Assessing satisfaction in simulation among nursing students: psychometric properties of the Satisfaction with Simulation Experience - Italian Version scale.

BACKGROUND: The Satisfaction with Simulation Experience scale is a 5-point Likert scale that measures students' satisfaction in medium and high-fidelity simulation scenarios. This study aims at investigating the psychometric properties of the Satisfaction with Simulation Experience - Italian Version scale. METHODS: A multi-centre cross-sectional study was conducted. The scale was administered to a sample of 266 undergraduate nursing students from two Italian universities after attending a medium- and high-fidelity simulation session in November 2022 and March 2023. Cronbach's alpha coefficient and item-total correlation were sorted out to assess internal consistency and reliability. The test-retest method was used as a measure of scale stability over time as well as the confirmatory factor analysis to verify construct validity. RESULTS: The Cronbach's alpha value was 0.94 for the overall scale, indicating excellent reliability, and it was 0.84 or higher for each subscales, indicating good reliability. A large correlation coefficient of 0.60 or higher was found between each item and its subscale and between each item and the overall scale score. A medium test-retest correlation coefficient was found for most items (r > 0.30). The confirmatory factor analysis confirmed the factorial structure found in the original study. CONCLUSIONS: Satisfaction is an important teaching and learning quality indicator along with the achievement of learning outcomes in simulation. The Satisfaction with Simulation Experience - Italian Version scale showed good reliability and validity; therefore, it could be a useful tool to assess simulation impact in Italian nursing students. The extensive utilization of the Satisfaction with Simulation Experience scale, along with its various validated versions, could facilitate assessing satisfaction in simulation across diverse contexts and enable comparisons of findings across studies in different countries.

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target.

The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138(+) cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138(+) cells. Gln-free incubation or treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138(+) cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.

IL21R expressing CD14+CD16+ monocytes expand in multiple myeloma patients leading to increased osteoclasts.

Bone marrow monocytes are primarily committed to osteoclast formation. It is, however, unknown whether potential primary alterations are specifically present in bone marrow monocytes from patients with multiple myeloma, smoldering myeloma or monoclonal gammopathy of undetermined significance. We analyzed the immunophenotypic and transcriptional profiles of bone marrow CD14+ monocytes in a cohort of patients with different types of monoclonal gammopathies to identify alterations involved in myeloma-enhanced osteoclastogenesis. The number of bone marrow CD14+CD16+ cells was higher in patients with active myeloma than in those with smoldering myeloma or monoclonal gammopathy of undetermined significance. Interestingly, sorted bone marrow CD14+CD16+ cells from myeloma patients were more pro-osteoclastogenic than CD14+CD16-cells in cultures ex vivo Moreover, transcriptional analysis demonstrated that bone marrow CD14+ cells from patients with multiple myeloma (but neither monoclonal gammopathy of undetermined significance nor smoldering myeloma) significantly upregulated genes involved in osteoclast formation, including IL21RIL21R mRNA over-expression by bone marrow CD14+ cells was independent of the presence of interleukin-21. Consistently, interleukin-21 production by T cells as well as levels of interleukin-21 in the bone marrow were not significantly different among monoclonal gammopathies. Thereafter, we showed that IL21R over-expression in CD14+ cells increased osteoclast formation. Consistently, interleukin-21 receptor signaling inhibition by Janex 1 suppressed osteoclast differentiation from bone marrow CD14+ cells of myeloma patients. Our results indicate that bone marrow monocytes from multiple myeloma patients show distinct features compared to those from patients with indolent monoclonal gammopathies, supporting the role of IL21R over-expression by bone marrow CD14+ cells in enhanced osteoclast formation.

The use of adhesive elastic tape for hand oedema control in patients with a wrist fracture treated in a cast: A pilot study.

BACKGROUND: The adhesive elastic tape use is indicated for controlling oedema, although currently there is not the definitive evidence regarding its effectiveness. Wrist fractures are a frequent occurrence, often leading to oedema development in patients treated with forearm casts. This pilot study aims to investigate the effects of elastic tape in controlling hand oedema among patients with forearm casts for wrist fractures and the feasibility of a future randomized controlled trial. METHODS: The study was conducted on adult patients with unilateral conservatively treated wrist fracture. The tape was applied to the intervention group after cast application, while the control group received the standard treatment. The circumference difference between baseline and the 7-day follow-up of both the 1st finger and the remaining 4 fingers merged together was evaluated. Ethical approval for the study has been obtained. RESULTS: 23 participants were enrolled. The intervention group showed a higher reduction in finger circumferences compared to the control group (median difference T1-T0 No tape vs Tape: 0 cm vs -0.2 cm for the 1st finger and 0.5 cm vs -0.5 cm for the remaining 4 fingers), although the changes were not statistically significant. CONCLUSION: Although the number of enrolled patients was limited due to Covid-19 pandemic, the study results suggest a potential reduction in oedema after the use of adhesive elastic tape, justifying the needed of a future full-scale study. Given its low cost and ease of use, we believe that tape can be considered in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04683887.

[Clinical trials approved by Aifa for Covid-19: report of the main results to fill the unmet medical need.] / Le sperimentazioni cliniche approvate dall'Aifa per Covid-19: report dei risultati principali per colmare l'unmet medical need.

INTRODUCTION: the rapidity with which the Coronavirus epidemic emergency exploded took the scientific community by surprise, unprepared for such an event. The objective of this work is to evaluate, to date, the state of the art of the clinical trials approved by Aifa, analyzing the characteristics of the single completed and published trials and the authorization status for the use of the drugs under study in the treatment of Covid-19. MATERIALS AND METHODS: The protocols available for each clinical study were extrapolated from the Aifa website relating to the management of clinical trials in Italy during the Covid-19 emergency; the unique EudraCT and Nct codes were extrapolated from these, verifying their publication using the PubMed search engine, the ClinicalTrials.gov platform, the EU Clinical Trials Register portal and the website of the pharmaceutical company identified as the promoter of the study. The characteristics of the individual trials useful for the analysis were extracted from the published papers. Finally, a comparison was made between the studies relating to experimental drugs which were subsequently authorized for the Covid-19 indication and the studies relating to drugs which have not yet been authorized to date. RESULTS: In total, Aifa approved 94 between March 2020 and March 2022; of these, 22 are not listed on ClinicalTrials.gov; of the 72 trials listed on ClinicalTrials.gov, 31 (43%) were published, for a total of 25 drugs. Of the authorized and published trials, 26 report the "mortality endpoint". The most studied drugs are remdesivir and tocilizumab with 3 studies each, methylprednisone and molnupravir with 2. 14 studies are phase III, of these 12 used a drug as an experimental treatment which was then approved for Covid-19. Of the 41 trials present on ClinicalTrials.gov that have not yet been published, 21 are terminated. The drugs anakinra, remdesivir, molnupravir, regdanvimab, tocilizumab, AZD1222 vaccine have been updated/registered for Covid-19 indication; anakinra, baricitinib, tocilizumab and sarilumab have been included in the list of Law 648/96; remdesivir, canakinumab and ruxolitinib have been entered into compassionate use programmes. DISCUSSION AND CONCLUSIONS: The methods of early access to therapy have allowed an alternative to patients who are not eligible for the ongoing trials. The challenge that the scientific community has faced has strengthened the culture of evidence-based medicine.

Randomised controlled prospective study of the use of adhesive elastic tape for the control of hand oedema in patients with a wrist fracture treated in a cast: a study protocol.

BACKGROUND: Wrist fractures are a common occurrence, affecting patients of all ages. Wrist fracture patients often develop oedema and the presence of a cast increases the risk. The use of adhesive elastic tape is indicated for oedema control, but there is no definitive evidence of its effectiveness. This study aims to evaluate the effectiveness of the tape in control of hand oedema in wrist fracture patients with a forearm cast. METHODS: We present a study protocol for a randomised controlled trial with blinded data processing. We will apply the tape to the intervention group after cast application, while the control group will receive the standard treatment. We will evaluate the circumference difference between baseline (T0) and the 7-day follow-up (T1) of both the thumb and of the other 4 fingers merged together. We will collect data regarding re-attendance to the Orthopedic Emergency Room due to "intolerance to the plaster cast". Sample size calculations resulted in a required total of 220 participants (110 per group). Ethical approval for the study has been obtained. DISCUSSION: We aim to demonstrate that the use of tape improves the tolerability of the cast by reducing the oedema formation, the feeling of constriction and pain. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT04683887.

Overexpression of HOXB7 and homeobox genes characterizes multiple myeloma patients lacking the major primary immunoglobulin heavy chain locus translocations.

Homeobox (HOX) gene transcription factors are frequently deregulated in hematologic malignancies and involved in leukemogenic transformation [1]. Moreover, their overexpression has been associated with tumoral-induced neoangiogenesis in solid cancer [2]. The expression and the role of these genes have not yet been completely elucidated in multiple myeloma (MM). Recently, we reported that a small fraction of MM patients shows a HOXB7 overexpression as compared with normal samples and that HOXB7 expression correlates with bone marrow angiogenesis and the production of the proangiogenic factors by MM cells [3]. Other authors previously reported that HOXA cluster genes are expressed in a small fraction of MM patients [4]. Herein, we extended our previous evidences with the evaluation of the expression level of HOXB7 and the other gene family members in a large number of primary MM cells in relationship with the different molecular subgroups of MM and the presence of specific chromosome translocations. We found that HOXB7 and other genes of HOX family have a preferential distribution based on the characteristics of molecular MM subtypes based on the translocations/cyclins (TC) classification, suggesting a potential relationship between HOX genes expression, angiogenesis, and molecular features of MM patients.

Assessment and pain management during the triage phase of children with extremity trauma. A retrospective analysis in a Pediatric Emergency Room after the introduction of the PIPER recommendations.

BACKGROUND AND AIM OF THE WORK: Pain is one of the most common symptoms in children who access the Pediatric Emergency Room (PER). However, many studies show that it is poorly evaluated and treated during the triage phase and that in many cases algometric scales aren't used for its evaluation. Faced with this, the Piacenza PER (Italy) implemented the Pain in Pediatric Emergency Room (PIPER) recommendations for the assessment and management of pain from the 1st July 2017. The aim of this study was to detect the possible differences in the trend of the outcomes for the detection and treatment of pain in July-October 2016, 2017, 2018. METHODS: A retrospective observational study was chosen. 811 discharge letters of extremity traumatized children aged 0-9 years were analyzed, of which 309 referred to the 2016 quarter, 243 to the 2017 quarter and 259 to the 2018 quarter. RESULTS: In 2016, the pain of 12 patients was assessed out of a total of 309, in 2017 of 227 out of 243 and in 2018 of 245 out of 259. The Chi Square test about assessed and not assessed pain, gave statistically significant value (p = 1.36E-98), comparing 2016vs2017 and gave not significant value comparing 2017vs2018 (p = 0.58). 4 patients were treated during the triage phase in 2016, 68 in 2017 and 70 in 2018. CONCLUSIONS: Recommendations introduction has increased the frequency of pain algometric measurements during the triage phase by leading to an improvement in the nursing care outcomes in terms of pediatric pain management.

Use of traffic crash as a risk assessment scale in hospitalized seniors: a perspective observational study.

BACKGROUND AND AIM: According to the World Health Organization (WHO), falls represent the second main cause of accidental and involuntary deaths worldwide, which led to define them as one of the "four giants of the geriatrician" that particularly affect the elderly aged ≥ 65 years. The study's aim is to evaluate whether the Traffic Crash scale is valid in identifying patients at risk of falling by comparing it to the Conley scale currently used. METHODS: Prospective observational study evaluating the fall risk using TC on a sample of patients aged ≥ 65 years, hospitalized in General Medicine Ward and Gastroenterology, after informed consent and favorable opinion of the AVEN Ethics Committee. The results are compared with those obtained from the Conley scale, and with those obtained from the indications of the Business Operating Instruction. The method of administration occurred concurrently and distinctly on the same patient by two researchers in order to demonstrate the scale inter-rater reliability. RESULTS: The final sample was made up of 88 patients. Data shows that 46 out of 55 patients (84%) are medium / high risk for both scales. According to the indications of the Company Operating Instruction, the entire sample is at risk. The inter-rater reliability was confirmed with Cohen's K which is equal to p = 1. CONCLUSIONS: The TC scale is comparable to Conley scale, for the fall risk identification but specifically the stratification is low-medium-high. Therefore, in future, this will make it possible to implement personalized prevention interventions in care planning.

The link between bone microenvironment and immune cells in multiple myeloma: Emerging role of CD38.

The relationship between bone and immune cells is well established both in physiological and pathological conditions. Multiple myeloma (MM) is a plasma cell malignancy characterized by an increase of number and activity of osteoclasts (OCLs) and a decrease of osteoblasts (OBs). These events are responsible for bone lesions of MM patients. OCLs support MM cells survival in vitro and in vivo. Recently, the possible role of OCLs as immunosuppressive cells in the MM BM microenvironment has been underlined. OCLs protect MM cells against T cell-mediated cytotoxicity through the expression of several molecules including programmed death-ligand (PD-L) 1, galectin (Gal) 9, CD200, and indoleamine-2,3-dioxygenase (IDO). Among the molecules that could be involved in the link between immune-microenvironment and osteoclastogenesis the role of CD38 has been hypothesized. CD38 is a well-known adhesion molecule and an ectoenzyme highly expressed by MM cells. Moreover, CD38 is expressed by OCLs and at the surface level on OCL precursors. Targeting CD38 with monoclonal antibodies showed inhibition of both osteoclastogenesis and OCL-mediated suppression of T cell function. This review elucidates this evidence indicating that osteoclastogenesis affect MM immune-microenvironment being a potential target to improve anti-MM immunity and to ameliorate bone disease.

Bone Marrow CX3CL1/Fractalkine is a New Player of the Pro-Angiogenic Microenvironment in Multiple Myeloma Patients.

C-X3-C motif chemokine ligand 1 (CX3CL1)/fractalkine is a chemokine released after cleavage by two metalloproteases, ADAM metallopeptidase domain 10 (ADAM10) and ADAM metallopeptidase domain 17 (ADAM17), involved in inflammation and angiogenesis in the cancer microenvironment. The role of the CX3CL1/ C-X3-C motif chemokine receptor 1(CX3CR1) axis in the multiple myeloma (MM) microenvironment is still unknown. Firstly, we analyzed bone marrow (BM) plasma levels of CX3CL1 in 111 patients with plasma cell disorders including 70 with active MM, 25 with smoldering myeloma (SMM), and 16 with monoclonal gammopathy of undetermined significance (MGUS). We found that BM CX3CL1 levels were significantly increased in MM patients compared to SMM and MGUS and correlated with BM microvessel density. Secondly, we explored the source of CX3CL1 in MM and BM microenvironment cells. Primary CD138⁺ cells did not express CXC3L1 but up-regulated its production by endothelial cells (ECs) through the involvement of tumor necrosis factor alpha (TNFα). Lastly, we demonstrated the presence of CX3CR1 on BM CD14⁺CD16⁺ monocytes of MM patients and on ECs, but not on MM cells. The role of CX3CL1 in MM-induced angiogenesis was finally demonstrated in both in vivo chick embryo chorioallantoic membrane and in vitro angiogenesis assays. Our data indicate that CX3CL1, present at a high level in the BM of MM patients, is a new player of the MM microenvironment involved in MM-induced angiogenesis.

Possible targets to treat myeloma-related osteoclastogenesis.

INTRODUCTION: Bone destruction is the hallmark of multiple myeloma (MM). About 80% of MM patients at diagnosis presents myeloma bone disease (MBD) leading to bone pain and pathological fractures, significantly affecting patients' quality of life. Bisphosphonates are the treatment of choice for MBD, but osteolytic lesions remain a critical issue in the current management of MM patients. Several studies clarified the mechanisms involved in MM-induced osteoclast formation and activation, leading to the identification of new possible targets and the development of better bone-directed therapies, that are discussed in this review. Areas covered: This review summarizes the latest advances in the knowledge of the pathophysiology of the osteoclast formation and activation induced by MM cells, and the new therapeutic targets identified. Recently, neutralizing antibodies (i.e. denosumab, siltuximab, daratumumab), as well as recombinant fusion proteins, and receptor molecular inhibitors, have been developed to block these targets. Clinical trials testing their anti-MBD potential are ongoing. The emerging role of exosomes and microRNAs in the regulation of osteoclast differentiation has been also discussed. Expert commentary: Although further studies are needed to arrive at a clinical approving, the basis for the development of better bone-directed therapies has been established.

Role of Osteocytes in Myeloma Bone Disease: Anti-sclerostin Antibody as New Therapeutic Strategy.

Osteocytes are terminally differentiated cells of the osteoblast lineage. They are involved in the regulation of bone remodeling by increasing osteoclast formation or decreasing bone formation by the secretion of the osteoblast inhibitor sclerostin. Monoclonal antibody anti-sclerostin, Romosozumab, has been developed and tested in clinical trials in patients with osteoporosis. In the last years, the role of osteocytes in the development of osteolytic bone lesions that occurs in multiple myeloma, have been underlined. Myeloma cells increase osteocyte death through the up-regulation of both apoptosis and autophagy that, in turn, triggers osteoclast formation, and activity. When compared to healthy controls, myeloma patients with bone disease have higher osteocyte cell death, but the treatment with proteasome inhibitor bortezomib has been shown to maintain osteocyte viability. In preclinical mouse models of multiple myeloma, treatment with blocking anti-sclerostin antibody increased osteoblast numbers and bone formation rate reducing osteolytic bone lesions. Moreover, the combination of anti-sclerostin antibody and the osteoclast inhibitor zoledronic acid increased bone mass and fracture resistance synergistically. However, anti-sclerostin antibody did not affect tumor burden in vivo or the efficacy of anti-myeloma drugs in vitro. Nevertheless, the combination therapy of anti-sclerostin antibody and the proteasome inhibitor carfilzomib, displayed potent anti-myeloma activity as well as positive effects on bone disease in vivo. In conclusion, all these data suggest that osteocytes are involved in myeloma bone disease and may be considered a novel target for the use of antibody-mediated anti-sclerostin therapy also in multiple myeloma patients.

Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties.

The use of Lenalidomide (LEN), to reverse tumor-mediated immune suppression and amplify multiple myeloma-specific immunity is currently being explored. Particularly, LEN effects on dendritic cells (DCs) are still unclear. In this study, we investigated the potential effect of LEN on DC differentiation and activity. DCs were differentiated either from CD14+ cells obtained from patients with multiple myeloma or from a human monocytic cell line. LEN, at the concentration range reached in vivo, significantly increased the median intensity expression of HLA-DR, CD86 and CD209 by DCs derived from both bone marrow and peripheral myeloma monocytes and enhanced the production of Interleukin-8, C-C motif chemokine ligand (CCL) 2, CCL5 and tumor necrosis factor-α. Consistently, LEN pre-treated DCs showed an increased ability to stimulate autologous CD3+ cell proliferation. LEN effect on dendritic differentiation was associated with the degradation of the Cereblon-related factors Ikaros and Aiolos. Moreover, we showed that LEN also blunted mesenchymal stromal cell inhibitory effect on dendritic differentiation, inhibiting Casein Kinase-1α levels. Finally, in vitro data were confirmed in ex vivo cultures obtained from relapsed myeloma patients treated with LEN, showing a significant increase of DC differentiation from peripheral blood monocytes. In conclusion, LEN increased the expression of mature dendritic markers both directly and indirectly and enhanced DC ability to stimulate T cell proliferation and to release chemokines. This suggests a new possible mechanism by which LEN could exert its anti-myeloma activity.

Expression of CD38 in myeloma bone niche: A rational basis for the use of anti-CD38 immunotherapy to inhibit osteoclast formation.

It is known that multiple myeloma (MM) cells express CD38 and that a recently developed human anti-CD38 monoclonal antibody Daratumumab mediates myeloma killing. However, the expression of CD38 and other functionally related ectoenzymes within the MM bone niche and the potential effects of Daratumumab on bone cells are still unknown. This study firstly defines by flow cytometry and immunohistochemistry the expression of CD38 by bone marrow cells in a cohort of patients with MM and indolent monoclonal gammopathies. Results indicate that only plasma cells expressed CD38 at high level within the bone niche. In addition, the flow cytometry analysis shows that CD38 was also expressed by monocytes and early osteoclast progenitors but not by osteoblasts and mature osteoclasts. Indeed, CD38 was lost during in vitro osteoclastogenesis. Consistently, we found that Daratumumab reacted with CD38 expressed on monocytes and its binding inhibited in vitro osteoclastogenesis and bone resorption activity from bone marrow total mononuclear cells of MM patients, targeting early osteoclast progenitors. The inhibitory effect was not observed from purified CD14+ cells, suggesting an indirect inhibitory effect of Daratumumab. Interestingly, all-trans retinoic acid treatment increased the inhibitory effect of Daratumumab on osteoclast formation. These observations provide a rationale for the use of an anti-CD38 antibody-based approach as treatment for multiple myeloma-induced osteoclastogenesis.

Cutaneous localization in multiple myeloma in the context of bortezomib-based treatment: how do myeloma cells escape from the bone marrow to the skin?

The skin is a possible site of extramedullary localization in multiple myeloma (MM) patients; however, the mechanisms involved in this process are poorly understood. We describe the case of a refractory MM patient who developed a cutaneous localization under bortezomib treatment and we further expanded observations in other eight MM patients. We focused on the expression of genes involved in plasma cell skin homing, including CCR10, which was highly expressed. Moreover, we observed a lack of CXCR4 surface expression and the down-regulation of ICAM1/CD54 throughout the progression of the disease, suggesting a possible mechanism driving the escape of MM cells from the bone marrow into the skin.

The Proteasome Inhibitor Bortezomib Maintains Osteocyte Viability in Multiple Myeloma Patients by Reducing Both Apoptosis and Autophagy: A New Function for Proteasome Inhibitors.

Multiple myeloma (MM) is characterized by severely imbalanced bone remodeling. In this study, we investigated the potential effect of proteasome inhibitors (PIs), a class of drugs known to stimulate bone formation, on the mechanisms involved in osteocyte death induced by MM cells. First, we performed a histological analysis of osteocyte viability on bone biopsies on a cohort of 37 MM patients with symptomatic disease. A significantly higher number of viable osteocytes was detected in patients treated with a bortezomib (BOR)-based regimen compared with those treated without BOR. Interestingly, both osteocyte autophagy and apoptosis were affected in vivo by BOR treatment. Thereafter, we checked the in vitro effect of BOR to understand the mechanisms whereby BOR maintains osteocyte viability in bone from MM patients. We found that osteocyte and preosteocyte autophagic death was triggered during coculturing with MM cells. Our evaluation was conducted by analyzing either autophagy markers microtubule-associated protein light chain 3 beta (LC3B) and SQSTM1/sequestome 1 (p62) levels, or the cell ultrastructure by transmission electron microscopy. PIs were found to increase the basal levels of LC3 expression in the osteocytes while blunting the myeloma-induced osteocyte death. PIs also reduced the autophagic death of osteocytes induced by high-dose dexamethasone (DEX) and potentiated the anabolic effect of PTH(1-34). Our data identify osteocyte autophagy as a new potential target in MM bone disease and support the use of PIs to maintain osteocyte viability and improve bone integrity in MM patients.

The osteoblastic niche in the context of multiple myeloma.

The osteoblastic niche has a critical role in the regulation of hemopoietic stem cell (HSC) quiescence and self-renewal and in the support of hematopoiesis. Several mechanisms are involved in the crosstalk between stem cells and osteoblasts, including soluble cytokines, adhesion molecules, and signal pathways such as the wingless-Int (Wnt), Notch, and parathyroid hormone pathways. According to the most recent evidence, there is an overlap between osteoblastic and perivascular niches that affects HSC function involving mesenchymal stromal and endothelial cells and a gradient of oxygen regulated by hypoxia inducible factor (HIF)-1α. Derived from plasma cells, multiple myeloma (MM) is a hematopoietic malignancy characterized by a peculiar dependency on the bone microenvironment. Quiescent MM cells may reside in the osteoblastic niche for protection from apoptotic stimuli; in turn, MM cells suppress osteoblast formation and function, leading to impairment of bone formation and the development of osteolytic lesions. Several recent studies have investigated the mechanisms involved in the relationship between osteoblasts and MM cells and identified potential therapeutic targets in the osteoblastic niche, including the HIF-1α, Runx2, and Wnt (both canonical and noncanonical) signaling pathways.

Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling.

Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease.