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Objective: In a scenario of new expensive cancer therapies entering the market, strategies of optimisation and cost containment are crucial in oncology care. Better management of drug waste and centralization of drug preparation can be effective strategies to achieve these goals. The aim of this work is to describe the economic management of a high cost anticancer drug (ipilimumab) in some Italian reference centres. Methods: This was an observational, multicentred study in which economical and clinical data of 21 cancer centres (418 patients) were collected during the enrollment period from February 2013 to August 2014. The follow-up period ended in July 2015. Results: Participants purchased 10.7% more vials of ipilimumab than necessary for compounding. The results were variable among centres, and only five centres had a deviation lower than 5% between the drug purchased and the drug prescribed. Hospitals applying the drug day reached a statistically significant residual of drug effectively used compared to the amount prescribed (P = 0.018). Consequently, the price for treating a model patient was significantly lower in those hospitals (median spare of 7456 euro per patient). Conclusions: This study demonstrated that the careful management of drug waste and the application of drug-day, through a proper selection of vial and the ability to use the leftover drug, can generate economic savings. However, tailoring the drug stock to clinical need is still an open issue which deserves further analysis. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of metastatic NSCLC and have become standard first-line therapy both as monotherapy, for patients with PD-L1 expression ≥50%, and in combination with chemotherapy (CT), regardless of PD-L1 expression. This study used an artificial intelligence technique, the IPDfromKM method, to reconstruct individual patient data from Kaplan-Meier curves of phase III randomised clinical trial results to provide a comparative overview of different first-line chemo-immunotherapy options. Overall survival (OS) was estimated using hazard ratios and restricted mean survival time (RMST). Ten clinical trials were included in the analysis. In the squamous population, combinations of cemiplimab + CT (HR = 0.56), pembrolizumab + CT (HR = 0.67), and nivolumab + ipilimumab + CT (HR = 0.71) significantly improved OS compared with CT alone, with no difference between treatments. At longer follow-up, nivolumab + ipilimumab + CT showed longer RMST compared to pembrolizumab + CT in the PD-L1 < 1% subgroup (24.9 months vs. 22.8 months). In non-squamous NSCLC, the survival benefit of ICIs + CT was much more homogeneous, with similar results across the different options. Overall, pembrolizumab + CT showed the best results both in terms of HR (0.68, 95%CI 0.60-0.77) and RMST at long follow-up (30.4 months in the PDL-1 ≥ 1% subgroup and 24 months in the PDL-1 < 1% population). In conclusion, there are some differences between frontline options for treating metastatic NSCLC based on tumour histology and PD-L1 expression. However, further head-to-head trials and longer follow-up are needed to clarify the clinical impact of these differences.

Background: Patients with locally advanced/metastatic urothelial cancer have been conventionally treated with platinum-based chemotherapy. Recently, numerous new treatments have been proposed to improve overall survival (OS) and reduce adverse effects, but no direct head-to-head comparisons among these agents are available., Methods: The treatments evaluated in our analyses included (a) monotherapy with immune checkpoint inhibitors (ICI); (b) combinations of an ICI with chemotherapy; and (c) combinations of an ICI with other drugs. Using OS as the endpoint, a series of indirect comparisons were performed to rank the most effective regimens against both chemotherapy and each other. Our analysis was based on the application of an artificial intelligence software program (IPDfromKM method) that reconstructs individual patient data from the information reported in the graphs of Kaplan-Meier curves., Results: A total of five studies published in six articles were included. In our main analysis, nivolumab plus chemotherapy showed better OS compared to chemotherapy (HR = 0.70, 95% CI: 0.59-0.82), while durvalumab plus tremelimumab showed no OS benefit (HR = 0.95, 95% CI 0.82-1.11). More interestingly, enfortumab vedotin plus pembrolizumab significantly prolonged OS compared to both chemotherapy alone (HR = 0.53, 95% CI 0.45-0.63) and nivolumab plus chemotherapy (HR = 0.76, 95% CI 0.60-0.97)., Discussion and Conclusion: Among new treatments for locally advanced and metastatic urothelial cancer, enfortumab vedotin plus pembrolizumab showed the best efficacy in terms of OS. Our results support the use of this combination as a first-line treatment in this setting.

Background: The proven efficacy of mTOR inhibitors (mTORIs), tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma (RCC) suggests that these agents should be investigated as adjuvant therapy with the aim of eliminating undetectable microscopic residual disease after curative resection. The aim of our study was to compare the efficacy of these treatments using an innovative method of reconstructing individual patient data., Methods: Nine phase III trials describing adjuvant RCC treatments were selected. The IPDfromKM method was used to reconstruct individual patient data from Kaplan-Meier (KM) curves. The combination treatments were compared with the control arm (placebo) for disease-free survival (DFS). Multi-treatment KM curves were used to summarize the results. Standard statistical tests were performed. These included hazard ratio and likelihood ratio tests for heterogeneity., Results: In the overall population, the study showed that two ICIs (nivolumab plus ipilimumab and pembrolizumab) and one TKI (sunitinib) were superior to the placebo, whereas both TKIs and mTORIs were inferior. As we assessed DFS as the primary endpoint for the adjuvant comparison, the overall survival benefit remains unknown., Conclusions: This novel approach to investigating survival has allowed us to conduct all indirect head-to-head comparisons between these agents in a context where no "real" comparative trials have been conducted.

Background: Recently, numerous combination therapies based on immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors have been proposed as first-line treatments for advanced renal cell carcinoma (aRCC). Our study aimed to compare the efficacy of these combination regimens by the application of an innovative method that reconstructs individual patient data., Methods: Six phase III studies describing different combination regimens for aRCC were selected. Individual patient data were reconstructed from Kaplan-Meier (KM) curves through the "Shiny method". Overall survival (OS) and progression-free survival (PFS) were compared among combination treatments and sunitinib. Results were summarized as multi-treatment KM curves. Standard statistical testing was used, including hazard ratio and likelihood ratio tests for heterogeneity., Results: In the overall population of aRCC patients, pembrolizumab + lenvatinib showed the longest median PFS and was expected to determine the longest OS. Pembrolizumab + axitinib, nivolumab + cabozantinib and nivolumab + ipilimumab were similar in terms of PFS, but pembrolizumab + axitinib also demonstrated a better OS. Our subgroup analysis showed that sunitinib is still a valuable option, whereas, in intermediate-poor risk patients, pembrolizumab + axitinib and nivolumab + ipilimumab significantly improve OS compared to sunitinib., Conclusion: The Shiny method allowed us to perform all head-to-head indirect comparisons between these agents in a context in which "real" comparative trials have not been performed.

In the area of evidence-based medicine, the IPDfromKM-Shiny method is an innovative method of survival analysis, midway between artificial intelligence and advanced statistics. Its main characteristic is that an original software investigates the Kaplan-Meier graphs of trials so that individual-patient data are reconstructed. These reconstructed patients represent a new form of original clinical material. The typical objective of investigations based on this method is to analyze the available evidence, especially in oncology, to perform indirect comparisons, and determine the place in therapy of individual agents. This review examined the most recent applications of the IPDfromKM-Shiny method, in which a new web-based software-published in 2021-was used. Reported here are 14 analyses, mostly focused on oncological treatments. Indirect comparisons were based on overall survival or progression free survival. Each of these analyses provided original information to compare treatments with one another and select the most appropriate depending on patient characteristics. These analyses can also be useful to assess equivalence from a regulatory viewpoint. All investigations stressed the importance of heterogeneity to better interpret the evidence generated by IPDfromKM-Shiny investigations. In conclusion, these investigations showed that the reconstruction of individual patient data through this online tool is a promising new method for analyzing trials based on survival endpoints. This new approach deserves further investigation, particularly in the area of indirect comparisons.

Background: In patients with advanced melanoma, immune-checkpoint inhibitors (ICIs) represent the mainstay for first line treatment. Recently, relatlimab+nivolumab was proposed as a new combination therapy. This review was aimed at summarizing the current data of effectiveness for ICIs. Progression-free survival (PFS) was the endpoint of our analysis., Methods: After a standard literature search, Phase II/III studies comparing different ICI regimens in previously untreated advanced melanoma patients were analyzed. Patient-level data were reconstructed from Kaplan-Meier curves by application of the IPDfromKM method. These reconstructed datasets were used to perform indirect comparisons between treatments. Standard statistical testing was used, including hazard ratio and medians. A secondary analysis employed the restricted mean survival time., Results: Six trials were included in our analysis. Information on PFS from these trials was pooled according to the following treatments: nivolumab or pembrolizumab as monotherapy, or in combination with ipilimumab, and relatlimab + nivolumab. Pembrolizumab+ipilimumab showed significantly better PFS compared with the other treatments; nivolumab+ipilimumab ranked second; the other treatments showed a similar survival pattern., Conclusions: The picture of comparative effectiveness resulting from our analysis is complex. The IPDfromKM method is advantageous because it accounts for the length of follow-up but loses the balance between treatment group and controls determined by randomization. Based on indirect comparisons, the combination of pembrolizumab+ipilimumab showed a particularly high efficacy, and so deserves further investigation. While the effect of between-trial differences in inclusion criteria plays an important role, our results do not support the proposal of relatlimab+nivolumab as a new standard of care., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: When COVID-19 pandemic started, Italian hospital pharmacists faced multiple challenges and change their work practices., Objectives: The aim of this study was to describe the impact of COVID-19 emergency on pharmaceutical care provided by pharmacists during the first wave of the pandemic. Issues related to pharmacist's involvement in the pandemic management were: changes in activities, support received by authorities and pharmacists' own perceived role in the Health System., Methods: A cross-sectional study based on a web survey was conducted between May and June 2020 collecting information from pharmacists, members of Italian Society of Clinical Pharmacy and Therapeutics. 113 (11.4%) completed the questionnaire. The cohort was divided in 2 arms: pharmacists who worked in severely COVID-19 affected areas (High Spread Regions) and those employed in less affected areas (Low Spread Regions)., Results: The changes in pharmacy work settings reflected the increase of logistics area and non-sterile clinical galenic, and reduction of clinical tasks. The most demanding challenge was referred to shortages of medical devices and drugs, 61/113 pharmacists reported difficulty in obtaining products compliant to quality standards. National Institutions and Regional Governments provided a greater perceived support. More than 50% of participants felt that their role did not change if compared to other health professionals., Conclusions: Despite some limitations related to their clinical activity, pharmacists played a crucial role in supplying personal protective equipment, medical devices and medications to improve health outcomes during this emergency. The results may guide pharmacists in future actions to improve the management of the pandemic.

Introduction: The clinical choice among recently approved cancer drugs is burdened by the absence of direct comparisons in terms of efficacy across these new agents. In this article we present the IPDfromKM method, an artificial intelligence (AI) application that aims to facilitate the analyses on efficacy based on secondary data., Methods: Seven therapeutic areas were selected in which at least three new agents were recently approved. Kaplan-Meier curves of related clinical trials were digitized. Then, the IPDfromKM method was employed to reconstruct patient-level survival data. This information allowed us to compare selected agents in each therapeutic area and to rank them in terms of efficacy., Results: We identified the most effective treatment in each of the seven selected therapeutic areas. In two cases, immunotherapies, sharing similar mechanisms of actions, were compared highlighting the most effective one. In the remaining cases, our comparison included also the standard of care, which proved to be superior to new agents in patients with osteosarcoma., Discussion: When randomized clinical trials are not available, indirect comparisons can be a valuable source of information. The experience described herein recommends the use of a new method endowed by two important advantages: remarkable speed of analysis and free access to computational tools. In assessing the place in therapy for newly developed agents, this approach can further promote the application of evidence-based principles.

Objective This paper presents a preliminary experience based on the "one-to-many" approach of the Shiny method. Numerous (or "many") treatments for advanced or metastatic urothelial carcinoma have recently been reviewed. More recently, "one" potentially innovative treatment has been made available. Our analysis was aimed at assessing the benefits of the new treatment in comparison with the alternatives developed previously. Materials and methods The Shiny method was employed to reconstruct patient-level survival data. This information allowed us to compare the Kaplan-Meier (KM) curves of five treatments previously available (i.e., pembrolizumab, nivolumab, atezolizumab, vinflunine, and standard chemotherapy) with the potentially innovative agent represented by enfortumab vedotin. Overall survival was evaluated for each agent. Statistical tests to assess head-to-head indirect comparisons were performed through standard survival analysis. The hazard ratio (HR) was the main parameter. Results In ranking the efficacy across these agents, enfortumab vedotin was first, followed by immune checkpoint inhibitors (ICIs). Standard chemotherapy and vinflunine were the least effective. The remarkable survival results of enfortumab were, to some extent, influenced by the slightly better prognosis of the population enrolled in the enfortumab trial in comparison with patients enrolled in the three ICI trials. Conclusions The experience described herein shows that, when a potential innovative treatment (enfortumab vedotin) is developed in an already investigated area (metastatic urothelial cancer), the Shiny method can be applied according to the "one-to-many" approach. This allows us to quickly assess the place in therapy of the new treatment (the "one") and to evaluate whether the new treatment determines a relevant incremental benefit in comparison with previous treatments (the "many")., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Messori et al.)

Health-related quality of life is frequently included in patient-reported outcomes aimed at evaluating the effectiveness of disease-modifying drugs for multiple sclerosis, but recent data about Italian patients are missing. A multicenter observational and cross-sectional study was performed by students of hospital pharmacy to update existing data on quality of life and to correlate it with the pharmacological and medical history of patients. Quality of life (QoL) was assessed using the MS-QoL54 questionnaire, and the pharmacist collected patients' characteristics, medical and pharmacological history, and Expanded Disability Status Scale (EDSS). Three hundred and forty-nine patients with multiple sclerosis were recruited from 16 centers between May 2018 and June 2019 (median age = 44.1 years; 68.9% women). The composite indexes of physical and mental well-being showed direct correlation with each other (R = 0.826; p < 0.001), and EDSS disability was an independent negative predictor of both indexes (R 2 = 35.08% p < 0.001 and R 2 = 15.74% p < 0.001, respectively). A trend of association between Physical Health Composite Score and different classes of oral disease-modifying drugs (DMDs) was observed. Our study found a decrease in QoL correlated with teriflunomide, which deserves further investigation. This experience demonstrates that joint action between scientific society and students association can be successful in conducting a no-profit multicenter observational study in a real-world setting.

Some anti-cancer treatments (e. g., immunotherapies) determine, on the long term, a durable survival in a small percentage of treated patients; in graphical terms, long-term survivors typically give rise to a plateau in the right tail of the survival curve. In analysing these datasets, medians are unable to recognize the presence of this plateau. To account for long-term survivors, both value-frameworks of ASCO and ESMO have incorporated post-hoc corrections that upgrade the framework scores when a survival plateau is present. However, the empiric nature of these post-hoc corrections is self-evident. To capture the presence of a survival plateau by quantitative methods, two approaches have thus far been proposed: the milestone method and the area-under-the-curve (AUC) method. The first approach identifies a long-term time-point in the follow-up ("milestone") at which survival percentages are extracted. The second approach, which is based on the measurement of AUC of survival curves, essentially is the rearrangement of previous methods determining mean lifetime survival; similarly to the milestone method, the application of AUC can be "restricted" to a pre-specified time-point of the follow-up. This Mini-Review examines the literature published on this topic. The main characteristics of these two methods are highlighted along with their advantages and disadvantages. The conclusion is that both the milestone method and the AUC method are able to capture the presence of a survival plateau.

Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and "under development" anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives.

Purpose: A high number of adverse drug reactions (ADRs), mainly caused by drug-drug interactions (DDIs), occur in neurological wards and few data are available about incidence and prevalence of DDIs in this context. This study investigated-(1) the prevalence of drug-drug and drug-disease interactions in patients admitted to a neurological unit in Italy, (2) the risk factors for DDIs, and (3) the diseases and the drug classes mostly involved in drug-drug and drug-disease interactions., Methods: For 2 months, we performed a retrospective, observational study in the neurological unit of St Bassiano Hospital, enrolling 79 patients who received a drug prescription at discharge., Results: About half of the patients were discharged with 5 or more prescribed drugs, and 72% of patients showed potential, clinically relevant DDIs. Linear correlations were observed between age and number of prescribed drugs ( P < .01) and between age and number of interactions ( P < .01). The number of prescribed drugs was associated with the number of detected DDIs ( P < .01). The application of drug interaction alerts and the use of medication inappropriateness criteria (ie, Beers criteria) were not satisfactory in choosing the best therapy for each patient. Therefore, multidisciplinary discussions of each clinical case was required., Conclusion: The study demonstrated that the neurological patient, especially if elderly, has a high risk of DDI and ADRs and that many of these can be avoided by case discussion in multidisciplinary team meetings, in which the presence of a dedicated clinical pharmacist is crucial.

In patients with metastatic melanoma, ipilimumab has been shown to improve long-term survival. This observational multicenter study reports clinical outcomes of 418 patients treated with second-line ipilimumab from February 2013 to August 2014. Median overall survival (OS) was 6.43 months (95%CI: 5.45-7.42; n = 300), while median progression-free survival (PFS) was 3.7 months (95%CI: 3.23-4.17; n = 188). Demographic factors, such as sex or number of previous therapies did not affect OS. Survival was shorter in patients with ECOG > 0 (Eastern Cooperative Oncology Group, Performance Status) (p < 0.001), while a longer OS was found in patients who completed all four therapy cycles (p < 0.001). Adverse events of any grade were reported for 66% of patients (mainly cutaneous and gastrointestinal), but most were low grade and easily managed. Adverse events of grades 3-4 were observed in 13% of patients. This study confirmed the efficacy and safety of this treatment in real practice.

Objectives: The purpose of this study was to assess the impact of medication reconciliation in the clinical practice from a hospital pharmacist point of view., Methods: A survey of the medication taken by cancer patients was performed on admission and on discharge in an oncological hospital, and then the subjects were followed up until discharge for 8 weeks. The pharmacist entered the data collected into a computer based tool which, by using Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions (STOPP criteria) and Micromedex™ interactions database, automatically produces a report indicating the possible inconsistencies. The report is to check all potentially inappropriate prescriptions (PIPs) correlated to the drugs assumption by the patient. The appropriateness of the medication was scored using a Medication Appropriateness Index (MAI index) which was used to reconcile the medication list accordingly., Results: Patients reconciled at admission were 98, while patients reconciled at discharge were 90, 8 patients dropped out due to death. After the intervention of the hospital pharmacist, the average value of MAI index showed a significant reduction (3,391 to 2,552 p=0.039) and the median number of drugs prescribed per patient was decreased (7 vs 6; p=0.8058)., Conclusion: Our study demonstrated that the forms used in the reconciliation process, in particular the record card, is a promising method to increase the quality of the information related to drug use in clinical decisions. We think that medication reconciliation softwares should be widely used by health care professionals involved in the recording of drug history or prescription process.

Objectives: Ipilimumab is the first licensed immune checkpoint inhibitor for treatment of melanoma. The promising results of the registration clinical study need confirmation in real practice and its clinical success comes together with a relevant budget impact due to the high price of this drug. The aim of this work is to describe a new model of economical sustainability of ipilimumab developed in an Italian reference center for melanoma treatment., Methods: This retrospective, observational, and monocentric study was carried out at the Veneto Institute of Oncology. Ipilimumab was administered to fifty-seven patients with advanced melanoma. Overall survival, progression free survival, and toxicity were evaluated. A local management procedure was evaluated together with the cost-saving strategies implemented by the Italian Medicines Agency (AIFA)., Results: We demonstrated that the use of ipilimumab for metastatic melanoma in real practice had an efficacy and toxicity similar to that reported in the literature. In this scenario, our management model (centralization of compounding + drug-day) permitted savings up to the 11.1 percent of the gross cost for the drug (calculated assuming that no cost saving procedures were applied) while the policy of cost containment designed by AIFA produced an additional 6.2 percent of savings., Conclusions: In real practice conditions, the centralized administration of ipilimumab allows to replicate the results of clinical studies and in the meantime to contain the cost associated with this drug. The local strategy of management can be readily applied to most of the high cost drugs compounded in the hospital pharmacy. Impact of findings on practice: (i) We describe a new model of economic sustainability (drug-day, centralization of compounding, payback systems) of an expensive and innovative drug, ipilimumab, for treatment of melanoma within an Italian cancer center. (ii) This pivotal study demonstrated that a cost containment strategy is feasible and it needs the cooperation of all healthcare providers (oncologists, pharmacists, nurses, and technicians) to guarantee the full efficiency of the process.

There is an increasing interest for monitoring circulating myeloid-derived suppressor cells (MDSCs) in cancer patients, but there are also divergences in their phenotypic definition. To overcome this obstacle, the Cancer Immunoguiding Program under the umbrella of the Association of Cancer Immunotherapy is coordinating a proficiency panel program that aims at harmonizing MDSC phenotyping. After a consultation period, a two-stage approach was designed to harmonize MDSC phenotype. In the first step, an international consortium of 23 laboratories immunophenotyped 10 putative MDSC subsets on pretested, peripheral blood mononuclear cells of healthy donors to assess the level of concordance and define robust marker combinations for the identification of circulating MDSCs. At this stage, no mandatory requirements to standardize reagents or protocols were introduced. Data analysis revealed a small intra-laboratory, but very high inter-laboratory variance for all MDSC subsets, especially for the granulocytic subsets. In particular, the use of a dead-cell marker altered significantly the reported percentage of granulocytic MDSCs, confirming that these cells are especially sensitive to cryopreservation and/or thawing. Importantly, the gating strategy was heterogeneous and associated with high inter-center variance. Overall, our results document the high variability in MDSC phenotyping in the multicenter setting if no harmonization/standardization measures are applied. Although the observed variability depended on a number of identified parameters, the main parameter associated with variation was the gating strategy. Based on these findings, we propose further efforts to harmonize marker combinations and gating parameters to identify strategies for a robust enumeration of MDSC subsets.

The expansion of myeloid derived suppressor cells (MDSCs), a suppressive population able to hamper the immune response against cancer, correlates with tumor progression and overall survival in several cancer types. We have previously shown that MDSCs can be induced in vitro from precursors present in the bone marrow and observed that these cells are able to actively proliferate in the presence of activated T cells, whose activation level is critical to drive the suppressive activity of MDSCs. Here we investigated at molecular level the mechanisms involved in the interplay between MDSCs and activated T cells. We found that activated T cells secrete IL-10 following interaction with MDSCs which, in turn, activates STAT3 phosphorylation on MDSCs then leading to B7-H1 expression. We also demonstrated that B7-H1+ MDSCs are responsible for immune suppression through a mechanism involving ARG-1 and IDO expression. Finally, we show that the expression of ligands B7-H1 and MHC class II both on in vitro-induced MDSCs and on MDSCs in the tumor microenvironment of cancer patients is paralleled by an increased expression of their respective receptors PD-1 and LAG-3 on T cells, two inhibitory molecules associated with T cell dysfunction. These findings highlight key molecules and interactions responsible for the extensive cross-talk between MDSCs and activated T cells that are at the basis of immune suppression.

Study of myeloid cells endowed with suppressive activity is an active field of research which has particular importance in cancer, in view of the negative regulatory capacity of these cells to the host's immune response. The expansion of these cells, called myeloid-derived suppressor cells (MDSCs), has been documented in many models of tumor-bearing mice and in patients with tumors of various origin, and their presence is associated with disease progression and reduced survival. For this reason, monitoring this type of cell expansion is of clinical importance, and flow cytometry is the technique of choice for their identification. Over the years, it has been demonstrated that MDSCs comprise a group of immature myeloid cells belonging both to monocytic and granulocytic lineages, with several stages of differentiation; their occurrence depends on tumor-derived soluble factors, which guide their expansion and determine their block of differentiation. Because of their heterogeneous composition, accurate phenotyping of these cells requires a multicolor approach, so that the expansion of all MDSC subsets can be appreciated. This review article focuses on identifying MDSCs and discusses problems associated with phenotyping circulating and tumor-associated MDSCs in humans and in mouse models., (© 2014 International Clinical Cytometry Society.)

Study of myeloid cells endowed with suppressive activity is an active field of research which has particular importance in cancer, in view of the negative regulatory capacity of these cells to the host's immune response. The expansion of these cells, called myeloid-derived suppressor cells (MDSCs), has been documented in many models of tumor-bearing mice and in patients with tumors of various origin, and their presence is associated with disease progression and reduced survival. For this reason, monitoring this type of cell expansion is of clinical importance, and flow cytometry is the technique of choice for their identification. Over the years, it has been demonstrated that MDSCs comprise a group of immature myeloid cells belonging both to monocytic and granulocytic lineages, with several stages of differentiation; their occurrence depends on tumor-derived soluble factors, which guide their expansion and determine their block of differentiation. Because of their heterogeneous composition, accurate phenotyping of these cells requires a multicolor approach, so that the expansion of all MDSC subsets can be appreciated. This review article focuses on identifying MDSCs and discusses problems associated with phenotyping circulating and tumor-associated MDSCs in humans and in mouse models. This article is protected by copyright. All rights reserved., (Copyright © 2014 Clinical Cytometry Society.)

The dynamic interplay between cancer and host immune system often affects the process of myelopoiesis. As a consequence, tumor-derived factors sustain the accumulation and functional differentiation of myeloid cells, including myeloid-derived suppressor cells (MDSCs), which can interfere with T cell-mediated responses. Since both the phenotype and mechanisms of action of MDSCs appear to be tumor-dependent, it is important not only to determine the presence of all MDSC subsets in each cancer patient, but also which MDSC subsets have clinical relevance in each tumor environment. In this review, we describe the differences between MDSC populations expanded within different tumor contexts and evaluate the prognostic significance of MDSC expansion in peripheral blood and within tumor masses of neoplastic patients., (© 2014 New York Academy of Sciences.)

Although the spleen is a major site where immune tolerance to circulating innocuous antigens occurs, the kidney also contributes. Circulating antigens smaller than albumin are constitutively filtered and concentrated in the kidney and reach the renal lymph node by lymphatic drainage, where resident dendritic cells (DCs) capture them and induce tolerance of specific cytotoxic T cells through unknown mechanisms. Here, we found that the coinhibitory cell surface receptor programmed death 1 (PD-1) on cytotoxic T cells mediates to their tolerance. Renal lymph node DCs of the CD8(+) XCR1(+) subset, which depend on the transcription factor Batf3, expressed the PD-1 cognate ligand PD-L1. Batf3-dependent DCs in the renal lymph node presented antigen that had been concentrated in the kidney and used PD-L1 to induce apoptosis of cytotoxic T cells. In contrast, T cell tolerance in the spleen was independent of PD-1, PD-L1, and Batf3. In summary, these results clarify how the kidney/renal lymph node system tolerizes the immune system against circulating innocuous antigens.

MDSCs have been recognized in the last years as tolerogenic cells, potentially dangerous in the context of neoplasia, since they are able to induce tolerance to a variety of anti-tumor effectors, including CD4(+) and CD8(+) T cells. It is currently believed that the origin of MDSCs is due to an arrest of the myeloid differentiation process caused by tumor-secreted factors released in the tumor microenvironment that are able to exert an effect on myeloid progenitors, rendering them unable to terminally differentiate into dendritic cells, granulocytes and macrophages. As a consequence, these immature myeloid cells acquire suppressive activity through the activation of several mechanisms, controlled by different transcription factors. The lack of consensus about the phenotypical characterization of human MDSCs is the result of the existence of different MDSC subsets, most likely depending on the tumor in which they expand and on the tumor specific cytokine cocktail driving their activation. This, in turn, might also influence the mechanisms of MDSC-mediated immune suppression. In this review article we address the role of tumor-derived factors (TDFs) in MDSC-recruitment and activation, discuss the complex heterogeneity of MDSC phenotype and analyze the crosstalk between activated T cells and MDSCs.