Neurokinin A levels predict survival in patients with stage IV well differentiated small bowel neuroendocrine neoplasms.

BACKGROUND: Recent European investigations have shown that persistently elevated (>50 pg/mL) plasma neurokinin A levels are associated with poor short-term survival in patients with midgut neuroendocrine neoplasms. We hypothesized that American patients with persistently elevated plasma neurokinin A levels (>50 pg/mL) will also have a poor short-term survival. METHODS: Serial plasma neurokinin A levels were collected from the charts of 180 patients with metastatic midgut neuroendocrine neoplasms. Patients were grouped according to their plasma neurokinin A values, and survival rates were calculated. Group 1 had plasma neurokinin A levels <50 pg/mL. Group 2 at one point had plasma neurokinin A levels >50 pg/mL, but are currently <50 pg/mL. Group 3 had plasma neurokinin A values consistently >50 pg/mL. RESULTS: Group 1 patients (n = 143) have not reached their median survival and have a 24-month survival of 93%. Thirteen of 14 (93%) group 2 patients are currently alive. Group 3 patients (n = 23) had a median survival of 20 months and a 24-month survival of 48%. CONCLUSION: Patients with midgut neuroendocrine neoplasms who have serial plasma neurokinin A levels <50 pg/mL have an excellent short-term prognosis, while patients with plasma neurokinin A levels >50 pg/mL have a poor short-term prognosis.

A prospective evaluation of the effect of chronic proton pump inhibitor use on plasma biomarker levels in humans.

OBJECTIVE: Proton pump inhibitors (PPIs) are used primarily to treat gastroesophageal reflux disease. Proton pump inhibitor-induced achlorhydria increases circulating gastrin and chromogranin A (CGA). Chromogranin is a widely used biomarker for the diagnosis and follow-up for gut-based neuroendocrine tumors (NETs). Proton pump inhibitor-induced increases in CGA or gastrin may falsely suggest the presence of a NET when none exists. Pancreastatin, a fragment of CGA, is also commonly used to diagnose and follow NETs. We hypothesized that chronic PPI use would increase circulating plasma gastrin, CGA, and pancreastatin levels. METHODS: Thirty patients who used PPIs for 6 months or more (mean ± SD duration, 3.1 ± 2.5 years) and a separate control group of 30 patients who never used antacid medications were prospectively evaluated with plasma gastrin, CGA, and pancreastatin determinations. RESULTS: Chronic PPI use resulted in significant increases in CGA (15.1 ± 11 vs 131 ± 207 ng/mL; P = 0.005) and significant increases in gastrin (34.8 ± 22.3 vs 167.8 ± 136.2 pg/mL; P = 0.001) compared to controls. In contrast, pancreastatin level in nonusers and chronic PPI users were identical (81.6 ± 36.4 vs 89.4 ± 43.4 pg/mL; P = 0.46). CONCLUSIONS: Pancreastatin levels do not change with chronic PPI use and normal pancreastatin levels may be used to distinguish between drug-induced changes in biomarkers and tumor-related increases in circulating biomarkers.

Validation of neurokinin a assays in the United States and Europe.

OBJECTIVES: International cooperative group trials require specific, sensitive biomarker assays that are validated between continents. Neurokinin A (NKA) has been shown to be a powerful independent predictor of a poor prognosis in well-differentiated midgut neuroendocrine tumors. We hypothesized that NKA concentrations of clinical specimens evaluated in NKA assays in the United States and the United Kingdom would be equivalent, even though assay techniques were significantly different. METHODS: Frozen clinical specimen aliquots were shipped from the United States to the United Kingdom (n = 67), and from United Kingdom to the United States (n = 50). In addition, spiked plasma standards and medium-spiked standards were exchanged. Samples from the United States were directly assayed in a radioimmunoassay, whereas the UK specimens were extracted, and the reconstituted specimens assayed in the radioimmunoassay. Neurokinin A values from the 2 studies were analyzed by regression analysis. RESULTS: The NKA values from the US and UK laboratories were essentially identical (United States to United Kingdom, r = 0.88, P < 0.0001; and United Kingdom to United States, r = 0.96, P < 0.0001). CONCLUSIONS: Validation of biomarker assays across continents will ensure that laboratory observations made by researchers are equivalent and that prediction of clinical outcomes based on these assays is also reliable.

Clinical value of monitoring plasma octreotide levels during chronic octreotide long-acting repeatable therapy in carcinoid patients.

OBJECTIVE: Octreotide is used to treat patients with neuroendocrine tumors. Previous reports show that octreotide long-acting repeatable (LAR) dose and patient body weight affect nadir plasma octreotide levels (approximately 1250, 2500, 5000, and 11,000 pg/mL for LAR doses of 10, 20, 30 and 60 mg/mo). However, plasma octreotide levels have decreased over time in patients receiving these doses of LAR. METHODS: From November 2004 until July 2007, trough plasma octreotide levels were determined in 86 patients on long-term octreotide LAR therapy at doses of 30, 60, and 120 mg/mo. Changes in plasma drug levels were analyzed over time using random effects models. RESULTS: Current plasma octreotide levels for octreotide LAR doses of 30, 60, and 120 mg/mo are approximately 2200, 5200, and 6500 pg/mL, respectively, representing a decrease of approximately 50% to 70% compared with previously reported plasma octreotide levels. The decreases in octreotide levels over time with the 30- and 60-mg/mo LAR doses are highly statistically significant (P = 0.0067, 0.0149, respectively). CONCLUSIONS: Current plasma octreotide values are significantly lower than previously reported for 30-, 60-, and 120-mg/mo LAR doses. Serial plasma octreotide value measurements should be used to determine if increasing symptoms or tumor growth are associated with suboptimal octreotide levels.

Effect of octreotide LAR dose and weight on octreotide blood levels in patients with neuroendocrine tumors.

OBJECTIVES: Octreotide long acting repeatable (LAR) is widely used for the control of symptoms of functional neuroendocrine tumors. At doses of 30 mg/mo, up to 40% of patients require subcutaneous octreotide "rescue" and up to 40% of patients are given more than 30 mg of LAR/mo. Octreotide acetate binds to the sst2 receptor with an affinity (Kd) of approximately 1 x 10(-9) mol/L (approximately equal to 1000 pg/mL), but higher (approximately equal to 10,000 pg/mL) concentrations of octreotide are required to completely saturate this receptor. Octreotide blood level measurement may be useful to guide LAR therapy in symptomatic patients or in patients who have tumor growth on traditional LAR doses. We hypothesize that LAR doses of 60 mg/mo will produce blood levels of 10,000 pg/mL or greater. At identical monthly LAR doses, patients with higher weights will require more medication to achieve similar plasma octreotide levels than individuals with lower body weights. METHODS: Trough plasma, serum, urine, and saliva octreotide levels were obtained from 52 patients with carcinoid syndrome receiving 20 (n = 8), 30 (n = 19), or 60 mg LAR/mo (n = 10). Octreotide levels were determined by radioimmunoassay. RESULTS: The mean +/- SD plasma octreotide levels for patients receiving 20, 30, or 60 mg LAR/mo were 2518 +/- 1020, 5241 +/- 3004, and 10,925 +/- 5330 pg/mL, respectively. Patient weight (kilograms) was inversely related to plasma octreotide levels. There was a significant correlation between plasma octreotide levels and octreotide levels measured in urine, saliva, and serum. CONCLUSIONS: Frequent measurement of octreotide levels may be useful to guide octreotide therapy in patients with poorly controlled symptoms or those patients experiencing tumor growth.