Comparison of the utility of Cocaine- and Amphetamine-Regulated Transcript (CART), chromogranin A, and chromogranin B in neuroendocrine tumor diagnosis and assessment of disease progression.

CONTEXT: Prognosis in patients with neuroendocrine tumors (NETs) is often poor, frequently reflecting delayed diagnosis. Hence, accurate and practical NET markers are needed. Cocaine- and amphetamine-regulated transcript (CART) peptide is a potential novel NET marker. DESIGN AND PARTICIPANTS: Circulating levels of CART peptide and the established NET markers chromogranin A (CgA) and chromogranin B (CgB) were measured using RIA in 353 patients with NET (normal renal function) and in controls. Clinical data were collected retrospectively. MAIN OUTCOME MEASURE(S): The comparative and combined utility of CART, CgA, and CgB for diagnosis and assessment of disease progression was measured in different NET subtypes. RESULTS: CgA and CgB in combination improved diagnostic accuracy in patients with gut NETs, nongastroenteropancreatic NETs, and NETs with an unknown primary origin compared with each biomarker alone. Measuring CART did not further improve diagnosis in these NET subtypes. For pancreatic NETs, CgB was superior to CgA and CART in detecting stable disease (P < .007), whereas CgA and CART in combination were most effective in identifying progressive disease. In phaeochromocytomas/paragangliomas (PCC/PGL), CART was the most useful biomarker for identifying stable (P < .001) and progressive (P = .001) disease. Consistent with this, plasma CART decreased following PCC/PGL tumor resection, remaining low in all patients in remission, but increasing in those with progressive disease. CONCLUSIONS: CART is a useful marker for identifying progressive pancreatic NETs. CART is superior to CgA and CgB in detecting stable and progressive PCC/PGLs, and may have a role as a surveillance marker for PCC/PGL patients.

Role of Ki-67 proliferation index in the assessment of patients with neuroendocrine neoplasias regarding the stage of disease.

BACKGROUND: Neuroendocrine neoplasias (NEN) of the gastroenteropancreatic (GEP) system frequently present with metastatic deposits. The proliferation marker Ki-67 is used for diagnosis and to assess the prognosis of disease. The aim of our study was to evaluate the usefulness of Ki-67 % in the assessment of NEN patients with regard to their disease stage in clinical practice. Additionally, a comparative analysis of Ki-67 levels among different sites of disease was performed. METHODS: This retrospective study included patients with GEP NEN referred to our center from 2010 to 2012. The NEN diagnosis was confirmed by standard histopathology. Ki-67 immunohistochemistry was done on paraffin-embedded sections using an automated Leica immunohistochemistry machine. NEN grading was carried out according to European Neuroendocrine Tumor Society recommendations (low grade [G1] to intermediate grade [G2], well to moderately differentiated neuroendocrine neoplasms; high-grade [G3], moderately to poorly differentiated neuroendocrine neoplasms). Results of tumor staging and grading were correlated. In a subgroup of cases, comparative analysis of Ki-67 levels in different sites of disease was carried out. RESULTS: One hundred sixty-one GEP NEN patients were included in the study. Metastatic disease was seen in 46.1 % (53/115) of G1 tumors, 77.8 % (28/36) of G2 tumors, and 100 % of (10/10) G3 tumors (p = 0.0002). When stratified according to primary tumor site, metastatic disease was documented in 42.9 % (36/84) of patients with pancreatic NEN and in 91.9 % (34/37) of those with small intestinal primary. Stage IV metastatic disease was present in 27.8 % (32/115) and 72.2 % (26/36) of the G1 and G2 tumors, respectively, and in 90 % (9/10) of the G3 tumors. Assessment of the Ki-67 index for a subset of cases at metastatic sites as well as the primary tumor site showed discrepancies in 35.3 % cases. In 7/9 (77.8 %) patients with liver metastases, Ki-67 % was higher in the liver lesions than in the primary tumor. CONCLUSIONS: Patients with GEP NEN exhibiting a high Ki-67 proliferation index present with metastatic disease in the vast majority of cases. Depending upon the primary tumor site, metastases are to be expected also in tumors with low Ki-67 %, although they are considered less aggressive. Different disease sites may express heterogeneous Ki-67 levels.

Clinical trial: switch to combined mycophenolate mofetil and minimal dose calcineurin inhibitor in stable liver transplant patients--assessment of renal and allograft function, cardiovascular risk factors and immune monitoring.

BACKGROUND: Calcineurin inhibitor (CNI)-related nephrotoxicity significantly contributes to chronic renal failure after liver transplantation. METHODS: In this prospective study, liver transplantation patients with renal dysfunction were randomized either to receive mycophenolate mofetil (MMF) followed by stepwise reduction of CNI with defined minimal CNI-trough levels (MMF group), or to continue their maintenance CNI dose (control group). Immune monitoring was performed in a subgroup of the patients. RESULTS: In the MMF group (n = 50), renal function assessed by serum creatinine improved >10% in 62% of patients, was stable in 36% and deteriorated >10% in 2% after 12 months compared with baseline values. Mean serum creatinine levels (+/- s.d.) significantly decreased from 1.90 +/- 0.44 mg/dL to 1.61 +/- 0.39 mg/dL and the corresponding calculated glomerular filtration rate significantly increased from 38.8 +/- 9.6 mL/min/1.73 m(2) to 47.0 +/- 11.8 mL/min/1.73 m(2) over a 12-month follow-up period. Blood pressure and levels of liver enzymes significantly decreased. In the control group (n = 25), there were no significant changes with respect to the investigated parameters. The MMF group had significantly lower numbers of circulating cytotoxic T cells compared with the controls; whereas regulatory T cells significantly increased. CONCLUSION: Combined MMF and minimal dose CNI therapy after liver transplantation is nephroprotective and may promote allograft tolerance.