Table 1.

Scientific questions on diagnosis and prediction of neuroendocrine liver metastases.

Questions	Sub-questions
Should patients with low Ki67 index be followed up for the detection of liver metastases?
	In patients with a primary NET, what is the predictive value of Ki67 index, mitotic count, or tumor grading, obtained from the primary tumor, in predicting the development of liver metastases?
Should genetic signatures and the presence of circulating tumor cells be used in the prediction of liver metastases and to inform treatment decisions?
	In patients with a primary NET, what is the predictive value of genetic signatures obtained from the primary tumor, in predicting the development of liver metastases?
	In patients with a primary NET, what is the predictive value of circulating tumor cells obtained from the primary tumor, in predicting the development of liver metastases?
	In patients with a primary NET, should genetic signatures be used in the treatment decision (surgery, locally ablative techniques, liver-directed techniques, peptide receptor radionuclide treatment, chemotherapy, targeted therapy, and biotherapy)?
	In patients with a primary NET, should the presence of circulating tumor cells be used in the treatment decision (surgery, locally ablative techniques, liver-directed techniques, peptide receptor radionuclide treatment, chemotherapy, targeted therapy, and biotherapy)?
Which biochemical markers should be used for detection and post treatment follow-up of liver metastases?
	In patients with a primary NET, what is the diagnostic accuracy of the available biochemical markers (eg, chromogranin A and B, Serotonin, neuron-specific-enolase (NSE), tumor specific hormones) in detecting liver metastases?
	In patients receiving a liver resection, what is the diagnostic accuracy of the available biochemical markers (eg, chromogranin A and B, serotonin, NSE, tumor specific hormones) obtained during follow-up, in detecting recurrent disease or disease progression?
Which morphological imaging modality should be used to assess resectability of liver metastases with a curative intent?
	In patients with NET liver metastases, what is the diagnostic accuracy of different morphological imaging modalities (US, CT, MRI) in identifying liver lesions and extrahepatic disease?
	In patients with NET liver metastases, what is the diagnostic accuracy of different morphological imaging modalities (US, CT, 3D-CT, MRI) in detecting vascular and biliary invasion, in order to assess resectability (R0/R1)?
Which functional imaging modality should be used to assess resectability of liver metastases with a curative intent?
	In patients with NET liver metastases, what is the diagnostic accuracy of different functional imaging modalities (octreoscan, DOTA-SSTR-PET/CT, F-18 FDG-PET/CT, DOPA PET, etc) in identifying liver lesions?
	In patients with NET liver metastases, what is the diagnostic accuracy of different functional imaging modalities (octreoscan, DOTA-SSTR-PET/CT, F-18 FDG-PET/CT, DOPA PET, other) in detecting extra-hepatic disease?
Do we need a biopsy of both the primary and liver metastases for the treatment decision of liver metastases?
	In patients with a primary NET and synchronous liver metastases, what is the agreement between the biopsy of the primary and the liver metastases with regards to tumor grading?
	In patients with metachronous liver metastases, what is the agreement between the biopsy of the primary and the liver metastases with regards to tumor grading?
	In patients with liver metastases, what is the agreement between single vs multiple liver biopsies with regards to tumor grading?
	In patients with NET liver metastases, do we need additional biopsies from normal parenchyma to detect micrometastases?