neurokinin-a and Neuroendocrine-Tumors

In this review, we focus on the use of biochemical markers for the diagnosis of neuroendocrine tumors and exclusion of conditions that masquerade as neuroendocrine tumors. In addition, we outline the use of biochemical markers for follow-up, response to intervention, and determination of prognosis. Previous publications have focused only on markers specific to certain tumor types, but the uniqueness of this chapter is that it presents a new approach ranging from biochemical markers that relate to symptoms to the use of markers that facilitate decision making with regard to optimizing the choices of therapy from the complex arrays of intervention, The sequence of presentation in this chapter is first to provide the usual view, that is, biochemical markers of each tumor type and thereafter the diagnosis of the underlying condition or exclusion thereof and finally the algorithm for their use from the clinical presentation to the suspected diagnosis and the biochemical markers to monitor progression and therapeutic choice. There is also a specific description of the properties of the most important biochemical markers and 2 complications, bone metastasis and carcinoid heart disease, from the biochemical point of view.

Topics: Biomarkers, Tumor; Chromogranin A; Disease Progression; Humans; Neuroendocrine Tumors; Neurokinin A; Pancreatic Hormones; Predictive Value of Tests; Prognosis

The measurement of general and specific biochemical markers in patients with neuroendocrine tumours assists with diagnosis and gives an indication of the effectiveness of treatment and they may be used as prognostic indicators. There is much agreement that chromogranin A is the most universally helpful marker; it is found to be elevated in the circulation of about 90% of patients with metastatic neuroendocrine tumours and there are several excellent commercially available kits which give reliable estimations. Specific markers are useful for diagnosis also, and are helpful indicators of the effectiveness of treatment, particularly where tumour bulk may not change as much as tumour activity. Sporadic pancreatic neuroendocrine tumours may secrete more than one peptide and this indicates a worsening prognosis. Because of the wide variation in the progression of neuroendocrine tumours, a prognostic indicator gives a significant advantage to the clinician in order to facilitate optimum treatment at the optimum stage of disease. Both chromogranin A and neurokinin A have been used as powerful prognostic indicators for midgut carcinoid tumours.

Topics: Biomarkers, Tumor; Chromogranin A; Chromogranins; Disease Progression; Gastrointestinal Neoplasms; Humans; Neuroendocrine Tumors; Neurokinin A; Pancreatic Neoplasms; Prognosis

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.. 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.. 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).. 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.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Female; Humans; Intestinal Neoplasms; Intestine, Small; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Neurokinin A; Predictive Value of Tests; Prognosis; Young Adult

A 52-year-old lady presented with a history of occasional, severe abdominal cramps, postprandial diarrhoea and weight loss. After routine gastrointestinal investigations, she was diagnosed with irritable bowel syndrome. Over six months, she developed occasional facial flushing prompting assessment of neuroendocrine tumour markers. Urinary 5HIAA, 5HT, chromogranin A and neurokinin A were significantly elevated. Scans showed extensive hepatic metastases but did not show the location of a primary tumour. Somatostatin analogue therapy was commenced but despite increasing doses, symptoms increased and biomarkers rose dramatically. Interferon alpha was introduced concomitant with somatostatin analogue therapy. Biomarkers were monitored regularly. Within six months, symptoms abated and biomarkers reduced, continuing to fall over the next year, close to reference range. To manage side-effects of interferon alpha, dose was reduced from time to time. During these short periods, neurokinin A showed significant transient increases (75-150 ng/L) and carcinoid symptoms returned. For more than seven years, and with the co-operation of the patient, a balance was achieved between interferon alpha side-effects and disease control. Scans showed tumour load to be stable. The patient survived for 10 years post diagnosis. She chose to discontinue interferon alpha and received peptide receptor radiation therapy in her final year. Throughout, neurokinin A remained the most sensitive monitor of her disease progression.

Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Carcinoid Tumor; Disease Progression; Drug Monitoring; Female; Humans; Interferon-alpha; Intestinal Neoplasms; Liver Neoplasms; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Neurokinin A; Somatostatin; Yttrium Radioisotopes

Neuroendocrine tumours (NETs) of the small bowel are difficult to diagnose as symptoms are non-specific and more often found in common gastrointestinal diseases. Chromogranin A (CGA), urinary 5 hydroxy indole acetic acid (U-5HIAA) and Neurokinin A (NKA) are used as laboratory diagnostic tests but results may be misleading or confusing.. To clarify the relevance of NET biomarkers for diagnosis of small bowel NETs.. A review of laboratory test results.. We reviewed 500 consecutive raised plasma CGA, U-5HIAA and plasma NKA, results from patients in N Ireland. The diagnosis of NET was confirmed by the Northern Ireland Cancer Registry.. In 500 specimens recording raised CGA, 52.2% were from patients with NETs, 13.6% being small bowel tumours, 5.4% of specimens from patients with auto-immune atrophic gastritis and 15.4% from patients taking proton pump inhibitors. In 500 specimens with raised U-5HIAA, 87.8% were from patients with NETs, 68.2% being small bowel tumours. Lung NETs contributed 12.2% and NETs from other sites, 7.4%. Of 500 specimens with raised NKA (reference range (RR) > 20 ng/L), 72.6% were from patients with small bowel NETs and 6% specimens from patients with other NETs. In 20% of specimens NKA concentrations were 21-23 ng/L, within limits of assay precision.. CGA remains the best general circulating marker for NETs although only half of raised test results are due to an NET. U-5HIAA is an excellent marker for small bowel and lung NETs with 80% of high test results confirming these diagnoses. NKA is the most specific biomarker for small bowel NETs.

Topics: Adult; Biomarkers, Tumor; Chromogranin A; Diagnosis, Differential; Female; Humans; Hydroxyindoleacetic Acid; Intestinal Neoplasms; Intestine, Small; Lung Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Neurokinin A; Northern Ireland; Registries; Reproducibility of Results

Assessing prognosis is important in patients with neuroendocrine tumours of the small bowel as disease progression and survival is variable. We previously identified raised Neurokinin A as an independent indicator of poor prognosis and have shown that prognosis worsens when circulating Neurokinin A rises ≥50 ng/L. In the present study we have examined survival in relation to Neurokinin A concentrations.. Patients in whom Neurokinin A rose ≥50 ng/L between January 1989 and December 2010 were identified. All circulating Neurokinin A concentrations were recorded and survival was followed up to 31 December 2014 or to death.. Median survival, from the date when Neurokinin A was first ≥50 ng/L was 11.1 (2.0-117.8) months if Neurokinin A remained ≥50 ng/L and 72.4 (4.8-152.6) months when Neurokinin A was reduced below 50 ng/L and controlled below that concentration for ≥3 months (P < 0.001). Survival was significantly better for patients attending the neuroendocrine tumour specialist clinic than for those not attending (P = 0.009). Comparing patients identified during 1989-2000, and those during 2001-2010, Neurokinin A was successfully reduced in the earlier period in 30.3% patients with median survival 23.2 (2.0-152.6) months and this improved in 58.1% with median survival of 43.3 (2.0-141.1) months in the later period (P = 0.019). Significance was greater between the earlier and later periods when only patients attending the neuroendocrine tumour clinic were compared (P = 0.016).. Circulating Neurokinin A ≥ 50 ng/L is a strong indicator of poor prognosis when Neurokinin A remains above this concentration. Lowering Neurokinin A below 50 ng/L indicates a significant improvement in prognosis (P < 0.001). This prognostic indicator reflects improved treatment and survival in more recent years.

Topics: Biomarkers, Tumor; Humans; Intestinal Neoplasms; Intestine, Small; Neoplasm Metastasis; Neuroendocrine Tumors; Neurokinin A; Prognosis; Radioimmunoassay; Survival Analysis

A critical requirement in neuroendocrine tumor (NET) management is a sensitive, specific and reproducible blood biomarker test. We evaluated a PCR-based 51 transcript signature (NETest) and compared it to chromogranin A (CgA), pancreastatin (PST) and neurokinin A (NKA). The multigene signature was evaluated in two groups: i) a validation set of 40 NETs and controls and ii) a prospectively collected group of NETs (n=41, 61% small intestinal, 50% metastatic, 44% currently treated and 41 age-sex matched controls). Samples were analyzed by a two-step PCR (51 marker genes) protocol and ELISAs for CgA, PST and NKA. Sensitivity comparisons included χ(2), non-parametric measurements, ROC curves and predictive feature importance (PFAI) analyses. NETest identified 38 of 41 NETs. Performance metrics were: sensitivity 92.8%, specificity 92.8%, positive predictive value 92.8% and negative predictive value 92.8%. Single analyte ELISA metrics were: CgA 76, 59, 65, and 71%; PST 63, 56, 59, and 61% and NKA 39, 93, 84, and 60%. The AUCs (ROC analysis) were: NETest: 0.96±0.025, CgA: 0.67±0.06, PST 0.56±0.06, NKA: 0.66±0.06. NETest significantly outperformed single analyte tests (area differences: 0.284-0.403, Z-statistic 4.85-5.9, P<0.0001). PFAI analysis determined NETest had most value (69%) in diagnosis (CgA (13%), PST (9%), and NKA (9%)). Test data were consistent with the validation set (NETest >95% sensitivity and specificity, AUC =0.98 vs single analytes: 59-67% sensitivity, AUCs: 0.58-0.63). The NETest is significantly more sensitive and efficient (>93%) than single analyte assays (CgA, PST or NKA) in NET diagnosis. Blood-based multigene analytic measurement will facilitate early detection of disease recurrence and can predict therapeutic efficacy.

Topics: Adult; Aged; Biomarkers, Tumor; Chromogranin A; Enzyme-Linked Immunosorbent Assay; Female; Hematologic Tests; Humans; Male; Middle Aged; Neuroendocrine Tumors; Neurokinin A; Pancreatic Hormones; Polymerase Chain Reaction; Reproducibility of Results

5-Hydroxyindoleacetic acid (5-HIAA) is used for the evaluation of neuroendocrine tumors (NETs) but currently requires a 24-hour urine collection.. 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.. 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.. Plasma fasting 5-HIAA values are proportional to urinary 5-HIAA values and yielded identical clinical correlation with other biomarkers.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Chromogranin A; Disease Progression; Fasting; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydroxyindoleacetic Acid; Intestinal Neoplasms; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Neurokinin A; Pancreatic Hormones; Prognosis; Reference Values; Sensitivity and Specificity; Serotonin

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.. 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.. 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%.. 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.

Topics: Biomarkers, Tumor; Humans; Intestinal Neoplasms; Intestine, Small; Neuroendocrine Tumors; Neurokinin A; Prognosis; Survival Rate

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.. 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.. 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).. 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.

Topics: Biomarkers, Tumor; Calibration; Clinical Laboratory Techniques; Humans; Kaplan-Meier Estimate; Neuroendocrine Tumors; Neurokinin A; Observer Variation; Predictive Value of Tests; Prognosis; Radioimmunoassay; Reference Standards; Regression Analysis; Reproducibility of Results; Sensitivity and Specificity; Specimen Handling