Use of Oleuropein and Hydroxytyrosol for Cancer Prevention and Treatment: Considerations about How Bioavailability and Metabolism Impact Their Adoption in Clinical Routine.

The fact that the Mediterranean diet could represent a source of natural compounds with cancer-preventive and therapeutic activity has been the object of great interest, especially with regard to the mechanisms of action of polyphenols found in olive oil and olive leaves. Secoiridoid oleuropein (OLE) and its derivative hydroxytyrosol (3,4-dihydroxyphenylethanol, HT) have demonstrated anti-proliferative properties against a variety of tumors and hematological malignancies both in vivo and in vitro, with measurable effects on cellular redox status, metabolism, and transcriptional activity. With this review, we aim to summarize the most up-to-date information on the potential use of OLE and HT for cancer treatment, making important considerations about OLE and HT bioavailability, OLE- and HT-mediated effects on drug metabolism, and OLE and HT dual activity as both pro- and antioxidants, likely hampering their use in clinical routine. Also, we focus on the details available on the effects of nutritionally relevant concentrations of OLE and HT on cell viability, redox homeostasis, and inflammation in order to evaluate if both compounds could be considered cancer-preventive agents or new potential chemotherapy drugs whenever their only source is represented by diet.

A Combination of Polymethoxyflavones from Citrus sinensis and Prenylflavonoids from Humulus lupulus Counteracts IL-1ß-Induced Differentiated Caco-2 Cells Dysfunction via a Modulation of NF-κB/Nrf2 Activation.

We here investigated the anti-inflammatory activity of a polymethoxylated flavone-containing fraction (PMFF) from Citrus sinensis and of a prenylflavonoid-containing one (PFF) from Humulus lupulus, either alone or in combination (MIX). To this end, an in vitro model of inflammatory bowel disease (IBD), consisting of differentiated, interleukin (IL)-1ß-stimulated Caco-2 cells, was employed. We demonstrated that non-cytotoxic concentrations of either PMFF or PFF or MIX reduced nitric oxide (NO) production while PFF and MIX, but not PMFF, also inhibited prostaglandin E2 release. Coherently, MIX suppressed both inducible NO synthase and cyclooxygenase-2 over-expression besides NF-κB activation. Moreover, MIX increased nuclear factor erythroid 2-related factor 2 (Nrf2) activation, heme oxygenase-1 expression, restoring GSH and reactive oxygen and nitrogen species (RONs) levels. Remarkably, these effects with MIX were stronger than those produced by PMFF or PFF alone. Noteworthy, nobiletin (NOB) and xanthohumol (XTM), two of the most represented phytochemicals in PMFF and PFF, respectively, synergistically inhibited RONs production. Overall, our results demonstrate that MIX enhances the anti-inflammatory and anti-oxidative effects of the individual fractions in a model of IBD, via a mechanism involving modulation of NF-κB and Nrf2 signalling. Synergistic interactions between NOB and XTM emerge as a relevant aspect underlying this evidence.

Anti-Inflammatory Effects of Nutritionally Relevant Concentrations of Oleuropein and Hydroxytyrosol on Peripheral Blood Mononuclear Cells: An Age-Related Analysis.

Immunosenescence and inflammaging facilitate the insurgence of chronic diseases. The Mediterranean diet is a non-invasive intervention to improve the chronic low-grade inflammatory status associated with aging. Olive oil oleuropein (OLE) and hydroxytyrosol (HT) demonstrated a controversial modulatory action on inflammation in vitro when tested at concentrations exceeding those detectable in human plasma. We studied the potential anti-inflammatory effects of OLE and HT at nutritionally relevant concentrations on peripheral blood mononuclear cells (PBMCs) as regards cell viability, frequency of leukocyte subsets, and cytokine release, performing an age-focused analysis on two groups of subjects: Adult (age 18-64 years) and Senior (age ≥ 65 years). OLE and HT were used alone or as a pre-treatment before challenging PBMCs with lipopolysaccharide (LPS). Both polyphenols had no effect on cell viability irrespective of LPS, but 5 µM HT had an LPS-like effect on monocytes, reducing the intermediate subset in Adult subjects. OLE and HT had no effect on LPS-triggered release of TNF-α, IL-6 and IL-8, but 5 µM HT reduced IL-10 secretion by PBMCs from Adult vs. Senior group. In summary, nutritionally relevant concentrations of OLE and HT elicit no anti-inflammatory effect and influence the frequency of immune cell subsets with age-related different outcomes.

Distribution of KIR Genes and Their HLA Ligands in Different Viral Infectious Diseases: Frequency Study in Sicilian Population.

Natural killer (NK) cells play a role in defence against viral infections by killing infected cells or by producing cytokines and interacting with adaptive immune cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leucocyte antigens (HLA). Ninety-six Sicilian patients positive to Human Immunodeficiency Virus-1 (HIV) and ninety-two Sicilian patients positive to SARS-CoV-2 were genotyped for KIRs and their HLA ligands. We also included fifty-six Sicilian patients with chronic hepatitis B (CHB) already recruited in our previous study. The aim of this study was to compare the distribution of KIR-HLA genes/groups of these three different infected populations with healthy Sicilian donors from the literature. We showed that the inhibitory KIR3DL1 gene and the KIR3DL1/HLA-B Bw4 pairing were more prevalent in individual CHB. At the same time, the frequency of HLA-C2 was increased in CHB compared to other groups. In contrast, the HLA-C1 ligand seems to have no contribution to CHB progression whereas it was significantly higher in COVID-19 and HIV-positive than healthy controls. These results suggest that specific KIR-HLA combinations can predict the outcome/susceptibility of these viral infections and allows to plan successful customized therapeutic strategies.

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells.

The number of people that are 65 years old or older has been increasing due to the improvement in medicine and public health. However, this trend is not accompanied by an increase in quality of life, and this population is vulnerable to most illnesses, especially to infectious diseases. Vaccination is the best strategy to prevent this fact, but older people present a less efficient response, as their immune system is weaker due mainly to a phenomenon known as immunosenescence. The adaptive immune system is constituted by two types of lymphocytes, T and B cells, and the function and fitness of these cell populations are affected during ageing. Here, we review the impact of ageing on T and B cells and discuss the approaches that have been described or proposed to modulate and reverse the decline of the ageing adaptive immune system.

How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells.

Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor. Alterations in function, number, subset, and distribution of blood neutrophils, monocytes, and natural killer and dendritic cells are detected in aging, thus potentially reducing the efficacy of vaccines in older individuals. In this paper, we focus on the immunosenescence of the innate blood immune cells. We discuss possible strategies to counteract the immunosenescence of innate immunity in order to improve the response to vaccination. In particular, we focus on advances in understanding the role and the development of new adjuvants, such as TLR agonists, considered a promising strategy to increase vaccination efficiency in older individuals.

Effects of Oleuropein and Hydroxytyrosol on Inflammatory Mediators: Consequences on Inflammaging.

Aging is associated with a low-grade, systemic inflammatory state defined as "inflammaging", ruled by the loss of proper regulation of the immune system leading to the accumulation of pro-inflammatory mediators. Such a condition is closely connected to an increased risk of developing chronic diseases. A number of studies demonstrate that olive oil phenolic compound oleuropein and its derivative hydroxytyrosol contribute to modulating tissue inflammation and oxidative stress, thus becoming attractive potential candidates to be used in the context of nutraceutical interventions, in order to ameliorate systemic inflammation in aging subjects. In this review, we aim to summarize the available data about the anti-inflammatory properties of oleuropein and hydroxytyrosol, discussing them in the light of molecular pathways involved in the synthesis and release of inflammatory mediators in inflammaging.

Immunopathology and Immunosenescence, the Immunological Key Words of Severe COVID-19. Is There a Role for Stem Cell Transplantation?

The outcomes of Coronavirus disease-2019 (COVID-19) vary depending on the age, health status and sex of an individual, ranging from asymptomatic to lethal. From an immunologic viewpoint, the final severe lung damage observed in COVID-19 should be caused by cytokine storm, driven mainly by interleukin-6 and other pro-inflammatory cytokines. However, which immunopathogenic status precedes this "cytokine storm" and why the male older population is more severely affected, are currently unanswered questions. The aging of the immune system, i.e., immunosenescence, closely associated with a low-grade inflammatory status called "inflammageing," should play a key role. The remodeling of both innate and adaptive immune response observed with aging can partly explain the age gradient in severity and mortality of COVID-19. This review discusses how aging impacts the immune response to the virus, focusing on possible strategies to rejuvenate the immune system with stem cell-based therapies. Indeed, due to immunomodulatory and anti-inflammatory properties, multipotent mesenchymal stem cells (MSCs) are a worth-considering option against COVID-19 adverse outcomes.

Healthy ageing and Mediterranean diet: A focus on hormetic phytochemicals.

Mediterranean diet (MedDiet) is rich in fruits and vegetables associated with longevity and a reduced risk of several age-related diseases. It is demonstrated that phytochemicals in these plant products enhance the positive effects of MedDiet by acting on the inflammatory state and reducing oxidative stress. Evidence support that these natural compounds act as hormetins, triggering one or more adaptive stress-response pathways at low doses. Activated stress-response pathways increase the expression of cytoprotective proteins and multiple genes that act as lifespan regulators, essential for the ageing process. In these ways, the hormetic response by phytochemicals such as resveratrol, ferulic acid, and several others in MedDiet might enhance cells' ability to cope with more severe challenges, resist diseases, and promote longevity. This review discusses the role of MedDiet phytochemicals in healthy ageing and the prevention of age-related diseases.

Analysis of T and NK cell subsets in the Sicilian population from young to supercentenarian: The role of age and gender.

Ageing dramatically affects number and function of both innate and adaptive arms of immune system, particularly T cell subsets, contributing to reduced vaccination efficacy, decreased resistance to infections and increased prevalence of cancer in older people. In the present paper, we analysed the age-related changes in the absolute number of lymphocytes in 214 Sicilian subjects, and in the percentages of T and natural killer (NK) cells in a subcohort of donors. We compared these results with the immunophenotype of the oldest living Italian supercentenarian (aged 111 years). The results were also sorted by gender. The correlation between number/percentage of cells and age in all individuals. and separately in males and females, was examined using a simple linear regression analysis. We did not record the increase in the rate of inversion of the CD4/CD8 ratio, frequently reported as being associated with ageing in literature. Our observation was the direct consequence of a flat average trend of CD4+ and CD8+ T cell percentages in ageing donors, even when gender differences were included. Our results also suggest that CD4+ and CD8+ subsets are not affected equally by age comparing females with males, and we speculated that gender may affect the response to cytomegalovirus (CMV) infection. The supercentenarian showed a unique immunophenotypic signature regarding the relative percentages of her T cell subsets, with CD4+ and CD8+ T cell percentages and CD4+ naive T cell values in line with those recorded for the octogenarian subjects. This suggests that the supercentenarian has a naive 'younger' T cell profile comparable to that of a >80-year-old female.

The Role of Immunogenetics in COVID-19.

Coronavirus disease 2019 (COVID-19) is induced by SARS-CoV-2 and may arise as a variety of clinical manifestations, ranging from an asymptomatic condition to a life-threatening disease associated with cytokine storm, multiorgan and respiratory failure. The molecular mechanism behind such variability is still under investigation. Several pieces of experimental evidence suggest that genetic variants influencing the onset, maintenance and resolution of the immune response may be fundamental in predicting the evolution of the disease. The identification of genetic variants behind immune system reactivity and function in COVID-19 may help in the elaboration of personalized therapeutic strategies. In the frenetic look for universally shared treatment plans, those genetic variants that are common to other diseases/models may also help in addressing future research in terms of drug repurposing. In this paper, we discuss the most recent updates about the role of immunogenetics in determining the susceptibility to and the history of SARS-CoV-2 infection. We propose a narrative review of available data, speculating about lessons that we have learnt from other viral infections and immunosenescence, and discussing what kind of aspects of research should be deepened in order to improve our knowledge of how host genetic variability impacts the outcome for COVID-19 patients.

Targeting multiple myeloma with natural polyphenols.

Multiple myeloma (MM) is still an incurable hematologic malignancy. Although new therapeutic strategies have been developed to target different pathways in malignant cells, such as proliferation, differentiation, and apoptosis, better survival rates have also been achieved by the introduction of autologous stem cell transplantation (ASCT). Hematopoietic stem cell transplantation and novel targeted agents, such as proteasome inhibitors, monoclonal antibodies, immunomodulatory drugs, check-point inhibitors and epigenetic modulators, have significantly achieved long remission time and increased survival rates. However, most patients relapse, develop resistance, and eventually die because of refractory disease. All these issues highlight the need to investigate newer therapeutic targets to improve patient outcomes. Natural products play an important role in anti-tumor drug discovery, for this reason, in the investigation of novel natural anti-MM agents, we focused on natural polyphenols. Moreover, plant extracts show no or low toxicity towards normal cells and some of them have also a favorable pharmacokinetic profile. The biological activities of plant extracts are mainly due to their content in polyphenols, flavonoids, and terpenoids. Numerous studies showed that polyphenols, generally recognized as antioxidants, possess anticancer and pro-apoptosis properties. Other studies reported the potential clinical applications of flavonoids for their well-known protective and therapeutic effects against cancer, cardiovascular, and neurodegenerative diseases. The combination of plant extracts with anti-cancer drugs may offer a relevant advantage for therapeutic efficacy by sensitizing malignant cells to drugs and overcoming drug-induced resistance in cancer. For all these reasons, a significant number of polyphenolic compounds isolated from plants are still used nowadays in cancer clinical practice in combination with other drugs, also against hematologic malignancies.

Determinants of inappropriate hospitalization in cataract surgery in the south of Italy: a retrospective study.

PURPOSE: To analyze the frequency of inappropriate hospitalization in cataract surgery and the type of related determinants. METHODS: A nested retrospective case-control study was carried out on 2708 consecutive cataract surgery patients operated between January 2013 and December 2015. All cases with inappropriate hospitalization (day surgery or ordinary hospitalization) were compared with a control group of cases treated in an appropriate (day service) regimen. The predictive value for inappropriate admissions to the hospital was assessed using a logistic regression model. Significant variables from the univariate analysis were included in a multivariate model. RESULTS: Forty-five cases (< 2%) of inappropriate hospital admissions were recorded. Residence, heart disease, tremors, anticoagulants, intraoperative floppy iris syndrome were not related to appropriateness, while psychotic disorder (OR 12.571, p = 0.018), anxiety-depressive syndrome (OR 7.818, p = 0.010) and use of antipsychotropic drugs (OR 7.724, p = 0.002) were related to the inappropriateness of admission by univariate and multivariate analysis. Previous systemic surgeries were predictors of ordinary hospitalization by logistic regression analysis. A greater presence of hypertension, diabetes mellitus and fellow eye pseudophakia was noticed in appropriate hospitalization cases. CONCLUSIONS: This study detects the predictive role of psychiatric disorders as determinants of hospitalization inappropriateness in cataract surgery. The negative correlation between inappropriate hospitalization and conditions such as hypertension and diabetes points out that in the elderly population common diseases are effectively addressed, in contrast to the difficult management of psychiatric patients. Prior systemic interventions represent factors inducing transfer from day service to ordinary hospitalization, highlighting communication problems related to difficult coping with an outpatient surgery setting.

Case-based surveillance of measles in Sicily during 2012-2017: The changing molecular epidemiology and implications for vaccine strategies.

Following the indication of the World Health Organization, a national plan for the elimination of measles was approved in Italy and this included the improvement of the molecular surveillance of measles viruses and the interruption of indigenous transmission of the disease. Nevertheless, large outbreaks continue to occur in almost all regions of the country, including Sicily. Here we describe the epidemiology and molecular dynamics of measles viruses as a result of the measles surveillance activity carried out by the "Reference Laboratory for Measles and Rubella" in Sicily over a 5-year period. Biological samples of 259 suspected measles cases were tested for viral RNA detection and a total of 223 (86.1%) were classified as laboratory confirmed. The median age of confirmed measles cases was 21.0 years and about half of them were adults aged 19 years and older. Overall, one-third of the patients showed clinical complications and these latter were more common among adults than children (44.9% vs. 25.7%). The vast majority of measles cases were unvaccinated (94.2%, n = 210). The phylogenetic analysis of 221 measles virus nucleotide sequences revealed sporadic detections of genotypes D4 and H1, while endemic circulation of genotypes D8 and B3 was documented. Genotype D8 was associated with epidemics occurred between 2013 and 2016, whereas genotype B3 was more recently introduced into Sicily characterizing the current measles outbreak. The results of this study confirm the autochthonous co-circulation of viral variants belonging to different genotypes during the study period, and emphasizes the need of measles surveillance programmes in order to investigate the viral dynamics, the pathways of disease transmission, and to eventually adapt the development of successfull vaccine formulations.

Potential Therapeutic Applications of MDA-9/Syntenin-NF-κB-RKIP Loop in Human Liver Carcinoma.

BACKGROUND: Overexpression of MDA-9/Syntenin occurs in multiple human cancer cell lines and is associated with higher grade of tumor classification, invasiveness and metastasis. In some cases, its role in cancer biology depends on relationships between MDA-9/Syntenin and NF-κB. OBJECTIVE: This study aims to analyze the presence of a regulation loop like that between MDA-9/Syntenin - NF-κB - RKIP in human liver carcinoma. METHODS: Transient transfection was performed with siRNA anti-MDA-9/Syntenin. Expression of different factors was evaluated by Real time-PCR and Western blotting, while NF-κB activation by TransAM assay. Invasion capacity was analyzed by Matrigel Invasion Assay and the effects of agents on cell viability were examined by MTS assay. RESULTS: We have examined basal expression of MDA-9/Syntenin in three cell lines of human liver carcinoma (HA22T/VGH, Hep3B and HepG2). In all cell lines there was an inverse relationship between MDA-9/Syntenin and RKIP expression levels, and a positive correlation between MDA-9/Syntenin expression and NF-κB activation levels. By silencing with a siRNA anti-MDA-9/Syntenin we observed in all cell lines a very strong increase of RKIP at mRNA level. Interestingly, in all cell lines, inhibition of MDA- 9/Syntenin expression induced NF-κB downregulation and contemporary a reduction in invasion ability MMP-2 dependent. Finally, we showed a good additive effect of MDA- 9/Syntenin siRNA when associated with Curcumin or Doxorubicin on cell growth inhibition. CONCLUSION: Our data confirm the key role of MDA-9/Syntenin in HCC biology. The presence of a regulation loop among MDA-9/Syntenin, NF-κB and RKIP provide new pharmacological approaches.

The impact of polypharmacy and drug interactions among the elderly population in Western Sicily, Italy.

AIM: Primary endpoint was to report polypharmacy distribution in the general population vs ≥65 years old people and to examine the frequency of drug-drug interactions (DDIs) in the Health Local Unit of Palermo, Italy, in relationship with patients' age. METHODS: Drug prescription data for the year 2014 were extracted from the database of the Local Health Unit of Palermo Province, Italy. Patients were divided into five age groups (0-13, 14-64, 65-69, 70-74, and ≥75 year old). The detection of potential DDIs in polypharmacy profiles was performed with NavFarma software (Infologic srl, Padova, Italia), with DDI classification provided by tool Micromedex Drug Reax (Truven Health Analitics, Michigan, USA). RESULTS: We analyzed data of 1,324,641 patients, and 15,801,191 medical prescription were recorded; of these, 11,337,796 regarded chronic conditions. The drug prescriptions reached the highest values in the 65-69 and 70-74 age groups (p = 0.005 and p = 0.008 vs age 14-64 respectively). An overall amount of 6,094,373 DDIs were detected, of which 47,173 were contraindicated. Median number of DDIs was higher in 65-69 and 70-74 age groups (p = 0.008 and p = 0.012 vs age 14-64, respectively). Regarding contraindicated DDIs a significant difference was detected comparing 14-64 vs ≥65 age groups (p = 0.010 vs 65-69 group, p = 0.005 vs 70-74 group and ≥75 group). CONCLUSIONS: Polypharmacy is a phenomenon acquiring increasing dimensions also in our province. It interests particularly the older subjects, and assumes a dramatic accent when it is put in relationship with the frequency of DDIs. A proactive vigilance about potential life threatening drug interactions is mandatory.

Trends of influenza B during the 2010-2016 seasons in 2 regions of north and south Italy: The impact of the vaccine mismatch on influenza immunisation strategy.

Influenza A and B viruses are responsible for respiratory infections, representing globally seasonal threats to human health. The 2 viral types often co-circulate and influenza B plays an important role in the spread of infection. A 6-year retrospective surveillance study was conducted between 2010 and 2016 in 2 large administrative regions of Italy, located in the north (Liguria) and in the south (Sicily) of the country, to describe the burden and epidemiology of both B/Victoria and B/Yamagata lineages in different healthcare settings. Influenza B viruses were detected in 5 of 6 seasonal outbreaks, exceeding influenza A during the season 2012-2013. Most of influenza B infections were found in children aged ≤ 14 y and significant differences were observed in the age-groups infected by the different lineages. B/Victoria strains prevailed in younger population than B/Yamagata, but also were more frequently found in the community setting. Conversely, B/Yamagata viruses were prevalent among hospitalized cases suggesting their potential role in the development of more severe disease. The relative proportions of viral lineages varied from year to year, resulting in different lineage-level mismatch for the B component of trivalent influenza vaccine. Our findings confirmed the need for continuous virological surveillance of seasonal epidemics and bring attention to the adoption of universal influenza immunization program in the childhood. The use of tetravalent vaccine formulations may be useful to improve the prevention and control of the influenza burden in general population.

Bone marrow B lymphocytes in multiple myeloma and MGUS: Focus on distribution of naïve cells and memory subsets.

BACKGROUND/AIMS: Multiple myeloma (MM) is caused by proliferation of clonal plasma cells (cPCs) in bone marrow (BM), associated with numerical and functional defects in immune subsets. An impairment of B cell compartment is involved in onset/progression of the disease. METHODS: By flow cytometry, we studied distribution of naïve/transitional (IgD(+)CD27(-)), memory unswitched (IgD(+)CD27(+)), memory switched (IgD(-)CD27(+)) and double negative (DN) (IgD(-)CD27(-)) B lymphocytes in BM of control subjects, and responding and relapsing patients. RESULTS: We observed an increased percentage of IgD(+)CD27(+) B cells in healthy controls vs responding patients (p<0.05). Treated non complete responders exhibited an expanded DN compartment vs stringent complete responders (p=0.011); in turn IgD(+)CD27(-) subpopulation was larger in stringent complete responders vs other responding patients (p=0.006). None of the studied B cell subsets showed clonal restriction. Correlation analysis revealed negative correlations between naïve/transitional and DN B cells in all groups, except in newly diagnosed subjects. CONCLUSIONS: This may be considered a feasible start point to explore the importance of B cells in the immunosuppressive MM BM microenvironment, correlating these findings with immunosenescence and therapy related increased risk of infection. Moreover, we propose a possible role of naïve/transitional and DN B cells as predictive markers in treated patients.

Utility of CD54, CD229, and CD319 for the identification of plasma cells in patients with clonal plasma cell diseases.

BACKGROUND: Multiparameter flow cytometry (MFC) identification and characterization of plasma cells (PCs) is a useful tool to support diagnosis, prognostication, and monitoring of PC diseases (PCD). Currently, the number of MFC markers suited for the identification of PC remains limited. Moreover, antibody therapies against PC-associated markers further compromise the utility of the most widely used reagents (e.g., CD38). Despite markers other than CD38 and CD138 are recognized as potentially useful PC-identification markers, no study has comparatively evaluated their performance in combination with CD38 and CD138. Here we compared the utility of CD229, CD54, and CD319 for the identification of normal and aberrant PCs. METHODS: Bone marrow (BM) samples from 5 healthy controls, two noninfiltrated nonHodgkin lymphoma cases and 46 PCD patients plus 3 extraosseous plasmocytomas, and normal peripheral blood (PB) specimens, were studied. RESULTS: Our results showed adequate performance of all three markers once combined with CD38. In contrast, when combined with CD138 for the identification of PC, only CD229 provided a good discrimination between PCs and all other cells for all BM and PB samples analyzed; in contrast, CD54 and CD319 showed limited utility for the identification of PCs, mainly because of significant overlap of the staining for these two markers on PCs and other myeloid cells in the sample. CONCLUSIONS: From the three markers evaluated, CD229 may be considered as the most reliable marker to replace CD38 or CD138 for the identification of PCs in patients undergoing anti-CD38 or anti-CD138 therapy, until a better alternative is available.

Correlation between CD117+ myeloma plasma cells and hematopoietic progenitor cells in different categories of patients.

BACKGROUND: Multiple myeloma (MM) is a neoplastic disorder of plasma cells interesting mainly the elderly. MM remains an incurable disease, mostly because of the strong interplay between clonal plasma cells (cPCs) and bone marrow (BM) microenvironment. Multiparameter flow cytometry (MFC) allows the simultaneous study of the cPC immunophenotype and alterations involving other cells in BM, but rarely these data are interpreted as connected. One exception to this habit are previous studies about relationship between CD117 cPC positivity and hematopoietic progenitor cell (HPC) distribution in newly diagnosed patients. Thus we were interested in verifying the distribution of BM CD34+ HPCs in healthy controls, and monoclonal gammopathy of undetermined significance (MGUS) patients and various categories of responding/relapsing MM subjects divided according to CD117 positivity. RESULTS: Our data completely agree with precedent reports as regards untreated patients. In the group with progression of disease, CD117- patients exhibited a lower CD34 + CD19-/CD34 + CD19+ ratio vs CD117+ subjects. Among CD117- cases, newly diagnosed patients exhibited differences in distribution of HPCs vs responding myeloma subjects and patients with progressive disease. These differences reached statistical significance comparing CD117- newly diagnosed with CD117- responding cases, as reflected by CD34 + CD19-/CD34 + CD19+ ratio. In turn, no differences emerged comparing CD117+ treated and untreated patients. CONCLUSIONS: We demonstrate that administration of treatment and depth of reached response/presence of relapse imply a distinct regulation in distribution of CD34+ HPC subsets in CD117- and CD117+ patients. These differences become evident comparing untreated and treated CD117- patients, but they are impossible to detect in CD117+ cases.