Plasma Pancreastatin Predicts the Outcome of Surgical Cytoreduction in Neuroendocrine Tumors of the Small Bowel.

OBJECTIVES: Elevated pancreastatin (PST) levels have been shown to be associated with poor prognosis in small bowel neuroendocrine tumors (NETs). We hypothesized that plasma PST levels that remain elevated following surgical cytoreduction portend a poor prognosis in well-differentiated small bowel NETs. METHODS: Patients diagnosed with small bowel NETs who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Only patients who had serial preoperative PST (PreopPST) and postoperative PST (PostopPST) levels were included in this study. Patients were sorted into groups by PST level to assess their response to surgical cytoreduction (group 1, PreopPST/PostopPST normal; group 2, PreopPST elevated/PostopPST normal; group 3, PreopPST/PostopPST elevated). Survival rates were calculated from the date of surgery. RESULTS: PreopPST and PostopPST levels were collected from 300 patients. Patients in groups 1 (n = 74) and 2 (n = 81) had a significant survival advantage compared with patients in group 3 (n = 145) (P < 0.0001). Kaplan-Meier 5- and 10-year survival rates were as follows: group 1: 93% and 82%; group 2: 91% and 65%; and group 3: 58% and 34%, respectively. CONCLUSIONS: Serial monitoring of plasma PST is useful in predicting long-term survival following surgical cytoreduction and can be helpful to identify patients who have a poor prognosis.

Plasma Neurokinin A Levels Predict Survival in Well-Differentiated Neuroendocrine Tumors of the Small Bowel.

OBJECTIVES: Elevated neurokinin A (NKA) levels are associated with poor prognosis in patients with small bowel neuroendocrine tumors. We hypothesized that patients with NKA levels that remain elevated despite treatment with surgical cytoreduction have a poor prognosis. METHODS: Patients diagnosed with small bowel neuroendocrine tumors who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Patients were grouped by the trend of their NKA levels (group 1, continuously normal; group 2, transiently elevated but normalized after therapy; group 3, remained elevated despite therapy). Survival rates were calculated from the date of the patient's first NKA level. RESULTS: Serial NKA values after surgical cytoreduction were monitored in 267 patients. Kaplan-Meier 2-year, 5-year, and 10-year survival rates were as follows: group 1 (n = 157), 97%, 89%, and 62%; group 2 (n = 78), 99%, 90%, and 78%; and group 3 (n = 32), 88%, 69%, and 0%. Survival rates were statistically significant between groups 1 and 3 and between groups 2 and 3 (P < 0.01). CONCLUSIONS: Serial monitoring of plasma NKA levels is useful in identifying patients who have a poor prognosis. Elevated NKA levels can indicate the need for immediate therapeutic intervention.

Development of effective prophylaxis against intraoperative carcinoid crisis.

STUDY OBJECTIVE: The prophylactic use of a preoperative, intraoperative, and postoperative high-dose continuous octreotide acetate infusion was evaluated for its ability to minimize the incidence of carcinoid crises during neuroendocrine tumor (NET) cytoreductive surgeries. DESIGN: A retrospective study was approved by the institutional review boards at Ochsner Medical Center-Kenner and Louisiana State University Health Sciences Center. SETTING: Ochsner Medical Center-Kenner operating room and multispecialty NET clinic. PATIENTS: One hundred fifty consecutive patients who underwent a total of 179 cytoreductive surgeries for stage IV, small bowel NETs. INTERVENTIONS: All patients received a 500-µg/h infusion of octreotide acetate preoperatively, intraoperatively, and postoperatively. MEASUREMENTS: Anesthesia and surgical records were reviewed. Carcinoid crisis was defined as a systolic blood pressure of less than 80mm Hg for greater than 10minutes. Patients who experienced intraoperative hypertension or hypotension, profound tachycardia, or a "crisis" according to the operative note were also reviewed. MAIN RESULTS: One hundred sixty-nine (169/179; 94%) patients had normal anesthesia courses. The medical records of 10 patients were further investigated for a potential intraoperative crisis using the aforementioned criteria. Upon review, 6 patients were determined to have had a crisis. The final incidence of intraoperative crisis was 3.4% (6/179). CONCLUSIONS: A continuous high-dose infusion of octreotide acetate intraoperatively minimizes the incidence of carcinoid crisis. We believe that the low cost and excellent safety profile of octreotide warrant the use of this therapy during extensive surgical procedures for midgut and foregut NETs.

A single fasting plasma 5-HIAA value correlates with 24-hour urinary 5-HIAA values and other biomarkers in midgut neuroendocrine tumors (NETs).

OBJECTIVES: 5-Hydroxyindoleacetic acid (5-HIAA) is used for the evaluation of neuroendocrine tumors (NETs) but currently requires a 24-hour urine collection. METHODS: We developed a gas chromatography mass spectroscopy-based plasma 5-HIAA assay. We compared 24-hour urine 5-HIAA values against plasma 5-HIAA values in 115 mixed-variety patients with NETs and in a subset of 72 patients with only small bowel NETs. We also compared the information gained from urinary and plasma 5-HIAA values with other biomarkers of midgut NET activity to determine the plasma assay's clinical implications. RESULTS: In a group of 115 patients with all types of NETS, in a subset of patients with midgut NET and in a subgroup of midgut NETS with liver metastasis, the correlation between the urine and fasting plasma 5-HIAA values were statistically significant (P ≤ 0.0001). Comparison of the proportion of normal or abnormal urinary and plasma 5-HIAA values to the proportion of chromogranin, serotonin, neurokinin, or pancreastatin values that were in the normal or abnormal range yielded essentially identical information. CONCLUSIONS: Plasma fasting 5-HIAA values are proportional to urinary 5-HIAA values and yielded identical clinical correlation with other biomarkers.

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.

Cardiac autonomic imbalance in newly diagnosed and established diabetes is associated with markers of adipose tissue inflammation.

INTRODUCTION: Diabetics die from cardiovascular disease at a much greater rate than nondiabetics. Cardiac autonomic imbalance predicts increased cardiovascular risk and mortality. We studied the relationship between cardiac autonomic imbalance and adipose tissue-derived inflammation in newly diagnosed and established type 2 diabetes. MATERIALS AND METHODS: Non-diabetics, newly diagnosed diabetics, and established diabetics were included. Anthropomorphic and biochemical measurements were obtained, and insulin resistance was approximated. Cardiac autonomic function was assessed using conventional measures and with power spectral analysis of heart rate. RESULTS AND DISCUSSION: Heart rate variability was reduced in all diabetics. Interleukin-6 was higher in diabetics, as was the high molecular weight adiponectin-to-leptin ratio. Interleukin-6 correlated negatively with measures of autonomic balance. Ratios of adiponectin to leptin correlated positively with measures of autonomic balance. Cardiac autonomic imbalance and inflammation occur early in diabetes and are interrelated. CONCLUSIONS: Cardiac autonomic imbalance correlates with the adipose tissue-derived inflammation seen early in type 2 diabetes.

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.

Modern laboratory evaluation of peptide and amines: a continuing role for radioimmunoassay?

Modern medicine, and specifically clinical diagnosis, relies, among other diagnostic procedures, on the measurements of the biogenic analytes for elucidation and correlation of specific neuroendocrine markers. Tremendous advances have been made in imaging and radioactive uptake procedures to elucidate tumor presence and characterization. However, such advances only partially provide the fundamental degree of tumor activity and clinical confirmational validity. The author points out in some detail the problems that may arise when the methodological differences presented by each investigational study and investigators are not standardized. This variation causes a concern with the specific objectives of the investigator and the specific aims of the research project at hand, and ultimately for the validity of the published results.

A prospective trial on the effect of body mass index and sex on plasma octreotide levels in patients undergoing long-term octreotide LAR therapy.

OBJECTIVES: Octreotide long acting repeatable (LAR) is commonly used to control the symptoms of patients with functional neuroendocrine tumors. Unfortunately, most patients escape control over time and require higher LAR doses or more frequent rescue therapy to remain asymptomatic. Previous work has shown that body weight and monthly LAR dose will significantly affect circulating plasma octreotide levels in patients undergoing therapy. METHODS: To determine if other parameters change circulating plasma octreotide levels, we prospectively studied 82 patients undergoing long-term LAR therapy. RESULTS: Multivariate analysis demonstrated that the plasma octreotide levels decrease by approximately 3.4% for each unit of body mass index (BMI) increase (P = 0.03), adjusting for sex and monthly LAR dose. Plasma octreotide levels for females were approximately 47.6% higher than those for males (P = 0.045), adjusting for BMI and monthly LAR dose. Initial and subsequent octreotide LAR doses should take into consideration sex and BMI. Males are estimated to require 14.1-mg (SD, 7.25) higher monthly LAR doses than females with the same BMI. CONCLUSIONS: We have shown that plasma octreotide levels are affected by not only monthly LAR dose but also BMI and sex. We hope these observations will make choosing initial and subsequent octreotide LAR doses easier for physicians.

Development of a highly sensitive and specific carboxy-terminal human pancreastatin assay to monitor neuroendocrine tumor behavior.

OBJECTIVE: Pancreastatin is a fragment of the chromogranin A (CgA) molecule. Existing pancreastatin assays, which depend on antibodies that cross-react in varying percents with the larger prohormone, may lack sensitivity and specificity to detect small changes in neuroendocrine tumor volume. METHODS: We developed a highly specific, sensitive pancreastatin assay. The antibody used recognizes the carboxyl terminal of the peptide hormone and was raised against a 17-amino acid porcine pancreastatin fragment with high homology with the carboxy-terminal amino acids 286-301 of the human CgA. RESULTS: Our assay measures more than 95% of circulating pancreastatin levels; has little or no cross-reactivity with CgA, even at plasma concentrations of 1000 ng/mL; and can detect pancreastatin levels of 17 pg/mL. Interassay reproducibility for the pancreastatin radioimmunoassay was determined from results of 3 quality control pools in 15 consecutive assays. Coefficients of variation for low, medium, and high pancreastatin levels were less than 20%. The sensitivity of serial pancreastatin assays to detect early liver tumor activity was demonstrated in 2 patients with slowly progressive neuroendocrine tumors and in patients undergoing surgical cytoreduction. CONCLUSIONS: This highly specific, sensitive pancreastatin assay can detect small changes in liver tumor progression and is up to 100-fold more sensitive and specific than CgA assays in the United States.

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.

Validation of serum versus plasma measurements of chromogranin a levels in patients with carcinoid tumors: lack of correlation between absolute chromogranin a levels and symptom frequency.

OBJECTIVE: Chromogranin A (CGA) levels are used to confirm the diagnosis and monitor the course of patients with neuroendocrine tumors. Chromogranin A levels are significantly reduced when patients are acutely treated with octreotide; however, limited data are available that correlates octreotide long-acting repeatable (LAR) dose or steady state octreotide blood levels to the absolute value of serum or plasma CGA. METHODS: Plasma, serum, and clinical information on carcinoid syndrome symptoms were collected anonymously from 40 patients treated with long-term octreotide LAR therapy for carcinoid syndrome. RESULTS: We found a strong positive linear relationship exists between serum and plasma CGA levels (r = 0.9858, P < 0.0001). No correlation existed between plasma octreotide levels or LAR dose and the static, absolute plasma/serum CGA levels. Although, higher mean CGA values were seen in the group whose diarrhea was "not under optimal control" than for the group "under optimal control," these results did not reach statistical significance (P = 0.24). Contrary to our hypotheses, a statistically significant inverse relationship was found between the frequency of flushing and the CGA levels (P = 0.0372). Higher mean CGA values were observed in the "under optimal control" group with flushing symptoms. CONCLUSIONS: Either serum or plasma can be used to measure CGA levels. Absolute (static) CGA levels do not positively correlate with symptom intensity during LAR therapy. Dynamic (serial) measurements of CGA are necessary to monitor the effectiveness of medical or surgical therapy.

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.