Search

The World Health Organization (WHO) assigns International Nonproprietary Names (INN) to pharmaceutical substances, including advanced therapy medicinal products, to ensure that each substance is globally recognized by a unique name. The majority of INN are published in the WHO Drug Information in accordance with the nomenclature rules of the International Union of Pure and Applied Chemistry. However, advanced therapy medicinal products, and in particular cell therapy and cell-based gene therapy substances, cannot be defined by such chemical nomenclature. Instead, they are published together with a textual definition paragraph to unambiguously describe their characteristics. These definitions are an integral part of the INN nomenclature system, and their presence contributes to pharmacovigilance and patient safety, as they help to distinguish regulated substances from cell-based interventions that have no INN and are marketed without regulatory oversight. Particular attention is therefore allocated to these descriptive paragraphs, as they form the basis for defining the uniqueness of a particular cell substance. This review describes the INN nomenclature system for cell-based substances and focuses on the progress made by the WHO INN Programme to develop and harmonize these definition paragraphs, which is reflected in a newly revised INN application form for cell therapy substances. [ABSTRACT FROM AUTHOR]

Abstract The Signature Series Symposium "Cellular Therapies for Orthopaedics and Musculoskeletal Disease Proven and Unproven Therapies—Promise, Facts and Fantasy" was held as a pre-meeting of the 26th International Society for Cellular Therapy (ISCT) annual congress in Montreal, Canada, May 2, 2018. This was the first ISCT program that was entirely dedicated to the advancement of cell-based therapies for musculoskeletal diseases. Cellular therapies in musculoskeletal medicine are a source of great promise and opportunity. They are also the source of public controversy, confusion and misinformation. Patients, clinicians, scientists, industry and government share a commitment to clear communication and responsible development of the field. Therefore, this symposium convened thought leaders from around the world in a forum designed to catalyze communication and collaboration to bring the greatest possible innovation and value to patients with musculoskeletal conditions. [ABSTRACT FROM AUTHOR]

The article discusses views of the 2015 International Society for Cellular Therapy (ISCT) on the issue of unproven cellular therapies for patients, which are not recognized on medical grounds.

In industrialized countries, health care associated infections, the fourth leading cause of disease, are a major health issue. At least half of all cases of nosocomial infections are associated with medical devices. Antibacterial coatings arise as an important approach to restrict the nosocomial infection rate without side effects and the development of antibiotic resistance. Beside nosocomial infections, clot formation affects cardiovascular medical devices and central venous catheters implants. In order to reduce and prevent such infection, we develop a plasma-assisted process for the deposition of nanostructured functional coatings on flat substrates and mini catheters. Silver nanoparticles (Ag NPs) are synthesized exploiting in-flight plasma-droplet reactions and are embedded in an organic coating deposited through hexamethyldisiloxane (HMDSO) plasma assisted polymerization. Coating stability upon liquid immersion and ethylene oxide (EtO) sterilization is assessed through chemical and morphological analysis carried out by means of Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). In the perspective of future clinical application, an in vitro analysis of anti-biofilm effect has been done. Moreover, we employed a murine model of catheter-associated infection which further highlighted the performance of Ag nanostructured films in counteract biofilm formation. The anti-clot performances coupled by haemo- and cytocompatibility assays have also been performed. [ABSTRACT FROM AUTHOR]

Background aims. Mesenchymal stromal/stem cells (MSCs) can be isolated from human bone marrow (BM), expanded ex vivo and identified via numerous surface antigens. Despite the importance of these cells in regenerative therapy programs, it is unclear whether the cell membrane signature defining MSC preparations ex vivo is determined during culture or may reflect an in vivo counterpart. BM-MSC phenotype in vivo requires further investigation. Methods. To characterize cells in their natural BM environment, we performed multi-parametric immunohistochemistry on trabecular bone biopsy specimens from multiple donors and described cells by different morphology and micro-anatomic localization in relationship to a precise pattern of MSC antigen expression. Results. Microscopically examined high-power field marrow sections revealed an overlapping in vivo expression of antigens characterizing ex vivo expanded BM-MSCs, including CD 10, CD73, CD 140b, CD 146, GD2 and CD27 1. Expanding this panel to proteins associated with pluripotency, such as Oct4, Nanog and SSEA-4, we were able to identify different cellular populations in the human trabecular bone and BM expressing different progenitor cell markers. Conclusions. Targeting several multipotency and pluripotency markers, we found that the BM contains iden- tifiable and distinct progenitor cells further justifying their introduction for a wide range of applications in regenerative medicine. [ABSTRACT FROM AUTHOR]

Bone and bone marrow are closely aligned physiologic compartments, suggesting that these tissues may represent a single functional unit with a common bone marrow progenitor that gives rise to both osteoblasts and hematopoietic cells. Although reports of multilineage engraftment by a single marrow-derived stem cell support this idea, more recent evidence has challenged claims of stem cell transdifferentiation and therefore the existence of a multipotent hematopoietic/osteogenic progenitor cell. Using a repopulation assay in mice, we show here that gene-marked, transplantable marrow cells from the plastic-nonadherent population can generate both functional osteoblasts/osteocytes and hematopoietic cells. Fluorescent in situ hybridization for the X and Y chromosomes and karyotype analysis of cultured osteoblasts confirmed the donor origin of these cells and excluded their generation by a fusion process. Molecular analysis demonstrated a common retroviral integration site in clonogenic hematopoietic cells and osteoprogenitors from each of seven animals studied, establishing a shared clonal origin for these ostensibly independent cell types. Our findings indicate that the bone marrow contains a primitive cell able to generate both the hematopoietic and osteocytic lineages. Its isolation and characterization may suggest novel treatments for genetic bone diseases and bone injuries. [ABSTRACT FROM AUTHOR]

The real-world, retrospective, NEROnE registry investigated the impact of next-generation sequencing (NGS) in advanced non-small-cell lung cancer (NSCLC) patients (pts) at three oncology units in the north of Italy between January 2020 and December 2022. We focused on the clinical characterization and outcomes of NSCLC with rare molecular alterations: EGFR exon 20 insertion, non-activating EGFR mutations, BRAF V600E and non-V600, ROS1 and RET rearrangements, MET, ErbB2, and FGFR mutations. Overall, these represented 6.4% (62/970) of the pts analysed with NGS in the daily practice. The most heavily represented rare alterations were ROS1 rearrangement (15 pts—24%) and MET exon 14 skipping mutation (11 pts—18%). No associations were found with the demographic and clinical features. Forty-nine pts received targeted therapies, of which 38.8% were first- and 9.8% were second-line. The remaining pts received chemotherapy and/or immunotherapy. In terms of the clinical outcomes, although not statistically significant, a tendency toward shorter OS was seen when therapies other than specific targeted therapies were used (HR: 1.84, 95% CI: 0.79–4.33, p = 0.158). The pts with co-mutations (19.4%) seemed to receive an advantage from the front-line chemotherapy-based regimen. Finally, an NLR score (a well-known inflammatory index) ≥ 4 seemed to be related to shorter OS among the pts treated with immunotherapy alone or in combination with chemotherapy (HR: 2.83, 95% CI: 1.08–7.40, p = 0.033). Prospective evaluations need to be performed to clarify whether these indexes may help to identify patients with oncogene-addicted NSCLC who could benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript. [ABSTRACT FROM AUTHOR]

Over the last two decades, the use of Next-Generation Sequencing (NGS) in medical oncology has increased the likelihood of identifying druggable mutations that may be potentially susceptible to targeted treatments. The European Society for Medical Oncology (ESMO) currently does not recommend the use of the NGS test to determine the therapeutic course of patients with metastatic breast cancer (mBC) in daily clinical practice. However, the aim of this work is to evaluate the potential contribution of the NGS test in selecting targeted therapies for patients with mBC. Data were retrospectively collected from 101 patients diagnosed with metastatic breast cancer and treated at the Modena Cancer Center between January 2015 and April 2022. A NGS test was performed on the tumor tissue of each patient at the Laboratory of Molecular Pathology of the University Hospital of Modena. This study analyzed the clinical–pathological characteristics and mutational profile of the population using NGS tests, with a focus on actionable mutations that could be targeted in advanced stages of clinical development. The indicator of this study was to quantify the actionable mutations that resulted in a change of cancer treatment. In total, 101 patients with metastatic breast cancer were analyzed, including 86 with luminal phenotype, 10 who were HER2-positive and 5 who were triple-negative. Median age was 52 years. NGS analysis was conducted on 47 samples of primary breast cancer, 52 on metastatic sites of disease and 2 on liquid biopsies. A total of 85 gene mutations were found. The most common mutations were identified in the PIK3CA (47%), FGFR (19%) and ERBB2 genes (12%), and to a lesser extent in other genes. Of the 61 patients with pathogenic mutations, 46 (75%) had at least one actionable mutation. Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. Median PFS for these patients was 3.8 months. The study results show that using the NGS test on cancer tissue of metastatic breast cancer could influence the therapeutic choices, considering the small sample size and limited follow-up. About 9% of the study population had their therapy modified based on the results of NGS. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active. [ABSTRACT FROM AUTHOR]

Despite recent advances, biliary tract cancer (BTC) remains one of the most lethal tumor worldwide due to late diagnosis, limited therapeutic strategies and resistance to conventional therapies. In recent years, high-throughput technologies have enabled extensive genome, and transcriptome sequencing unveiling, among others, the regulatory potential of microRNAs (miRNAs). Compelling evidence shown that miRNA are attractive therapeutic targets and promising candidates as biomarkers for various therapy-resistant tumors. The analysis of miRNA profile successfully identified miR-181c and -181d as significantly downregulated in BTC patients. Low miR-181c and -181d expression levels were correlated with worse prognosis and poor treatment efficacy. In fact, progression-free survival analysis indicated poor survival rates in miR-181c and -181d low expressing patients. The expression profile of miR-181c and -181d in BTC cell lines revealed that both miRNAs were dysregulated. Functional in vitro experiments in BTC cell lines showed that overexpression of miR-181c and -181d affected cell viability and increased sensitivity to chemotherapy compared to controls. In addition, by using bioinformatic tools we showed that the miR-181c/d functional role is determined by binding to their target SIRT1 (Sirtuin 1). Moreover, BTC patients expressing high levels of miR-181 and low SIRT1 shown an improved survival and treatment response. An integrative network analysis demonstrated that, miR-181/SIRT1 circuit had a regulatory effect on several important metabolic tumor-related processes. Our study demonstrated that miR-181c and -181d act as tumor suppressor miRNA in BTC, suggesting the potential use as therapeutic strategy in resistant cancers and as predictive biomarker in the precision medicine of BTC. [ABSTRACT FROM AUTHOR]

The global COVID-19 pandemic has prompted urgent need for potential therapies for severe respiratory consequences resulting from coronavirus infection. New therapeutic agents that will attenuate ongoing inflammation and at the same time promote regeneration of injured lung epithelial cells are urgently needed. Cell-based therapies, primarily involving mesenchymal stromal cells (MSCs) and their derivatives, are currently investigated worldwide for SARS-CoV-2–induced lung diseases. A significant number of academic centers and companies globally have already initiated such trials. However, at a time of unprecedented need, it is also foreseen that families and caregivers will seek all available options, including access to cell-based and other investigational products, even before proven safety and efficacy as well as regulatory approval. This should not be an excuse for opportunists to sell or advertise unproven therapies of any kind. "Compassionate use" should be conducted in the context of a clinical investigation framed by strict ethical and regulatory permissions, with the goal of obtaining mechanistic information wherever possible. [ABSTRACT FROM AUTHOR]

Introduction: Vaginal cancer is a rare gynecologic malignancy. While in a localized disease, concurrent chemoradiation grants local control and better overall survival, in a metastatic setting, the management options are very limited. Furthermore, recurrent cervical, vulvar, and vaginal carcinomas notoriously develop resistance to treatment, and consequently, their prognosis is still poor. Case Presentation: We herein present the case of a woman with a nodal relapse of vaginal carcinoma, effectively treated with third-line immunotherapy. We will also provide a review of the literature on the new therapeutic strategies for advanced vaginal carcinoma, with a focus on pembrolizumab immunotherapy. Conclusion: Pembrolizumab might represent a promising option for the management of vaginal and vulvar cancer, but data to support its use in this setting are still lacking. This case highlights the need for further investigation and trial designs for this rare disease. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) are polymorphic, adherent cells with the capability to stimulate tissue regeneration and modulate immunity. MSCs have been broadly investigated for potential therapeutic applications, particularly immunomodulatory properties, wound healing and tissue regeneration. The exact physiologic role of MSCs, however, remains poorly understood, and this gap in knowledge significantly impedes the rational development of therapeutic cells. Here, we considered interferon γ (IFN-γ) and tumor necrosis factor alpha (TNF-α), two cytokines likely encountered physiologically and commonly used in cell manufacturing. For comparison, we studied interleukin-10 (IL-10) (anti-inflammatory) and interleukin-4 (IL-4) (type 2 cytokine). We directly assessed the effects of these cytokines on bone marrow MSCs by comparing RNA Seq transcriptional profiles. Western blotting and flow cytometry were also used to evaluate effects of cytokine priming. The type 1 cytokines (IFN-γ and TNF-α) induced striking changes in gene expression and remarkably different profiles from one another. Importantly, priming MSCs with either of these cytokines did not increase variability among multiple donors beyond what is intrinsic to non-primed MSCs from different donors. IFN-γ–primed MSCs expressed IDO1 and chemokines that recruit activated T cells. In contrast, TNF-α–primed MSCs expressed genes in alternate pathways, namely PGE2 and matrix metalloproteinases synthesis, and chemokines that recruit neutrophils. IL-10 and IL-4 priming had little to no effect. Our data suggest that IFN-γ–primed MSCs may be a more efficacious immunosuppressive therapy aimed at diseases that target T cells (ie, graft-versus-host disease) compared with TNF-α–primed or non-primed MSCs, which may be better suited for therapies in other disease settings. These results contribute to our understanding of MSC bioactivity and suggest rational ex vivo cytokine priming approaches for MSC manufacturing and therapeutic applications. [ABSTRACT FROM AUTHOR]

Background: prostate-specific membrane antigen (PSMA) ligand PET has been recently incorporated into international guidelines for several different indications in prostate cancer (PCa) patients. However, there are still some open questions regarding the role of PSMA ligand PET in castration-resistant prostate cancer (CRPC). The aim of this work is to assess the clinical value of PSMA ligand PET/CT in patients with CRPC. Results: PSMA ligand PET has demonstrated higher detection rates in comparison to conventional imaging and allows for a significant reduction in the number of M0 CRPC patients. However, its real impact on patients' prognosis is still an open question. Moreover, in CRPC patients, PSMA ligand PET presents some sensitivity and specificity limitations. Due to its heterogeneity, CRPC may present a mosaic of neoplastic clones, some of which could be PSMA−/FDG+, or vice versa. Likewise, unspecific bone uptake (UBU) and second primary neoplasms (SNPs) overexpressing PSMA in the neoangiogenic vessels represent potential specificity issues. Integrated multi-tracer imaging (PSMA ligand and [18F]FDG PET) together with a multidisciplinary discussion could allow for reaching the most accurate evaluation of each patient from a precision medicine point of view. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) still ranks as the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Despite the recent progress in the therapeutic algorithm of the advanced disease with the advent of immune checkpoint inhibitors (ICIs) and next-generation HER2-directed therapies, survival rates remain poor, with a median survival hardly exceeding 12 months. Furthermore, only 40% of patients remain eligible for second- and later-line treatments due to the aggressiveness of the disease and the rapid deterioration of performance status (PS). Thus, current research is focusing either on the identification of novel treatment options or the development of personalized strategies to optimize the continuum of care and ultimately improve patients' outcome. In this article, we provide an overview of the current treatment landscape for advanced GC with a particular emphasis on later-line treatments and outline novel perspectives on the horizon. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the author discusses various reports within the issue on topics including the concept of unproven cellular therapy, parameters in cell manufacturing, and the regulatory landscape for cell-based product manufacturing.

Simple Summary: De novo metastatic hormone-sensitive prostate cancer usually has a dismal prognosis, which has slightly improved in recent years thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. The randomized clinical trials that have furnished the current therapeutic options stratified patients according to clinical criteria that do not necessarily reflect the biological rationale of the chosen therapy. With the accumulation of data on genomic features and transcriptomic profiling, several ongoing clinical trials are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment with the aim of defining a personalized treatment for de novo metastatic hormone-sensitive prostate cancer. De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5–10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities for de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have modified the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road toward personalized treatment for de novo mHSPC is still long, considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that did not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as a predictive biomarker requires further validation, and it remains to be ascertained how the genomic variants detected in mHSPC, which are regarded as predictive in the castration-resistant disease, can be exploited in the mHSPC setting. [ABSTRACT FROM AUTHOR]

The Corning Epic® label-free (ELF) system is an innovative technology widely used in drug discovery, immunotherapy, G-protein-associated studies, and biocompatibility tests. Here, we challenge the use of ELF to further investigate the biocompatibility of resins used in manufacturing of blood filters, a category of medical devices representing life-saving therapies for the increasing number of patients with kidney failure. The biocompatibility assays were carried out by developing a cell model aimed at mimicking the clinical use of the blood filters and complementing the existing cytotoxicity assay requested by ISO10993-5. Experiments were performed by putting fibroblasts in both direct contact with two types of selected resins, and indirect contact by means of homemade customized well inserts that were precisely designed and developed for this technology. For both types of contact, fibroblasts were cultured in medium and human plasma. ELF tests confirmed the biocompatibility of both resins, highlighting a statistically significant different biological behavior of a polyaromatic resin compared to control and ion-exchanged resin, when materials were in indirect contact and soaking with plasma. Overall, the ELF test is able to mimic clinical scenarios and represents a promising approach to investigate biocompatibility, showing peculiar biological behaviors and suggesting the activation of specific intracellular pathways. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Germline pathogenic variants (PV) of the PALB2 tumor suppressor gene are associated with an increased risk of breast, pancreatic, and ovarian cancer. In previous research, PALB2‐associated breast cancer showed aggressive clinicopathological phenotypes, particularly triple‐negative subtype, and higher mortality regardless of tumor stage, type of chemotherapy nor hormone receptor status. The identification of this germline alteration may have an impact on clinical management of breast cancer (BC) from the surgical approach to the systemic treatment choice. We herein report the case of a patient with a germline PV of PALB2, diagnosed with locally advanced PD‐L1 positive triple‐negative BC, who progressed after an immune checkpoint inhibitor (ICI)‐containing regimen and then experienced a pathologic complete response after platinum‐based chemotherapy. This case report hints a major role of the germline PALB2 alteration compared to the PD‐L1 expression as cancer driver and gives us the opportunity to extensively review and discuss the available literature on the optimal management of PALB2‐associated BC. Overall, our case report and review of the literature provide additional evidence that the germline analysis of PALB2 gene should be included in routine genetic testing for predictive purposes and to refine treatment algorithms. [ABSTRACT FROM AUTHOR]

In this article, the authors offer comments on the complexity of marrow stromal cells (MSC). They contend over the generation of bone-forming cells through the consideration of adipose-derived mesenchymal cells. They argue that since neuroectodermal differentiated human MSC protects rodent from a neurotoxin-induced damage, it also provides a potential to regenerate neurodegenerative diseases.

Stem cells have important clinical and experimental potentials. Trophoblast stem (TS) cells possess the ability to differentiate into trophoblast subtypes in vitro and contribute to the trophoblast lineage in vivo. Suppressor of cytokine signaling 3 (50C53) is a negative regulator of cytokine signaling. Targeted disruption of SOCS3 revealed embryonic lethality on E12.5; it was caused by placental defect with enhanced leukemia inhibitory factor receptor signaling. A complementation of the wild-type (WT) placenta by using tetraploid rescue technique showed that the embryonic lethality in SOCS3-deficient embryo was due to the placental defect. Here we demonstrate that TS cells supplementation rescues placental defect in SOCS3-deficient embryos. In the rescued placenta, TS cells were integrated into the placental structure, and a substantial structural improvement was observed in the labyrinthine layer that was disrupted in the SOCS3-deficient placenta. Importantly, by supplying TS cells, living SOCS3-deficient embryos were detected at term. These results indicate a functional contribution of TS cells in the placenta and their potential application. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, the authors will discuss the highlights of early onset colon cancer (EOCRC), an increasing but still unclear phenomenon. Indeed, the risk factors are largely similar to classic colon cancer (CRC), but it is still unclear what causes an increased risk of CRC at an early age. In addition, the issue of screening, which allows early diagnosis of the disease, is also important; the younger segment of the population is not included in such programs except if they belong to the highest-risk groups. If the phenomenon of EOCRC becomes more prominent, screening programs will have to be reviewed but with consideration of the consequences for health economics. In this review, we will focus on the epidemiological, prognostic, clinico-pathological, molecular, and therapeutic features of EOCRC; in particular, we will try to highlight the characteristics of the metastatic stage and the differences with CRC in older segments of the population. Despite a recent overall decrease in colorectal cancer (CRC) incidence and mortality, there has been a significant rise in CRC diagnoses in young adults. Early onset colorectal cancer (EOCRC) is defined as CRC diagnosed before the age of 50. Possible predisposing conditions include not only genetic syndromes but also other risk factors, such as microbiome alteration, antibiotic exposure, obesity, diabetes mellitus, and inflammatory bowel disease. EOCRC tends to be diagnosed later than in the older counterpart because of a lack of awareness and the fact that screening for CRC usually starts at the age of 50. Furthermore, CRC in young adults seems to be related to unique molecular features and more aggressive clinical behavior. This paper aims to provide an in-depth review of this poorly understood subject, with a comprehensive review of the state of the art and considerations for future perspectives. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cell carcinoma (RCC) is the most common type of kidney cancer. The therapeutic strategies are based on surgery and/or specific therapies able to inhibit growth factors that have been shown to promote the growth and spread of tumors. Currently, there is no established biomarker which helps in early diagnosis and in better disease monitoring with a high sensitivity. Much information could be provided by body fluids, especially blood liquid biopsy (LB), that are increasingly interesting to researchers. LB is a non- or minimally invasive procedure that could allow clinicians to monitor cancer evolution, also thanks to the presence of small vesicles known as extracellular vesicles (EVs) secreted by tumor cells and containing useful information. In particular, growing interest is focused on small RNA molecules (miRNAs) that are involved in tumor growth and could represent potential diagnostic, prognostic, and predictive biomarkers in RCC, as we summarize in this review. Renal cell carcinoma (RCC) is the second most common cancer of the urinary system. The current therapeutic strategies are based on partial or total nephrectomy and/or targeted therapies based on immune checkpoint inhibitors to which patients are often refractory. Preventive and screening strategies do not exist and the few available biomarkers for RCC are characterized by a lack of sensitivity, outlining the need for novel noninvasive and sensitive biomarkers for early diagnosis and better disease monitoring. Blood liquid biopsy (LB) is a non- or minimally invasive procedure for a more representative view of tumor heterogeneity than a tissue biopsy, potentially allowing the real-time monitoring of cancer evolution. Growing interest is focused on the extracellular vesicles (EVs) secreted by either healthy or tumoral cells and recovered in a variety of biological matrices, blood included. EVs are involved in cell-to-cell crosstalk transferring their mRNAs, microRNAs (miRNAs), and protein content. In particular, transferred miRNAs may regulate tumorigenesis and proliferation also impacting resistance to apoptosis, thus representing potential useful biomarkers. Here, we present the latest efforts in the identification of circulating miRNAs in blood samples, focusing on the potential use of EV-derived miRNAs as RCC diagnostic and prognostic markers. [ABSTRACT FROM AUTHOR]

The proapoptotic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is physiologically expressed by immune cells and performs regulatory functions in infections, autoimmune diseases and cancer, where it acts as a tumor suppressor. Adipose-derived mesenchymal stromal cells (AD-MSCs) also may play immunomodulatory roles in both primary and acquired immune responses. We have previously demonstrated the efficacy of an anticancer gene therapy based on AD-MSC engineered to secrete a soluble TRAIL variant (sTRAIL) against pancreatic cancer. However, the impact of AD-MSC sTRAIL on leukocyte subsets has been not yet considered also to predict a possible immunotoxicity profile in the clinical translation of this cell-based anticancer strategy. Monocytes, polymorphonuclear cells and T lymphocytes were freshly isolated from the peripheral blood of healthy donors. Immunophenotype and functional (DR4 and DR5) and decoy (DcR1 and DcR2) TRAIL receptors were tested by flow cytometry. The viability of white blood cells treated with sTRAIL released by gene-modified AD-MSC or co-cultured with AD-MSC sTRAIL was then evaluated by both metabolic assays and flow cytometry. In addition, cytokine profile in co-cultures was analyzed by multiplex enzyme-linked immunosorbent assay. Monocytes and polymorphonuclear cells showed high positivity for DR5 and DcR2, respectively, whereas T cells revealed negligible expression of all TRAIL receptors. Irrespective of TRAIL receptors' presence on the cell membrane, white blood cells were refractory to the proapoptotic effect displayed by sTRAIL secreted by gene-modified AD-MSC, and direct cell-to-cell contact with AD-MSC sTRAIL had negligible impact on T-cell and monocyte viability. Cytokine crosstalk involving interleukin 10, tumor necrosis factor alpha, and interferon gamma secreted by T lymphocytes and vascular endothelial growth factor A and interleukin 6 released by AD-MSC was highlighted in T-cell and AD-MSC sTRAIL co-cultures. In summary, this study demonstrates the immunological safety and thus the clinical feasibility of an anticancer approach based on AD-MSC expressing the proapoptotic molecule sTRAIL. [ABSTRACT FROM AUTHOR]

Lesion characteristics had the aspect of a probable melanocytic or non-melanocytic skin tumor, but we couldn't exclude the possible diagnosis of an inflammatory disease, due to the unspecific morphology of vessels and the diffuse ulceration. Dear Editor, Nail unit melanoma (NUM) is a rare melanoma that originates from the nail unit apparatus. Nodular nail unit melanoma mimicking a non-healing ulcer: Dermoscopic and reflectance confocal microscopic features. [Extracted from the article]

Hereditary cancer syndromes are inherited disorders caused by germline pathogenic variants (PVs) that lead to an increased risk of developing certain types of cancer, frequently at an earlier age than in the rest of the population. The germline PVs promote cancer development, growth and survival, and may represent an ideal target for the personalized treatment of hereditary tumors. PARP inhibitors for the treatment of BRCA and PALB2-associated tumors, immune checkpoint inhibitors for tumors associated with the Lynch Syndrome, HIF-2α inhibitor in the VHL-related cancers and, finally, selective RET inhibitors for the treatment of MEN2-associated medullary thyroid cancer are the most successful examples of how a germline PVs can be exploited to develop effective personalized therapies and improve the outcome of these patients. The present review aims to describe and discuss the personalized systemic therapies for inherited cancer syndromes that have been developed and investigated in clinical trials in recent decades. [ABSTRACT FROM AUTHOR]

Simple Summary: Bone metastases and health are crucial issues in prostate cancer patient management. The aim of our review was to describe the biology of bone metastases and their clinical implications in prostate cancer patients, and current therapeutic strategies. In addition, "bone health" should be evaluated and specific treatments considered. In this way, we aimed to attract attention to the risk of both "bad" bone health and bone metastasis, and also to the available care options for these patients. Clinically relevant bone metastases are a major cause of morbidity and mortality for prostate cancer patients. Distinct phenotypes are described: osteoblastic, the more common osteolytic and mixed. A molecular classification has been also proposed. Bone metastases start with the tropism of cancer cells to the bone through different multi-step tumor–host interactions, as described by the "metastatic cascade" model. Understanding these mechanisms, although far from being fully elucidated, could offer several potential targets for prevention and therapy. Moreover, the prognosis of patients is markedly influenced by skeletal-related events. They can be correlated not only with bone metastases, but also with "bad" bone health. There is a close correlation between osteoporosis—a skeletal disorder with decreased bone mass and qualitative alterations—and prostate cancer, in particular when treated with androgen deprivation therapy, a milestone in its treatment. Systemic treatments for prostate cancer, especially with the newest options, have improved the survival and quality of life of patients with respect to skeletal-related events; however, all patients should be evaluated for "bone health" and osteoporotic risk, both in the presence and in the absence of bone metastases. Treatment with bone-targeted therapies should be evaluated even in the absence of bone metastases, as described in special guidelines and according to a multidisciplinary evaluation. [ABSTRACT FROM AUTHOR]

Locally advanced non-small-cell lung cancer still represents a "grey zone" in terms of the best treatment choice and optimal clinical outcomes. Indeed, most patients may be suitable to receive different treatments with similar outcomes such as chemo-radiotherapy (CHT-RT) followed by immunotherapy (IO) or surgery followed by adjuvant local/systemic therapies. We report a clinical case of a patient submitted to primary thoracic surgery who developed a mediastinal nodal recurrence successfully treated by CHT-RT-IO. Subsequently, a single brain lesion was found to have been successfully treated by single fraction stereotactic ablative radiotherapy. The patient is still on follow-up and she is free from disease having a good quality of life. In this report, we also perform a mini review about the role of CHT-RT followed by IO in treating loco-regional relapse after surgery. The role of SABR after IO is also evaluated, finding that it is safe and well tolerated. More robust and larger clinical data are needed in this particular setting to better define the role of the combination of systemic and local treatments in the management of intrathoracic and intracranial relapse for patients already submitted to CHT-RT followed by immunotherapy. [ABSTRACT FROM AUTHOR]

In recent years, the molecular subtyping of gastric cancer has led to the identification of novel clinically relevant biomarkers as well as promising therapeutic targets. In parallel, the advent of checkpoint inhibitors has expanded treatment options beyond conventional chemotherapy. Compelling evidence has shown unprecedented efficacy results for anti-PD1-based therapies in the molecular subgroups of dMMR/MSI-h, EBV+ and PD-L1 CPS+ patients, to the point that these are granted approval for gastric cancer adenocarcinoma (AGC) in several countries. Despite this, cytotoxic chemotherapy remains the only treatment choice for the considerable proportion of biomarkers-negative patients. In this context, little is known about the association between subtypes-defining biomarkers (HER2, MMR/MSI, PD-L1, and EBV) and the efficacy of standard chemotherapy in non-Asian AGC. Here, we aimed to investigate the prevalence, the clinic-pathologic features, and the impact on treatment outcome of clinical molecular subtypes in a new-diagnosed Western cohort of AGC. [ABSTRACT FROM AUTHOR]

Several authors reported an increased risk of cancer in SSc patients, including breast cancer (BC). Nevertheless, the mechanisms underlying this association have not yet been clarified. SSc and BC share several molecular pathways, which seem to play a common etiopathogenetic role. The previously published Sclero-Breast study demonstrated the development of BC with a good prognosis among these patients, which could be explained by an autoimmune background as a possible mechanism for limiting tumor extension. Here, we report the results of an IHC analysis of molecular pathways known to be common drivers for both diseases, with the aim to better define the mechanisms underlying a good prognosis of BC in patients affected by SSc. The analysis demonstrated higher TILs rates in all BC subgroups, with a high rate of PD-L1 expression especially in TNBC and HER2-positive BC, suggesting a less aggressive behavior in these patients compared to the general population. These results support a possible de-escalation strategy of cancer therapies in these fragile patients. These data could represent a starting point for future prospective studies based on the clinical application of these biomarkers with a larger sample size to promote a personalized and targeted oncological treatment for this specific subset of patients. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is a highly aggressive malignancy that accounts for about 14% of all lung cancers. Platinum-based chemotherapy has been the only available treatment for a long time, until the introduction of immune checkpoint inhibitors (ICIs) recently changed first-line standard of care and shed light on the pivotal role of the immune system. Despite improved survival in a subset of patients, a lot of them still do not benefit from first-line chemo-immunotherapy, and several studies are investigating whether different combination strategies (with both systemic and local treatments, such as radiotherapy) may improve patient outcomes. Moreover, research of biomarkers that may be used to predict patients' outcomes is ongoing. In addition to ICIs, immunotherapy offers other different strategies, including naked monoclonal antibodies targeting tumor associated antigens, conjugated antibody, bispecific antibodies and cellular therapies. In this review, we summarize the main evidence available about the use of immunotherapy in SCLC, the rationale behind combination strategies and the studies that are currently ongoing in this setting, in order to give the reader a clear and complete view of this rapidly expanding topic. [ABSTRACT FROM AUTHOR]

Osteonecrosis of the femoral head (ONFH) is a progressive degenerative disease that ultimately requires a total hip replacement. Mesenchymal stromal/stem cells (MSCs), particularly the ones isolated from bone marrow (BM), could be promising tools to restore bone tissue in ONFH. Here, we established a rabbit model to mimic the pathogenic features of human ONFH and to challenge an autologous MSC-based treatment. ON has been originally induced by the synergic combination of surgery and steroid administration. Autologous BM-MSCs were then implanted in the FH, aiming to restore the damaged tissue. Histological analyses confirmed bone formation in the BM-MSC treated rabbit femurs but not in the controls. In addition, the model also allowed investigations on BM-MSCs isolated before (ON-BM-MSCs) and after (ON+BM-MSCs) ON induction to dissect the impact of ON damage on MSC behavior in an affected microenvironment, accounting for those clinical approaches foreseeing MSCs generally isolated from affected patients. BM-MSCs, isolated before and after ON induction, revealed similar growth rates, immunophenotypic profiles, and differentiation abilities regardless of the ON. Our data support the use of ON+BM-MSCs as a promising autologous therapeutic tool to treat ON, paving the way for a more consolidated use into the clinical settings. [ABSTRACT FROM AUTHOR]

Background: Allogeneic mesenchymal stromal cells (MSCs) have been used extensively in various clinical trials. Nevertheless, there are concerns about their efficacy, attributed mainly to the heterogeneity of the applied populations. Therefore, producing a consistent population of MSCs is crucial to improve their therapeutic efficacy. This study presents a good manufacturing practice (GMP)-compatible and cost-effective protocol for manufacturing, banking, and lot-release of a homogeneous population of human bone marrow-derived clonal MSCs (cMSCs). Methods: Here, cMSCs were isolated based on the subfractionation culturing method. Afterward, isolated clones that could reproduce up to passage three were stored as the seed stock. To select proliferative clones, we used an innovative, cost-effective screening strategy based on lengthy serial passaging. Finally, the selected clones re-cultured from the seed stock to establish the following four-tired cell banking system: initial, master, working, and end of product cell banks (ICB, MCB, WCB, and EoPCB). Results: Through a rigorous screening strategy, three clones were selected from a total of 21 clones that were stored during the clonal isolation process. The selected clones met the identity, quality, and safety assessments criteria. The validated clones were stored in the four-tiered cell bank system under GMP conditions, and certificates of analysis were provided for the three-individual ready-to-release batches. Finally, a stability study validated the EoPCB, release, and transport process of the frozen final products. Conclusion: Collectively, this study presents a technical and translational overview of a GMP-compatible cMSCs manufacturing technology that could lead to the development of similar products for potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Background. More than 50% of operable GEA relapse after curative-intent resection. We aimed at externally validating a nomogram to enable a more accurate estimate of individualized risk in resected GEA. Methods. Medical records of a training cohort (TC) and a validation cohort (VC) of patients undergoing radical surgery for c/uT2-T4 and/or node-positive GEA were retrieved, and potentially interesting variables were collected. Cox proportional hazards in univariate and multivariate regressions were used to assess the effects of the prognostic factors on OS. A graphical nomogram was constructed using R software's package Regression Modeling Strategies (ver. 5.0-1). The performance of the prognostic model was evaluated and validated. Results. The TC and VC consisted of 185 and 151 patients. ECOG:PS > 0 (p < 0.001), angioinvasion (p < 0.001), log (Neutrophil/Lymphocyte ratio) (p < 0.001), and nodal status (p = 0.016) were independent prognostic values in the TC. They were used for the construction of a nomogram estimating 3- and 5-year OS. The discriminatory ability of the model was evaluated with the c-Harrell index. A 3-tier scoring system was developed through a linear predictor grouped by 25 and 75 percentiles, strengthening the model's good discrimination (p < 0.001). A calibration plot demonstrated a concordance between the predicted and actual survival in the TC and VC. A decision curve analysis was plotted that depicted the nomogram's clinical utility. Conclusions. We externally validated a prognostic nomogram to predict OS in a joint independent cohort of resectable GEA; the NOMOGAST could represent a valuable tool in assisting decision-making. This tool incorporates readily available and inexpensive patient and disease characteristics as well as immune-inflammatory determinants. It is accurate, generalizable, and clinically effectivex. [ABSTRACT FROM AUTHOR]

The resorption rate of autologous fat transfer (AFT) is 40–60% of the implanted tissue, requiring new surgical strategies for tissue reconstruction. We previously demonstrated in a rabbit model that AFT may be empowered by adipose-derived mesenchymal stromal/stem cells (AD-MSCs), which improve graft persistence by exerting proangiogenic/anti-inflammatory effects. However, their fate after implantation requires more investigation. We report a xenograft model of adipose tissue engineering in which NOD/SCID mice underwent AFT with/without human autologous AD-MSCs and were monitored for 180 days (d). The effect of AD-MSCs on AFT grafting was also monitored by evaluating the expression of CD31 and F4/80 markers. Green fluorescent protein-positive AD-MSCs (AD-MSC-GFP) were detected in fibroblastoid cells 7 days after transplantation and in mature adipocytes at 60 days, indicating both persistence and differentiation of the implanted cells. This evidence also correlated with the persistence of a higher graft weight in AFT-AD-MSC compared to AFT alone treated mice. An observation up to 180 d revealed a lower resorption rate and reduced lipidic cyst formation in the AFT-AD-MSC group, suggesting a long-term action of AD-MSCs in support of AFT performance and an anti-inflammatory/proangiogenic activity. Together, these data indicate the protective role of adipose progenitors in autologous AFT tissue resorption. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic horizons of various cancers. However, immune-related adverse events have been reported, including interstitial lung diseases. Our aim was to describe the clinical and radiological features and survival of a multicentre cohort of patients who developed ICI-related lung toxicity. Methods: Six Italian centres were involved in the study. Patients who were treated with anti-PD-1/PD-L1 and CTLA-4 mAbs and developed ICI-related lung toxicity were recruited retrospectively to study clinical, radiological, immunological and survival data. Results: A total of 41 patients (25 males, 66.8 ± 9.9 years) were enrolled. Lung toxicity occurred after 204.3 ± 208.3 days of therapy, with ground glass opacities being the most common HRCT pattern (23 cases). Male sex, lung cancer and acute respiratory failure were associated with a shorter latency of toxicity (p = 0.0030, p = 0.0245 and p = 0.0390, respectively). Patients who required high-flow oxygen therapy showed significantly worse survival (p = 0.0028). Conclusions: Our cohort showed heterogeneous clinical and radiological aspects of ICI-related lung toxicity, with a latency not limited to the first year of treatment. Severity was mainly mild to moderate, although life-threatening events did occur. Our data indicate that strict long-term follow-up is needed to enable early diagnosis and appropriate management. [ABSTRACT FROM AUTHOR]

The current treatment approach for type 1 diabetes is based on daily insulin injections, combined with blood glucose monitoring. However, administration of exogenous insulin fails to mimic the physiological activity of the islet, therefore diabetes often progresses with the development of serious complications such as kidney failure, retinopathy and vascular disease. Whole pancreas transplantation is associated with risks of major invasive surgery along with side effects of immunosuppressive therapy to avoid organ rejection. Replacement of pancreatic beta-cells would represent an ideal treatment that could overcome the above mentioned therapeutic hurdles. In this context, transplantation of islets of Langerhans is considered a less invasive procedure although long-term outcomes showed that only 10 % of the patients remained insulin independent five years after the transplant. Moreover, due to shortage of organs and the inability of islet to be expanded ex vivo, this therapy can be offered to a very limited number of patients. Over the past decade, cellular therapies have emerged as the new frontier of treatment of several diseases. Furthermore the advent of stem cells as renewable source of cell-substitutes to replenish the beta cell population, has blurred the hype on islet transplantation. Breakthrough cellular approaches aim to generate stem-cell-derived insulin producing cells, which could make diabetes cellular therapy available to millions. However, to date, stem cell therapy for diabetes is still in its early experimental stages. This review describes the most reliable sources of stem cells that have been developed to produce insulin and their most relevant experimental applications for the cure of diabetes. [ABSTRACT FROM AUTHOR]

The article discusses the commercialization of unproven cell therapies and cell-based products which depends on regulation in pre- and post-marketing phases of product development.

Endocrine therapy (ET), associated with CDK 4/6 inhibitors, represents the first choice of treatment for HR+/HER2- metastatic breast cancer (mBC). Primary or secondary endocrine resistance could develop; however validated biomarkers capable of predicting such a conditions are not available. Several studies have shown that HR+/HER2- mBC comprises five intrinsic subtypes. The purpose of this systematic review was to analyze the potential correlations between intrinsic subtype, efficacy of treatment, and patient outcome. Five papers that analyzed the intrinsic subtype with PAM50 assay in patients (pts) with HR+/HER2- mBC treated with ET (alone or in combination) within seven phase III clinical trials (EGF30008, BOLERO-2, PALOMA-2,3, MONALEESA-2,3,7) were identified. Non-luminal subtypes are more frequent in endocrine-resistant pts and in metastatic sites (vs. primary tumors), have less benefit from ET, and worse prognosis. Among these, HER2-enriched subtypes are similar to HER2+ tumors and benefit from the addition of anti-HER2 agents (lapatinib) and, for less clear reasons, of ribociclib (unconfirmed data for palbociclib and everolimus). Basal-like subtypes are similar to triple-negative tumors, making them more sensitive to chemotherapy. The intrinsic subtype is also not static but can vary over time with the evolution of the disease. Currently, the intrinsic subtype does not play a decisive role in the choice of treatment in clinical practice, but has potential prognostic and predictive value that should be further investigated. [ABSTRACT FROM AUTHOR]

Objective: No-visitor policies adopted to prevent coronavirus disease-19 (COVID-19) spread in hospital wards have deeply impacted communication with patients and their relatives. Whereas in pre-COVID-19 era family-clinician meetings were held in person, during the pandemic interactions often took place over the phone, frequently causing feelings of uncertainty and distress to the close ones at home. The goal of this study was to assess and improve the effectiveness of structured telephone-based communication with hospitalized onco-hematological patients' relatives in COVID-19 era. Methods: After no-visitor policy was adopted in the Onco-Hematological Unit of Modena, inpatients' relatives were contacted daily for clinical updates. After discharge, a telephone satisfaction survey was administered to all contact people of patients consecutive admitted between December 2020 and January 2021 (n = 97). Mean score of response and potential statistically significative differences depending on respondents' characteristics were assessed. Results: Most relatives were satisfied with the communication received with a mean total score of 4.69 on a 5-point Likert scale (standard deviation: 0.60). Results showed high satisfaction rate with both the informative (mean ± SD: 4.66 ± 0.64) and emotional (mean ± SD: 4.66 ± 0.58) content, with no significant difference depending on respondents' demographic characteristics (p > 0.05). Conclusion: A structured telephone-based communication may be a reasonable substitute for face-to-face meetings; especially if regular in time, conducted by the same doctor and integrated with video calls. Our findings might assist health workers in implementing measures to minimize the psychological effects of no-visitor policies during hospitalization. Clinical updates delivery through structured phone calls and video calls could become an opportunity also in post-COVID era. [ABSTRACT FROM AUTHOR]

Background: Current guidelines consider T-DM1 the standard 2nd line therapy for HER2 positive metastatic breast cancer (MBC) patients following trastuzumab (T) + pertuzumab (P) and taxane 1st line treatment. Despite this, there are no prospective studies supporting this sequence.Methods: We performed a meta-analysis using real world data to determine the efficacy of T-DM1 after 1st line TP in HER2 positive MBC patients. We used a random-effect model to find differences in the rate of 1-year progression free survival (PFS) between TP pre-treated population and the EMILIA phase III pivotal trial.Results: Seven studies were eligible. The meta-analysis showed a combined 1-year PFS risk difference for T-DM1 efficacy after TP in 2nd or more lines of -0.122, with lower and upper limits of -0.253 and 0.010, respectively (p = 0.07), with low heterogeneity among studies (I2 0.01%, p = 0.836). Considering the four studies on T-DM1 in 2nd line setting, 1-year PFS risk was -0.034 (95% CI -0.207 - 0,139; p = 0.701) (I2 0.01%, p = 0.91).Conclusion: Overall, the efficacy of T-DM1 after TP seems to be similar to that previously reported in the EMILIA trial. In the second line setting, data are not mature enough to confirm T-DM1 efficacy in TP pre-treated population. [ABSTRACT FROM AUTHOR]

Simple Summary: The world of small molecules in solid tumors as cancer stem cells (CSCs), circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs) continues to be under-debated, but not of minor interest in recent decades. One of the main problems in regard to cancer is the development of tumor recurrence, even in the early stages, in addition to drug resistance and, consequently, ineffective or an incomplete response against the tumor. The findings behind this resistance are probably justified by the presence of small molecules such as CSCs, CTCs and CAFs connected with the tumor microenvironment, which may influence the aggressiveness and the metastatic process. The mechanisms, connections, and molecular pathways behind them are still unknown. Our review would like to represent an important step forward to highlight the roles of these molecules and the possible connections among them. The importance of defining new molecules to fight cancer is of significant interest to the scientific community. In particular, it has been shown that cancer stem cells (CSCs) are a small subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity; on the other side, circulating tumor cells (CTCs) seem to split away from the primary tumor and appear in the circulatory system as singular units or clusters. It is becoming more and more important to discover new biomarkers related to these populations of cells in combination to define the network among them and the tumor microenvironment. In particular, cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment with different functions, including matrix deposition and remodeling, extensive reciprocal signaling interactions with cancer cells and crosstalk with immunity. The settings of new markers and the definition of the molecular connections may present new avenues, not only for fighting cancer but also for the definition of more tailored therapies. [ABSTRACT FROM AUTHOR]

Introduction: Immunotherapy dramatically changed history of melanoma patients with a clinical benefit never seen before. Nevertheless, severe and unexpected adverse effects can occur, fortunately rarely. Case presentation: We reported the case of a 75-year-old male patient affected by metastatic melanoma who developed myocarditis and acute rhabdomyolysis with secondary diaphragmatic dysfunction and consequent pulmonary restrictive syndrome after Nivolumab monotherapy. Blood tests and ultrasonography of the diaphragm revealing left hypokinesis suggested a Nivolumab-related rhabdomyolysis, as an immune-mediated adverse event. The rhabdomylolysis involved the diaphragm with consequent diaphragmatic weakness and respiratory distress. Management & outcome: The patient had a slow but slight and progressive improvement of symptoms and vital signs post-treatment with high-dose corticosteroids. Discussion: With this case report, we want to highlight the importance of rapid recognition and treatment of rare and unexpected, but potential serious immune-related adverse events. These events might happen despite the remarkable clinical benefits of immune checkpoint inhibitors. We do not know which patients will benefit from these therapies and why, when and in which cases adverse event will occur: we must not lower our attention. [ABSTRACT FROM AUTHOR]

Background: Dendritic cell vaccination (DCV) strategies, thanks to a complex immune response, may flare tumor regression and improve patients' long-term survival. This meta-analysis aims to assess the efficacy of DCV for newly diagnosed glioblastoma patients in clinical trials. Methods: The study databases, including PubMed, Web of Knowledge, Google Scholar, Scopus, and Cochrane, were searched by two blinded investigators considering eligible studies based on the following keywords: "glioblastoma multiforme", "dendritic cell", "vaccination", "immunotherapy", "immune system", "immune response", "chemotherapy", "recurrence", and "temozolomide". Among the 157 screened, only 15 articles were eligible for the final analysis. Results: Regimens including DCV showed no effect on 6-month progression-free survival (PFS, HR = 1.385, 95% CI: 0.822–2.335, p = 0.673) or on 6-month overall survival (OS, HR = 1.408, 95% CI: 0.882–2.248, p = 0.754). In contrast, DCV led to significantly longer 1-year OS (HR = 1.936, 95% CI: 1.396–2.85, p = 0.001) and longer 2-year OS (HR = 3.670, 95% CI: 2.291–5.879, p = 0.001) versus control groups. Hence, introducing DCV could lead to increased 1 and 2-year survival of patients by 1.9 and 3.6 times, respectively. Conclusion: Antitumor regimens including DCV can effectively improve mid-term survival in patients suffering glioblastoma multiforme (GBM), but its impact emerges only after one year from vaccination. These data indicate the need for more time to achieve an anti-GBM immune response and suggest additional therapeutics, such as checkpoint inhibitors, to empower an earlier DCV action in patients affected by a very poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Approaches based on expression signatures of prostate cancer (PCa) have been proposed to predict patient outcomes and response to treatments. The transcription factor NF-Y participates to the progression from benign epithelium to both localized and metastatic PCa and is associated with aggressive transcriptional profile. The gene encoding for NF-YA, the DNA-binding subunit of NF-Y, produces two alternatively spliced transcripts, NF-YAs and NF-YAl. Bioinformatic analyses pointed at NF-YA splicing as a key transcriptional signature to discriminate between different tumor molecular subtypes. In this study, we aimed to determine the pathophysiological role of NF-YA splice variants in PCa and their association with aggressive subtypes. Methods: Data on the expression of NF-YA isoforms were extracted from the TCGA (The Cancer Genome Atlas) database of tumor prostate tissues and validated in prostate cell lines. Lentiviral transduction and CRISPR-Cas9 technology allowed the modulation of the expression of NF-YA splice variants in PCa cells. We characterized 3D cell cultures through in vitro assays and RNA-seq profilings. We used the rank-rank hypergeometric overlap approach to identify concordant/discordant gene expression signatures of NF-YAs/NF-YAl-overexpressing cells and human PCa patients. We performed in vivo studies in SHO-SCID mice to determine pathological and molecular phenotypes of NF-YAs/NF-YAl xenograft tumors. Results: NF-YA depletion affects the tumorigenic potential of PCa cells in vitro and in vivo. Elevated NF-YAs levels are associated to aggressive PCa specimens, defined by Gleason Score and TNM classification. NF-YAl overexpression increases cell motility, while NF-YAs enhances cell proliferation in PCa 3D spheroids and xenograft tumors. The transcriptome of NF-YAs-spheroids has an extensive overlap with localized and metastatic human PCa signatures. According to PCa PAM50 classification, NF-YAs transcript levels are higher in LumB, characterized by poor prognosis compared to LumA and basal subtypes. A significant decrease in NF-YAs/NF-YAl ratio distinguishes PCa circulating tumor cells from cancer cells in metastatic sites, consistently with pro-migratory function of NF-YAl. Stratification of patients based on NF-YAs expression is predictive of clinical outcome. Conclusions: Altogether, our results indicate that the modulation of NF-YA isoforms affects prostate pathophysiological processes and contributes to cancer-relevant phenotype, in vitro and in vivo. Evaluation of NF-YA splicing may represent a new molecular strategy for risk assessment of PCa patients. [ABSTRACT FROM AUTHOR]

Recently, genetically modified mesenchymal stem cells ( MSCs) have been exploited to deliver anti-cancer bio-drugs directly within the tumour mass. Here, we explored whether adipose-derived MSCs ( AD- MSCs), engineered to express the pro-apoptotic ligand TRAIL (also known as TNFSF10), kill multiple myeloma ( MM) cells and migrate towards MM cells in vitro. Different MM cell lines were assessed for their sensitivity to recombinant human (rh) TRAIL alone and in combination with the proteasome inhibitor bortezomib, which was shown to enhance the effect of rh TRAIL. TRAIL+- AD- MSCs were co-cultured with bortezomib-pretreated MM cells and their killing activity was evaluated in presence or absence of caspase inhibition. AD- MSC migration towards media conditioned by both myeloma cells and myeloma bone fragments was also investigated. Despite moderate MM cell sensitivity to rh TRAIL, TRAIL+- AD- MSCs in combination with bortezomib significantly induced myeloma cell death. This effect was associated with caspase-8 activation and abrogated by capsase inhibition. On the other hand, co-culture experiments were performed to evaluate whether unmodified AD- MSCs affect myeloma cell growth in vitro. AD- MSCs appeared ineffective on myeloma cell growth and showed migratory capacity towards MM cells in vitro. These data emphasize the anti-myeloma activity of TRAIL-engineered AD- MSCs and provide support for a future model of a cell-based approach against MM. [ABSTRACT FROM AUTHOR]

Bone marrow transplantation (BMT) has changed the course of treatment for an array of diseases, including disorders of bone. Hematopoietic stem cells (HSC) within the marrow are known to be the precursors of osteoclastic bone cells, and trials of BMT in osteopetrosis, a disorder characterized by a deficiency of osteoclasts, have resulted in significant clinical improvement in patients. The origin of the other major bone cell, the osteoblast, remains uncertain, although studies have identified osteoprogenitor cells within the marrow, leading to further investigation of both mesenchymal stromal cells (MSC) and HSC as candidates for this role. A better understanding of the source of osteoblasts and normal bone metabolism is crucial to efforts to develop effective cell therapy for bone disorders characterized by deficient or abnormal osteoblast function. This review focuses on systemic and local cell therapy in the treatment of several genetic bone disorders and osteoporosis, an acquired disorder caused by abnormal bone metabolism, with the intent of presenting both the progress and challenges associated with this emerging form of therapy. Although the risks of systemic transplantation must be carefully considered, cell therapy for disorders of bone carries the potential for long-term and potentially curative benefits, justifying further intensive research on this important treatment option. [ABSTRACT FROM AUTHOR]

Introduction: Adipose tissue (AT) has become a source of mesenchymal stromal/stem cells (MSC) for regenerative medicine applications, in particular skeletal disorders. Several enzymatic or mechanical procedures have been proposed to process AT with the aim to isolate cells that can be locally implanted. How AT is processed may impact its properties. Thus, we compared AT processed by centrifugation (C-AT) to microfragmentation (MF-AT). Focusing on MF-AT, we subsequently assessed the impact of synovial fluid (SF) alone on both MF-AT and isolated AT-MSC to better understand their cartilage repair mechanisms. Materials and methods: MF-AT and C-AT from the same donors were compared by histology and qRT-PCR immediately after isolation or as ex vivo cultures using a micro-tissue pellet system. The in vitro impact of SF on MF-AT and AT-MSC was assessed by histological staining and molecular analysis. Results: The main AT histological features (i.e., increased extracellular matrix and cellularity) of the freshly isolated or ex vivo-cultured MF-AT persisted compared to C-AT, which rapidly deteriorated during culture. Based on our previous studies of HOX genes in MSC, we investigated the involvement of Homeobox Protein HOX-B7 (HOXB7) and its target basic Fibroblast Growth Factor (bFGF) in the molecular mechanism underlying the improved performance of MF-AT. Indeed, both these biomarkers were more prominent in freshly isolated MF-AT compared to C-AT. SF alone preserved the AT histological features of MF-AT, together with HOXB7 and bFGF expression. Increased cell performance was also observed in isolated AT-MSC after SF treatment concomitant with enhanced HOXB7 expression, although there was no apparent association with bFGF. Conclusions: Our findings show that MF has a positive effect on the maintenance of AT histology and may trigger the expression of trophic factors that improve tissue repair by processed AT. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal/stem cells (MSCs) have been widely tested against many diseases, with more than 1000 registered clinical trials worldwide. Despite many setbacks, MSCs have been approved for the treatment of graft-versus-host disease and Crohn disease. However, it is increasingly clear that MSCs exert their therapeutic functions in a paracrine manner through the secretion of small extracellular vesicles (sEVs) of 50–200 nm in diameter. Unlike living cells that can persist long-term, sEVs are non-living and non-replicative and have a transient presence in the body. Their small size also renders sEV preparations highly amenable to sterilization by filtration. Together, acellular MSC-sEV preparations are potentially safer and easier to translate into the clinic than cellular MSC products. Nevertheless, there are inherent challenges in the development of MSC-sEV drug products. MSC-sEVs are products of living cells, and living cells are sensitive to changes in the external microenvironment. Consequently, quality control metrics to measure key identity and potency features of MSC-sEV preparations have to be specified during development of MSC-sEV therapeutics. The authors have previously described quantifiable assays to define the identity of MSC-sEVs. Here the authors discuss requirements for prospective potency assays to predict the therapeutic effectiveness of the drug substance in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Although potency assays should ideally reflect the mechanism of action (MoA), this is challenging because the MoA for the reported efficacy of MSC-sEV preparations against multiple diseases of diverse underlying pathology is likely to be complex and different for each disease and difficult to fully elucidate. Nevertheless, robust potency assays could be developed by identifying the EV attribute most relevant to the intended biological activity in EV-mediated therapy and quantifying the EV attribute. Specifically, the authors highlight challenges and mitigation measures to enhance the manufacture of consistent and reproducibly potent sEV preparations, to identify and select the appropriate EV attribute for potency assays despite a complex "work-in-progress" MoA and to develop assays likely to be compliant with regulatory guidance for assay validation. [Display omitted] [ABSTRACT FROM AUTHOR]