A Case of Atypical Delayed and Prolonged Hematologic Toxicity With Azacitidine in Chronic Myelomonocytic Leukemia (CMML) and Review of Literature

Hypomethylating drugs are useful and have been approved for the treatment of myelodysplastic syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS, have included only a small number of patients with CMML, and there are just a few specific reports on CMML patients. The Azacitidine is actually authorised for the treatment of CMML patients with 10–29% marrow blasts without myeloproliferative disorder, who are not eligible for haematopoietic stem cell transplantation. This hypomethylating agent in MDS is known for causing transient cytopenias, most often occurring during the first 2 cycles. Here we report a case of an atypical delayed and prolonged hematologic toxicity during Azacitidine treatment in a CMML patient; furthermore we also reviewed the literature regarding the efficacy of the drug and the management of hematologic adverse effects, in term of dose adjustments or alternative schedule of administration, in specific CMML setting

Successful treatment with T depleted autologous peripheral blood stem cell transplantation of refractory chronic autoimmune thrombocytopenic purpura

Autoimmune thrombocytopenia (AITP) is a disorder due to specific platelet auto-antibodies directed against platelet surface glycoproteins. AITP in adults is usually chronic, idiopathic and frequently refractory to conventional treatments. Myelo- and immuno- suppressive chemotherapy followed by autologous peripheral blood stem cell (PBSC) transplantation is an experimental approach for severe chronic refractory AITP. We report a case of a woman with AITP, refractory to the conventional therapy, submitted to T-cell-depleted autologous PBSC transplantation, which obtained long term stable response on platelet count. We deem that the positive outcome of our patient depends on T-cells depletion of the graft, which reduces autoreactive T clones

Shape-specific microfabricated particles for biomedical applications: a review

The storied history of controlled the release systems has evolved over time; from degradable drug-loaded sutures to monolithic zero-ordered release devices and nano-sized drug delivery formulations. Scientists have tuned the physico-chemical properties of these drug carriers to optimize their performance in biomedical/pharmaceutical applications. In particular, particle drug delivery systems at the micron size regime have been used since the 1980s. Recent advances in micro and nanofabrication techniques have enabled precise control of particle size and geometry–here we review the utility of microplates and discoidal polymeric particles for a range of pharmaceutical applications. Microplates are defined as micrometer scale polymeric local depot devices in cuboid form, while discoidal polymeric nanoconstructs are disk-shaped polymeric particles having a cross-sectional diameter in the micrometer range and a thickness in the hundreds of nanometer range. These versatile particles can be used to treat several pathologies such as cancer, inflammatory diseases and vascular diseases, by leveraging their size, shape, physical properties (e.g., stiffness), and component materials, to tune their functionality. This review highlights design and fabrication strategies for these particles, discusses their applications, and elaborates on emerging trends for their use in formulations. GRAPHICAL ABSTRACT: [Image: see text

Ethmoidal arteries variability: an anatomical and radiological study

Understanding the location of ethmoidal arteries (EAs) is crucial during endo- scopic sinus surgery or skull base surgery. The aim of this study was to evaluate the anatomical variability of EAs, considering their presence and position within the ethmoid bone and their position in relation to the skull base (SB) and the frontal sinus (FS). Fourteen human heads underwent a cone-beam CT scan and an endoscopic dissection was carried out to evaluate the anatomy of the EAs. Several features were assessed both radiologically and in the lab setting: presence; position according to the “5 doors theory” (1); position respect to the SB; distance from the SB; relation with the FS (2); dehiscence of the bony canal. Anterior EA and posterior EA were present in all cases, whereas the prevalence of the middle EA was 28.57±16.73%. Anterior EA was most frequently found (64.29%) in the basal lamella of the middle turbinate; it originated from the SB in 60.71% of cases and it was separated from the FS by a single bony lamella in 46.43%. Its canal was dehiscent in 46.43±18.47%. Posterior EA was almost equally found posterior to the basal lamella of the middle turbinate, in the basal lamella of the superior turbinate and posterior to it. It was found in the SB in 82.14% of the cases and its canal was dehiscent in the 28.57±16.73%. Middle EA was found posterior to the basal lamella of the middle turbinate in 62.50% of cas- es and it was found in the SB in 75.00% of the cases. These data demonstrate that, despite their constant presence, anterior and posterior EAs showed a variable position and relationship with the SB; in addition, the data showed a non-negligible number of cases in which the middle MEA was present. Therefore, because of these several anatomical variability in EAs, a high-spatial-resolution CT should be provided for the preoperative anatomical assessment

Tumor Infiltrating Neutrophils Are Enriched in Basal-Type Urothelial Bladder Cancer

15noBackground: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy. Methods: By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b(+) tumor-associated-neutrophils (TAN) and CD3(+) T cells. Bioinformatics analysis of UBC datasets and gene expression analysis of UBC cell lines were additionally performed. Results: Basal type BC contained a significantly higher density of CD66b(+) TAN compared to the luminal type. This finding was validated on TCGA, GSE32894 and GSE124305 datasets by computing a neutrophil signature. Of note, basal-type MIBC display a significantly higher level of chemokines (CKs) attracting neutrophils. Moreover, pro-inflammatory stimuli significantly up-regulate CXCL1, CXCL2 and CXCL8 in 5637 and RT4 UBC cell lines and induce neutrophil chemotaxis. In term of survival, a high density of T cells and TAN was significantly associated to a better outcome, with TAN density showing a more limited statistical power and following a non-linear predicting model. Conclusions: TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance.openopenMandelli, Giulio Eugenio; Missale, Francesco; Bresciani, Debora; Gatta, Luisa Benerini; Scapini, Patrizia; Caveggion, Elena; Roca, Elisa; Bugatti, Mattia; Monti, Matilde; Cristinelli, Luca; Belotti, Sandra; Simeone, Claudio; Calza, Stefano; Melocchi, Laura; Vermi, WilliamMandelli, Giulio Eugenio; Missale, Francesco; Bresciani, Debora; Gatta, Luisa Benerini; Scapini, Patrizia; Caveggion, Elena; Roca, Elisa; Bugatti, Mattia; Monti, Matilde; Cristinelli, Luca; Belotti, Sandra; Simeone, Claudio; Calza, Stefano; Melocchi, Laura; Vermi, Willia

Prospective evaluation of minimal residual disease in the phase II FORTE trial: a head-to-head comparison between multiparameter flow cytometry and next-generation sequencing

Background: Limited data are available on the concordance between multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for minimal residual disease (MRD) detection in a large trial for multiple myeloma (MM) patients. Methods: MRD was explored in the FORTE trial for transplant-eligible MM patients randomised to three carfilzomib-based induction-intensification-consolidation treatments and carfilzomib-lenalidomide (KR) vs R maintenance. MRD was assessed by 8-colour 2nd-generation flow cytometry in patients with ≥very good partial response before maintenance. NGS was performed in case of suspected complete response (CR) in a correlative subanalysis. Biological/prognostic concordance between MFC and NGS, conversion to MRD negativity during maintenance, and 1-year/2-year sustained MRD negativity were explored. Findings: Between September 28, 2015 and December 22, 2021, 2020 samples were available for MFC and 728 for the simultaneous MFC/NGS correlation in the "suspected CR population". Median follow-up was 62 months. Biological agreement was 87% at the 10-5 and 83% at the 10-6 cut-offs. A remarkable prognostic concordance was observed: hazard ratios in MFC-MRD and NGS-MRD-negative vs -positive patients were 0.29 and 0.27 for progression-free survival (PFS) and 0.35 and 0.31 for overall survival, respectively (p < 0.05). During maintenance, 4-year PFS was 91% and 97% in 1-year sustained MFC-MRD-negative and NGS-MRD-negative patients (10-5), respectively, and 99% and 97% in 2-year sustained MFC-MRD-negative and NGS-MRD-negative patients, regardless of treatment received. The conversion rate from pre-maintenance MRD positivity to negativity during maintenance was significantly higher with KR vs R both by MFC (46% vs 30%, p = 0.046) and NGS (56% vs 30%, p = 0.046). Interpretation: The significant biological/clinical concordance between MFC and NGS at the same sensitivity suggests their possible use in the evaluation of one of the currently strongest predictors of outcome. Funding: Amgen, Celgene/Bristol Myers Squibb, Multiple Myeloma Research Foundation