with the control group. Conclusions. Because new therapies have improved survival in patients with the malignant carcinoid syndrome, cardiac involvement has become a major cause of morbidity and mortality. Valve surgery is the only definitive treatment. Although cardiac surgery carries a high perioperative mortality, marked symptomatic improvement occurs in survivors. Surgical intervention should therefore be considered when cardiac symptoms become severe.

Neuroendocrine tumours may originate from the lungs, thymus, stomach, gastrointestinal tract and endocrine pancreas. A majority of the tumours are malignant. Metastases occur to regional and distal lymph nodes, liver, bones, lungs, mammary glands, subcutaneous tissue, central nervous system and adrenal glands. Although most neuroendocrine tumours are relatively slowly growing, poorly differentiated neuroendocrine carcinomas are fast growing neoplasms with high proliferative activity. A characteristic feature of many neuroendocrine tumours is the ability to produce and secrete various hormones and peptides, leading to endocrine symptoms that can be very disabling and cause substantial morbidity. Small bowel carcinoids, for example, produce serotonin giving rise to the classical carcinoid syndrome with flushing, diarrhea, right-sided heart disease and asthma. A prerequisite for the carcinoid syndrome to occur is usually the presence of liver metastases. Lung carcinoids rarely produce serotonin, but may instead secrete histamine causing an atypical carcinoid syndrome with generalized flushing, diarrhea, periorbital oedema, lacrimation and asthma. They may also produce adrenocorticotropic hormone or corticotropin-releasing factor, resulting in an ectopic Cushing's syndrome. Endocrine pancreatic tumours may as well secrete various hormones, such as gastrin, insulin, glucagon, vasoactive intestinal polypeptide (VIP) or somatostatin, resulting in the corresponding syndrome. The treatment of patients with metastatic neuroendocrine tumours is based on primary tumour origin, tumour biology, stage and grade and includes debulking by surgery, liver embolization with particles, chemoembolization, radioembolization, radiofrequency ablation and peptide receptor radionuclide therapy (PRRT) with 90Yttrium-DOTATOC or 177Lutetium-DOTATATE. Medical treatment consists of biotherapy with alpha-interferon and somatostatin analogues, various chemotherapy regimens, angiogenesis inhibitors, tyrosine kinase inhibitors and mTOR inhibitors. In this special issue in the International Journal of Hepatology, focus is on the various specific treatment possibilities for patients with neuroendocrine tumours metastatic to the liver. There are two papers describing the role of surgery in these patients, and one clinical study reporting the results of liver transplantation. Surgical debulking should always be considered, and liver transplantation may in selected cases be an option. Because of the immunosuppression, it is however of utmost importance that every effort is made to exclude remaining tumour outside the liver before transplantation. Three papers deals with hepatic arterial embolization, one of them reviews the role of hepatic arterial embolization for debulking of liver metastases. Another paper is about a clinical study and a review of radioembolization, which is a promising alternative for this patient group with possible long-lasting effect and few serious adverse effects. An important disadvantage (also with particle and chemoembolization) is that most patients with neuroendocrine tumours metastatic to the liver in addition have spread of the tumour to lymph nodes and/or other distant organs such as the bones, necessitating systemic therapy. In patients with normal bone marrow and renal function, PRRT is thus often preferred to radioembolization, which however may be considered if the patient shows progression later after PRRT. A randomized clinical trial comparing the various embolization methods, particle embolization, chemoembolization and radioembolization, would nevertheless be highly desirable. Three papers review the possible systemic therapies for patients with liver metastases from neuroendocrine tumours. This year, two new drugs have been approved for treatment of patients with metastatic endocrine pancreatic tumours, everolimus and sunitinib. This represents an important progress in the therapeutic arsenal for patients with neuroendocrine tumours. There is however still a need for more new drugs, and especially for patients with midgut carcinoids, in whom the therapeutic options are limited after progression. In addition, there is an urgent need to learn how to use, combine and sequence the various therapeutic alternatives, including chemotherapy, biotherapy, newer drugs and PRRT. Dan Granberg Wouter de Herder Dermot O'Toole Larry Kvols

The liver is the predominant site of metastases among patients with advanced neuroendocrine tumors (NETs). Prior retrospective studies have reported high response rates in patients treated with transarterial embolization (TAE). NETs are highly vascular and are known to express vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR). We hypothesized that administration of sunitinib, a VEGFR inhibitor, following TAE would extend progression-free survival (PFS).Patients with metastatic NETs to the liver underwent a series of selective TAEs followed by sunitinib (until disease progression or maximum of 12 months). Radiographic response (by RECIST), survival, and safety parameters were monitored.Thirty-nine patients were enrolled. The overall response rate was 72% [95% confidence interval (CI), 0.58-0.86]. Median PFS was 15.2 months. Rates of overall survival (OS) at 1 and 4 years were 95% (95% CI, 0.88-1.00) and 59% (95% CI, 0.38-0.80), respectively. A significant 34% rise in serum VEGF was observed following the initial TAE (P = 0.03).Hepatic TAE is a highly active treatment option for patients with metastatic NETs to the liver. Embolization stimulates release of VEGF into the circulation. Sunitinib, an oral VEGFR inhibitor, can be safely administered following embolization. The high rates of PFS and OS associated with this sequence of therapies are encouraging.

Somatostatin receptors are expressed on certain neural crest-derived tumors, including pancreatic islet cell and carcinoid tumors, medullary thyroid carcinomas, pheochromocytomas, and paragangliomas. The authors evaluated the expression of high affinity somatostatin receptors in childhood neuroblastoma using autoradiography techniques with the somatostatin analogue 125I-octreotide or 125I-[Leu8,D-Trp22,Tyr25]-SS-28 as the radioligand. Thirty tumors from 30 children with neuroblastoma were analyzed. Twenty-three of 30 tumors that were tested expressed somatostatin receptors. Correlation of somatostatin receptor expression with survival was statistically significant. The survival of those patients whose tumors expressed somatostatin receptors was of longer duration than that of patients whose tumors did not. This was an independent prognostic factor. Somatostatin receptors were expressed more frequently in tumor tissue from patients with lower stages of disease and in those with no evidence of N-myc amplification. Tumoral somatostatin receptors are expressed in a subgroup of patients with childhood neuroblastoma. Survival analysis in this group of patients indicates that somatostatin receptor expression is a favorable prognostic factor. This finding may have important implications for the therapy of children with this malignancy.

Patients with metastatic carcinoid tumors and the malignant carcinoid syndrome have benefited immensely from diagnostic and therapeutic advances during the past decade. Magnetic resonance imaging and whole body scintigraphy with radiolabelled analogues of somatostatin have improved our ability to diagnose, detect, stage and follow response to therapy. Surgical, medical, and radiation therapy may all contribute to the management of these patients. This disease is variable in its presenting symptoms and the biologic behavior of the tumor. The spectrum of clinical manifestations varies depending upon the type and quantity of polypeptide hormones or biogenic amines being produced. Although the tumors are usually indolent in their growth, the more dedifferentiated or anaplastic tumors can be quite aggressive. Thanks to new treatments that are very effective in the subgroup of anaplastic neuroendocrine carcinomas it is vital to recognize this subset. As research scientists and clinicians we must be aware of the natural history of the disease in order to optimize each patient’s treatment. This highly selective review focuses on studies performed in collaboration with Dr. Charles Moertel along with other colleagues at the Mayo Clinic, have done in the past few years.

Background/Aims: Carcinoid patients show a hypertonic colonie motor response postprandially. Ondansetron reduces postprandial colonie tone in health. It was hypothesized that ondansetron, a selective 5HT 3 antagonist, corrects the colonic motor response to eating in carcinoid diarrhea. Methods: The effects of ondansetron and placebo on fasting and postprandial colonic tone and motility in 10 patients with carcinoid diarrhea were compared using a manometry-barostat assembly positioned in the upper descending colon. Results: Fasting colonic tone and motility indices were similar in the placebo and ondansetron groups; ondansetron did not affect fasting motility. The placebo group showed a significant reduction in barostat balloon volume (signifying increased tone) from 207 ± 29 ml (mean ± SEM) during fasting to 106 ± 14 ml postprandially ( P = 0.01). With ondansetron, a tonic colonie response was induced postprandially (198 ± 37 mL to 151 ± 30 mL; P = 0.053). However, the increment in tone in the ondansetron group (23% ± 7%) was significantly lower than in the placebo group (48% ± 5%; P = 0.02) and was similar to that observed in untreated healthy subjects (24% ± 3%). Postprandial manometric pressure activity increased significantly in the placebo group ( P = 0.01); in the ondansetron group there was a trend ( P = 0.09) to increased phasic activity. Conclusions: Ondansetron reduces the postprandial colonie hypertonic response in carcinoid diarrhea to levels previously reported in health; further clinical studies of this class of antagonists in carcinoid diarrhea appear warranted.

In a European multicenter trial, a combination of conventional imaging methods (CIM) detected tumor sites in 88% of patients with gastroenteropancreatic endocrine tumors, whereas [111In-DTPA-D-Phe1]-octreotide scintigraphy was positive in 80% of the patients. The highest success rates of [111In-DTPA-D-Phe1]-octreotide scintigraphy were observed in patients with glucagonomas (100%), vipomas (88%), carcinoids (87%) and nonfunctioning islet cell tumors (82%). In addition to 297 out of 388 localizations found with CIM [111In-DTPA-D-Phe1]-octreotide scintigraphy revealed another 166 unsuspected lesions of which 40% were subsequently confirmed as true-positive findings based on the results of additional imaging procedures or histology obtained during a follow-up period. Overall, the scintigraphic findings led to management changes in 40% of the 235 patients for whom these data were available.

Peptide and growth factor receptors are frequently expressed in high density in human tumors. A particularly high abundance of receptors for the peptide somatostatin (SS) is found in neuroendocrine tumors of the pancreas and gastrointestinal tract. 90% of the carcinoids and a majority of islet cell carcinomas, including their metastases, have usually a high density of SS receptors. The number of receptors correlates with the degree of differentiation of the tumor. Several different SS receptor subtypes can be expressed by these tumors, the SSTR2 subtype being the most frequently and abundantly expressed. The somatostatin receptors in tumors are identified with in vitro binding methods, molecular biology techniques or in vivo imaging techniques; the latter allow the precise localization of the tumors and their metastases in the patients. Since SS receptors in human hormone-producing gastroenteropancreatic tumors are functional, their identification can be used to predict the therapeutic efficacy of octreotide to inhibit excessive hormone release. Undifferentiated tumors, such as atypical carcinoids, exocrine pancreatic carcinomas and most of the colorectal carcinomas, usually do not express SS receptors in the tumor itself, but, interestingly, may trigger the expression of SS receptors in the peritumoral veins, where SS may play a role in hemodynamic tumor-host interactions.

Palladin is a metastasis-associated gene regulating cell motility. The expression of palladin protein in pancreatic neuroendocrine tumors (PET) and carcinomas (PECA) is not known.A tissue microarray (TMA) of well-differentiated (WD) PETs/PECAs (AJCC 2010) and non-neoplastic, histologically normal pancreatic tissue/islets (HNPIs) was immunostained with palladin antibody and quantified using the Allred score. The results were correlated with the presence or absence of liver metastases.The retrospective study included 19 males and 19 females of age 27-79 years (mean 54). Tumor size was 0.9-11.5 cm (mean 3.8). Palladin expression was cytoplasmic and/or membranous. The tumors with high palladin expression were associated with liver metastasis (p0.0001). All 14 primary PECA with hepatic metastases (MP-PECAs) exhibited palladin expression whereas 14 out of 24 (58%) clinically-localized primary PET (CLP-PETs) expressed palladin (p0.01) with median Allred scores of 5 (range 3-7) and 2 (range 0-6) respectively (p0.0001). The mean Allred score for the HNPIs in the MP-PECAs (N=6) was higher (4.2) as compared to that in the CLP-PETs (2.5,N=11) (p=0.23).Palladin may identify primary pancreatic endocrine neoplasms with a propensity to metastasize to the liver.

Purpose The American Joint Committee on Cancer (AJCC) staging manual (seventh edition) has introduced its first TNM staging classification for pancreatic neuroendocrine tumors (NETs) derived from the staging algorithm for exocrine pancreatic adenocarcinomas. This classification has not yet been validated. Methods Patients with pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I to IV) based on the new AJCC classification. Kaplan-Meier analyses for overall survival (OS) were performed based on age, race, histologic grade, incidental diagnosis, and TNM staging (European Neuroendocrine Tumors Society [ENETS] v AJCC) using log-rank tests. Survival time was measured from time of initial diagnosis to date of last contact or date of death. Multivariate modeling was performed using Cox proportional hazards regression. Weighted Cohen's κ coefficient was computed to evaluate the agreement of ENETS and AJCC classifications. Results We identified 425 patients with pancreatic NETs. On the basis of histopathologic grade, 5-year survival rates for low-, intermediate-, and high-grade tumors were 75%, 62%, and 7%, respectively (P < .001). When using the ENETS classification, 5-year OS rates for stages I, II, III, and IV were 100%, 88%, 85%, and 57%, respectively (P < .001). Subsequently, using the AJCC classification, 5-year OS rates for stages I, II, III, and IV were 92%, 84%, 81%, and 57%, respectively (P < .001). Both the novel AJCC classification and the ENETS classification were highly prognostic for survival. Conclusion The AJCC TNM classification for pancreatic NETs is prognostic for OS and can be adopted in clinical practice.

BACKGROUND The carcinoid syndrome is a rare cause of acquired valvular heart disease. Although the typical echocardiographic features of carcinoid heart disease are well recognized, this large series provides new information about unusual manifestations of the disease as well as the role of Doppler echocardiography. METHODS AND RESULTS Between 1980 and 1989, 132 patients with carcinoid syndrome underwent echocardiographic study. The echocardiographic, Doppler, and clinical features of the 74 patients (56%) with echocardiographic evidence of carcinoid heart disease are described. Among these patients, 97% had shortened, thickened tricuspid leaflets. Tricuspid regurgitation was present in all 69 patients with carcinoid heart disease who underwent Doppler examination, and it was of moderate or severe degree in 62 patients (90%). Severe tricuspid regurgitation was characterized by a dagger-shaped Doppler spectral profile with an early peak pressure and rapid decline. The pressure half-time was prolonged (mean, 116 msec), which is consistent with associated tricuspid stenosis. The pulmonary valve appeared thickened, retracted, and immobile in 36 patients (49%) and was diminutive to the extent of not being visualized in an additional 29 patients (39%). Among the 47 patients who underwent Doppler evaluation of the pulmonary valve, regurgitation was present in 81%, and stenosis was present in 53%. Left-sided valvular involvement was present in five patients (7%), four of whom had patent foramen ovale or carcinoid tumor involving the lung. Previously undescribed myocardial metastases were present in three patients (4%) and were confirmed by biopsy in each case. Small pericardial effusions were present in 10 patients (14%). Patients with and without echocardiographic evidence of carcinoid heart disease did not differ with regard to sex, age, location of the primary tumor, duration of diagnosis, or duration of symptoms of carcinoid syndrome. However, the mean pretreatment level of urinary 5-hydroxyindoleacetic acid was higher in patients with carcinoid heart disease than in patients without carcinoid heart disease (270 versus 131 mg/24 hrs, p < 0.001). The symptom of dyspnea was more prevalent among patients with carcinoid heart disease than in patients without the disease (54% versus 27%, p = 0.003); as expected, heart murmurs were also noted more frequently in patients with disease (92% versus 43%, p < 0.0001). Treatment regimens and response to therapy were similar in the two groups. Survival of patients with echocardiographic evidence of carcinoid heart disease was reduced compared with those without cardiac involvement (p = 0.0003). ECG and chest roentgenographic findings in patients with carcinoid heart disease were nonspecific. CONCLUSIONS The broad spectrum of carcinoid heart disease is detailed in this large series. This includes not only right-sided valvular lesions but also left-sided involvement, pericardial effusion, and myocardial metastases.

Patients with metastatic carcinoid tumors and the malignant carcinoid syndrome have benefited immensely from diagnostic and therapeutic advances during the past decade. Magnetic resonance imaging and whole body scintigraphy with radiolabelled analogues of somatostatin have improved our ability to diagnose, detect, stage and follow response to therapy. Surgical, medical, and radiation therapy may all contribute to the management of these patients. This disease is variable in its presenting symptoms and the biologic behavior of the tumor. The spectrum of clinical manifestations varies depending upon the type and quantity of polypeptide hormones or biogenic amines being produced. Although the tumors are usually indolent in their growth, the more dedifferentiated or anaplastic tumors can be quite aggressive. Thanks to new treatments that are very effective in the subgroup of anaplastic neuroendocrine carcinomas it is vital to recognize this subset. As research scientists and clinicians we must be aware of the natural history of the disease in order to optimize each patient's treatment. This highly selective review focuses on studies performed in collaboration with Dr. Charles Moertel along with other colleagues at the Mayo Clinic, have done in the past few years.