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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

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: 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Between 1982 and 1989, 10 patients with carcinoid heart disease underwent tricuspid valve replacement with a mechanical prosthesis at our institution. Pulmonary vasectomy was performed in nine patients and pulmonary valve replacement with a pulmonary homograft was performed in one. Two patients had carcinoid tumor metastatic to the heart, involving the right atrium in one case and both ventricles in the other. One patient had concomitant coronary artery bypass with the saphenous vein, and one patient had a quadruple valve replacement for histologically proved carcinoid disease of all four valves. The 30-day mortality was 10% and the late mortality was 30%. The remaining six patients were alive 4, 4, 4, 7, 24, and 46 months postoperatively. A review of the English literature identified 28 additional patients who underwent tricuspid valve replacement for carcinoid heart disease. There was no significant difference in the survival of patients with a bioprosthesis versus a mechanical valve in the tricuspid position. The 4-year survival for the 38 patients undergoing tricuspid valve replacement for carcinoid heart disease was 48% ±13%. Symptomatic patients who have carcinoid heart disease and whose metastatic malignant disease is not an imminent threat to life should be offered valve replacement. Operating soon after the onset of increasing cardiac symptoms, before the often rapid deterioration in right ventricular failure, optimizes the benefits. (J T horac C ardiovasc S urg 1992;104:475-81)

Forty-five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide 130 mg/m2/d for 3 days plus cisplatin 45 mg/m2/d on days 2 and 3. Both drugs were given by continuous intravenous infusion. Among 27 patients with well-differentiated carcinoid tumors or islet cell carcinomas, only two partial objective tumor regressions were observed (7%). Among 18 patients prospectively classified as having anaplastic neuroendocrine carcinomas, however, there were nine partial regressions and three complete regressions, an overall regression rate of 67%. For anaplastic disease, the median duration of regression was 8 months (range to 21 months). Tumor response was unrelated to primary site, endocrine hyperfunction, or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months; this seemed favorable when considering the small experiences with these rare tumors reported in the literature. Toxicity, which was severe for most patients, consisted primarily of vomiting, leukopenia, thrombocytopenia, anemia, alopecia, and neuropathy. The anaplastic neuroendocrine tumor is strongly responsive to therapy with combined etoposide and cisplatin. Patients with undifferentiated carcinomas, originating in typical neuroendocrine tumor sites (small and large bowel, pancreas, and stomach) or of unknown origin, who have consistent histologic findings by light microscopy should be evaluated for this possibility with appropriate immune staining or electron microscopy.

Octreotide acetate is a somatostatin analogue that has been shown to ameliorate the side effects of excessive secretion of hormone from benign and malignant tumors. The ability of this drug to inhibit the growth of malignant cells and to control gastrointestinal hemorrhage will prompt additional clinical trials. Because some of these patients may have thrombocytopenia, platelet dysfunction, or a coagulopathy, we studied tests of platelet function and blood coagulation in 15 patients before and after 14 days of therapy with octreotide acetate at a dosage of 500 micrograms three times daily. We found no substantial change in the results of these tests, and no patient experienced bleeding or thrombosis. These results suggest that octreotide acetate does not adversely affect platelet function or the coagulation system in humans.

Background: Pancreatectomy for ductal adenocarcinoma has been performed with increasing frequency since the late 1980s as postoperative mortality decreased and long-term survival became more common. However, the belief persists among some clinicians that pancreatectomy offers little survival benefit. This report reviews our institutional experience with pancreatectomy for pancreatic adenocarcinoma and provides a critical overview of the controversies regarding the benefits of surgical intervention for patients who are candidates for curative resection. Methods: We determined the survival of 142 patients who underwent pancreatectomy for ductal adenocarcinoma with curative intent (stage IA‐IIB) at Moffitt Cancer Center during the last two decades by using data obtained from review of the medical record, the Moffitt Cancer Registry, and the Social Security Death Index. Histologic diagnosis was confirmed by expert review of stained sections cut from fixed surgical specimens. Results: In the 137 patients who survived at least 30 days after surgery, the median survival was 21.2 months after resection, with Kaplan-Meier 3- and 5-year disease-specific survival rates of 36% and 32%, respectively. One patient has survived without evidence of recurrent disease for more than 15 years after pancreatectomy. Survival for patients greater than 75 year of age did not differ from that of younger patients. The postoperative mortality rate was 1.5% during the most recent years of highest operative volume (2003 to 2006) and 3.5% for the entire patient cohort. Conclusions: Review of our 20-year experience with resection of pancreatic adenocarcinoma indicates that pancreatectomy with curative intent offers a real chance of long-term survival to patients with this highly lethal disease for which there is no other curative modality. Pancreatectomy with curative intent offers the possibility of long-term survival to patients with this usually lethal disease.

Cushing's syndrome due to ectopic production of adrenocorticotropic hormone (corticotropin) has been recognized for many years. Traditionally, clinicians have thought that most cases were due to lung carcinomas and that the clinical manifestations differed from those for pituitary-dependent Cushing's syndrome. We report two cases of corticotropin-producing bronchial carcinoid tumors that were clinically and biochemically indistinguishable from pituitary-dependent Cushing's syndrome. Review of the literature revealed that bronchial carcinoid tumors are the most common cause of Cushing's syndrome due to ectopic secretion of corticotropin. On biochemical and anatomic studies, they are frequently indistinguishable from pituitary-dependent Cushing's syndrome and thus may be difficult to diagnose. Inferior petrosal sinus sampling for corticotropin and computerized imaging of the chest may be the best aids in making the diagnosis.

The cause of testicular cancer, like most other cancers, is unknown. Certain risk factors such as cryptorchidism, carcinoma in situ, and a preceding contralateral testicular germ cell neoplasm are known to predispose a person to the subsequent development of a testicular malignant lesion. Familial testicular cancer has been debated as a potential and possibly independent risk factor. Evidence in favor of such a hypothesis, based on various genetic studies reported during the past few decades, is reviewed. We add to the existing literature our experience with six cases of familial testicular cancer encountered during a 10-year period, consisting of four father-and-son pairs, one pair of nontwin brothers, and a 23-year-old man who had a maternal uncle with a history of testicular cancer.

The heart is an exceedingly rare site of metastatic involvement in carcinoid tumors. Only nineteen cases have been described in the literature over the past 30 years. We report here on a patient who presented with progressive carcinoid syndrome despite surgical resection of her liver metastases. She was found to have cardiac metastases on inidium-111-pentetreotide scintigraphy and subsequently underwent external beam radiation to the heart resulting in symptomatic palliation of her syndrome and objective radiographic response. To our knowledge, this is the first reported case of metastatic cardiac carcinoid treated with external beam irradiation.

Background: The expression of somatostatin receptors (SSTRs) on endocrine tumor (ET) cells forms the basis for somatostatin analog treatment of patients with SSTR-positive, hormonally active ETs. In patients with SSTRnegative ETs, the clinical response is generally absent or suboptimal, while nonfunctioning ETs with SSTR positivity show a variable response to such therapy. Methods: We retrospectively studied SSTR subtype expression in hepatic metastases from 14 adult patients with primary endocrine carcinomas (ECAs) of the small intestine and pancreas and compared SSTR subtype expression among the primary and metastatic ECAs. Polyclonal antibodies against the 5 SSTR subtypes were used on formalin-fixed, paraffin sections from each primary and metastatic ECA. Both qualitative and semiquantitative evaluation of the stained ECA sections was carried out. Results: Eleven (61%) of 18 hepatic metastases from small intestinal and pancreatic ECAs were positive for SSTR-1, 15 (83%) for SSTR-2, 13 (72%) for SSTR-3, 10 (56%) for SSTR-4, and 15 (83%) for SSTR-5. Among 11 hepatic ECA metastases from small intestinal ECAs (carcinoids), 7 (63%) expressed SSTR-1, 9 (81%) expressed SSTR-2, 8 (72%) expressed SSTR-3, 6 (54%) expressed SSTR-4, and 10 (91%) expressed SSTR-5. Of 7 hepatic ECA metastases from pancreatic ECAs, 4 expressed SSTR-1 and SSTR-4, 6 expressed SSTR-2, and 5 expressed SSTR-3 and SSTR-5 each. We also observed the immunohistochemical evidence of heterogeneity of expression of various SSTR subtypes in the primary enteropancreatic ECAs and their hepatic metastases. Conclusions: SSTR subtype expression needs to be correlated to somatostatin analog therapy. Immunohistochemical profiling of various SSTR subtypes as a part of routine surgical pathologic analysis of enteropancreatic ETs may become a useful predictor of responsiveness of ETs to various SSTR analogs. In patients with gastroenteropancreatic

Background. Small bowel adenocarcinoma is a rare gastrointestinal malignancy that is treated primarily with surgery. Even with optimal resection, however, survival is poor and recurrences are common. Response rates to palliative combination chemotherapy are low, and the median duration of survival for metastatic disease is less than 1 year. This study aimed to document the response rate and survival time for patients with advanced small bowel adenocarcinoma who were not surgically curable and were treated with a regimen of 5-fluorouracil (5-FU), mitomycin C (Mutamycin®; Bristol-Myers Squibb; Princeton, NJ), and doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH), the FAM regimen. Methods. This multi-institutional study was performed by the Eastern Cooperative Oncology Group (ECOG). Between November, 1983 and December, 1985, 39 patients with advanced or recurrent disease were enrolled. Chemotherapy was given as follows: 5-FU, 600 mg/m2 on days 1, 8, 29 and 36; mitomycin C, 10 mg/m2 on day 1; and doxorubicin, 30 mg/m2 on days 1 and 29. Eligibility criteria included an ECOG performance status score of 0–2, measurable disease, and adequate baseline organ function. Prior chemotherapy was allowed. Response was measured by examination and imaging techniques. Survival time and time to progression were evaluated by the method of Kaplan and Meier, and these outcomes were stratified by clinical and laboratory covariates. Results. Of the 39 evaluated patients, 38 were eligible and 36 were evaluable for response. Grade 3–5 toxicities were experienced by a total of 26 patients (20 grade 3, 5 grade 4, 1 grade 5). The most common adverse events were neutropenia and vomiting. Responses were seen in a total of seven patients (2 complete responses, 5 partial responses), for a response rate of 18.4% (95% confidence interval of 7.8%–34.4%). The median survival time was 8 months. Conclusions. The FAM regimen was active and tolerable for patients with advanced small bowel adenocarcinoma; however, the results were no better than those seen with other chemotherapy combinations.

The challenge for internal therapy is to deliver the highest possible dose to the tumor while sparing normal organs from damage. Currently, the potential risk of kidney and red marrow toxicity limits the amount of radioactivity that may be administered. An accurate dosimetry method that would provide reliable dose estimates to these critical organs and to tumors before therapy would allow the clinician to plan a specific therapeutic regimen and also select those patients who would benefit the most from treatment. The dosimetry for (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide is usually based on quantitative imaging at different time points that provides information on activity retention in organs over time and on stylized models representing average individuals. Because the therapeutic agent labeled with (90)Y is not suitable for quantitative imaging, the peptide surrogate labeled with the positron emitter (86)Y can be considered the most appropriate tracer for measuring distribution and retention of the radiopharmaceutical over time. Dose calculations in target organs are generally performed using the MIRDOSE program, in which S values from source to target are integrated. Significant improvement of dose estimates may be achieved by introducing patient-specific adjustments to the standard models. The use of individual kidney volumes assessed by CT instead of the use of a fixed volume for males and females may significantly improve the determination of kidney radiation doses. The use of actual CT-derived tumor volumes has also shown a dose-efficacy relationship. Additional improvements in this field include the validation and use of an (111)In surrogate to avoid the complexity of (86)Y use and the consideration of radiobiologic parameters, such as fractionation effects and the specific biologic efficacy of internally deposited radiation, which are probably underestimated using currently available methods.

The ideal radiation sensitizer would reach the tumor in adequate concentrations and act selectively in the tumor compared with normal tissue. It would have predictable pharmacokinetics for timing with radiation treatment and could be administered with every radiation treatment. The ideal radiation sensitizer would have minimal toxicity itself and minimal or manageable enhancement of radiation toxicity. The ideal radiation sensitizer does not exist today. This review outlines the concept of combining 2 modalities of cancer treatment, radiation and drug therapy, to provide enhanced tumor cell kill in the treatment of human malignancies and discusses molecules that target DNA and non-DNA targets. Combining drugs that have unique mechanisms of action and absence of overlapping toxicities with systemically administered radiotherapy should be exploited in future clinical trials. This is an exciting time in clinical oncology research, because we have a plethora of new molecules to evaluate.

Nephrotoxicity is the major limiting factor during therapy with the radiolabeled somatostatin analog (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). Pretherapeutic assessment of kidney absorbed dose could help to minimize the risk of renal toxicity. The aim of this study was to evaluate the contribution of patient-specific adjustments to the standard dosimetric models, such as the renal volume and dose rate, for estimating renal absorbed dose during therapy with (90)Y-DOTATOC. In particular, we investigated the correlation between dose estimates and effect on renal function after therapy. METHODS: Eighteen patients with neuroendocrine tumors (9 men and 9 women; median age, 59 y) underwent treatment with (90)Y-DOTATOC (8.1-22.9 GBq) after pretherapeutic biodistribution study with (86)Y-DOTATOC. Kidney uptake and residence times were measured and the absorbed dose (KAD) was computed using either the MIRDOSE3.1 software assuming a standard kidney volume (KAD(StdVol)) or the MIRD Pamphlet 19 values and the actual kidney cortex volume determined by pretherapeutic CT (KAD(CTVol)). For each patient, the biologic effective dose (BED) was calculated according to the linear quadratic model to take into account the effect of dose rate and fractionation. Renal function was evaluated every 6 mo by serum creatinine and creatinine clearance (CLR) during a median follow-up of 35.5 mo (range, 18-65 mo). The individual rate of decline of renal function was expressed as CLR loss per year. RESULTS: KAD(CTVol) ranged between 19.4 and 39.6 Gy (mean, 28.9 +/- 5.34 Gy). BED, obtained from KAD(CTVol), ranged between 27.7 and 59.3 Gy (mean, 40.4 +/- 10.6 Gy). The CLR loss per year ranged from 0% to 56.4%. In 12 of 18 patients, CLR loss per year was 20% received a BED >45 Gy. Patients who were treated with low fractionation were those with the highest rate of renal function impairment. Conclusion: Radiation nephrotoxicity after (90)Y-DOTATOC therapy is dose dependent. Individual renal volume, dose rate, and fractionation play important roles in an accurate dosimetry estimation that enables prediction of risk of renal function impairment.

BACKGROUND: Infusion of amino acids (AAs) can reduce renal uptake of radiolabelled somatostatin analogues resulting in a lower kidney exposure during peptide radiotherapy of patients with neuroendocrine tumours. In this study, we investigated the metabolic effects related to the infusion of large amounts of amino acids in patients undergoing positron emission tomography (PET) studies with [(86)Y]DOTA(0)-D-Phe(1)-Tyr(3)-octreotide. METHODS: Twenty-four patients, in four consecutive groups of six, received a 4 h infusion of 120 g of mixed AAs and, in addition, either a 4 h infusion of 50 g of L-lysine (n = 6), a 10 h infusion of 240 g of mixed AAs (n = 6), a 4 h infusion of 50 g of L-lysine + L-arginine (Lys-Arg; n = 6) or no infusion (control; n = 6) in randomly ordered crossover studies. A number of clinical and biochemical parameters in blood and urine were measured over 24 h, including calculation of creatinine clearance, tubular reabsorption of inorganic phosphate (TRP) and fractional urate excretion. RESULTS: No clinical side effects occurred during the infusions except for nausea and vomiting under mixed AAs. Patients in the latter group showed an increase in serum urea, whereas patients receiving L-lysine showed an increase in serum potassium and chloride. Inorganic phosphate levels dropped at 2.5 h in all groups except controls, and a significant decrease in TRP was observed with mixed AAs but not with L-lysine or Lys-Arg. CONCLUSION: Although infusion of AA solutions can improve the effect of therapy by allowing the administration of higher doses of radiolabelled somatostatin analogues, each preparation has specific sides effects that should be taken into account with this type of therapy.

BACKGROUND: Staging for pancreatic neuroendocrine tumors (PNET) considers tumor size and lymph node (LN) status; however, correlation with survival remains unclear. METHODS: A single-institution database of patients with resected PNET was analyzed. RESULTS: 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 (LN1). Procedure and tumor size did not predict LN1. Perineural invasion (P 5 .016) and lymphovascular (P , .001) invasion, however, were more common in LN1. Multivariate analysis showed poor/moderate differentiation predicted LN1. 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. CONCLUSIONS: PNET has an unclear prognosis based on variables factored into stage. In this study, tumor size did not predict LN1; furthermore, LN1 did not impact overall survival or DFS. Tumor differentiation appears to be more important in determining prognosis. Pancreatic neuroendocrine tumors (PNET) are uncommon, with an annual incidence of 2.2 per 1,000,000, based on the 2000 US population data from the Surveillance, Epidemiology, and End Results database, with men

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder characterized by skin abnormalities that appear in infancy, skeletal abnormalities, juvenile cataracts and other manifestations of premature aging, and a predisposition to malignancy. The diagnosis is made on clinical grounds as no consistent laboratory test has been identified. Chromosome studies have been reported for only three patients with RTS and in two of these three, trisomy 8 mosaicism was found. We performed a variety of cytogenetic and molecular genetic studies on two siblings with RTS and on their phenotypically normal parents. Two chromosomally abnormal clones involving either trisomy 8 or i(8q) were found in both patients with RTS. These clones were present in vivo, as they were seen in interphase buccal smears and lymphocytes from unstimulated preparations using both conventional cytogenetic studies and fluorescence in situ hybridization (FISH) with a centromere probe for chromosome 8. These results suggest that RTS is associated with in vivo clonal chromosomal rearrangements causing an acquired somatic mosaicism.

The glucagonoma syndrome is a rare disorder characterized by weight loss, necrolytic migratory erythema (NME), diabetes, stomatitis, and diarrhea. We identified 21 patients with the glucagonoma syndrome evaluated at the Mayo Clinic from 1975 to 1991. Although NME and diabetes help identify patients with glucagonomas, other manifestations of malignant disease often lead to the diagnosis. If the diagnosis is made after the tumor is metastatic, the potential for cure is limited. The most common presenting symptoms of the glucagonoma syndrome were weight loss (71%), NME (67%), diabetes mellitus (38%), cheilosis or stomatitis (29%), and diarrhea (29%). Although only 8 of the 21 patients had diabetes at presentation, diabetes eventually developed in 16 patients, 75% of whom required insulin therapy. Symptoms other than NME or diabetes mellitus led to the diagnosis of an islet cell tumor in 7 patients. The combination of NME and diabetes mellitus led to a more rapid diagnosis (7 months) than either symptom alone (4 years). Ten patients had diabetes mellitus before the onset of NME. No patients had NME clearly preceding diabetes mellitus. Increased levels of secondary hormones, such as gastrin (4 patients), vasoactive intestinal peptide (1 patient), serotonin (5 patients), insulin (6 patients, clinically significant in 1 only), human pancreatic polypeptide (2 patients), calcitonin (2 patients) and adrenocorticotropic hormone (2 patients), contributed to clinical symptoms leading to the diagnosis of an islet cell tumor before the onset of the full glucagonoma syndrome in 2 patients. All patients had metastatic disease at presentation. Surgical debulking, chemotherapy, somatostatin, and hepatic artery embolization offered palliation of NME, diabetes, weight loss, and diarrhea. Despite the malignant potential of the glucagonomas, only 9 of 21 patients had tumor-related deaths, occurring an average of 4.91 years after diagnosis. Twelve patients were still alive, with an average age follow-up of 3.67 years.

e14579 Background: Octreotide LAR is indicated for treatment of the malignant carcinoid syndrome, and has been studied at doses of 10-30mg intramuscularly every 4 weeks. It has also been proven to delay time to progression of metastatic midgut carcinoid tumors at a dose of 30mg every 4 weeks. In clinical practice, higher doses are often prescribed for patients who experience refractory carcinoid syndrome (flushing and/or diarrhea) or tumor growth while on the maximal labeled dose. We performed a retrospective, longitudinal review of octreotide LAR administration at a tertiary institution to determine the frequency of ‘above-label’ dosing and outcomes. Methods: A retrospective chart-review was performed using a database of patients with metastatic small-bowel carcinoid tumors treated at the Moffitt Cancer Center between the years 2000 and 2010. Data included the maximal dose of octreotide LAR administered, reasons for change in dose or frequency (above the labeled dose of 30mg every 4 weeks), and clinical responses to dose change. Results: 337 patients were considered evaluable, among whom 99 patients (27%) underwent at least one increase in dose or frequency of octreotide-LAR above the standard labeled dose. The most common maximal doses were 40mg every 4 weeks (37 patients), 60mg every 4 weeks (34 patients), and 30mg every 3 weeks (17 patients). The indications for dose increase were worsening carcinoid syndrome (60 patients), radiographic progression (33 patients) and rising urine 5-HIAA (6 patients). Among patients whose doses were increased for refractory carcinoid syndrome, 62% experienced improvement in diarrhea and 56% experienced improvement in flushing. Conclusions: In clinical practice, octreotide LAR is commonly prescribed in doses or schedules above the labled dose and frequency. Patients with refractory carcinoid syndrome appear to experience a clinical benefit from the change. Prospective data is needed to evaluate this strategy.

Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carcinoid and pancreatic endocrine tumors. A phase III, randomized, placebo-controlled trial has now demonstrated that octreotide long-acting repeatable (LAR) 30 mg can significantly prolong time to tumor progression among patients with metastatic midgut NETs regardless of functional status, chromogranin A level or age. In addition to significantly lengthening time to tumor progression in the overall study population, subset analysis suggests that patients with low tumor burden are most likely to experience disease stabilization with octreotide LAR 30 mg, supporting the early use of octreotide LAR in patients with metastatic disease. Further research efforts are underway to evaluate the use of somatostatin analogs as antiproliferative agents in other types of gastroenteropancreatic-NETs. Ongoing studies are also evaluating novel somatostatin analogs and somatostatin analogs in combination with other anti-tumor therapies.