Serum Inflammation-based Scores in Endocrine Tumors.

CONTEXT: Serum inflammation-based scores reflect systemic inflammatory response and/or patients' nutritional status, and may predict clinical outcomes in cancer. While these are well-described and increasingly used in different cancers, their clinical usefulness in the management of patients with endocrine tumors is less known. EVIDENCE ACQUISITION: A comprehensive PubMed search was performed using the terms "endocrine tumor," "inflammation," "serum inflammation-based score," "inflammatory-based score," "inflammatory response-related scoring," "systemic inflammatory response markers," "neutrophil-to-lymphocyte ratio," "neutrophil-to-platelet ratio," "lymphocyte-to-monocyte ratio," "Glasgow prognostic score," "neutrophil-platelet score," "Systemic Immune-Inflammation Index," and "Prognostic Nutrition Index" in clinical studies. EVIDENCE SYNTHESIS: The neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio are the ones most extensively investigated in patients with endocrine tumors. Other scores have also been considered in some studies. Several studies focused in finding whether serum inflammatory biomarkers may stratify the endocrine tumor patients' risk and detect those at risk for developing more aggressive and/or refractory disease, particularly after endocrine surgery. CONCLUSIONS: In this review, we summarize the current knowledge on the different serum inflammation-based scores and their usefulness in predicting the phenotype, clinical aggressiveness, and disease outcomes and prognosis in patients with endocrine tumors. The value of such serum inflammation-based scores in the management of patients with endocrine tumors has been emerging over the last decade. However, further research is necessary to establish useful markers and their cut-offs for routine clinical practice for individual diseases.

Endocrine Tumors Causing Arterial Hypertension: Pathophysiological Mechanisms and Clinical Implications.

Some tumors are a relatively rare and amendable cause of hypertension, often associated with a higher cardiovascular morbidity and mortality, as compared with that of both general population and patients with essential hypertension. This worse prognosis is not entirely related to blood pressure increase, because the release of substances from the tumor can directly influence blood pressure behavior. Diagnostic approach is challenging and needs a deep knowledge of the different neuro-hormonal and genetic mechanisms determining blood pressure increase. Surgical tumor removal can, but not always, cause blood pressure normalization, depending on how early was tumor detection, since a long-standing history of hypertension is often associated with a much weaker effect on blood pressure. Moreover, target organ damage can be affected by the substances themselves released by the tumors as well as by tumor removal. In this review we consider the phenotype and genetic features of patients with tumor-induced hypertension and focus on their diagnostic work-up.

[Circulating microRNAs in the diagnostics of endocrine neoplasms]. / Keringo mikroRNS-ek az endokrin daganatok diagnosztikájában.

MicroRNAs (miRNA, miR) are short - 19-25 nucleotide long - single stranded (in their mature form), non-coding RNA molecules that regulate gene expression mostly at the posttranscriptional level. microRNAs are involved in the regulation of various physiological processes such as cell differentiation and proliferation, development, haematopoesis, cell death, while their aberrant expression is observed in numerous diseases, like autoimmune disorders, inflammations, vascular diseases or tumorigenesis. microRNAs are expressed in a tissue specific fashion. Beyond their appearance in tissues, they can be found in body fluids as well. microRNAs are present in blood, mother milk, semen, saliva, urine, etc. MicroRNAs in body fluids, especially the blood-borne circulating microRNAs can be exploited as minimally invasive biomarkers of tumor diagnosis. The number of endocrine tumor-associated circulating microRNA alterations is relatively low, mostly described for papillary thyroid cancer, adrenocortical cancer, ovarian and neuroendocrine tumors. As the histological diagnosis including the establishment of malignancy of some of these neoplasms is difficult, studies on circulating microRNAs might have great perspectives. Orv. Hetil., 2017, 158(13), 483-490.

Circulating miRNAs as biomarkers for endocrine disorders.

Specific, sensitive and non-invasive biomarkers are always needed in endocrine disorders. miRNAs are short, non-coding RNA molecules with well-known role in gene expression regulation. They are frequently dysregulated in metabolic and endocrine diseases. Recently it has been shown that they are secreted into biofluids by nearly all kind of cell types. As they can be taken up by other cells they may have a role in a new kind of paracrine, cell-to-cell communication. Circulating miRNAs are protected by RNA-binding proteins or microvesicles hence they can be attractive candidates as diagnostic or prognostic biomarkers. In this review, we summarize the characteristics of extracellular miRNA's and our knowledge about their origin and potential roles in endocrine and metabolic diseases. Discussions about the technical challenges occurring during identification and measurement of extracellular miRNAs and future perspectives about their roles are also highlighted.

Biochemical Testing in Patients with Neuroendocrine Tumors.

Neuroendocrine tumors are usually slow-growing tumors. Many of these are capable of secreting peptide hormones or biogenic amines that may lead to endocrine syndromes. Nonfunctioning tumors can either secrete no hormones at all, or secrete hormones not giving rise to endocrine symptoms, such as chromogranin A, chromogranin B or pancreatic polypeptide. Chromogranin A is produced by the majority of endocrine tumors, both functioning and nonfunctioning, and is the best available marker for diagnosis, follow-up and treatment monitoring of patients with differentiated neuroendocrine tumors. Examples of endocrine syndromes are classical carcinoid syndrome caused by serotonin (measured in the urine as its metabolite 5-HIAA), insulinoma syndrome caused by insulin or proinsulin, Zollinger-Ellison syndrome resulting from gastrin secretion, glucagonoma syndrome caused by glucagon, WDHA syndrome caused by vasoactive intestinal peptide, or Cushing's syndrome resulting from ectopic production of adrenocorticotropic hormone or corticotropin-releasing hormone. In case there is uncertainty about the diagnosis, specific tests can be applied, such as the secretin test for diagnosis of gastrinomas and the 72-hour fast for diagnosis of an insulinoma. In patients with suspicion of an inherited syndrome, such as multiple endocrine neoplasia (MEN) 1 and MEN2 syndromes, genetic testing is indicated.

Placental site trophoblastic tumor with multiple metastases and complete response to salvage BEP regimen: a case report and review of the literature.

Placental site trophoblastic tumor is a rare form of gestational trophoblastic disease, derived from invasive implantation site (intermediate) trophoblastic cells. It is frequently resistant to chemotherapy. Patients with metastases, however, frequently have progressive disease and die despite surgery and multiagent chemotherapy. In this case, a 24-year-old woman was referred because of intermittent vaginal bleeding episodes for 5 months following delivery. Multiple metastases in lungs, liver, kidneys, breast, pancreas, and adrenal and thyroid glands were detected. Combination therapy including surgery and multiagent chemotherapy was planned. Hysterectomy and pelvic lymph node dissection were performed. All metastatic lesions disappeared with EMA-CO treatment. However four courses of BEP regimen, salvage therapy, was performed for plateauing hCG level. Surgery and multiagent chemotherapy seem mainstay of treatment of cases having multiple metastases of PSTTs.

Tachykinins in endocrine tumors and the carcinoid syndrome.

OBJECTIVE: A new antibody, active against the common tachykinin (TK) C-terminal, was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs). METHOD: TK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients. RESULTS: All MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin-producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms. In a Spearman partial rank test, the correlation of P-TK with daily diarrhea was independent of both U-5HIAA and CgA levels. CONCLUSION: We found that TK synthesis occurs in serotonin-IR tumors and that P-TK levels are significantly correlated with symptoms of flush and diarrhea in patients with MSPCs. This is, to our knowledge, the first report demonstrating an independent correlation of P-TKs with carcinoid diarrhea, a symptom that is customarily regarded as serotonin mediated. Further investigations may present opportunities for new therapeutic possibilities.

The current role of venous sampling in the localization of endocrine disease.

Endocrine venous sampling plays a specific role in the diagnosis of endocrine disorders. In this article, we cover inferior petrosal sinus sampling, selective parathyroid venous sampling, hepatic venous sampling with arterial stimulation, adrenal venous sampling, and ovarian venous sampling. We review their indications and the scientific evidence justifying these indications in the diagnosis and management of Cushing's syndrome, hyperparathyroidism, pancreatic endocrine tumors, Conn's syndrome, primary hyperaldosteronism, pheochromocytomas, and androgen-secreting ovarian tumors. For each sampling technique, we compare its diagnostic accuracy with that of other imaging techniques and, where possible, look at how it impacts patient management. Finally, we incorporate venous sampling into diagnostic algorithms used at our institution.

[How to interprete hypercalcitoninemia?]. / Comment interpréter une hypercalcitoninémie?

PURPOSE: Today, calcitonin assay is used for the diagnosis of thyroid medullary cancer in the context of nodular thyroid disease. Calcitonin is an excellent marker of thyroid medullary cancer but some hypercalcitoninemia can also be related to other diseases, such as renal failure, endocrine tumors other than thyroid medullary cancer and sometimes to C cell hyperplasia, which is a not well-defined situation. Recent studies contributed to define calcitoninemia thresholds, which guide decision and avoid excessive invasive treatment. CURRENT KNOWLEDGE AND KEY POINTS: After a brief reminder of physiological role of calcitonin and assays, the difficulties encountered in interpreting hypercalcitoninemia and its potential causes other than thyroid medullary cancer are addressed. Recent studies, on large series, now allow a better knowledge of specificity and sensitivity of calcitonin measurement in patients with nodular thyroid disease and a well-argued management. FUTURE PROSPECTS AND PROJECTS: In the future, calcitonin dosage will be ordered even more frequently, as some authors recommend it for the diagnosis of thyroid nodule. It is up to us to know how to use this remarkable marker, by considering all possible situations of benign hypercalcitoninemia and reserving aggressive treatments for patients who really need them.

Asymptomatic calcitonin-secreting tumor of the pancreas. A case report.

CONTEXT: Pancreatic endocrine tumors are unusual tumors arising from cells belonging generically to the amine precursor uptake and decarboxylation system. CASE REPORT: We present a case of a calcitonin-secreting pancreatic endocrine tumor in a 59-year-old male who presented at our Center with elevated calcitonin values. The patient was asymptomatic. Further investigation revealed a tumor, 80 mm in diameter, in the pancreatic body and tail along with three metastatic lesions in segments III, V, and VIII of the liver. Following a distal pancreatectomy, splenectomy and wedge resection of segments III and V along with radiofrequency ablation of the segment VIII lesion, his serum calcitonin reached normal values. CONCLUSIONS: Calcitonin-secreting pancreatic endocrine tumors are often malignant and have a poor prognosis. We believe that an aggressive surgical approach may improve survival.

A panel of 11 region-specific radioimmunoassays for measurements of human chromogranin A.

INTRODUCTION: The primary structure of human chromogranin A (CgA) not only contains 10 pairs of basic amino acids, which are potential cleavage sites for specific endogenous proteases, but also other sites in the molecule can be subjected to cleavage. Several CgA-related peptides have been identified in tissue, and many of the biological effects attributed to CgA seem to be mediated by these peptides. MATERIALS AND METHODS: Peptides homologous to defined parts of the human CgA molecule were selected and synthesised. Antibodies were raised, and 11 specific radioimmunoassays were developed. Plasma samples from 20 patients with neuroendocrine tumours were collected and measured in all assays. RESULTS: All assays measured circulating levels of CgA-derived peptides. Only four of the assays measured concentrations that correlated with that of total CgA. However, concentrations of the individual CgA-related peptides were generally lower than the concentration of total CgA. Different neuroendocrine tumours seem to process CgA differently. The ratio between a given region-specific assay and total CgA is inversely correlated to tumour activity. CONCLUSION: The assays presented allow measurements of defined regions of CgA and will thus become important tools for further studies of processing of CgA.

Glandular regulation of interstitial diffusion: a model and simulation of a novel physiological mechanism.

In endocrine glands, vigorous and coordinated responses are often elicited by modest changes in the concentration of the agonist molecule. The mammalian parathyroid gland is a representative case. Small (5%) changes in serum calcium result in 10-fold (1,000%) changes in glandular parathyroid hormone (PTH) release. In vitro, single isolated cells are observed to secrete fewer hormones than cells residing within a connected group, suggesting that a network has emergent regulatory properties. In PTH-secreting tumors, however, the ability to respond quickly to changes in calcium is strongly damped. A unifying hypothesis that accounts for these phenomena is realized by extracellular modulation of calcium diffusivity. A theoretical model and computational experiments demonstrate qualitative agreement with published experimental results. Our results suggest that, in addition to the cellular mechanisms, endocrine glandular networks may have regulatory prowess at the level of interstitial transport.

Mutations of RegIalpha are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia.

BACKGROUND & AIMS: The RegIalpha gene (Reg) encodes a secretory protein proposed to regulate islet beta-cell and gastric mucous cell growth. Reg is expressed in rat gastric enterochromaffin-like (ECL) cells. The aim of this study was to examine Reg expression in human corpus and to determine the identity of Reg in ECL cell carcinoid tumors in hypergastrinemic patients. METHODS: Reg messenger RNA (mRNA) abundance was quantified by Northern blot in extracts of gastric corpus from patients with and without ECL cell tumors and in AR4-2J cells stimulated by gastrin; cellular origins were determined by immunocytochemistry. Mutations of Reg were determined by reverse-transcription polymerase chain reaction, cloning, and sequencing, and the mutated protein was expressed in HIT-T15 cells. RESULTS: Reg mRNA abundance was increased approximately threefold in the corpus of hypergastrinemic patients compared with controls, and was enriched in 3 of 7 ECL cell carcinoid tumors but not in non-endocrine cell gastric polyps. In AR4-2J cells, gastrin stimulated Reg mRNA abundance; this was eliminated by the gastrin/cholecystokinin B antagonist L-740,093 (10(-9) mol/L). Immunocytochemistry indicated that Reg was located in both chief cells and ECL cells in human corpus. Mutations of Reg were identified in 3 of 5 patients with ECL cell carcinoid tumors; in 2 cases, mutation of the initiator methionine residue led to exclusion of the protein from the secretory pathway. CONCLUSIONS: Gastrin regulates Reg mRNA abundance in human corpus. Mutations of Reg that prevent secretion are associated with ECL cell carcinoids, suggesting a function as an autocrine or paracrine tumor suppressor.

111In-octreotide scintigraphy: a tool to select patients with endocrine pancreatic tumors for octreotide treatment?

The results of octreotide scintigraphy, performed in two patients with malignant endocrine pancreatic tumors, were compared with the effect of somatostatin-14 and its analogue octreotide on hormonal levels and clinical outcome. Radiolabeled octreotide failed to demonstrate any tumor localisation in a patient with a malignant insulinoma. Nevertheless, IV injection of somatostatin and octreotide resulted in a significant decrease in peripheral insulin levels. Moreover in this patient, chronic treatment with a high dose of octreotide subcutaneously was able to transiently lower the incidence of hypoglycemic events. In a second patient with metastatic PP-oma, 111In-octreotide disclosed a pancreatic tumor in the tail of the pancreas and metastatic supraclavicular lymph nodes. In this patient IV administration of somatostatin and octreotide inhibited the hormonal secretion of the tumor but subcutaneous injection of octreotide induced hardly any decrease in plasma PP levels and failed to affect tumor growth. These observations find a possible reason for this in the heterogeneous affinity of the somatostatin receptors in endocrine pancreatic tumors. They indicate that octreotide scintigraphy alone should not be used to select patients with neuroendocrine tumors who can benefit from chronic treatment with the somatostatin analogue.

Islet amyloid polypeptide (IAPP) in patients with neuroendocrine tumours.

Although IAPP was first discovered and isolated from amyloid deposits in an endocrine pancreatic tumour (EPT), surprisingly few reports have investigated the potential use of IAPP as a marker for neuroendocrine tumour growth. In this study we present results from plasma measurements of IAPP in 102 patients with neuroendocrine tumours. Four of 35 patients (11%) with midgut carcinoid tumours, but none of the patients (4 and 5, respectively) with lung carcinoids or with rectal carcinoids displayed elevated plasma levels of IAPP. Five of 31 patients (16%) with sporadic EPT and 3 of 27 patients (11%) with EPT and multiple endocrine neoplasia type 1 syndrome disclosed elevated IAPP levels. Within the different syndromes, 1/11 individuals with insulinoma, 2/16 with gastrinoma, 0/2 with glucagonoma, 0/3 with VIPoma and 5/26 with non-functioning tumours showed elevated plasma levels of IAPP. In two patients, the plasma IAPP levels were extremely elevated. These patients also exhibited altered glucose homeostasis. In response to a standardised mixed meal test, IAPP increased in parallel to the insulin, pancreatic polypeptide, gastrin and glucose responses. In MEN1 patients with hypercalcaemia due to increased secretion of parathyroid hormone, the plasma levels of IAPP were significantly higher before than after surgical removal of the parathyroid adenomas. However in normocalcaemic patients, no correlation between the blood calcium and plasma IAPP levels was found. Immunocytochemical staining of tumour tissue showed that 9/13 (69%) of insulin producing tumours, 4/14 (29%) of non-functioning tumours and 1/9 (11%) of gastrin producing tumours were IAPP immunoreactive. Amyloid deposits were always IAPP immunoreactive. In conclusion, increased circulating levels of IAPP occurred in 12% of 102 patients with neuroendocrine tumours. In 2 patients with extremely elevated plasma levels of IAPP, effects on glucose homeostasis were recorded. Thus, IAPP may be useful as an additional marker for neuroendocrine tumour growth in selected cases.

Venous sampling: its role in localization of endocrine tumours.

Despite recent instrumentation advancement in morphologic imaging, venous sampling remains a sensitive physiological investigation for functional localization of hormonal hypersecretion. The test requires technical expertise and reliable laboratory support, and should be selectively applied to address individual clinical problems in coordination with other imaging modalities. Depending on the venous anatomy, sampling may achieve regional localization or lateralization of the endocrine tumour. Adrenal venous sampling serves to lateralize functioning tumour, and to differentiate it from hyperplasia. Inferior petrosal sinus sampling confirms pituitary Cushing's disease and lateralizes the adenoma. Systemic venous sampling identifies the site of ectopic hormonal secretion. In the localization of pancreatic islet cell tumours, the test is further enhanced by sampling after intraarterial injection of hormonal secretagogue. The experience of venous sampling in a regional referral hospital is discussed, including the patient selection, its technical details, pitfalls and effectiveness in achieving tumour localization for patient management.

Increased basic fibroblast growth factor in plasma from multiple endocrine neoplasia type 1: relation to pituitary tumor.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroids, pancreatic islets, and anterior pituitary. We previously reported a basic fibroblast growth factor (bFGF)-like substance in the plasma of subjects with MEN1. In the present study we used a novel sensitive specific 2-site immunoradiometric assay to test for bFGF in plasma. The assay employs immobilized affinity-purified N-terminal-specific anti-bFGF antibodies (antigen capture) and high affinity binding to radioiodinated heparin. bFGF-like immunoreactivity was undetectable (< 0.2 ng/mL) in normal subjects and in most unaffected relatives of MEN1 subjects. We found detectable bFGF ranging from 0.24-1.28 ng/mL in 21 of 50 subjects with MEN1. Seven of 8 MEN1 subjects with untreated pituitary tumors had detectable plasma bFGF-like immunoreactivity. Plasma bFGF-like immunoreactivity decreased after surgery for pituitary tumor in 4 patients and after initiation of bromocryptine therapy in 4 patients. bFGF was increased in the plasma of several subjects with sporadic endocrine disorders, including 3 with untreated or persistent acromegaly. We conclude that pituitary tumor is a possible source of high circulating bFGF immunoreactivity in MEN1 plasma.

Islet amyloid polypeptide-like immunoreactivity in human tissue and endocrine tumors.

We have detected islet amyloid polypeptide (IAPP)-like immunoreactivity (-LI) in human pancreas and in a range of endocrine tumors, including oat cell carcinoma of the lung and pancreatic tumours producing insulin, gastrin, glucagon, and vasoactive intestinal peptide. Gel permeation chromatography of the IAPP-LI revealed that, except in the carcinoid, more than 80% coeluted with synthetic human IAPP. The remaining immunoreactivity consisted of variable amounts of larger and smaller molecular forms. The concentration of IAPP-LI in the circulation of patients with diagnosed pancreatic endocrine tumors was not significantly elevated above normal fasting levels. IAPP is, therefore, produced by a range of endocrine tumors and may relate to the deposition of endocrine amyloid.

Distribution and elimination of the somatostatin analogue (111In-DTPA-D-Phe1)-Octreotide (OctreoScan111).

The distribution and elimination characteristics of the 111In-labelled somatostatin analogue OctreoScan111 were studied in 23 patients with malignant tumours. The substance exhibited a rapid blood elimination following a bi-phasic pattern. The initial part of the elimination curves showed a t1/2a of between 0.27 and 3.6 h. The patients investigated had creatinine clearance rates ranging from 33 to 124 ml/min. However, within this range, no apparent correlation was found between the OctreoScan111 elimination rate and kidney function. Also no correlation was observed between the amount of administered activity and the elimination rate of OctreoScan111. The serum radioactivity of 6 patients was analyzed with respect to molecular size. These experiments showed that OctreoScan111 circulated unbound in serum. About 3% of the radioactivity, most probably representing 111In-chloride of DTPA-111In-chloride, circulated protein-bound. The elimination of OctreoScan111 radioactivity in urine displayed a bi-phasic pattern. Size separation of the radioactivity appearing in the urine after 24 h showed a higher molecular weight when compared with OctreoScan111, indicating the existence of a metabolite of the injected substance. The results obtained are discussed in the light of a potential role for the substance in systemic radiotherapy.