A single institution's experience with surgical cytoreduction of stage IV, well-differentiated, small bowel neuroendocrine tumors.

BACKGROUND: Well-differentiated neuroendocrine tumors (NETs) of the gastrointestinal tract are rare, slow-growing neoplasms. Clinical outcomes in a group of stage IV, well-differentiated patients with NETs with small bowel primaries undergoing cytoreductive surgery and multidisciplinary management at a single center were evaluated. STUDY DESIGN: The charts of 189 consecutive patients who underwent surgical cytoreduction for their small bowel NETs were reviewed. Information on the extent of disease, complications, and Kaplan-Meier survival were collected from the patient records. RESULTS: A total of 189 patients underwent 229 cytoreductive operations. Ten percent of patients required an intraoperative blood transfusion and 3% (6 of 229) had other intraoperative complications. For all 229 procedures performed, mean (± SD) stay in the ICU was 4 ± 3 days and in the hospital was 9 ± 10 days. Before discharge, 51% of patients had no postoperative complications and 39% of patients had only minor complications. In a 30-day follow-up period from discharge, 85% of patients had no additional complications and 13% had only minor complications. The 30-day postoperative death rate was 3% (5 of 189). Mean survival from histologic diagnosis of NET was 236 months. The 5-, 10-, and 20-year Kaplan-Meier survival rates from diagnosis were 87%, 77%, and 41%, respectively. CONCLUSIONS: Cytoreductive surgery in patients with well-differentiated midgut NETs has low mortality and complication rates and is associated with prolonged survival. We believe that cytoreductive surgery is a key component in the care of patients with NETs.

A study of pipeline drugs in neuroendocrine tumors.

PURPOSE: Inhibition of neovessel development can stabilize tumor growth. A rapid in vitro method that can evaluate the effectiveness of anti-angiogenic drugs would aid in drug development. We tested a series of investigational agents to determine their ability to inhibit angiogenesis in our in vitro human angiogenesis model. METHODS: A total of 74 neuroendocrine tumors were tested with five therapeutic agents for anti-angiogenic activity. Angiogenic responses were assessed visually and the percent of tumor explants that developed an angiogenic response was determined. The extent of neovessel growth was rated using a validated semi-quantitative visual scale. Analysis of variance was used to compare treatment outcome results to control values for these angiogenic parameters. RESULTS: Vatalanib (2 × 10(-5) M) and patupilone (1 × 10(-8) M) were highly effective inhibitors of human tumor angiogenesis (mean overall angiogenic response for drug versus control 1.3 vs. 5.9 and 0.2 vs. 5.2, respectively) and were statistically significant at p <0.0001. Imatinib (2.5 × 10(-6) M) and everolimus (1 × 10(-8) M) were also effective (mean overall angiogenic response for drug versus control 2.2 vs. 5.9 and 4.5 vs. 5.9, respectively), and these were also statistically significant at p <0.0001. Pasireotide (1 × 10(-8) M) had no effect on angiogenesis (mean overall angiogenic response for drug vs. control 5.5 vs. 5.2). CONCLUSIONS: Significant differences in angiogenic response to test drugs were noted in this neuroendocrine patient population. In vitro screening of a large series of fresh human tumors may be a cost-effective way to select drugs for continued clinical development.

Surgical treatment of advanced-stage carcinoid tumors: lessons learned.

OBJECTIVE: To evaluate clinical outcomes in a large group of advanced-stage carcinoid patients (stage IV) following multimodal surgical therapy. SUMMARY BACKGROUND DATA: Patients with advanced-stage carcinoid have traditionally experienced poor 5-year survival (18%-30%). Few recent series have evaluated a large number of patients treated with aggressive surgical rescue therapy. METHODS: This single-center retrospective review analyzes the records of 82 consecutive carcinoid patients treated by the same 2 surgeons, from August 1998 through August 2004 with a 3- to 72-month follow-up. RESULTS: Surprisingly, one third of 26 (32%) patients were found to have intestinal obstructions; 10 being moribund at presentation. Mesenteric encasement with intestinal ischemia was successfully relieved in 10 of 12 cases. Five of eighty-two "terminal" patients were rendered free of macroscopic disease. Karnofsky performance scores improved from 65 to 85 (P < 0.0001). Two- and four-year survival for patients with no or unilateral liver metastases (n = 23) was 89%, while 2- and 4-year survival for patients with bilateral liver disease (n = 59) was 68% and 52% (P = 0.072), respectively. CONCLUSION: We think that all patients with advanced-stage carcinoid should be evaluated for possible multimodal surgical therapy. Primary tumors should be resected, even in the presence of distant metastases to prevent future intestinal obstruction. The "wait and see" method of management of this slow-growing cancer no longer has merit. We offer an algorithm for the surgical evaluation and management of these patients.

Development of a novel in vitro human tissue-based angiogenesis assay to evaluate the effect of antiangiogenic drugs.

OBJECTIVE: To describe a novel in vitro human tissue-based angiogenic model that can predict an individual tumor's response to antiangiogenic drugs. SUMMARY BACKGROUND DATA: A number of in vitro and in vivo angiogenesis assays exist, but they do not provide potentially useful information for the treatment of an individual patient. Clonogenic assays have been used to evaluate the response of an individual's tumor to antineoplastic agents, but these tumor fragments are cultured in an environment that does not lead to neovessel growth. The authors have previously demonstrated that human vein disks or human tumor xenograft fragments incorporated into a 0.3% fibrin-thrombin clot will develop angiogenic vessel growth from the cut edge of the vessel disk or xenograft fragment. METHODS: Fresh human tumor or normal tissue disks (2 x 1 mm) from fresh surgical specimens were incorporated into fibrin-thrombin clots overlain with nutrient medium containing either 20% fetal bovine serum alone or in combination with Epothilone B, a tubulin inhibitor with antiangiogenic properties. Tissue disks were visually assessed over time to determine the percentage of wells that developed an angiogenic response. Neovessel growth, density, and length were graded at intervals using a semiquantitative visual neovessel growth-rating scheme (angiogenic index, 0-16 scale) devised in the authors' laboratory. RESULTS: Epothilone B treatment at doses of 10-6 mol/L and 10-8 mol/L decreased the number of wells that developed an invasive angiogenic response and limited the development of vessels that invaded the matrix. At these doses, Epothilone B also caused regression of vessels in wells that had been allowed to develop an angiogenic response. Treatment of tumors or normal tissues with Epothilone B at doses less than 10-8 mol/L was ineffective. CONCLUSIONS: Epothilone B may be an effective antiangiogenic agent in a variety of tumor types. The authors speculate that this in vitro model might provide useful information to the clinician on the effect of specific antiangiogenic agents on individual tumors. This may be particularly useful in patients with tumors that, as a group, are unresponsive to treatment with antineoplastic agents.