Introduction Neuroendocrine tumors (NETs) frequently metastasize to the liver. Surgical debulking offers symptomatic relief and improved survival. However, the frequent presence of multifocal, bilobar disease and high recurrence rates introduce doubt regarding their optimal management. Parenchyma-sparing debulking (PSD) procedures (ablation, enucleation, wedge resections) may offer similar survival improvements as resection, while minimizing morbidity and preserving functional liver tissue. Methods Clinicopathologic variables from 228 patients with small bowel (SBNETs) or pancreatic NETs (PNETs) managed surgically at one institution were collected. Liver-directed surgery (LDS) was carried out when significant debulking was deemed feasible. Survival was assessed using the Kaplan-Meier method. Results 108 PNET and SBNET patients underwent LDS with primarily PSD procedures. Nearly two-thirds of patients achieved 70% cytoreduction and 84% had concurrent resection of their primary. The median number of lesions treated was 6 (range 1–36). There were no 30-day operative mortalities. The 30-day major complication rate was 13.0%. Patients that achieved 70% cytoreduction enjoyed improved progression free (median 3.2 years) and overall survival (median not reached). Conclusion PSD procedures are safe and can achieve significant cytoreduction, which is associated with improved survival. Lowering the debulking target threshold to 70% may benefit NET patients by increasing eligibility for cytoreduction.

Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs(PNETs) that correlated with high level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A knockdown cells although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients.

Medullary thyroid cancer (MTC) is an aggressive form of thyroid cancer, which occurs in both heritable and sporadic forms. Discovery that mutations in the RET protooncogene predispose to familial cases of this disease has allowed for presymptomatic identification of gene carriers and prophylactic surgery to improve the prognosis of these patients. A significant number of patients with the sporadic type of MTC and even with familial disease, still present with nodal or distant metastases, making surgical cure difficult. Over the past several decades, many different types of therapy for metastatic disease have been attempted, with limited success. Improved understanding of the molecular defects and pathways involved in both familial and sporadic MTC has resulted in new hope for these patients with the development of drugs targeting the specific alterations responsible. This new era of targeted therapy with kinase inhibitors represents a significant step forward from previous trials of chemotherapy, radiotherapy, and hormonal therapy. Although much progress has been made, additional agents and strategies are needed to achieve durable, long-term responses in patients with metastatic MTC. This article reviews the history and results of medical management for metastatic MTC from the early 1970s up until the present day.

Background Ligands binding the somatostatin receptor type 2 (SSTR2) are useful for imaging and treatment of neuroendocrine tumors (NETs), but not all tumors express high levels of these receptors. The aim of this study was to evaluate gene expression of new therapeutic targets in NETs relative to SSTR2. Methods RNA was extracted from 103 primary small bowel (SBNET) and pancreatic neuroendocrine tumors (PNET), matched normal tissue, and 123 metastases. Expression of 12 candidate genes was measured by quantitative PCR normalized to internal controls; candidate gene expression was compared to SSTR2. Results Relative to normal tissue, primary NET expression of SSTR2, GPR98, BRS3, GIPR, GRM1, and OPRK1 were increased by 3, 8, 13, 13, 17, and 20-fold, respectively. Similar changes were found in metastases. While most candidate genes showed lower absolute expression than SSTR2, absolute GIPR expression was closest to SSTR2 (mean dCT 3.6 vs. 2.7, p=0.01). Absolute OPRK1 and OXTR expression varied significantly by primary tumor type and was close to SSTR2 in SBNETs but not PNETs. Conclusions Compared to the current treatment standard SSTR2, GIPR has only somewhat lower absolute gene expression in tumor tissue but much lower expression in normal tissue, making it a promising new target for NET imaging and therapy.

Rectal surgery is associated with high complication rates, but tools to prospectively define surgical risk are lacking. Improved preoperative risk assessment could better inform patients and refine decision making by surgeons. Our objective was to develop a validated model for proctectomy risk prediction. We reviewed non-emergent ACS-NSQIP proctectomy data from 2005-2011 (n=13,385). Logistic regression identified variables available prior to surgery showing independent association with 30-day morbidity in 2010-2011 (n=5,570). The resulting risk model's discrimination and calibration were tested against the NSQIP-supplied morbidity model, and performance was validated against independent 2005-2009 data. Overall morbidity for proctectomy in 2010-2011 was 40.2%; significantly higher than the 23.0% rate predicted by the NSQIP-provided general and vascular surgery risk model. Frequent complications included bleeding (16.3%), superficial infection (9.2%), and sepsis (7.4%). Our novel model incorporating 17 preoperative variables provided better discrimination and calibration (p<0.05) than the NSQIP model, and was validated against 2005-2009 data. A web-based calculator makes this new model available for prospective risk assessment. We conclude that the NSQIP-supplied risk model underestimates proctectomy morbidity and that this new, validated risk model and risk-prediction tool (http://myweb.uiowa.edu/sksherman) may allow clinicians to counsel patients with accurate risk estimates using data available in the preoperative setting.

IMPORTANCE Unregulated drug prices increase cancer therapy costs. After induction chemotherapy, patients with metastatic colon cancer can receive maintenance capecitabine and bevacizumab therapy based on improved progression-free survival, but whether this treatment's cost justifies its benefits has not been evaluated in the United States. OBJECTIVE This study sought to determine the influence of capecitabine and bevacizumab drug prices on cost-effectiveness from a Medicare payer's perspective. DESIGN, SETTING, AND PARTICIPANTS The incremental cost-effectiveness of capecitabine and bevacizumab maintenance therapy was determined with a Markov model using a quality-of-life penalty based on outcomes data from the CAIRO phase 3 randomized clinical trial (RCT), which included 558 adults in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. The outcomes were modeled using Markov chains to account for patients who had treatment complications or cancer progression. Transition probabilities between patient states were determined, and each state's costs were determined using US Medicare data on payments for capecitabine and bevacizumab treatment. Deterministic and probabilistic sensitivity analyses identified factors affecting cost-effectiveness. MAIN OUTCOMES AND MEASURES Life-years gained were adjusted using CAIRO3 RCT quality-of-life data to determine quality-adjusted life-years (QALYs). The primary end point was the incremental cost-effectiveness ratio, representing incremental costs per QALY gained using a capecitabine and bevacizumab maintenance regimen compared with observation alone. RESULTS Markov model estimated survival and complication outcomes closely matched those reported in the CAIRO3 RCT, which included 558 adults (n = 197 women, n = 361 men; median age, 64 and 63 years for patients in the observation and maintenance therapy groups, respectively) in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. Incremental costs for a 3-week maintenance chemotherapy cycle were $6601 per patient. After 29 model iterations corresponding to 60 months of follow-up, mean per-patient costs were $105 239 for maintenance therapy and $21.10 for observation. Mean QALYs accrued were 1.34 for maintenance therapy and 1.20 for observation. The incremental cost-effectiveness ratio favored maintenance treatment, at an incremental cost of $725 601 per QALY. The unadjusted ratio was $438 394 per life-year. Sensitivity analyses revealed that cost-effectiveness varied with changes in drug costs. To achieve an incremental cost-effectiveness ratio of less than $59 039 (median US household income) per unadjusted life-year would require capecitabine and bevacizumab drug costs to be reduced from $6173 (current cost) to $452 per 3-week chemotherapy cycle. CONCLUSIONS AND RELEVANCE Antineoplastic therapy is expensive for payers and society. The price of capecitabine and bevacizumab mainten...

Introduction Somatostatin receptor scintigraphy (SRS; Octreoscan) is used in neuroendocrine tumors to locate the primary tumor site and delineate extent of disease. SRS has decreased sensitivity for small bowel neuroendocrine tumors (SBNETs). The reasons for SRS nonlocalization are not clear. We sought to determine factors that correlate with successful primary tumor localization by SRS in patients with resected SBNETs, and also identify factors that confound interpretation of SRS reports. Methods Records of patients with resected SBNETs were reviewed for SRS results, tumor size, multifocality, N, and M status. Somatostatin receptor 2 (SSTR2) expression was analyzed in resected tumors by quantitative PCR. SRS reports were reviewed and categorized as localizing the primary tumor or not. A nuclear medicine physician independently reviewed available images. Results Of 37 patients with preoperative SRS, the primary tumor was localized in 37%. Of all the factors tested, only small tumor size correlated significantly with SRS non-localization. Overexpression of SSTR2 was not significantly different between tumors that were or were not localized by SRS, regardless of tumor size. There were three instances where the SRS report did not agree with the nuclear medicine physician's interpretation as to whether SRS localized the primary tumor. In each case, uptake in mesenteric adenopathy was a confounding factor. Conclusions SBNETs less than 2 cm are most likely to be missed by SRS. SSTR2 expression did not correlate with SRS non-localization of the primary tumor. Uptake in mesenteric nodes may help indicate an SBNET primary, but can also interfere with its visualization within the small bowel.

Introduction The primary tumor site is unknown prior to treatment in approximately 20% of small bowel (SBNET) and pancreatic (PNET) neuroendocrine tumors despite extensive workup. It can be difficult to discern a PNET from an SBNET on hematoxylin and eosin (H&E) stains, and thus more focused diagnostic tests are required. Immunohistochemistry (IHC) and gene expression profiling are two methods used to identify the tissue of origin from biopsied metastases. Methods Tissue microarrays were created from surgical specimens and stained with up to 7 antibodies used in the NET-specific IHC algorithm. Expression of 4 genes for differentiating between PNETs and SBNETs was determined by qPCR and then used in a previously validated gene expression classifier (GEC) algorithm designed to determine the primary site from gastrointestinal (GI) NET metastases. Results The accuracy of the IHC algorithm in identifying the primary tumor site from a set of 37 metastases was 89.1%, with only 1 incorrect call. Three other samples were indeterminate due to pan-negative staining. The GEC’s accuracy in a set of 136 metastases was 94.1%. It identified the primary tumor site in all cases where IHC failed. Conclusion Performing IHC, followed by GEC for indeterminate cases, accurately identifies the primary site in SBNET and PNET metastases in virtually all patients.