Search

The chromogranin-secretogranin secretory proteins-granins-are acidic proteins localized in granules of endocrine cells and neurons. The chromogranin family includes chromogranins A (CgA) and B, as well as secretogranin II (once called chromogranin C). Members of this family undergo catalytic proteolysis to produce active peptides. The CgA-derived peptides vasostatin-1 and vasostatin-2, in particular, appear to protect against atherosclerosis, suppressing the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, as well as exerting vasodilatory effects by enhancing nitric oxide bioavailability. Vasostatin-1 also suppresses vasoconstriction and abnormal angiogenesis. Vasostatin-1 and vasostatin-2 may be novel therapeutic targets for atherosclerosis and coronary heart disease, also protecting the myocardium against ischaemic damage., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chromogranin A (CHGA), a member of the granin family of proteins, has been an attractive therapeutic target and candidate biomarker for several cardiovascular, neurological, and inflammatory disorders. The prominence of CHGA stems from the pleiotropic roles of several bioactive peptides (e.g., catestatin, pancreastatin, vasostatins) generated by its proteolytic cleavage and by their wide anatomical distribution. These peptides are emerging as novel modulators of cardiometabolic diseases that are often linked to high blood cholesterol levels. However, their impact on cholesterol homeostasis is poorly understood. The dynamic nature of cholesterol and its multitudinous roles in almost every aspect of normal body function makes it an integral component of metabolic physiology. A tightly regulated coordination of cholesterol homeostasis is imperative for proper functioning of cellular and metabolic processes. The deregulation of cholesterol levels can result in several pathophysiological states. Although studies till date suggest regulatory roles for CHGA and its derived peptides on cholesterol levels, the mechanisms by which this is achieved still remain unclear. This review aims to aggregate and consolidate the available evidence linking CHGA with cholesterol homeostasis in health and disease. In addition, we also look at common molecular regulatory factors (viz., transcription factors and microRNAs) which could govern the expression of CHGA and genes involved in cholesterol homeostasis under basal and pathological conditions. In order to gain further insights into the pathways mediating cholesterol regulation by CHGA/its derived peptides, a few prospective signaling pathways are explored, which could act as primers for future studies., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The GNAS R201 gain-of-function mutation is the single most frequent cancer-causing mutation across all heterotrimeric G proteins, driving oncogenesis in various low-grade/benign gastrointestinal and pancreatic tumors. In this study, we investigated the role of GNAS and its product Gαs in tumor progression using peritoneal models of colorectal cancer (CRC). GNAS was knocked out in multiple CRC cell lines harboring GNAS R201C/H mutations (KM12, SNU175, SKCO1), leading to decreased cell-growth in 2D and 3D organoid models. Nude mice were peritoneally injected with GNAS-knockout KM12 cells, leading to a decrease in tumor growth and drastically improved survival at 7 weeks. Supporting these findings, GNAS overexpression in LS174T cells led to increased cell-growth in 2D and 3D organoid models, and increased tumor growth in PDX mouse models. GNAS knockout decreased levels of cyclic AMP in KM12 cells, and molecular profiling identified phosphorylation of β-catenin and activation of its targets as critical downstream effects of mutant GNAS signaling. Supporting these findings, chemical inhibition of both PKA and β-catenin reduced growth of GNAS mutant organoids. Our findings demonstrate oncogene addiction to GNAS in peritoneal models of GNAS R201C/H tumors, which signal through the cAMP/PKA and Wnt/β-catenin pathways. Thus, GNAS and its downstream mediators are promising therapeutic targets for GNAS mutant tumors., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.

The extensive use of amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of amphetamines and amphetamine-related drugs. We have previously shown that acute amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G 13 and to G S α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G 13 -mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission.

Little is known about the relevance of chromogranins (Cgs) and secretogranins (Sgs) in Parkinson's disease (PD). In this study, we determined serum levels of CgA, CgB, and SgII in PD patients and assessed their association with disease severity. PD patients were recruited, identified, and classified as having early (n = 14), intermediate (n = 18), or late (n = 4) stage disease according to Hoehn-Yahr scores. The serum concentrations of CgA, CgB, and SgII in patients with well-defined PD (n = 36) and in healthy controls (n = 52) were measured by enzyme-linked immunosorbent assay. Compared with controls, serum CgA levels were significantly elevated and serum SgII levels were significantly reduced in PD patients (both P < 0.05). There was no difference in serum CgB levels between the two groups. Both serum CgA and SgII levels changed progressively over time from early to intermediate to late stage (P < 0.05). Spearman correlation analysis revealed that serum CgA and SgII levels correlated with Hoehn-Yahr and UPDRS scores (P < 0.001). These results indicate that changes in serum levels of CgA and SgII may be closely related to the severity of PD., (© 2019 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

This paper investigates the fundamental knowledge, build-up, as well as essential structural and important features of the big family of chromogranins/secretogranins. Previously the different properties and the slightly diverging funcional relations of the two family members were in focus. Later on, it has been discovered that they are essentially two similar compounds with identical structures and functions, and they are chemically, biochemically related. From details discovered so far we can tell that they are long polypeptid chains formed from amino acids. Based on insights gained until now we can also state that these compounds are formed in Ca ++ containing environments with acidic pH. Among the compounds there are several molecules which have characteristic oligosacharid groups. This is especially interesting because oligosacharid chains with sialic acid in terminal position play an important role in the recognising and connectional processes. The chromogranins/secretogranins are mostly formed in neuroendocrine cells, but are also capable of building up in any cell type in the organism during pathological processes. Intracellular biogenesis takes place in the dense endoplasmatic reticulum across the mitochondrium, developing biogenetic granulums, followed by the stimulus-motivated secretum (exocytosis). The next stage of the molecular development is the specific break-up of the long polypeptid chains into shorter fragments. These fragments have individual effects. Some important clinical (diagnostic, prognostic) significance and connections are also touched upon in this paper, however, the cardiovascular, immunological systems and the tumors are mostly in focus. There are more immunological, cardiovascular and tumoral data. It is stated that as these molecules are in close connection with all of the organisms and systems of the body, a new chief organisator system has been identified. This chief organisator is closely connected with the central nervous system. Orv Hetil. 2017; 158(28): 1092-1099.

Background: Prostasomes are nanosized extracellular vesicles exocytosed by prostate epithelial cells. They have been assigned many roles propitious to sperm in favor of fertilization. Prostatic cancer cells can also produce and secrete extracellular vesicles., Methods: We assessed using ELISA, the surface expression of chromogranin proproteins on prostasomes and malignant extracellular vesicles of four different prostate cancer cell-lines, two hormone sensitive and two hormone refractory. We used a panel of chromogranin A and chromogranin B antibodies against peptides in-between hypothetical cleavage sites along the proproteins., Results: A diverging pattern of chromogranin peptides was apparent when comparing prostasomes and malignant extracellular vesicles indicating a phenotypical change. We also compared western blot patterns (prostasomes and malignant extracellular vesicles) for selected antibodies that displayed high absorbances in the ELISA. Western blot analyses revealed various cleavage patterns of those proproteins that were analyzed in prostasomes and extracellular vesicles., Conclusion: Chromogranins are constituents of not only prostasomes but also of malignant prostate cell-derived extracellular vesicles with different amino acid sequences exposed at the membrane surface giving rise to a mosaic pattern. These findings may be of relevance for designing new assays for detection or even possible treatment of prostate cancers., (© 2015 Wiley Periodicals, Inc.)

To elucidate the biological and clinicopathological significance of endocrine differentiation in gastric adenocarcinoma, an immunohistochemical study was made of 127 cases with ascertained five-year survivals, and of 45 recent cases of bromodeoxyuridine (BrdU) labeling. Endocrine differentiated cancer cells were demonstrated in 37 out of the 127 cases (29.1%) evaluated by chromogranin A (CGA) immunoreactivity, and all CGA-positive tumors were classified as advanced gastric cancer. Analysis of retrospective five-year survival rates revealed the adenocarcinomas with endocrine differentiation to have had significantly longer survival times than those without endocrine immunoreactivity in stage II, but not in stages III or IV. Double immunolabeling for CGA and BrdU in the other 45 adenocarcinoma cases showed only a single CGA-positive cancer cell with BrdU incorporation among a total of 454 CGA-positive cells examined. There was no significant difference between the labeling indices of the general cancer population and the cancer cells adjacent to CGA-positive cells. In conclusion, endocrine differentiation of gastric cancer is not uncommon, particularly in advancing cancer, and it would be a useful marker for a better prognosis in stage II. Probably, endocrine differentiated cancer cells are almost dormant with virtually no DNA synthesizing activity, and their paracrine effect is most unlikely to work in vivo.

Background/Aim: Preeclampsia, a significant cause of maternal morbidity and mortality, is linked to increased cardiovascular risks. Catestatin regulates cardiovascular function which indicates its usefulness in understanding pathophysiology of preeclampsia and its severity. Aim of this study was to evaluate association of catestatin in preeclamptic women and control non preeclamptic women and assess its association with presence and severity of preeclampsia. Methods: A case-control study at Al-Zahraa Teaching Hospital, Iraq, performed from January to December 2023 involved 90 pregnant women: 30 with severe preeclampsia, 30 with mild preeclampsia and 30 healthy controls. Inclusion criteria were preeclamptic pregnant women at 27-40 weeks of gestation and age ranging from 20-40 years and similar non-eclamptic controls. Exclusions were smokers, chronic drug users and those with chronic illnesses. Data collection included general and clinical information, BMI, vital signs, examinations and laboratory tests including serum catestatin. Results: Catestatin levels varied significantly among severe preeclampsia, mild preeclampsia and control groups. Average catestatin level in severe preeclampsia group was markedly lower at 29.01 ng/mL, compared to 43.67 ng/mL in mild preeclampsia and 59.96 ng/mL in controls. The diagnostic performance of catestatin for severe preeclampsia was notable, with a cutoff point of ≤ 37.165 ng/mL, sensitivity of 80 % and specificity of 83.3 %, highlighting its potential as a critical biomarker in preeclampsia evaluation. Conclusion: Catestatin level was significantly lower in sever preeclampsia compared to mild and control group, which may indicate its association with preeclampsia. Lower catestatin in sever preeclampsia suggest its inverse relation with preeclampsia severity. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examines the validity of the NETest, a blood biomarker, in patients with small intestinal neuroendocrine neoplasms (Si-NENs). Two groups were studied: those with metastatic Si-NENs (Group 1) and those without macroscopic disease, post-operatively (Group 2). In Group 1, results showed that NETest scores were associated with progression-free survival (PFS) and overall survival (OS) in metastatic Si-NENs. Factors including tumour growth rate (TGR), elevated chromogranin A (CgA) levels, and presence of lung metastases were also predictive of PFS or OS. In Group 2, NETest monitoring after surgery may have potential in helping to predict early local or metastatic disease recurrence. This study suggests potential benefits of using NETest alongside other predictors for Si-NEN management. Further research with longer follow-up periods is needed to confirm the utility of the NETest. Current biomarkers do not adequately predict the behaviour of neuroendocrine neoplasms (NENs). This study assessed the NETest, a multianalyte blood biomarker, in patients with small intestinal NENs (Si-NENs). We studied two patient groups: Group 1: metastatic Si-NENs (n = 102) and Group 2: post-operatively disease-free according to 68Ga-DOTATATE PET (n = 16). NETest scores were ≤20% (normal), 21–40% (low), 41–79% (intermediate), or ≥80% (high). Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan–Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. In Group 1, the median NETest score was 40% (IQR: 33.3–46.7%). The NETest value (HR: 1.032, 95% CI: 1.003–1.062, p = 0.033) and high-risk NETest category (HR: 10.5, 95% CI: 1.35–81.7, p = 0.025) were independent predictors of PFS, along with presence of lung metastases, CgA levels > 10 × ULN, and tumour growth rate (TGR). Independent predictors of OS were the NETest value (HR: 1.035, 95% CI: 1.005–1.066, p = 0.024) and high-risk NETest category (HR: 15.2, 95% CI: 1.52–151, p = 0.02), along with presence of lung metastases and CgA levels > 10 × ULN. In Group 2, ROC analysis identified an AUC of 0.909 (95% CI: 0.75–0.100) for prediction of local or metastatic recurrence. Blood NETest scores were associated with PFS and OS in patients with metastatic Si-NENs, along with TGR, CgA > 10 × ULN, and presence of lung metastases. [ABSTRACT FROM AUTHOR]

The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP‐NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP‐NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP‐NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP‐NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP‐NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix. [ABSTRACT FROM AUTHOR]

This study explores the predictive and monitoring capabilities of clinical and multiparametric MR parameters in assessing capecitabine and temozolomide (CAPTEM) therapy response in patients with neuroendocrine tumors (NET). This retrospective study (n = 44) assessed CAPTEM therapy response in neuroendocrine liver metastases (NELM) patients. Among 33 monitored patients, as a subgroup of the overall study cohort, pretherapeutic and follow-up MRI data (size, apparent diffusion coefficient [ADC] values, and signal intensities), along with clinical parameters (chromogranin A [CgA] and Ki-67%), were analyzed. Progression-free survival (PFS) served as the reference. Responders were defined as those with PFS ≥ 6 months. Most patients were male (75%) and had G2 tumors (76%) with a pancreatic origin (84%). Median PFS was 5.7 months; Overall Survival (OS) was 25 months. Non-responders (NR) had higher Ki-67 in primary tumors (16.5 vs. 10%, p = 0.01) and increased hepatic burden (20% vs. 5%, p = 0.007). NR showed elevated CgA post-treatment, while responders (R) exhibited a mild decrease. ADC changes differed significantly between groups, with NR having decreased ADCmin (−23%) and liver-adjusted ADCmean/ADCmean liver (−16%), compared to R's increases of ADCmin (50%) and ADCmean/ADCmean liver (30%). Receiver operating characteristic (ROC) analysis identified the highest area under the curve (AUC) (0.76) for a single parameter for ∆ ADC mean/liver ADCmean, with a cut-off of < 6.9 (76% sensitivity, 75% specificity). Combining ∆ Size NELM and ∆ ADCmin achieved the best balance (88% sensitivity, 60% specificity) outperforming ∆ Size NELM alone (69% sensitivity, 65% specificity). Kaplan-Meier analysis indicated significantly longer PFS for ∆ ADCmean/ADCmean liver < 6.9 (p = 0.024) and ∆ Size NELM > 0% + ∆ ADCmin < −2.9% (p = 0.021). Survival analysis emphasizes the need for adapted response criteria, involving combined evaluation of CgA, ADC values, and tumor size for monitoring CAPTEM response in hepatic metastasized NETs. [ABSTRACT FROM AUTHOR]

Background In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs. Materials and Methods SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN. Results Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication. Conclusions LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile. [ABSTRACT FROM AUTHOR]

Background: Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)‐SCLC, to assess whether conventional NE markers are predictive of ICIs. Methods: Patients with untreated ED‐SCLC who received first‐line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first‐line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI‐chemo group) and with chemotherapy alone (chemo group). Results: A total of 227 patients were included in the ICI‐chemo and chemo groups, respectively. The progression‐free survival (PFS) tended to be better in patients in the ICI‐chemo group than those treated with chemotherapy alone in patients with NE marker‐positive SCLC. In particular, it was statistically significant in patients with chromogranin A‐positive SCLC (p = 0.036). In patients with NE marker‐negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. Conclusion: Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker‐negative SCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival and disease recurrence for pancreatic neuroendocrine tumors differs greatly. The aim of our retrospective study was to investigate prognostic factors influencing recurrence and survival of 413 patients. For outcome evaluation the cohort was split in three groups: those under surveillance, those who had surgery with the intention to cure, and those with unresectable disease. For small tumors (<2 cm) under surveillance only 1 of 59 required surgery. For those who had surgery 20% had recurrence within 5-years with tumor size, high Ki-67 index, and location in the pancreatic head as risk factors. Half of the patients with unresectable tumors survived longer than approximately 2 years with high age, high chromogranin A levels, and increased markers of tumor proliferation being linked to survival. In conclusion, the current results add valuable knowledge in terms of predicting outcomes for individuals with pancreatic neuroendocrine neoplasms. Introduction: The prognosis and impact of different prognostic factors in pancreatic neuroendocrine neoplasms (pNEN) remain controversial. Aim: To investigate prognostic factors for recurrence-free survival and disease-specific survival in patients with pNEN, divided into three groups: patients undergoing surveillance (tumor size < 2 cm, group 1), patients followed after curative-intended surgery (group 2), and patients with unresectable disease or residual tumors after resection (group 3). Method: A single-center retrospective study including consecutive patients over a 20-year period. Multivariate Cox regression analyses were performed to identify risk factors. Results: 413 patients were included, with a mean (SD) age of 62 ± 14 years. In group 1 (n = 51), median (IQR) follow-up was 29 (21–34) months, and tumor size was 1.0 (0.8–1.4) cm. One progressed and had a tumor resection. In group 2 (n = 165), follow-up 59 (31–102) months, median tumor size 2 (1.2–3.4) cm, median Ki-67 index 5 (3–10)%, the 5-year recurrence rate was 21%. Tumor size (p < 0.001), Ki-67 index (p = 0.02), and location in the pancreatic head (p < 0.001) were independent risk factors. In group 3 (n = 197), follow-up 19 (6–46) months, median tumor size 4.2 (2.6–7.0) cm, Ki-67 index 17 (9–64)%, the median disease-specific survival was 22 (6–75) months—99 in NET G1; 54 in NET G2; 14 in NET G3; and 6 months in neuroendocrine carcinomas (NEC). Age (p = 0.029), plasma chromogranin A (p = 0.014), and proliferation, expressed by grade (p = 0.001) and Ki-67 index (p < 0.001), were risk factors. Conclusion: Growth in pNET < 2 cm requiring surgery was observed in 1/51. Tumor size, Ki-67 index, and location in the head were prognostic factors for disease recurrence, while age, plasma chromogranin A, and proliferation predicted mortality in patients with unresectable disease or residual tumors after resection. [ABSTRACT FROM AUTHOR]

Simple Summary: Peptide receptor radionuclide therapy is a well-established therapy for the treatment of neuroendocrine tumors. Therapy typically consists of four cycles administered in 8–10 week intervals, resulting in an average treatment length of 8–10 months. Given the extensive treatment length, early identification of patients with disease progression could help to optimize disease management. Blood-based biomarkers such as chromogranin A, alkaline phosphatase (ALP), or the De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) are continually assessed during treatment and represent a noninvasive and easily accessible source for the intratherapeutic monitoring of patients. Our exploratory analysis indicates that a considerable intratherapeutic increase in ALP may serve as a tool to identify patients who are at a higher risk of early disease progression after PRRT. If our results can be confirmed by other studies, these patients might benefit from intensified follow-up. Background: Pretherapeutic chromogranin A, alkaline phosphatase (ALP), or De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) are prognostic factors in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). However, their value for intratherapeutic monitoring remains unclear. We evaluated if changes in plasma markers during PRRT can help identify patients with unfavorable outcomes. Methods: A monocentric retrospective analysis of 141 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC was conducted. Changes in laboratory parameters were calculated by dividing the values determined immediately before each cycle of PRRT by the pretherapeutic value. Patients with low vs. high PFS were compared with the Wilcoxon rank-sum test. Results: Progression, relapse, or death after PRRT was observed in 103/141 patients. Patients with low PFS showed a significant relative ALP increase before the third (p = 0.014) and fourth (p = 0.039) cycles of PRRT. Kaplan–Meier analysis revealed a median PFS of 24.3 months (95% CI, 20.7–27.8 months) in patients with decreasing ALP values (Δ > 10%) during treatment, 12.5 months (95% CI, 9.2–15.8 months) in patients with increasing ALP values (Δ > 10%), and 17.7 months (95% CI, 13.6–21.8 months) with stable ALP values (Δ ± 10%). Conclusions: Based on these exploratory data, a rise in plasma ALP might indicate disease progression and should be interpreted cautiously during therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are now classified as lung neuroendocrine carcinomas (NECs) and have different treatment strategies compared with non-SCLC. Although these NECs are less frequently resected by surgery, the diagnosis of LCNEC is particularly difficult in some cases because staining for neuroendocrine markers is necessary in addition to morphological features. In our retrospective study of pathology specimens from 42 surgically resected SCLCs and 44 LCNECs, we demonstrated that immunohistochemical staining with Musashi-1, a marker of neural stem cells, more diffusely and intensely stained SCLC and LCNEC tissues. The findings of this study may improve and simplify the diagnosis of NECs in surgical and biopsy specimens and increase the opportunity to provide more appropriate treatment for patients. Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) have recently been grouped as lung neuroendocrine carcinomas (NECs). Because these lung NECs are clinically malignant and their treatment strategies differ from those of non-SCLC, the quality of diagnosis has a significant prognostic impact. The diagnosis of LCNEC requires positive immunohistochemical staining with chromogranin A, synaptophysin, and CD56, along with a morphological diagnosis, and insulinoma-associated protein 1 (INSM1) has been proposed as an additional marker but is still not an ideal or better marker. We investigated Musashi-1 as a novel immunohistochemical marker in 42 patients with SCLCs and 44 with LCNECs who underwent lung resection between 1998 and 2020 at our institution. We found Musashi-1 expression in 98% (41/42) SCLC and in 90% (40/44) LCNEC. These findings were similar to CD56 expression and superior to synaptophysin, chromogranin A, and INSM1. Musashi-1 also tended to show more diffuse and intense staining, especially in LCNEC, with more cases staining > 10% than any other existing markers (Musashi-1, 77%; INSM1, 45%; chromogranin A, 34%; synaptophysin, 41%; and CD56, 66%). In conclusion, we identified Musashi-1 as a novel immunohistochemical staining marker to aid in the diagnosis of lung NEC. [ABSTRACT FROM AUTHOR]

[Figure: see text].

Background: Insulinoma in women during pregnancy and postpartum is very rare; approximately 65% of cases are diagnosed early in pregnancy and ~ 35% immediately after delivery, few being found in middle or late pregnancy, likely due to increased insulin resistance seen after early-stage pregnancy. We successfully treated a case of insulinoma in which severe hypoglycemic coma immediately after delivery occasioned detailed investigation and diagnosis. Case presentation: Our patient experienced hypoglycemic coma in the 3rd month of pregnancy (initially considered due to her hyperemesis gravidarum) that improved spontaneously during the gestational period. No abnormalities of plasma glucose or body weight were found in regular checkups during her pregnancy; however, recurrence of hypoglycemic coma after delivery led us to suspect insulinoma. While contrast enhanced computer tomography and endoscopic ultrasonography (EUS) initially failed to detect a tumor in the pancreas, selective arterial calcium stimulation test revealed an insulin-secreting tumor localized in the pancreatic body. She then underwent spleen-preserving distal pancreatectomy; a 10-mm tumor positive for chromogranin A, synaptophysin and insulin was identified. Conclusions: Although pregnancy can mask insulinoma-associated symptoms and make diagnosis challenging, hypoglycemic episodes during early pregnancy, which were observed in this case, are suggestive of insulinoma. Importantly, in this case, accurate preoperative localization of the tumor enabled prompt curative surgery after delivery. Thus, clinical vigilance for the occurrence of insulinoma and its localization is appropriate for pregnant women suffering severe hypoglycemia. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study was to evaluate the diagnostic effectiveness of pro-gastrin-releasing peptide (ProGRP) and chromogranin A (CgA) in the diagnosis of neuroendocrine neoplasms of the lung (LNENs), (290 cases) and compared these results with controls (54 cases). The median ProGRP levels in LNEN patients were higher compared to controls (136.4 pg/mL vs. 6.5 pg/mL). The majority of the LNEN was well-differentiated tumors (262) (typical and atypical carcinoid). Based on the results (sensitivity, specificity, and area under the curve) of ProGRP in LNENs vs. controls, we can conclude that ProGRP should be considered as an effective marker for the diagnosis of LNEN patients. There is a lack of effective biomarkers for diagnosing lung neuroendocrine neoplasms (LNENs). A known small cell lung cancer (SCLC) biomarker is a pro-gastrin-releasing peptide (ProGRP), but not for all LNENs, especially for bronchopulmonary carcinoids. This study aimed to evaluate the diagnostic value of ProGRP and chromogranin A (CgA) in diagnosing LNENs. The ProGRP and CgA levels in 290 cases of LNENs and 54 healthy controls (HCs) were measured. The median ProGRP concentration in the group of LNEN patients was 136.4 pg/mL, higher than that of HCs at 6.5 pg/mL. Most of the LNEN cohort was well-differentiated tumors (typical and atypical carcinoids, n = 262, 91.7% of all LNENs). The sensitivity, specificity, and area under the curve (AUC) of ProGRP when distinguishing LNENs vs. HCs were 94.8%, 100%, and 0.995. CgA (AUC = 0.375) could not determine LNENs vs. HCs. Therefore, based on these results, ProGRP may be considered as an effective marker for diagnosing LNENs. [ABSTRACT FROM AUTHOR]

* Context.--Although several neuroendocrine cell types constitute gastroenteropancreatic neuroendocrine tumors (NETs), the clinical and prognostic implications of the expression of multiple peptide hormones have not been comprehensively evaluated in rectal NETs. Objective.--To identify the clinicopathologic characteristics and prognostic impact of peptide hormone expression. Design.--We evaluated the expression of peptide YY (PYY), glucagon, somatostatin, serotonin, insulin, and gastrin using immunolabeling in 446 endoscopically or surgically resected rectal NETs. Results.--PYY, glucagon, serotonin, somatostatin, insulin, and gastrin were expressed in 261 of 389 (67.1%), 205 of 446 (46.0%), 36 of 446 (8.1%), 33 of 446 (7.4%), 2 of 446 (0.4%), and 1 of 446 cases (0.2%), respectively. Immunoreactivity to any peptide hormone was present in 345 of 446 cases (77.4%). Tumors expressing serotonin or somatostatin were associated with lymphovascular invasion, chromogranin A expression, and shorter disease-free survival (DFS). Rectal NETs were classified as L-cell, enterochromaffin-cell, D-cell, null-expression, or mixedexpression type based on peptide hormonal expression status. Patients with D-cell NET had the shortest DFS (10-year DFS, 54.5%), followed by those with enterochromaffin-cell NET (89.5%), null expression (97.0%), L-cell NET (99.6%), and mixed-expression NET (100%; P < .001). Multivariable analyses revealed that somatostatin expression was an independent indicator of poor prognosis with respect to DFS in rectal NETs (P < .001). Conclusions.--Somatostatin expression is a poor prognostic indicator in patients with rectal NETs. Therefore, additional peptide hormonal immunolabeling, including somatostatin, serotonin, and PYY, in rectal NETs can provide more information regarding DFS. [ABSTRACT FROM AUTHOR]

Pheochromocytoma is a catecholamine-producing tumor that originates from adrenal medullary chromaffin cells. It affects 1–8 per million people annually and accounts for 5% of adrenal incidentalomas. Here, we report a 62-year-old man with sudden excessive sweating, palpitations, and headaches. He has a history of type 2 diabetes mellitus, hypertension, and an adrenal mass found incidentally by ultrasonography. Clinical history and further imaging suggest a pheochromocytoma; however, the presence of subclinical Cushing's syndrome and a normal urine vanillylmandelic acid level have led to diagnostic challenges. Finally, the patient underwent a left adrenalectomy. Histopathology showed the tumor as thick nests of cells, positive chromogranin A staining, and negative inhibin staining that confirmed the diagnosis of pheochromocytoma. In conclusion, our patient had pheochromocytoma that was thought to produce adrenocorticotropic hormone ectopically, resulting in subclinical Cushing's syndrome. [ABSTRACT FROM AUTHOR]

Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, suppresses SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.

Simple Summary: Pancreatic neuroendocrine neoplasms (PanNENs) represent approximately 30% of all gastro-entero-pancreatic NENs. According to current knowledge, the association between PanNENs and metabolic syndrome (MS) is not known. The study aimed to assess the relationships between selected serum biomarkers and metabolic syndrome (MS). We identified PanNEN patients with MS as having higher CEA levels, while those with a higher BMI and female sex showed higher leptin levels. This might reflect the relevant function of CEA and leptin in the metabolic abnormality diagnostics of PanNENs and deserves further evaluation to increase knowledge about the metabolic syndrome in PanNENs. Metabolic abnormalities are well-known risk factors for many cancers, even though no clearly established link with pancreatic neuroendocrine neoplasms (PanNENs) has yet been investigated. This research aimed to assess the serum levels of leptin, chromogranin A (CgA), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) in patients with PanNENs and to search for associations between PanNENs, these selected serum biomarkers, and metabolic abnormalities in the form of metabolic syndrome (MS). Second, we aimed to investigate whether MS increases the risk of PanNENs. The serum concentrations of biomarkers, metabolic parameters (glucose, cholesterol, triglycerides), and anthropometric measurements (weight, height, BMI) were assessed in 106 patients with PanNENs and 40 healthy volunteers. Patients with PanNENs showed higher serum concentrations of CA19-9, CEA, and CgA in comparison to controls (p < 0.001, p = 0.042, and p = 0.025, respectively). Statistically significant differences in CEA levels were found in PanNENs patients with MS (p = 0.043). PanNENs patients with a BMI ≥ 25 kg/m2 and who were female exhibited significantly higher leptin levels (p < 0.001 and p = 0.013, respectively). Additionally, this study reflects the importance of determining markers. Future research should focus on understanding the impact of metabolic disturbances on PanNENs and accounting for the relationship between PanNENs and MS, such as other malignancies. [ABSTRACT FROM AUTHOR]

Objectives: The bidirectional relationship between diabetes mellitus and chronic periodontitis is well known from clinical trials. Periodontitis in diabetic patients is characterized by severe inflammation and tissue destruction. The purpose of this study was to investigate the levels of chromogranin A (CgA), a stress marker, and myeloid-related protein (MRP)-8/14, an inflammatory marker, in saliva from patients with periodontitis and diabetes mellitus, and to investigate the relationship between CgA and MRP-8/14 in all individuals and in the three groups separately. Method and materials: Stimulated saliva was collected from 20 diabetic patients with chronic periodontitis, 16 patients with chronic periodontitis, and 21 healthy individuals. Salivary CgA and MRP-8/14 were determined with enzyme-linked immunosorbent assay. Salivary CgA and MRP-8/14 levels were assessed in the saliva of diabetic periodontitis and periodontitis patients, and the relationship with periodontal disease severity was investigated. Results: CgA values in saliva samples from chronic periodontitis patients and diabetic patients with chronic periodontitis were significantly higher than those of the control group. MRP-8/14 values in saliva from chronic periodontitis patients and diabetic patients with chronic periodontitis was significantly higher than that in the control group. Salivary CgA level was positively correlated to MRP-8/14 in all individuals, but there was no significant correlation within the chronic periodontitis patient group, diabetic patients with chronic periodontitis group, and the healthy patient group. No significant correlation between salivary CgA/ MRP-8/14 and clinical parameters of periodontitis was found in the three groups. Conclusions: The results suggest that salivary CgA and MRP-8/14 could be related to the pathogenesis of periodontitis and diabetes. CgA concentration in saliva was positively associated with increased MRP-8/14 in all individuals [ABSTRACT FROM AUTHOR]

Genome sequencing was performed on matched normal and tumor tissue from a 6.5-yr-old boy with a diagnosis of recurrent medulloblastoma. A pathogenic heterozygous c.432+1G>A canonical splice donor site variant in GNAS was detected on analysis of blood DNA. Analysis of tumor DNA showed the same splice variant along with copy-neutral loss of heterozygosity on Chromosome 20 encompassing GNAS, consistent with predicted biallelic loss of GNAS in the tumor specimen. This case strengthens the evidence implicating GNAS as a tumor-suppressor gene in medulloblastoma and highlights a scenario in which therapeutics targeting the cAMP pathway may be of great utility.

Oncodriver genes are usually identified when mutations recur in multiple tumours. Different drivers often converge in the activation or repression of key cancer-relevant pathways. However, as many pathways contain multiple members of the same gene family, individual mutations might be overlooked, as each family member would necessarily have a lower mutation frequency and thus not identified as significant in any one-gene-at-a-time analysis. Here, we looked for mutated, functional sequence positions in gene families that were mutually exclusive (in patients) with another gene in the same pathway, which identified both known and new candidate oncodrivers. For instance, many inactivating mutations in multiple G-protein (particularly Gi/o) coupled receptors, are mutually exclusive with Gαs oncogenic activating mutations, both of which ultimately enhance cAMP signalling. By integrating transcriptomics and interaction data, we show that the Gs pathway is upregulated in multiple cancer types, even those lacking known GNAS activating mutations. This suggests that cancer cells may develop alternative strategies to activate adenylate cyclase signalling in multiple cancer types. Our study provides a mechanistic interpretation for several rare somatic mutations in multi-gene oncodrivers, and offers possible explanations for known and potential off-label cancer treatments, suggesting new therapeutic opportunities.

Carcinoma of unknown primary (CUP) is a heterogeneous group of oncological diseases in which it is impossible to determine the primary tumor. The incidence is 3-5% of oncologic patients, but the survival time varies from 6 weeks to 5 months. The diagnostics should begin with a clinical evaluation and basic laboratory tests. For CUP placed in head and neck the positron emission tomography -- computed tomography is recommended; pancreatic or lung neoplasms are diagnosed with the computed tomography as well. Recently, the magnetic resonance, especially whole-body diffusion-weighted imaging has been introduced to the imaging panel. The lesion obtained during surgically removed metastases or biopsy material should be histopathological and molecularly examined to define the type of tumor. The basic immunoexpression panel should include cytokeratin-5/6, -7 and -20, EMA, synaptophysin, chromogranin, vimentin and GATA3 and molecular expression of ERBB2, PIK3CA, NF1, NF2, BRAF, IDH1, PTEN, FGFR2, EGFR, MET and CDK6. During the accurate diagnostics enable to classify malignancy of undefined primary origin as provisional CUP or finally confirmed CUP in which the primary place of tumor remains undetectable. The detailed diagnostics should be performed in highly specified centers to establish an accurate diagnosis and to initiate personalized treatment. Majority of patients are diagnosed with adenocarcinoma (70%), undifferentiated carcinoma (20%), squamous cell or transitional cell/uroepithelial carcinoma (5-10%), neuroendocrine tumor (5%) and with minor incidence other histological types, including melanoma. [ABSTRACT FROM AUTHOR]

Introduction: Pheochromocytomas are catecholamine-secreting tumors arising from the chromaffin cells of the adrenal medulla. We describe an unusual case of pheochromocytoma located in the infrarenal area and associated with bilateral adrenal hyperplasia. Case presentation: A 70-year-old patient was admitted for syncope, diaphoresis, and high blood pressure. Computed tomography showed a 73×70×72 mm retroperitoneal mass of the left infrarenal area. High levels of metanephrine and noradrenaline were found in the urine. A tumor resection was performed. A few days after surgery, the blood pressure suddenly decreased and could not be restored, resulting in the death of the patient. Histopathological examination of the surgical specimen revealed a proliferation of monotonous cells, with eosinophilic cytoplasm, round nuclei with prominent nucleoli arranged in clusters, and capsular and vascular invasion. The tumor cells expressed synaptophysin and chromogranin, without positivity for inhibin A or S100 protein. At the autopsy, both adrenal glands showed hyperplasia but unrelated to the tumor mass. The histological aspect, location, and immunophenotype indicated an ectopic infrarenal pheochromocytoma. Conclusions: In patients with pheochromocytoma developed on ectopic adrenal tissue, clinical management might be difficult, and diagnosis can be sometimes established only based on post-mortem histopathological examination. Autopsy can be extremely useful in such cases with unexplained evolution. [ABSTRACT FROM AUTHOR]

Catestatin (CST) is a metabolite of chromogranin A, a soluble protein in catecholamine storage vesicles acting as a feedback inhibitor of catecholamine secretion. This study aims to investigate the correlation of catestatin with dipper and non-dipper status in hypertensive patients. Hypertensive (n=355) and healthy subjects (n=129) were randomly selected at an outpatient clinic. Blood pressure and heart rate were measured according to relevant guidelines. Plasma catestatin level, plasma glucose, lipid levels were measured. An ambulatory blood pressure monitor was performed to determine the dipping patterns in hypertensive subjects. Univariate and multivariate analyses were conducted to assess factors affecting catestatin levels. Left ventricular mass was higher among hypertensives compared with healthy controls (178±47 g versus 213±52 g in healthy controls and hypertensives, p<0.05), but there was no significant difference between the two hypertensive groups 205±43 g versus 228±77 g in dippers versus non-dippers, p=0.54). Average systolic blood pressure (SBP) and the percentage of systolic blood pressure dipping were statistically significantly negative correlated with CST (r=-0.316, p<0.05 for systolic dipping%, r=-0.283, p<0.05 for ASBP). In multivariate analysis for the prediction of catestatin levels, systolic dipping % and mean SBP were found to be independent predictors of plasma catestatin level. Plasma catestatin levels were lower among hypertensives compared to healthy controls and modest inverse correlations between catestatin and dipping percentage of systolic blood pressure and also between catestatin and average systolic blood pressure were noted. In hypertensive subjects, lower plasma catestatin levels may alert clinicians to the non-dipping status of the blood pressure. [ABSTRACT FROM AUTHOR]

Background & aimsMutations at hotspots in GNAS, which encodes stimulatory G-protein, α subunits, are detected in approximately 60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We generated mice with KRAS-induced IPMNs that also express a constitutively active form of GNAS in pancreas and studied tumor development.MethodsWe generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras;Gnas mice); pancreatic tissues of these mice express activated KRAS and also express a mutant form of GNAS (GNASR201C) upon doxycycline administration. Mice that were not given doxycycline were used as controls, and survival times were compared by Kaplan-Meier analysis. Pancreata were collected at different time points after doxycycline administration and analyzed by histology. Pancreatic ductal adenocarcinomas (PDACs) were isolated from mice and used to generate cell lines, which were analyzed by reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and colony formation and invasion assays. Full-length and mutant forms of yes-associated protein (YAP) were expressed in PDAC cells. IPMN specimens were obtained from 13 patients with IPMN undergoing surgery and analyzed by immunohistochemistry.ResultsAll Kras;Gnas mice developed pancreatic cystic lesions that resemble human IPMNs; the grade of epithelial dysplasia increased with time. None of the control mice developed cystic lesions. Approximately one third of Kras;Gnas mice developed PDACs at a median of 30 weeks after doxycycline administration, whereas 33% of control mice developed PDACs. Expression of GNASR201C did not accelerate the development of PDACs compared with control mice. However, the neoplasms observed in Kras;Gnas mice were more differentiated, and expressed more genes associated with ductal phenotypes, than in control mice. PDACs isolated from Kras;Gnas mice had activation of the Hippo pathway; in cells from these tumors, phosphorylated YAP1 was sequestered in the cytoplasm, and this was also observed in human IPMNs with GNAS mutations. Sequestration of YAP1 was not observed in PDAC cells from control mice.ConclusionsIn mice that express activated KRAS in the pancreas, we found expression of GNASR201C to cause development of more differentiated tumors, with gene expression pattern associated with the ductal phenotype. Expression of mutant GNAS caused phosphorylated YAP1 to be sequestered in the cytoplasm, altering tumor progression.

Life-threatening diseases challenge immunity with a release of chromogranins. This report focuses on Chromogranin A (CGA) and some of its derived peptides in critically ill patients, with attention paid to their potential to become biomarkers of severity and actors of defense. First, we studied whether circulating CGA may be a biomarker of outcome in non-selected critically ill patients: CGA concentrations were reliably associated with short-term death, systemic inflammation, and multiple organ failure. Additionally, when studying Vasostatin-I, the major N-terminal fragment of CGA, we noted its reliable prognostic value as early as admission if associated with age and lactate. In trauma patients, CGA concentrations heralded the occurrence of care-related infections. This was associated with an in vitro inhibitor impact of Chromofungin on both NF-kappa B- and API-transcriptional activities. Secondly, in life-threatening disease-induced oxidative stress, the multimerization of Vasostatin-I occurs with the loss of its anti-microbial properties ex vivo. In vivo, a 4%-concentration of non-oxidized albumin infusion reversed multimerization with a decrease in care-related infections. Finally, in vitro Catestatin impacted the polymorphonuclear cells-Ca++-dependent, calmodulin–regulated iPLA2 pathway by releasing immunity-related proteins. Furthermore, human Cateslytin, the active domain of Catestatin, helped destroy S. aureus: this prompted the creation of synthetic D-stereoisomer of CGA-derived peptides against superbugs for the protection of implanted devices. In conclusion, CGA consideration in the critically ill is only starting, but it offers interesting perspectives for improved outcomes. [ABSTRACT FROM AUTHOR]

Context.--Molecular analysis of poorly differentiated/ undifferentiated sinonasal neoplasms has resulted in identification of a growing number of genetically defined tumors. SMARCA4-deficient sinonasal carcinoma is one such recently described entity that emerged from within sinonasal undifferentiated carcinoma (SNUC), neuroendocrine carcinoma (NEC), and teratocarcinosarcoma (TCS). Objective.--To identify SMARCA4-deficient sinonasal carcinomas from a large institutional cohort of poorly differentiated/undifferentiated carcinomas and evaluate their clinicopathologic features. Design.--SMARCA4/BRG1 immunohistochemistry was performed on all tumors diagnosed as SNUC, poorly differentiated carcinoma, NEC, and TCS during a 12-year period. SMARCA2/BRM and INSM1 immunostaining was performed in SMARCA4-deficient cases. Results.--Twelve SMARCA4-deficient sinonasal carcinomas were identified among 299 cases. Morphologically, 5 cases were large cell NEC, 2 cases were small cell NEC, and 5 were TCS. SMARCA4 loss was diffuse and comp in 10 cases, while 2 cases showed focal retention. Most cases showed diffuse cytokeratin staining accompanied by weak, usually focal staining for chromogranin and synaptophysin. INSM-1 showed negativity in most cases. All cases showed retained SMARCA2 expression. IDH1/2 mutation was absent in all cases analyzed. Four of 7 patients died of disease, and aggressive multimodality treatment provided better outcome. Conclusions.--SMARCA4-deficient sinonasal carcinomas are morphologically akin to sinonasal poorly differentiated NECs and TCS, display cytokeratin positivity and only focal staining for neuroendocrine markers, and have aggressive biological behavior. Inclusion of SMARCA4 in the immunohistochemical panel for diagnostic workup of all sinonasal NEC and TCS phenotypes will facilitate their early recognition. Comprehensive germline and somatic mutational analyses of these tumors are necessary for further insights into their molecular pathogenesis. [ABSTRACT FROM AUTHOR]

The increasing resistance to antibiotic treatments highlights the need for the development of new antimicrobial agents. Antimicrobial peptides (AMPs) have been studied to be used in clinical settings for the treatment of infections. Endogenous AMPs represent the first line defense of the innate immune system against pathogens; they also positively interfere with infection-associated inflammation. Interestingly, AMPs influence numerous biological processes, such as the regulation of the microbiota, wound healing, the induction of adaptive immunity, the regulation of inflammation, and finally express anticancer and cytotoxic properties. Numerous peptides identified in chromaffin secretory granules from the adrenal medulla possess antimicrobial activity: they are released by chromaffin cells during stress situations by exocytosis via the activation of the hypothalamo-pituitary axis. The objective of the present review is to develop complete informations including (i) the biological characteristics of the AMPs produced after the natural processing of chromogranins A and B, proenkephalin-A and free ubiquitin, (ii) the design of innovative materials and (iii) the involvement of these AMPs in human diseases. Some peptides are elective biomarkers for critical care medicine, may play an important role in the protection of infections (alone, or in combination with others or antibiotics), in the prevention of nosocomial infections, in the regulation of intestinal mucosal dynamics and of inflammation. They could play an important role for medical implant functionalization, such as catheters, tracheal tubes or oral surgical devices, in order to prevent infections after implantation and to promote the healing of tissues. [ABSTRACT FROM AUTHOR]

Sinonasal small cell neuroendocrine carcinoma (SNEC) is an extremely rare and aggressive neoplasm that can arise in the sinonasal region. These tumors are associated with high morbidity and mortality, are difficult to diagnose, and are hard to treat. We describe 2 cases of this poorly understood malignancy and review imaging, pathology, and treatment decisions. A 41-year-old male and a 64-year-old female presented to a tertiary center in 2019 after developing nasal obstruction and were found to have sinonasal masses on imaging. Both biopsies showed strong expression of pancytokeratin with dot-like reactivity and expression of neuroendocrine markers chromogranin and synaptophysin. The findings were diagnostic of SNEC. Staging positron emission tomography/computed tomography and brain MRI were performed, and patients were discussed at a multidisciplinary tumor board. Neither had distant metastatic disease at presentation. One patient had no intracranial or orbital disease and underwent a subtotal endoscopic resection with adjuvant chemoradiation. The other patient demonstrated middle cranial fossa, dural, and orbital involvement as well as cranial nerve V palsy. This patient was treated with induction chemotherapy, followed by concurrent chemoradiation. Both patients are presently alive at 4 months follow-up, but one with persistent local disease and the other distant metastasis. Sinonasal small cell neuroendocrine carcinoma is a rare and poorly understood malignancy with an aggressive clinical course. Continued careful review of pathology and study of molecular features are needed for improved understanding of SNEC, and particularly for head and neck SNEC, to establish a staging system and better formulate treatment protocols. [ABSTRACT FROM AUTHOR]

Chromogranin A (CgA), a ∼ 49 kDa acidic secretory protein, is ubiquitously distributed in endocrine and neuroendocrine cells and neurons. As a propeptide, CgA is proteolytically cleaved to generate several peptides of biological importance, including pancreastatin (PST: hCgA 250 – 301), Vasostatin 1 (VS1: hCgA 1–76), and catestatin (CST: CgA 352 – 372). VS1 represents the most conserved fragment of CgA. A 20 amino acid domain within VS1 (CgA 47–66) exhibits potent antimicrobial and anti-inflammatory activities. Autism is known to be associated with inflammation. Therefore, we seek to test the hypothesis that VS1 modulates autism behaviors by reducing inflammation in the hippocampus. Treatment of C57BL/6 (B6) and BTBR (a mouse model of idiopathic autism) mice with VS1 revealed the following: BTBR mice showed a significant decrease in chamber time in the presence of a stranger or a novel object. Treatment with VS1 significantly increased chamber time in both cases, underscoring a crucial role for VS1 in improving behavioral deficits in BTBR mice. In contrast to chamber time, sniffing time in BTBR mice in the presence of a stranger was less compared to B6 control mice. VS1 did not improve this latter parameter. Surprisingly, sniffing time in BTBR mice in the presence of a novel object was comparable with B6 mice. Proinflammatory cytokines such as IL-6 and IL-1b, as well as other inflammatory markers, were elevated in BTBR mice, which were dramatically reduced after supplementation with VS1. Interestingly, even Beclin-1/p62, pAKT/AKT, and p-p70-S6K/p70-S6K ratios were notably reduced by VS1. We conclude that VS1 plays a crucial role in restoring autistic spectrum disorders (ASD) plausibly by attenuating neuroinflammation. • Proinflammatory cytokines are involved in ASD-like behavior in BTBR mice. • Vasostatin-1 was able to counteract behavioral deficits typical of ASD. • Vasostatin-1 has shown anti-inflammatory properties in BTBR mice. [ABSTRACT FROM AUTHOR]

Pheochromocytomas are catecholamine-producing tumors derived from the adrenomedullary chromaffin cells. The presentation is a classic triad of episodic headaches, sweating, and tachycardia. Hypertensive crisis can occur due to profuse catecholamine excess. Unusual manifestations mimicking cardiogenic shock, arrhythmia, and myocarditis have been rarely reported in children. We present a case with uncommon manifestations of pheochromocytoma in a child, including the episodes of exercised-induced presyncope with QT prolongation, and subsequently cardiogenic shock due to fulminant myocarditis. He later developed hypertensive crisis. The adrenal mass on abdominal computed tomography with an increased chromogranin A level and elevated plasma normetanephrine, and the histological study confirmed the diagnosis of pheochromocytoma. Cardiac functions completely recovered after adrenalectomy. Genetic testing was positive for von Hippel-Lindau syndrome. We describe pheochromocytoma crisis presenting with prolonged QT and catecholamine-induced myocarditis. We discuss the clues to assist in the diagnosis of this condition and its appropriate treatment. [ABSTRACT FROM AUTHOR]

Chronic watery diarrhea poses a diagnostic and therapeutic challenge and is often a disabling condition for patients. Although acute diarrhea is likely to be caused by infection, the causes of chronic diarrhea (>4 weeks in duration) are more elusive. We review the pathophysiology, diagnosis, and treatment of chronic diarrhea. Drawing on recent insights into the molecular mechanisms of intestinal epithelial transport and barrier function, we discuss how diarrhea can result from a decrease in luminal solute absorption, an increase in secretion, or both, as well as derangements in barrier properties. We also describe the various extraepithelial factors that activate diarrheal mechanisms. Finally, clinical evaluation and tests used in the assessment of patients presenting with chronic diarrhea are reviewed, and an algorithm guiding therapeutic decisions and pharmacotherapy is presented.