Potential clinical impact of T-cell lymphocyte kinetics monitoring in patients with B cell precursors acute lymphoblastic leukemia treated with blinatumomab: a single-center experience

Blinatumomab is a bispecific anti-CD3 and anti-CD19 antibody that acts as a T-cell engager: by binding CD19+ lymphoblasts, blinatumomab recruits cytotoxic CD3+ T-lymphocytes to target the cancer cells. Here we describe seven different patients affected by B-cell precursor acute lymphoblastic leukemia (Bcp-ALL) and treated with blinatumomab, on which we evaluated the potential association between the amount of different T-cells subsets and deep molecular response after the first cycle, identified as a complete remission in the absence of minimal residual disease (CR/MRD). The immune-system effector cells studied were CD3+, CD4+ effector memory (T4-EM), CD8+ effector memory (T8-EM), and T-regulatory (T-reg) lymphocytes, and myeloid-derived suppressor cells (MDSC). Measurements were performed in the peripheral blood using flow cytometry of the peripheral blood at baseline and after the first cycle of blinatumomab. The first results show that patients with a higher proportion of baseline T-lymphocytes achieved MRD negativity more frequently with no statistically significant difference (p=0.06) and without differences in the subpopulation count following the first treatment. These extremely preliminary data could potentially pave the way for future studies, including larger and less heterogeneous cohorts, in order to assess the T-cell kinetics in a specific set of patients with potential synergy effects in targeting myeloid-derived suppressor cells (MDSC), commonly known to have an immune evasion mechanism in Bcp-ALL

Therapeutic Innovation for Multi-Resistant Candidemics: Synergy of Isavuconazole and Caspofungin Association

Fungal infections occurring in immunocompromised patients after immuno-chemotherapy treatment, are often difficult to eradicate and capable of even being fatal. Systemic mycoses affecting severely immunocompromised patients often manifest acutely with rapidly progressive pneumonia, fungemia, or manifestations of extrapulmonary dissemination. Opportunistic fungal infections (mycoses) include several pathogens elements, as Candidiasis, Aspergillosis, Mucormycosis (zygomycosis) and Fusariosis. Prompt diagnosis and effective therapy are needed to improve the associated morbidity and mortality, especially in cases with non-canonical fungal localizations and not responsive to the available antifungal drugs

Hemophagocytic Syndrome in a Patient with ALL: Morphology Still Matters

We report a case of a young patient suffering from very-high risk B-acute lymphoblastic leukemia (ALL) refractory to first-line therapy with early central nervous system relapse, sequentially treated with inotuzumab. At this timepoint, the patient showed persistent transfusion-refractory thrombocytopenia (platelets < 5000/uL), fever and cytomegalovirus infection. A bone marrow revaluation showed complete remission of ALL, but hemophagocytic elements and activated macrophages were present. At physical examination, the spleen was palpable. Blood chemistry showed hyperferritinemia (1419 ng/mL, normal range 24–336), NK cells suppression (11 cells/microL, minimum value 90) and IL-6 increase (119.1 pg/dL, normal values < 1.8). Triglycerides and fibrinogen were normal. A diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made according to HLH-2004 criteria. The patient was treated with the IL-1 inhibitor anakinra at escalating dosage. After an initial improvement in altered HLH parameters, a clinical worsening occurred with progressing thrombocytopenia and anemia and a remarkable increase in ferritin (4066 ng/mL). The patient then underwent rituximab-based salvage treatment but died due to HLH and B-ALL progression. HLH could be a rare complication in ALL patients. Despite increasing biological knowledge, prognosis remains poor, and more efforts are needed in order to improve survival in these patients

Very low calorie ketogenic diet and common rheumatic disorders: A case report

BACKGROUND The scientific literature provides evidence that nutritional ketosis can be an important support in the treatment of pathologies in which inflammation is present, as recent studies have shown that ketone bodies have anti-inflammatory activity in numerous diseases, including rheumatic diseases. We report the case of a 22-year-old woman with class I obesity and juvenile idiopathic arthritis who started treatment with a very low calorie ketogenic diet (VLCKD). CASE SUMMARY The patient was a 22-year-old woman diagnosed with juvenile idiopathic arthritis at age 4 years and with a body mass index (BMI) of 30.8 kg/m2, waist circumference (WC) 80 cm, fat mass (FM) 28.1 kg, free FM 45.7 kg, and visceral adipose tissue (VAT) 3.5 kg, assessed on bioimpedance analysis. She was treated using a commercial VLCKD weight-loss program (PNK® method); this program provides high-biological-value protein preparations and natural foods. Each protein preparation contains 15 g protein, 4 g carbohydrate, 3 g fat, and 50 mg omega-3 docosahexaenoic acid, with an energy content of 90–120 kcal. After four months on the program, the BMI was 28.6 kg/m2, WC 73 cm, FM 23.2 kg, free FM 41.9 kg, and VAT 2.9 kg. CONCLUSION VLCKD enabled the patient to reach her target weight and to reduce her joint pain and headaches. Laboratory inflammatory indices also normalized

<i>Saprochete capitata</i>: Emerging Infections from Uncommon Microorganisms in Hematological Diseases

Infections occurring in immunocompromised patients after intensive chemotherapy are often difficult to eradicate and are capable of even being fatal. New emergent and dangerous drug-resistant micro-organisms are likely to appear in these specific scenarios. Clinical features mainly include progressive pneumonia, bacteriemia/fungemia, or extrapulmonary dissemination among infections. The treatment of these microorganisms is still an open challenge since there is a lack of clear treatment guidelines. Indeed, infections from these microorganisms can lead to a rapidly fatal clinical course in immunocompromised patients, especially those who have acute leukemia. We describe the case of a young patient with acute myeloid leukemia who contracted an infection from Saprochaete capitata during post-chemotherapy aplasia

Saprochete capitata: Emerging Infections from Uncommon Microorganisms in Hematological Diseases

Infections occurring in immunocompromised patients after intensive chemotherapy are often difficult to eradicate and are capable of even being fatal. New emergent and dangerous drug-resistant micro-organisms are likely to appear in these specific scenarios. Clinical features mainly include progressive pneumonia, bacteriemia/fungemia, or extrapulmonary dissemination among infections. The treatment of these microorganisms is still an open challenge since there is a lack of clear treatment guidelines. Indeed, infections from these microorganisms can lead to a rapidly fatal clinical course in immunocompromised patients, especially those who have acute leukemia. We describe the case of a young patient with acute myeloid leukemia who contracted an infection from Saprochaete capitata during post-chemotherapy aplasia

Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough?

Despite the progress in the development of new therapeutic strategies, relapsed/refractory (R/R) acute myeloid leukemia (AML) still represents a high unmet medical need. Treatment options in this setting include enrollment into clinical trials, allogeneic stem cell transplantation and/or targeted therapy. Nevertheless, it is associated with poor outcomes. Thus, the development of new treatments, which could ameliorate the prognosis of these patients with a good safety profile are highly demanded. Recently, venetoclax (VEN) has been approved for na&iuml;ve AML patients unfit for intensive chemotherapy. In this regard, regimens including VEN could represent a valuable treatment option even in those with R/R disease and several studies have been conducted to demonstrate its role in this clinical setting. This review aims to summarize the current evidence on the use of VEN regimens in the treatment of R/R AML

Target Therapy for Extramedullary Relapse of <i>FLT3</i>-ITD Acute Myeloid Leukemia: Emerging Data from the Field

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase family member. Mutations in FLT3, as well known, represent the most common genomic alteration in acute myeloid leukemia (AML), identified in approximately one-third of newly diagnosed adult patients. In recent years, this has represented an important therapeutic target. Drugs such as midostaurin, gilteritinib, and sorafenib, either alone in association with conventional chemotherapy, play a pivotal role in AML therapy with the mutated FLT3 gene. A current challenge lies in treating forms of AML with extramedullary localization. Here, we describe the general features of myeloid sarcoma and the ability of a targeted drug, i.e., gilteritinib, approved for relapsed or refractory disease, to induce remission of these extramedullary leukemic localizations in AML patients with FLT3 mutation, analyzing how in the literature, there is an important development of cases describing this promising potential for care

Identification of RNA-binding proteins in exosomes capable of interacting with different types of RNA: RBP-facilitated transport of RNAs into exosomes.

The RNA that is packaged into exosomes is termed as exosomal-shuttle RNA (esRNA); however, the players, which take this subset of RNA (esRNA) into exosomes, remain largely unknown. We hypothesized that RNA binding proteins (RBPs) could serve as key players in this mechanism, by making complexes with RNAs and transporting them into exosomes during the biosynthesis of exosomes. Here, we demonstrate the presence of 30 RBPs in exosomes that were shown to form RNA-RBP complexes with both cellular RNA and exosomal-RNA species. To assess the involvement of these RBPs in RNA-transfer into exosomes, the gene transcripts encoding six of the proteins identified in exosomes (HSP90AB1, XPO5, hnRNPH1, hnRNPM, hnRNPA2B1, and MVP) were silenced by siRNA and subsequent effect on esRNA was assessed. A significant reduction of total esRNA was observed by post-transcriptional silencing of MVP, compared to other RBPs. Furthermore, to confirm the binding of MVP with esRNA, a biotinylated-MVP was transiently expressed in HEK293F cells. Higher levels of esRNA were recovered from MVP that was eluted from exosomes of transfected cells, as compared to those of non-transfected cells. Our data indicate that these RBPs could end up in exosomes together with RNA molecules in the form of RNA-ribonucleoprotein complexes, which could be important for the transport of RNAs into exosomes and the maintenance of RNAs inside exosomes. This type of maintenance may favor the shuttling of RNAs from exosomes to recipient cells in the form of stable complexes

Epigenetic dysregulation in neuroblastoma: A tale of miRNAs and DNA methylation

In neuroblastoma, the epigenetic landscape is more profoundly altered in aggressive compared to lower grade tumors and the concomitant hypermethylation of many genes, defined as "methylator phenotype", has been associated with poor outcome. DNA methylation can interfere with gene expression acting at distance through the methylation or demethylation of the regulatory regions of miRNAs. The multiplicity of miRNA targets may result in the simultaneous alteration of many biological pathways like cell proliferation, apoptosis, migration and differentiation. We have analyzed the methylation status of a set of miRNAs in a panel of neuroblastoma cell lines and identified a subset of hypermethylated and down-regulated miRNAs (miRNA 34b-3p, miRNA 34b-5p, miRNA34c-5p, and miRNA 124-2-3p) involved in the regulation of cell cycle, apoptosis and in the control of MYCN expression. These miRNAs share, in part, some of the targets whose expression is inversely correlated to the methylation and expression of the corresponding miRNA. To simulate the effect of the demethylation of miRNAs, we transfected the corresponding miRNA-mimics in the same cell lines and observed the down-regulation of a set of their target genes as well as the partial block of the cell cycle and the activation of the apoptotic pathway. The epigenetic alterations of miRNAs described in the present study were found also in a subset of patients at high risk of progression. Our data disclosed a complex network of interactions between epigenetically altered miRNAs and target genes, that could interfere at multiple levels in the control of cell homeostasis