To investigate the association between serum calcium and risk of breast cancer using a large cohort and a systematic review with meta-analysis. From the Swedish Apolipoprotein Mortality Risk (AMORIS) Study we included 229,674 women who had baseline measurements of serum total calcium and albumin. Multivariable Cox regression was used to assess the association between total and albumin-corrected calcium and breast cancer risk. For the systematic review, an electronic search of MEDLINE and EMBASE databases was performed to identify other prospective cohorts assessing the relationship between serum calcium and breast cancer risk. We pooled the results of our AMORIS cohort with other eligible studies in a meta-analysis using a random effects model. I² test was used to assess heterogeneity. In the AMORIS study, 10,863 women were diagnosed with breast cancer (mean follow-up: 19 years). We found an inverse association between total serum calcium and breast cancer when comparing the fourth quartile to the first quartile (HR: 0.94, 95% CI: 0.88-0.99, p value for trend 0.04) and similar results using albumin-corrected calcium. In the systematic review, we identified another two prospective cohorts evaluating pre-diagnostic serum total calcium and breast cancer. Combining these studies and our findings in AMORIS in a meta-analysis showed a protective effect of serum calcium against breast cancer, with a summary RR of 0.80 (95% CI: 0.66-0.97). No substantial heterogeneity was observed. Our findings in AMORIS and the meta-analysis support an inverse association between serum calcium and breast cancer risk, which warrants mechanistic investigations.

Patients with advanced chronic kidney disease exhibit an increase in cardiovascular mortality. Recent works have shown that low levels of magnesium are associated with increased cardiovascular and all-cause mortality in hemodialysis patients. Epidemiological studies suggest an influence of low levels of magnesium on the occurrence of cardiovascular disease, which is also observed in the normal population. Magnesium is involved in critical cellular events such as apoptosis and oxidative stress. It also participates in a number of enzymatic reactions. In animal models of uremia, dietary supplementation of magnesium reduces vascular calcifications and mortality; in vitro, an increase of magnesium concentration decreases osteogenic transdifferentiation of vascular smooth muscle cells. Therefore, it may be appropriate to evaluate whether magnesium replacement should be administered in an attempt to reduce vascular damage and mortality in the uremic population In the present manuscript, we will review the magnesium homeostasis, the involvement of magnesium in enzymatic reactions, apoptosis and oxidative stress and the clinical association between magnesium and cardiovascular disease in the general population and in the context of chronic kidney disease. We will also analyze the role of magnesium on kidney function. Finally, the experimental evidence of the beneficial effects of magnesium replacement in chronic kidney disease will be thoroughly described.

Dietary patterns influence cancer risk. However, systematic reviews have not evaluated relationships between a priori defined diet quality scores and adult cancer risk and mortality. The aims of this systematic review are to (1) describe diet quality scores used in cohort or cross-sectional research examining cancer outcomes; and (2) describe associations between diet quality scores and cancer risk and mortality. The protocol was registered in Prospero, and a systematic search using six electronic databases was conducted through to December 2014. Records were assessed for inclusion by two independent reviewers, and quality was evaluated using a validated tool. Sixty-four studies met inclusion criteria from which 55 different diet quality scores were identified. Of the 35 studies investigating diet quality and cancer risk, 60% (n = 21) found a positive relationship. Results suggest no relationship between diet quality scores and overall cancer risk. Inverse associations were found for diet quality scores and risk of postmenopausal breast, colorectal, head, and neck cancer. No consistent relationships between diet quality scores and cancer mortality were found. Diet quality appears to be related to site-specific adult cancer risk. The relationship with cancer mortality is less conclusive, suggesting additional factors impact overall cancer survival. Development of a cancer-specific diet quality score for application in prospective epidemiology and in public health is warranted.

The pathogenesis of endometriosis is unknown, but some evidence supports a genetic predisposition. The purpose of this study was to evaluate the recent literature on the genetic characterization of women affected by endometriosis and to evaluate the influence of polymorphisms of the wingless-type mammalian mouse tumour virus integration site family member 4 (WNT4), vezatin (VEZT), and follicle stimulating hormone beta polypeptide (FSHB) genes, already known to be involved in molecular mechanisms associated with the proliferation and development of endometriotic lesions in the Sardinian population. Materials and Methods: In order to provide a comprehensive and systematic tool for those approaching the genetics of endometriosis, the most cited review, observational, cohort and case-control studies that have evaluated the genetics of endometriosis in the last 20 years were collected. Moreover, 72 women were recruited for a molecular biology analysis of whole-blood samples-41 patients affected by symptomatic endometriosis and 31 controls. The molecular typing of three single nucleotide polymorphisms (SNPs) was evaluated in patients and controls: rs7521902, rs10859871 and rs11031006, mapped respectively in the WNT4, VEZT and FSHB genes. In this work, the frequency of alleles, genotypes and haplotypes of these SNPs in Sardinian women is described. Results: From the initial search, a total of 73 articles were chosen. An analysis of the literature showed that in endometriosis pathogenesis, the contribution of genetics has been well supported by many studies. The frequency of genotypes observed in the groups of the study population of 72 women was globally coherent with the law of the Hardy-Weinberg equilibrium. For the SNP rs11031006 (FSHB), the endometriosis group did not show an increase in genotypic or allelic frequency due to this polymorphism compared to the control group (p = 0.9999, odds ratio (OR) = 0.000, 95% confidence interval (CI), 0.000-15.000 and p = 0.731, OR = 1639, 95% CI, 0.39-683, respectively, for the heterozygous genotype and the polymorphic minor allele). For the SNP rs10859871 (VEZT), we found a significant difference in the frequency of the homozygous genotype in the control group compared to the affected women (p = 0.0111, OR = 0.0602, 95% CI, 0.005-0.501). For the SNP rs7521902 (WNT4), no increase in genotypic or allelic frequency between the two groups was shown (p = 0.3088, OR = 0.4133, 95% CI, 0.10-1.8 and p = 0.3297, OR = 2257, 95% CI, 0.55-914, respectively, for the heterozygous genotype and the polymorphic minor allele). Conclusion: An analysis of recent publications on the genetics of endometriosis showed a discrepancy in the results obtained in different populations. In the Sardinian population, the results obtained do not show a significant association between the investigated variants of the genes and a greater risk of developing endometriosis, although several other studies in the literature have shown the opposite. Anyway, the data underline the importance of evaluating genetic variants in different populations. In fact, in different ethnic groups, it is possible that specific risk alleles could act differently in the pathogenesis of the disease.

Chagas disease remains a major social and public health problem in Latin America. Benznidazole (BZN) is the main drug with activity against Trypanosoma cruzi. Due to the high number of adverse drug reactions (ADRs), BZN is underprescribed. The goal of this study was to evaluate the genetic and transcriptional basis of BZN adverse reactions.

The efficacy and safety of first-line disease-modifying therapies (DMT) for relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in pivotal, randomized trials, but these studies do not reflect the routine care setting where treatment gaps or switches are common. The Avonex as Treatment Option for Untreated MS Patients (AXIOM) trial assessed the efficacy of newly-initiated intramuscular interferon beta-1a (IM IFNb-1a) after a treatment-free interval, with particular consideration of the previous course of disease and therapy. The AXIOM trial was an open, 12-month, observational, non-interventional study with a retrospective and a prospective part conducted in Germany. RRMS patients with a treatment-free interval of at least three months were included and treated with IFNb-1a for up to 12 months. Relapse rate, disability progression, injection-related parameters and quality of life observed during the prospective part were compared with retrospectively-collected data. Two hundred and thirty five RRMS patients participated in AXIOM. The mean relapse rate decreased from 1.1 in the three months before baseline to 0.2 per quarter during the twelve-month observational period; the Multiple Sclerosis Functional Composite score improved during twelve months of IM IFNb-1a treatment, while the Expanded Disability Status Scale score did not change over the course of this study. Compared to previous DMTs (IM IFNb-1a, subcutaneous IFNb-1a (SC IFNb-1a), SC IFNb-1b, glatiramer acetate), the patients experienced less injection site reactions and flu-like symptoms, with a stated improved quality of life. IM IFNb-1a was effective and well accepted in RRMS patients with no or discontinued previous therapy. These results from the routine care setting may inform optimization of DMT treatment in RRMS, but need confirmation in further studies.

A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (1⁻16) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist 4 shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.p.). However, only H3R antagonist 13, without appreciable protective effects in MES- and PTZ-induced seizure, fully protected animals in the strychnine (STR)-induced GTCS following acute systemic pretreatment (10 mg/kg, i.p.). Moreover, the protective effect observed with H3R antagonist 4 in MES-induced seizure was completely abolished when animals were co-administered with the H3R agonist (R)-α-methylhistamine (RAMH, 10 mg/kg, i.p.). However, RAMH failed to abolish the full protection provided by the H3R antagonist 4 in PTZ-induced seizure and H3R antagonist 13 in STR-induced seizure. Furthermore, in vitro antiproliferative effects or possible metabolic interactions could not be observed for compound 4. Additionally, the predictive in silico, as well as in vitro, metabolic stability for the most promising H3R antagonist 4 was assessed. The obtained results show prospective effects of non-imidazole H3R antagonists as innovative antiepileptic drugs (AEDs) for potential single use against epilepsy.

Heat shock proteins (HSPs) constitute a major part of the molecular chaperone system and play a fundamental role in cell proteostasis. The HSPA (HSP70) family groups twelve highly homologous HSPA proteins. Certain HSPAs are regarded as important cancer-related proteins, prospective therapeutic targets for cancer treatment, and also as potential cancer biomarkers. Heat Shock Protein A2 (HSPA2), a testis-enriched chaperone and one of the least characterized members of the HSPA family, has recently emerged as an important cancer-relevant protein with potential biomarker significance. Nevertheless, conflicting conclusions have been recently drawn both according to HSPA2 role in cancer cells, as well as to its prognostic value. In this work we have shown that one of the serious limitations in HSPA2 protein research is cross-reactivity of antibodies marketed as specific for HSPA2 with one or more other HSPA(s). Among non-specific antibodies were also those recently used for HSPA2 detection in functional and biomarker studies. We showed how using non-specific antibodies can generate misleading conclusions on HSPA2 expression in non-stressed cancer cells and tumors, as well as in cancer cells exposed to proteotoxic stress. Our findings addressed concerns on some published studies dealing with HSPA2 as a cancer-related protein.

Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (Zn(II)) thiosemicarbazone complexes [Zn(atc-Et)₂] (1) and [Zn(atc-Ph)₂] (2) (atc-R: monovalent anion of 2-acetylpyridine N4-R-thiosemicarbazone) were synthesized and fully characterized in the solid state and in solution via elemental analysis, Fourier transform infrared (FTIR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (¹H NMR) spectroscopy, conductometry and single-crystal X-ray diffraction. The cytotoxicity of these complexes was evaluated in the HepG2, HeLa, MDA-MB-231, K-562, DU 145 and MRC-5 cancer cell lines. The strongest antiproliferative results were observed in MDA-MB-231 and HepG2 cells, in which these complexes displayed significant selective toxicity (3.1 and 3.6, respectively) compared with their effects on normal MRC-5 cells. In vivo studies were performed using an alternative model (Artemia salina L.) to assure the safety of these complexes, and the results were confirmed using a conventional model (BALB/c mice). Finally, tests of oral bioavailability showed maximum plasma concentrations of 3029.50 µg/L and 1191.95 µg/L for complexes 1 and 2, respectively. According to all obtained results, both compounds could be considered as prospective antiproliferative agents that warrant further research.

Althoughanti-inflammatory drug therapy has been identified as potentially beneficial for patients suffering from chronic subdural hematoma (cSDH), contemporary literature presents contradictory results. In this meta-analysis, we aimed to investigate the impact of anti-inflammatory drug therapy on mortality and outcome. We searched for eligible randomized, placebo-controlled prospective trials (RTCs) on PubMed, Embase and Medline until July 2022. From 97 initially identified articles, five RTCs met the criteria and were included in our meta-analysis. Our results illustrate significantly lower rates of recurrent cSDH (OR: 0.35; 95% CI: 0.21-0.58, p = 0.0001) in patients undergoing anti-inflammatory therapy. In the subgroup of patients undergoing primary conservative treatment, anti-inflammatory therapy was associated with lower rates of "switch to surgery" cases (OR: 0.30; 95% CI: 0.14-0.63, p = 0.002). Despite these findings, anti-inflammatory drugs seemed to be associated with higher mortality rates in patients undergoing surgery (OR: 1.76; 95% CI: 1.03-3.01, p = 0.04), although in the case of primary conservative treatment, no effect on mortality has been observed (OR: 2.45; 95% CI: 0.35-17.15, p = 0.37). Further multicentric prospective randomized trials are needed to evaluate anti-inflammatory drugs as potentially suitable therapy for asymptomatic patients with cSDH to avoid the necessity of surgical hematoma evacuation on what are predominantly elderly, vulnerable, patients.

A new combination of Toceranib (Toc; 5-[(5Z)-(5-Fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrrole-3-carboxamide) with nanohydroxyapatite (nHAp) was proposed as an antineoplastic drug delivery system. Its physicochemical properties were determined as crystallinity, grain size, morphology, zeta potential and hydrodynamic diameter as well as Toceranib release. The crystalline nanorods of nHAp were synthesised by the co-precipitation method, while the amorphous Toceranib was obtained by its conversion from the crystalline form during nHAp-Toc preparation. The surface interaction between both compounds was confirmed using Fourier-transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV-Vis) and scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDS). The nHAp-Toc showed a slower and prolonged release of Toceranib. The release behaviour was affected by hydrodynamic size, surface interaction and the medium used (pH). The effectiveness of the proposed platform was tested by comparing the cytotoxicity of the drug combined with nHAp against the drug itself. The compounds were tested on NI-1 mastocytoma cells using the Alamar blue colorimetric technique. The obtained results suggest that the proposed platform shows high efficiency (the calculated IC50 is 4.29 nM), while maintaining the specificity of the drug alone. Performed analyses confirmed that nanohydroxyapatite is a prospective drug carrier and, when Toceranib-loaded, may be an idea worth developing with further research into therapeutic application in the treatment of canine mast cell tumour.

Since myeloproliferative neoplasms (MPN) pose a significant risk for vascular and thrombotic complications, cytoreductive therapies, such as hydroxyurea (HU), interferon (IFN) inhibitors, and Janus kinase (JAK) inhibitors are recommended for patients at high risk. However, these agents also place patients at increased risk for drug-related cutaneous adverse events. Herein, we review the literature on skin toxicity related to the use of drugs for the treatment of MPN. Overall, the cytoreductive agents used for MPN are generally well tolerated and considered to be safe, except IFN, for which dropout rates as high as 25% have been reported. While IFN is known to give rise to flu syndrome, it rarely leads to hematological alterations. The most common hematological side effects of HU are mild and include granulocytopenia, anemia, and thrombocytopenia. The JAK inhibitor ruxolitinib has been associated with cytopenia and a higher incidence of viral infections, as well as increased risk for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Based on the present analysis, it can be concluded that cutaneous toxicity is not a negligible complication of commonly used treatments for MPN. While further research is needed, patients on these agents, and especially those with a history of cutaneous malignancies, should undergo thorough skin examination before and during therapy. In addition, detailed history is critical since many patients who develop non-melanoma skin cancer have multiple preexisting risk factors for cutaneous carcinogenesis.

Head and neck squamous cell carcinoma (HNSCC) is a group of tumours which exhibit low 5 year survival rates. Thus, there is an urgent need to identify biomarkers that may improve the clinical utility of patients with HNSCC. Emerging studies support a role of toll-like receptors (TLRs) in carcinogenesis. Therefore, this systematic review and meta-analysis was performed to assess the prognostic value of TLR immunoexpression in HNSCC patients. We compiled the results of thirteen studies comprising 1825 patients, of which six studies were deemed qualified for quantitative synthesis. The higher immunoexpression of TLR-1 to 5 and 9 was associated with a worsening of the clinical parameters of patients with HNSCC. Furthermore, induced levels of TLR-3, 4, 5, 7 and 9 were found to predict the patients' survival time. The meta-analysis revealed that TLR-7 overexpression is associated with a decreased mortality risk in HNSCC patients (HR 0.51; 95%CI 0.13-0.89; I2 34.6%), while a higher expression of TLR-5 predicted shorter, but non-significant, survival outcome. In conclusion, this review suggests that TLRs may represent some prognostic value for patients with HNSCC. However, due to small sample sizes and other inherent methodological limitations, more well designed studies across different populations are still needed before TLRs can be recommended as a reliable clinical risk-stratification tool.

Oxidative stress is involved in a wide range of age-related diseases. A critical role has been proposed for mitochondrial oxidative stress in initiating or promoting these pathologies and the potential for mitochondria-targeted antioxidants to fight them, making their search and testing a very urgent task. In this study, the mitochondria-targeted antioxidants SkQ1, SkQ3 and MitoQ were examined as they affected isolated rat liver mitochondria and yeast cells, comparing SkQ3 with clinically tested SkQ1 and MitoQ. At low concentrations, all three substances stimulated the oxidation of respiratory substrates in state 4 respiration (no ADP addition); at higher concentrations, they inhibited the ADP-triggered state 3 respiration and the uncoupled state, depolarized the inner mitochondrial membrane, contributed to the opening of the mPTP (mitochondrial permeability transition pore), did not specifically affect ATP synthase, and had a pronounced antioxidant effect. SkQ3 was the most active antioxidant, not possessing, unlike SkQ1 or MitoQ, prooxidant activity with increasing concentrations. In yeast cells, all three substances reduced prooxidant-induced intracellular oxidative stress and cell death and prevented and reversed mitochondrial fragmentation, with SkQ3 being the most efficient. These data allow us to consider SkQ3 as a promising potential therapeutic agent to mitigate pathologies associated with oxidative stress.

In this study, we investigated the effects of temozolomide (TMZ)/Poly (lactide-co-glycolide)(PLGA)/nano-hydroxyapatite microspheres on the behavior of U87 glioma cells. The microspheres were fabricated by the "Solid/Water/Oil" method, and they were characterized by using X-Ray diffraction, scanning electron microscopy and differential scanning calorimetry. The proliferation, apoptosis and invasion of glioma cells were evaluated by MTT, flow cytometry assay and Transwell assay. The presence of the key invasive gene, α(V)β3 integrin, was detected by the RT-PCR and Western blot method. It was found that the temozolomide/PLGA/nano-hydroxyapatite microspheres have a significantly diminished initial burst of drug release, compared to the TMZ laden PLGA microspheres. Our results suggest they can significantly inhibit the proliferation and invasion of glioma cells, and induce their apoptosis. Additionally, α(V)β3 integrin was also reduced by the microspheres. These data suggest that by inhibiting the biological behavior of glioma cells in vitro, the newly designed temozolomide/PLGA/nano-hydroxyapatite microspheres, as controlled drug release carriers, have promising potential in treating glioma.

We demonstrate strong spectral dependence of the efficiency of fluorescence quenching in molecular systems composed of organic dyes and gold nanoparticles. In order to probe the coupling with metallic nanoparticles we use dyes with varied spectral overlap between the plasmon resonance and their absorption. Hybrid molecular structures were obtained via conjugation of metallic nanoparticles with the dyes using biotin-streptavidin linkage. For dyes featuring absorption above the plasmon excitation in gold nanoparticles, laser excitation induces minute changes in the fluorescence intensity and its lifetime for both conjugated and non-conjugated mixtures, which are the reference. In contrast, when the absorption of the dye overlaps with the plasmon resonance, the effect is quite dramatic, reaching 85% and 95% fluorescence quenching for non-conjugated and conjugated mixtures, respectively. The degree of fluorescence quenching strongly depends upon the concentration of metallic nanoparticles. Importantly, the origin of the fluorescence quenching is different in the case of the conjugated mixture, as evidenced by time-resolved fluorescence. For conjugated mixtures of dyes resonant with plasmon, excitation features two-exponential decay. This is in contrast to the single exponential decay measured for the off-resonant configuration. The results provide valuable insight into spectral dependence of the fluorescence quenching in molecular assemblies involving organic dyes and metallic nanoparticles.

Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64-10.43, I2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC.

Background: Immune checkpoint inhibitors (ICI) have represented a revolution in the treatment of non-small-cell lung cancer (NSCLC). To improve these results, combined approaches are being tested. The addition of stereotactic ablative radiotherapy (SABR) to ICI seems promising. A systematic review was performed in order to assess the safety and efficacy of SABR-ICI combination. Material and Methods: MEDLINE databases from 2009 to March 3, 2019 were reviewed to obtain English language studies reporting clinical outcomes of the combination of ICI-SABR in NSCLC. 18 out of the 429 initial results fulfilled the inclusion criteria and were selected for review. Results: Eighteen articles, including six prospective studies, describing 1736 patients treated with an ICI-SABR combination fulfilled the selection criteria. The reported mean rates for local control and distant/abscopal response rates were 71% and 41%, respectively. Eleven studies reported progression-free survival and overall survival, with a mean of 4.6 and 12.4 months, respectively. Toxicity rates were consistent with the ones attributable to ICI treatment alone. Conclusions: The ICI-SABR combination has a good safety profile and achieves high rates of local control and greater chances of obtaining abscopal responses than SABR alone, with a relevant impact on PFS. More studies are needed to improve patient selection for an optimal benefit from this approach.

FcRn plays a major role in regulating immune homeostasis, but it is also able to transport biologics across cellular barriers. The question of whether FcRn could be an efficient transporter of biologics across the nasal epithelial barrier is of particular interest, as it would allow a less invasive strategy for the administration of biologics in comparison to subcutaneous, intramuscular or intravenous administrations, which are often used in clinical practice. A focused systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was registered on the international prospective register of systematic reviews PROSPERO, which helped in identifying articles that met the inclusion criteria. Clinical and preclinical studies involving FcRn and the nasal delivery of biologics were screened, and the risk of bias was assessed across studies using the Oral Health Assessment Tool (OHAT). Among the 12 studies finally included in this systematic review (out of the 758 studies screened), 11 demonstrated efficient transcytosis of biologics through the nasal epithelium. Only three studies evaluated the potential toxicity of biologics' intranasal delivery, and they all showed that it was safe. This systematic review confirmed that FcRn is expressed in the nasal airway and the olfactory epithelium, and that FcRn may play a role in IgG and/or IgG-derived molecule-transcytosis across the airway epithelium. However, additional research is needed to better characterize the pharmacokinetic and pharmacodynamic properties of biologics after their intranasal delivery.

The biologic and prognostic value of focal neuroendocrine differentiation (NED) in conventional prostate adenocarcinoma (PC) patients who undergo radical prostatectomy (RP) remains controversial. In this systematic review and meta-analysis, we assessed the association of focal NED in conventional PC with oncological outcomes after RP. A literature search using PubMed, Scopus, Web of Science, and Cochrane Library was conducted on December 2018 to find relevant studies according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We used a fixed-effect model to analyze the impact of focal NED in RP specimen on progression-free survival defined by biochemical recurrence (BCR). A total of 16 studies with the outcomes of disease progression and survival were eligible. No patient in these studies received androgen deprivation therapy prior to RP. Eleven studies found no significant correlation between focal NED and outcomes of interest, while five studies reported a significant association of focal NED assessed by immunohistochemical chromogranin A or serotonin staining with BCR or survival. Focal NED was associated with higher BCR rates after RP with a pooled HR of 1.39 (95% CI 1.07‒1.81) in five studies. No heterogeneity was reported in this analysis (I² = 21.7%, p = 0.276). In conclusion, focal NED in conventional PC is associated with worse prognosis after RP. Its presence should be reported in pathologic reports and its true clinical impact should be assessed in well-designed prospective controlled studies.