Liver Metastases Arising from Well-Differentiated Pancreatic Endocrine Neoplasms Demonstrate Increased VEGF-C Expression

Hansel, Donna E.; Rahman, Asifur; Hermans, John J.; Krijger, Ronald R. de; Ashfaq, Raheela; Yeo, Charles J.; Cameron, John L.; Maitra, Anirban

doi:10.1097/01.mp.0000077416.68489.50

Cited by 58 publications

(36 citation statements)

References 27 publications

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“…In our series, VEGF-C was variably expressed in PENs, and VEGF-C expression was correlated to malignant clinical behavior. A similar variable expression of VEGF-C in PENs has recently been reported by another group (30). Taken together with our observation that LVD is unrelated to lymph node metastasis, these data point to the requirement for a second element for the development of lymphogenous metastases, namely, activities of VEGF-C that are unrelated to lymphangiogenesis.…”

Section: Discussionsupporting

confidence: 71%

Lymphatic Vessel Density and Vascular Endothelial Growth Factor-C Expression Correlate with Malignant Behavior in Human Pancreatic Endocrine Tumors

Rubbia‐Brandt

Terris²,

Giostra

et al. 2004

Clinical Cancer Research

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Metastatic dissemination of tumor cells to regional lymph nodes is a common early feature of many human cancers including pancreatic adenocarcinoma. In contrast, lymph node metastasis is more variably observed in pancreatic endocrine tumors. The objective of this study was to assess the lymphatic system of human pancreatic endocrine tumors and correlate this to clinical behavior. Immunohistochemistry was performed using antibodies to two recently identified markers of lymphatic endothelium, namely, LYVE-1 and podoplanin, and to the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C. As has been reported previously, we observed that in the normal pancreas, islets of Langerhans are devoid of intra-islet lymphatics, but that lymphatics are present in connective tissue in association with ducts and blood vessels. We found that both benign and malignant pancreatic endocrine tumors contain intratumoral lymphatic vessels. Lymphatic vessel density was related to the size of the tumor in benign tumors and to the presence of liver metastasis but not to lymph node metastasis in malignant tumors. VEGF-C was expressed in tumor cells: 4 of 19 (21%) benign tumors were positive, whereas 6 of 9 (67%) borderline tumors and 9 of 11 (82%) carcinomas were positive. These findings strongly suggest that lymphangiogenesis occurs in pancreatic endocrine tumors and that lymphatic invasion and the development of metastases are associated with VEGF-C expression.

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Section: Discussionsupporting

confidence: 71%

Lymphatic Vessel Density and Vascular Endothelial Growth Factor-C Expression Correlate with Malignant Behavior in Human Pancreatic Endocrine Tumors

Rubbia‐Brandt

Terris²,

Giostra

et al. 2004

Clinical Cancer Research

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“…6 Another confirmed partial response was observed in a patient with heavily pretreated metastatic pancreatic islet cell carcinoma with liver metastases. High expression of EGFR, phosphorylated EGFR, extracellular signal-regulated kinase, and phosphorylated extracellular signal-regulated kinase as well as VEGF-C and its receptors (VEGFR-2/VEGFR-3) has been recently reported in neuroendocrine tumors, suggesting involvement of these molecular mechanisms in tumor growth and metastasis and therefore representing appropriate targets (46,47). Lastly, a third patient who achieved a confirmed partial response had metastatic small bowel adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors

Durán

Hotte

Hirte

et al. 2007

Clinical Cancer Research

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Purpose: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies.This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. Experimental Design: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. Results: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100 %) followed by diarrhea (15 patients; 88 %), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. Conclusions: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.

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“…There was a limited VEGF-A protein expression in both the primary tumor (n 5 19) and the liver metastases (n 5 7). Although VEGF-C expression was limited in primary tumors, liver metastases did show high expression (30). In another study, expression of all VEGF subtypes was quantified with real-time polymerase chain reaction in 25 patients with ileal NETs.…”

Section: Discussionmentioning

confidence: 99%

Everolimus Reduces ⁸⁹Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors

et al. 2014

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Everolimus increases progression-free survival in patients with advanced neuroendocrine tumors (NETs). Currently, no biomarkers are available for early selection of patients who will benefit from everolimus. Everolimus can reduce vascular endothelial growth factor A (VEGF-A) production by tumor cells. Therefore, we aimed to investigate the effect of everolimus on tumor uptake of the radioactive-labeled VEGF-A antibody bevacizumab with PET in NET patients. Methods: Patients with advanced progressive well-differentiated NETs underwent 89 Zr-bevacizumab PET scans before and at 2 and 12 wk during everolimus treatment. 89 Zr-bevacizumab uptake was quantified by the maximum standardized uptake value (SUV max ). Tumor response and the percentage change in the sum of target lesion diameters were determined according to Response Evaluation Criteria in Solid Tumors 1.1 on CT (3 monthly). Results: In 4 of the 14 patients entered, no tumor lesions were visualized with 89 Zr-bevacizumab PET. In the remaining patients, 19% of tumor lesions 1 cm or greater known by CT were visualized. Tumor SUV max decreased during everolimus treatment, with a median of −7% at 2 wk (P 5 0.09) and a median of −35% at 12 wk (P , 0.001). The difference in SUV max at 2 and 12 wk with respect to SUV max at baseline correlated with percentage change on CT at 6 mo (r 2 5 0.51, P , 0.05, and r 2 5 0.61, P , 0.01, respectively). Conclusion: This study demonstrates variable 89 Zr-bevacizumab PET tumor uptake in NET patients. 89 Zr-bevacizumab tumor uptake diminished during everolimus treatment. Serial 89 Zr-bevacizumab PET might be useful as an early predictive biomarker of anti-VEGFdirected treatment in NET patients.

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Liver Metastases Arising from Well-Differentiated Pancreatic Endocrine Neoplasms Demonstrate Increased VEGF-C Expression

Cited by 58 publications

References 27 publications

Lymphatic Vessel Density and Vascular Endothelial Growth Factor-C Expression Correlate with Malignant Behavior in Human Pancreatic Endocrine Tumors

Lymphatic Vessel Density and Vascular Endothelial Growth Factor-C Expression Correlate with Malignant Behavior in Human Pancreatic Endocrine Tumors

Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors

Everolimus Reduces ⁸⁹Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors

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Liver Metastases Arising from Well-Differentiated Pancreatic Endocrine Neoplasms Demonstrate Increased VEGF-C Expression

Cited by 58 publications

References 27 publications

Lymphatic Vessel Density and Vascular Endothelial Growth Factor-C Expression Correlate with Malignant Behavior in Human Pancreatic Endocrine Tumors

Lymphatic Vessel Density and Vascular Endothelial Growth Factor-C Expression Correlate with Malignant Behavior in Human Pancreatic Endocrine Tumors

Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors

Everolimus Reduces 89Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors

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Product

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Everolimus Reduces ⁸⁹Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors