Myelodysplastic syndromes with ring sideroblasts.

Myelodysplastic syndromes (MDS) are acquired bone marrow malignant disorders characterized by ineffective hematopoiesis, resulting from a complex interaction between genetic and epigenetic mutations, alterations of the marrow microenvironment, and the immune system. In 2001, the World Health Organization (WHO) proposed a classification that integrates morphologic and genetic information, considering the MDS with ring sideroblasts (MDS-RS) as a distinct entity. Considering the strong association between MDS-RS and SF3B1 mutation and its importance in the development of MDS, the last WHO classification replaced the prior entity of MDS-RS with MDS with SF3B1 mutation. Several studies were performed to explore this genotype-phenotype correlation. Mutant SF3B1 protein deregulates the expression of genes implicated in developing hematopoietic stem and progenitor cells. Of paramount importance are PPOX and ABCB7 involved in iron metabolism. Another essential role in hemopoiesis is played by the transforming growth factor-beta (TGF-ß) receptor. This gene exerts its effects on SMAD pathways, regulating hematopoiesis through effects on balancing proliferation and apoptosis cell inactivity, differentiation, and migration. Luspatercept (ACE-536) is a soluble fusion protein that inhibits molecules in the TGF-ß superfamily. Since its structure resembles the TGF-ß family receptor, it catches TGF-ß superfamily ligands before binding to the receptor, resulting in reduced activation of SMAD signaling, thus enabling erythroid maturation. Luspatercept was investigated in the phase III trial MEDALIST, showing promising efficacy in treating anemia compared to placebo. Nowadays, further studies are needed to explore the real potential of luspatercept, investigating the biological features likely associated with treatment response, the potential use in combination treatments, and its role in the treatment of naïve MDS.

Iron chelation therapy.

Iron overload is a pathological condition resulting from a congenital impairment of its regulation, increased intestinal iron absorption secondary to bone marrow erythroid hyperplasia, or a chronic transfusional regimen. In normal conditions, intracellular and systemic mechanisms contribute to maintaining iron balance. When this complex homeostatic mechanism fails, an iron overload could be present. Detecting an iron overload is not easy. The gold standard remains the liver biopsy, even if it is invasive and dangerous. Identifying iron using noninvasive techniques allowed a better understanding of the rate of iron overload in different organs, with a low risk for the patient. Estimating serum ferritin (mg/L) is the easiest and, consequently, the most employed diagnostic tool for assessing body iron stores, even if it could be a not specific method. The most common hematological causes of iron overload are myelodysplastic syndromes, sickle cell disease, and thalassemia. In all of these conditions, three drugs have been approved for the treatment of iron overload: deferiprone, deferoxamine, and deferasirox. These chelators have been demonstrated to help lower tissue iron levels and prevent iron overload complications, improving event-free survival (EFS). Nowadays, the decision to start chelation and which chelator to choose remains the joint decision of the clinician and patient.

Ado-trastuzumab emtansine (T-DM1) in HER2+ advanced breast cancer patients: does pretreatment with pertuzumab matter?

AIM: We evaluated the outcomes of patients treated with ado-trastuzumab emantasine (T-DM1) after first-line pertuzumab/trastuzumab, compared with those receiving a trastuzumab-only-based regimen. PATIENTS & METHODS: Patients who received second-line T-DM1 after pertuzumab/trastuzumab (n = 34) were compared with those who received only trastuzumab (n = 73). RESULTS: Overall response rate was 33.3% in patients with prior pertuzumab and 57.1% in the remaining subjects. Disease control rate was 47 and 43%, respectively, and the clinical benefit rate was 43.3 and 71.1%, respectively. Median progression-free survival was 5.0 and 11.0 months, respectively (hazard ratio: 2.02; 95% CI: 1.14-3.58; p = 0.01). CONCLUSION: Patients treated with T-DM1 who previously received pertuzumab present poorer clinical outcomes compared with those receiving a trastuzumab-only-based regimen in the first-line setting.

Tumour-associated macrophages correlate with microvascular bed extension in colorectal cancer patients.

Tumour-associated macrophages (TAMs) represent pivotal components of tumour microenvironment promoting angiogenesis, tumour progression and invasion. In colorectal cancer (CRC), there are no conclusive data about the role of TAMs in angiogenesis-mediated tumour progression. In this study, we aimed to evaluate a correlation between TAMs, TAM immunostained area (TAMIA) microvascular density (MVD), endothelial area (EA) and cancer cells positive to VEGF-A (CCP-VEGF-A) in primary tumour tissue of locally advanced CRC patients undergone to radical surgery. A series of 76 patients with CRC were selected and evaluated by immunohistochemistry and image analysis. An anti-CD68 antibody was employed to assess TAMs and TAMIA expression, an anti-CD34 antibody was utilized to detect MVD and EA expression, whereas an anti-VEGF-A antibody was used to detect CCP-VEGF-A; then, tumour sections were evaluated by image analysis methods. The mean ± S.D. of TAMs, MVD and CCP-VEGF-A was 65.58 ± 21.14, 28.53 ± 7.75 and 63% ± 37%, respectively; the mean ± S.D. of TAMIA and EA was 438.37 ± 124.14µ(2) and 186.73 ± 67.22µ(2) , respectively. A significant correlation was found between TAMs, TAMIA, MVD and EA each other (r ranging from 0.69 to 0.84; P ranging from 0.000 to 0.004). The high level of expression of TAMs and TAMIA in tumour tissue and the significant correlation with both MVD and EA illustrate that TAMs could represent a marker that plays an important role in promoting angiogenesis-mediated CRC. In this context, novel agents killing TAMs might be evaluated in clinical trials as a new anti-angiogenic approach.

Sorafenib: 10 years after the first pivotal trial.

Sorafenib is an oral multikinase inhibitor with anticancer activity against a wide spectrum of cancers. It is currently approved for the treatment of patients with hepatocellular carcinoma, advanced renal cell carcinoma or progressive, locally advanced or metastatic differentiated thyroid carcinoma. In this review, we present a number of studies that investigated the efficacy and safety of sorafenib in these settings. We also discuss the perspectives on the use of this molecule, including the role of sorafenib as comparator for the development of new drugs, the combination of sorafenib with additional therapies (such as transarterial chemoembolization for hepatocellular carcinoma) and the use of this treatment in several other advanced refractory solid tumors.

Biweekly combination of trastuzumab, docetaxel and gemcitabine for HER2-positive metastatic breast cancer: results of a Phase II GOIM study.

AIMS: Clinical activity of chemotherapy plus trastuzumab in HER2 overexpressing advanced breast cancer has been documented. We report the activity and safety results of biweekly combination of trastuzumab, docetaxel and gemcitabine as first-line therapy in HER2-positive advanced breast cancer. PATIENTS & METHODS: Patients were biweekly treated with trastuzumab (4 mg/kg), gemcitabine (1000 mg/m(2)) and docetaxel (50 mg/m(2)). The primary end point was overall response rate, secondary time to progression, clinical benefit rate (partial response plus complete response plus stable disease for ≥ 24 weeks) and tolerability. RESULTS: A total of 65 patients with HER2-positive advanced breast cancer have been enrolled. In total, 47 patients responded (73%; 95% CI, 60-84), 11 achieved complete response (17%; 95% CI: 8.9-28.7), 36 achieved partial response (56%; 95% CI: 43-68.6). The clinical benefit rate was 87.5% (95% CI: 77-94). Three patients (4.7%) experienced progressive disease. The median time to progression was 14.2 months (95% CI: 10.6-17.8), the median overall survival was 39.3 months and the 36-month survival rate was 55.5% (95% CI: 58-73). The worst toxicities were grade 3 neutropenia (12%), thrombocytopenia (6%) and diarrhea (6%). No cardiac toxicity was reported. CONCLUSION: As first-line therapy, this combination allowed the delivery of polychemotherapy in association to targeted therapy, with clinical activity and mild toxicity. The promising results should be further explored in Phase III randomized clinical trials.

Impact of anemia management with EPO on psychologic distress in cancer patients: results of a multicenter patient survey.

AIM: We investigated the role of erythropoietin (EPO) in reducing anemia and preventing the development of psychological distress in patients treated with chemotherapy. PATIENTS & METHODS: This prospective observational study enrolled 591 adult patients receiving EPO at a dose of 30,000 IU administered once weekly for chemotherapy-induced anemia (mean baseline hemoglobin [Hb] level was 9.55 g/dl) over a 12-month period. RESULTS: The majority of patients (371 [71%] patients) achieved a Hb increase >2 g/dl after 4 weeks of treatment. Interestingly, the nonresponder group had a statistically significant deterioration of their psychological conditions as indicated by psychological distress score (p = 0.01). However, within the group of responders to EPO, the Psychological Distress Inventory score remained unchanged. In the present study, severe side effects associated with EPO were not recorded. CONCLUSION: Hb increase, induced by EPO, ameliorates the psychological conditions of cancer patients.

Essential Oils from Southern Italian Aromatic Plants Synergize with Antibiotics against Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis Cell Growth and Biofilm Formation.

The spread of antibiotic-resistant pathogens has prompted the development of novel approaches to identify molecules that synergize with antibiotics to enhance their efficacy. This study aimed to investigate the effects of ten Essential Oils (EOs) on the activity of nine antibiotics in influencing growth and biofilm formation in Escherichia coli, Pseudomonas aeruginosa, and Enterococcus faecalis. The effects of the EOs alone and in combination with antibiotics on both bacterial growth and biofilm formation were analyzed by measuring the MIC values through the broth microdilution method and the crystal violet assay, respectively. All EOs inhibited the growth of E. coli (1.25 ≤ MIC ≤ 5 mg/mL) while the growth of P. aeruginosa and E. faecalis was only affected by EOs from Origanum vulgare, (MIC = 5 mg/mL) and O. vulgare (MIC = 1.25 mg/mL) and Salvia rosmarinus (MIC = 5 mg/mL), respectively. In E. coli, most EOs induced a four- to sixteen-fold reduction in the MIC values of ampicillin, ciprofloxacin, ceftriaxone, gentamicin, and streptomycin, while in E. faecalis such a reduction is observed in combinations of ciprofloxacin with C. nepeta, C. bergamia, C. limon, C. reticulata, and F. vulgare, of gentamicin with O. vulgare, and of tetracycline with C. limon and O. vulgare. A smaller effect was observed in P. aeruginosa, in which only C. bergamia reduced the concentration of tetracycline four-fold. EO-antibiotic combinations also inhibit the biofilm formation. More precisely, all EOs with ciprofloxacin in E. coli, tetracycline in P. aeruginosa, and gentamicin in E. faecalis showed the highest percentage of inhibition. Combinations induce up- and down-methylation of cytosines and adenines compared to EO or antibiotics alone. The study provides evidence about the role of EOs in enhancing the action of antibiotics by influencing key processes involved in resistance mechanisms such as biofilm formation and epigenetic changes. Synergistic interactions should be effectively considered in dealing with pathogenic microorganisms.

Optimizing maintenance therapy in acute myeloid leukemia: where do we stand in the year 2024?

INTRODUCTION: Despite the prognosis of patients affected by acute myeloid leukemia (AML) improved in the last decade, most patients relapse. Maintenance therapy after a chemotherapy approach with or without allogeneic stem cell transplantation could be a way to control the undetectable residual burden of leukemic cells. Several studies are being carried out as maintenance therapy in AML. Some critical points need to be defined, how the physician can choose among the various drugs available. AREAS COVERED: This review discusses the advances and controversies surrounding maintenance therapy for AML patients. EXPERT OPINION: Patients withFLT3-positive AML should receive midostaurin or quizartinib in the first-linesetting. For a patient initially receiving midostaurin, consider switching to sorafenib in the post-transplant setting. Because of the improved safety profile and potency, many experts will lean toward using a second-generation FLT3 inhibitor such as quizartinib or gilteritinib. Finally, no data indicate whether maintenance therapy should be prolonged until progression or for a defined period.

Safety and Tolerability of Antimicrobial Agents in the Older Patient.

Older patients are at high risk of infections, which often present atypically and are associated with high morbidity and mortality. Antimicrobial treatment in older individuals with infectious diseases represents a clinical challenge, causing an increasing burden on worldwide healthcare systems; immunosenescence and the coexistence of multiple comorbidities determine complex polypharmacy regimens with an increase in drug-drug interactions and spread of multidrug-resistance infections. Aging-induced pharmacokinetic and pharmacodynamic changes can additionally increase the risk of inappropriate drug dosing, with underexposure that is associated with antimicrobial resistance and overexposure that may lead to adverse effects and poor adherence because of low tolerability. These issues need to be considered when starting antimicrobial prescriptions. National and international efforts have been made towards the implementation of antimicrobial stewardship (AMS) interventions to help clinicians improve the appropriateness and safety of antimicrobial prescriptions in both acute and long-term care settings. AMS programs were shown to decrease consumption of antimicrobials and to improve safety in hospitalized patients and older nursing home residents. With the abundance of antimicrobial prescriptions and the recent emergence of multidrug resistant pathogens, an in-depth review of antimicrobial prescriptions in geriatric clinical practice is needed. This review will discuss the special considerations for older individuals needing antimicrobials, including risk factors that shape risk profiles in geriatric populations as well as an evidence-based description of antimicrobial-induced adverse events in this patient population. It will highlight agents of concern for this age group and discuss interventions to mitigate the effects of inappropriate antimicrobial prescribing.

Occupation, Literacy, Anthropometric Traits, and Life Expectancy of Italian Men Born 1900-1910: Evidence From Military Conscription Registers.

OBJECTIVE: The aim is to explore the role of anthropometric traits and sociodemographic characteristics on human survival. METHODS: Anthropometrics and sociodemographic data of 1944 conscripts born in the first decade of the 20th century in rural municipalities of Calabria (Southern Italy) who underwent medical examinations for military service were collected. Medical examinations were linked to individual survival data. RESULTS: Height and type of occupation influenced life expectancy. For taller men, the risk of mortality increases by about 20% when compared with men with middle height, while farmers exhibited a significant survival advantage compared to those with other working experiences. DISCUSSION: Height and type of occupation were associated with human mortality. These results are likely to be related to the effect of healthy dietary patterns and physical activity on life expectancy. Further studies are needed to understand to what extent these results obtained in a rural context can be generalized to other contexts.

Safety and efficacy of caplacizumab in a case of thrombotic thrombocytopenic purpura in the postpartum period.

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disease for which pregnancy and the postpartum period represent risk factors. Here, we present the case of a 39-year-old woman at the 31st week of gestation, who presented with cutaneous haemorrhagic symptoms. The complete blood count showed anaemia, thrombocytopenia, increase in haemolysis indices and undetectable ADAMTS13 activity. Acquired TTP was diagnosed, and she started daily plasma exchange (PEX) and methylprednisolone. After 5 days, an emergency caesarean section was performed with success because of pathologic cardiotocographic findings. After 7 days of PEX, the patient showed an initial laboratoristic improvement; unfortunately, 3 days later, she had a recurrence of disease and started daily PEX, caplacizumab and steroid, obtaining a haematological improvement. No literature data about caplacizumab use in pregnant or breastfeeding patients are available. In the present study, we describe that caplacizumab in the postpartum period could be well tolerated and effective.

Toll-like receptors and NLRP3 inflammasome-dependent pathways in Parkinson's disease: mechanisms and therapeutic implications.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder characterized by motor and non-motor disturbances as a result of a complex and not fully understood pathogenesis, probably including neuroinflammation, oxidative stress, and formation of alpha-synuclein (α-syn) aggregates. As age is the main risk factor for several neurodegenerative disorders including PD, progressive aging of the immune system leading to inflammaging and immunosenescence may contribute to neuroinflammation leading to PD onset and progression; abnormal α-syn aggregation in the context of immune dysfunction may favor activation of nucleotide-binding oligomerization domain-like receptor (NOD) family pyrin domain containing 3 (NLRP3) inflammasome within microglial cells through interaction with toll-like receptors (TLRs). This process would further lead to activation of Caspase (Cas)-1, and increased production of pro-inflammatory cytokines (PC), with subsequent impairment of mitochondria and damage to dopaminergic neurons. All these phenomena are mediated by the translocation of nuclear factor kappa-B (NF-κB) and enhanced by reactive oxygen species (ROS). To date, drugs to treat PD are mainly aimed at relieving clinical symptoms and there are no disease-modifying options to reverse or stop disease progression. This review outlines the role of the TLR/NLRP3/Cas-1 pathway in PD-related immune dysfunction, also focusing on specific therapeutic options that might be used since the early stages of the disease to counteract neuroinflammation and immune dysfunction.

GPER deletion triggers inhibitory effects in triple negative breast cancer (TNBC) cells through the JNK/c-Jun/p53/Noxa transduction pathway.

The G protein-coupled estrogen receptor (GPER) mediates estrogen action in different pathophysiological conditions, including cancer. GPER expression and signaling have been found to join in the progression of triple-negative breast cancer (TNBC), even though controversial data have been reported. In present study, we aimed at providing new mechanistic and biological discoveries knocking out (KO) GPER expression by CRISPR/Cas9 technology in MDA-MB-231 TNBC cells. GPER KO whole transcriptome respect to wild type (WT) MDA-MB-231 cells was determined through total RNA sequencing (RNA-Seq) and gene ontology (GO) enrichment analysis. We ascertained that anti-proliferative and pro-apoptotic gene signatures characterize GPER KO MDA-MB-231 cells. Thereafter, we determined that these cells exhibit a reduced proliferative, clonogenic and self-renewal potential along with an increased mitochondria-dependent apoptosis phenotype. In addition, we recognized that decreased cAMP levels trigger the JNK/c-Jun/p53/Noxa axis, which in turn orchestrates the pro-apoptotic effects observed in GPER KO cells. In accordance with these data, survival analyses in TNBC patients of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset indicated that high Noxa expression correlates with improved outcomes in TNBC patients. Furthermore, we demonstrated that GPER KO in TNBC cells impairs the expression and secretion of the well-acknowledged GPER target gene named CTGF, thus resulting in the inhibition of migratory effects in cancer-associated fibroblasts (CAFs). Overall, the present study provides novel mechanistic and biological insights on GPER KO in TNBC cells suggesting that GPER may be considered as a valuable target in comprehensive therapeutic approaches halting TNBC progression.

The Ephrin tyrosine kinase a3 (EphA3) is a novel mediator of RAGE-prompted motility of breast cancer cells.

BACKGROUND: The receptor for advanced glycation-end products (RAGE) and its ligands have been implicated in obesity and associated inflammatory processes as well as in metabolic alterations like diabetes. In addition, RAGE-mediated signaling has been reported to contribute to the metastatic progression of breast cancer (BC), although mechanistic insights are still required. Here, we provide novel findings regarding the transcriptomic landscape and the molecular events through which RAGE may prompt aggressive features in estrogen receptor (ER)-positive BC. METHODS: MCF7 and T47D BC cells stably overexpressing human RAGE were used as a model system to evaluate important changes like cell protrusions, migration, invasion and colony formation both in vitro through scanning electron microscopy, clonogenic, migration and invasion assays and in vivo through zebrafish xenografts experiments. The whole transcriptome of RAGE-overexpressing BC cells was screened by high-throughput RNA sequencing. Thereafter, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses allowed the prediction of potential functions of differentially expressed genes (DEGs). Flow cytometry, real time-PCR, chromatin immunoprecipitation, immunofluorescence and western blot assays were performed to investigate the molecular network involved in the regulation of a novel RAGE target gene namely EphA3. The clinical significance of EphA3 was explored in the TCGA cohort of patients through the survivALL package, whereas the pro-migratory role of EphA3 signaling was ascertained in both BC cells and cancer-associated fibroblasts (CAFs). Statistical analysis was performed by t-tests. RESULTS: RNA-seq findings and GSEA analysis revealed that RAGE overexpression leads to a motility-related gene signature in ER-positive BC cells. Accordingly, we found that RAGE-overexpressing BC cells exhibit long filopodia-like membrane protrusions as well as an enhanced dissemination potential, as determined by the diverse experimental assays. Mechanistically, we established for the first time that EphA3 signaling may act as a physical mediator of BC cells and CAFs motility through both homotypic and heterotypic interactions. CONCLUSIONS: Our data demonstrate that RAGE up-regulation leads to migratory ability in ER-positive BC cells. Noteworthy, our findings suggest that EphA3 may be considered as a novel RAGE target gene facilitating BC invasion and scattering from the primary tumor mass. Overall, the current results may provide useful insights for more comprehensive therapeutic approaches in BC, particularly in obese and diabetic patients that are characterized by high RAGE levels.

The AGEs/RAGE Transduction Signaling Prompts IL-8/CXCR1/2-Mediated Interaction between Cancer-Associated Fibroblasts (CAFs) and Breast Cancer Cells.

Advanced glycation end products (AGEs) and the cognate receptor, named RAGE, are involved in metabolic disorders characterized by hyperglycemia, type 2 diabetes mellitus (T2DM) and obesity. Moreover, the AGEs/RAGE transduction pathway prompts a dysfunctional interaction between breast cancer cells and tumor stroma toward the acquisition of malignant features. However, the action of the AGEs/RAGE axis in the main players of the tumor microenvironment, named breast cancer-associated fibroblasts (CAFs), remains to be fully explored. In the present study, by chemokine array, we first assessed that interleukin-8 (IL-8) is the most up-regulated pro-inflammatory chemokine upon AGEs/RAGE activation in primary CAFs, obtained from breast tumors. Thereafter, we ascertained that the AGEs/RAGE signaling promotes a network cascade in CAFs, leading to the c-Fos-dependent regulation of IL-8. Next, using a conditioned medium from AGEs-exposed CAFs, we determined that IL-8/CXCR1/2 paracrine activation induces the acquisition of migratory and invasive features in MDA-MB-231 breast cancer cells. Altogether, our data provide new insights on the involvement of IL-8 in the AGEs/RAGE transduction pathway among the intricate connections linking breast cancer cells to the surrounding stroma. Hence, our findings may pave the way for further investigations to define the role of IL-8 as useful target for the better management of breast cancer patients exhibiting metabolic disorders.

Eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer patients: safety and efficacy. An Italian experience.

BACKGROUND: Chemotherapy plus targeted therapy is the established treatment for human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer (BC). Limited data regarding the safety and activity of the combination of eribulin and trastuzumab (E/T) in pretreated HER2-positive advanced BC (ABC) are available. The aim of this observational, retrospective, multicenter study was to examine the tolerability and the clinical activity of E/T in this setting. METHODS: Patients treated with eribulin mesylate plus standard dose of trastuzumab were included. Data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were reported. RESULTS: Between October 2012 and November 2015, 24 consecutive patients with HER2-positive ABC were included. All patients were heavily pretreated: the median number of prior chemotherapy regimens for ABC was 3 (range 2-9). The median number of cycles with E/T was 11.5 (range 2-26). The ORR was 41.7%. Median PFS was 5.4 months, median postprogression survival was 5.4 months, and median OS was 8 months. Neutropenia was the most common grade 3/4 clinical adverse event (16.7%). CONCLUSIONS: Tolerability and clinical activity of the E/T combination schedule are encouraging. The results of this study indicate that this combination might be considered for treatment of pretreated HER2 ABC.