The promising approach of 3D bioprinting for diabetic foot ulcer treatment: A concise review of recent developments

Diabetic foot ulcer (DFU), one of the most significant complications of diabetes, is a condition that causes anatomical and functional alterations of the foot resulting in an important social and economic impact, related to disability and health care costs. Recently, three-dimensional bioprinting - which allows the fabrication of complex and biocompatible structures - has been identified as a promising approach in the field of regenerative medicine to promote the healing of chronic wounds, such as DFU. In this concise review we highlight the most relevant and recent attempts of using 3D bioprinted constructs in vivo - both on animals and people - in order to treat non-healing diabetic ulcers and prevent their worsening. Finally, we briefly focus on the future implications of bioprinting, suggesting its forthcoming importance not only for DFU treatment but also for other areas of clinical care

Sustained response off therapy after fostamatinib: A chronic refractory ITP case report

Fostamatinib is a SYK-inhibitor drug recently approved by the FDA and EMA for treating chronic immune thrombocytopenia. This drug induces a response in about 40% of patients and has a good toxicity profile. It is known that discontinuing thrombopoietin receptor agonists (TRAs) with the maintenance of sustained response off therapy is possible. On fostamatinib, we do not yet have such information. In this case report, we describe the story of a woman with a multirefractory immune thrombocytopenia (steroids, splenectomy, rituximab, both available TRAs). After 16 years from diagnosis, she started fostamatinib therapy within a clinical trial and achieved a complete response. Grade 1-2 headache and diarrhea occurred during the first months of therapy. These adverse events were resolved with dose reduction of fostamatinib. Despite the dose reduction, the platelet count remained steadily above 80 x 109/L. After 4 years, fostamatinib was gradually reduced and finally discontinued with no drop in platelet count. This is the first case in which fostamatinib discontinuation resulted in a sustained response off therapy

IMMUNE THROMBOCYTOPENIA ONSET AND RELAPSE DURING THE COVID19 PANDEMIC. A MONOCENTER STUDY

Background And Objectives: Several infections and vaccinations can provoke immune thrombocytopenia (ITP) onset or relapse. Information on ITP epidemiology and management during the Covid-19 pandemic is scarce. In a large monocenter ITP cohort, we assessed the incidence and risk factors for: 1) ITP onset/relapse after Covid19 vaccination/ infection; 2) Covid19 infection.Methods: Information on the date/type of anti-Covid-19 vaccine, platelet count before and within 30 days from the vaccine, and date/grade of Covid-19 was collected via phone call or during hematological visits. ITP relapse was defined as a drop in PLT count within 30 days from vaccination, compared to PLT count before vaccination that required a rescue therapy OR a dose increase of an ongoing therapy OR a PLT count <30 x109/L with >= 20% decrease from baseline.Results: Between February 2020 and January 2022, 60 new ITP diagnoses were observed (30% related to Covid-19 infection or vaccination). Younger and older ages were associated with a higher probability of ITP related to Covid19 infection (p=0.02) and vaccination (p=0.04), respectively. Compared to Covid-19-unrelated ITP, Infection-and vaccine-related ITP had lower response rates (p=0.03) and required more prolonged therapy (p=0.04), respectively. Among the 382 patients with known ITP at the pandemic start, 18.1% relapsed; relapse was attributed to Covid-19 infection/vaccine in 52.2%. The risk of relapse was higher in patients with active disease (p<0.001) and previous vaccine-related relapse (p=0.006). Overall, 18.3% of ITP patients acquired Covid19 (severe in 9.9%); risk was higher in unvaccinated patients (p<0.001). Conclusions: All ITP patients should receive >= 1 vaccine dose and laboratory follow-up after vaccination, with a case-by-case evaluation of completion of the vaccine program if vaccine-related ITP onset/relapse and with tempest initiation of antiviral therapy in unvaccinated patients

Ruxolitinib in cytopenic myelofibrosis: Response, toxicity, drug discontinuation, and outcome

Background: Patients with cytopenic myelofibrosis (MF) have more limited therapeutic options and poorer prognoses compared with patients with the myeloproliferative phenotype. Aims and methods: Prognostic correlates of cytopenic phenotype were explored in 886 ruxolitinib-treated patients with primary/secondary MF (PMF/SMF) included in the RUX-MF retrospective study. Cytopenia was defined as: leukocyte count <4 × 109 /L and/or hemoglobin <11/<10 g/dL (males/females) and/or platelets <100 × 109 /L. Results: Overall, 407 (45.9%) patients had a cytopenic MF, including 249 (52.4%) with PMF. In multivariable analysis, high molecular risk mutations (p = .04), intermediate 2/high Dynamic International Prognostic Score System (p < .001) and intermediate 2/high Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia Prognostic Model (p < .001) remained associated with cytopenic MF in the overall cohort, PMF, and SMF, respectively. Patients with cytopenia received lower average ruxolitinib at the starting (25.2 mg/day vs. 30.2 mg/day, p < .001) and overall doses (23.6 mg/day vs. 26.8 mg/day, p < .001) and achieved lower rates of spleen (26.5% vs. 34.1%, p = .04) and symptom (59.8% vs. 68.8%, p = .008) responses at 6 months compared with patients with the proliferative phenotype. Patients with cytopenia also had higher rates of thrombocytopenia at 3 months (31.1% vs. 18.8%, p < .001) but lower rates of anemia (65.6% vs. 57.7%, p = .02 at 3 months and 56.6% vs. 23.9% at 6 months, p < .001). After competing risk analysis, the cumulative incidence of ruxolitinib discontinuation at 5 years was 57% and 38% in patients with cytopenia and the proliferative phenotype (p < .001), whereas cumulative incidence of leukemic transformation was similar (p = .06). In Cox regression analysis adjusted for Dynamic International Prognostic Score System score, survival was significantly shorter in patients with cytopenia (p < .001). Conclusions: Cytopenic MF has a lower probability of therapeutic success with ruxolitinib as monotherapy and worse outcome. These patients should be considered for alternative therapeutic strategies

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

CONVENTIONAL GLUCOCORTICOID REPLACEMENT THERAPY VS. DUAL-RELEASE HYDROCORTISONE: EFFECTS ON INFLAMMATION AND IMMUNE PROFILE IN PATIENTS WITH PRIMARY ADRENAL INSUFFICIENCY AND IMPLICATIONS OF THERAPY RESPONSE PREDICTORS

Primary adrenal insufficiency (PAI), whose autoimmune adrenalitis is the main cause, is characterised by an inadequate cortisol secretion, due to a destruction of adrenal gland and a consequent lack of glucocorticoid and mineralocorticoid production. Autoimmune conditions are caused by a loss of tolerance for self-antigens, with regulatory T lymphocytes failing in limiting auto-reactivity, and the increase of pro-inflammatory processes. Generally, corticosteroids exert anti-inflammatory and immunosuppressive actions by regulating the expression of inflammatory and immunomodulatory proteins and by modulating the lymphocyte pattern, including the regulatory T-cells (Tregs) induction. Conventional glucocorticoids - including cortisone acetate and hydrocortisone administered two or three times a day - are the mainstay of the treatment of patients with PAI, but in the most recent years the innovative dual-release hydrocortisone (DR-HC) - administered once daily - has been used as replacement therapy. DR-HC has shown favourable effects on cardiovascular risk factors, glucose metabolism and bone parameters compared to conventional steroids. Moreover, it has shown to improve the immune system cell profile expression, restoring a more physiological circadian glucocorticoid rhythm. According to this evidence, this study investigates whether conventional replacement steroid (CRS) or DR-HC elicit different response in terms of anti-inflammatory or immunomodulatory effects, by measurement of anthropometric, metabolic, serum inflammatory parameters and gene expression levels of IL-6, IL-17A, COX-2, HSP-70, IDO, PD-L1, hnRNPA2/B, iNOS and TXN-1. Additionally, a cytofluorimetric analysis was performed to evaluate a modulation in the activation status of T-cells, including CD4+CD25+Foxp3+Treg population. The study included 15 patients with PAI on conventional glucocorticoid therapy and 15 patients on DR-HC. The outcomes of the study were evaluated by isolation of peripheral blood mononuclear cells at baseline and after 12 months of treatment. 10 healthy patients (controls) were evaluated at the time of enrolment. In patients treated with CRS, a significant increase in c-reactive protein, erythrocyte sedimentation rate and fibrinogen were observed after 12 months of treatment compared to baseline. At 12 months, significantly lower waist circumference, glucose, c-reactive protein, erythrocyte sedimentation rate and neutrophile-to-lymphocyte ratio was observed in patients treated with DR-HC compared to those treated with conventional treatment. A significant decrease in the transcription of COX-2 and HSP-70 (along with IL-6) was observed together with a significant increase in mRNA expression of IDO and PD-L1 in patients treated with DR-HC after 12 months of observation. Compared to CRS, DR-HC treatment improves the inflammatory and immune patterns in patients with PAI modulating several proteins involved in inflammatory response in a Treg-independent manner. Moreover, we can suppose that the transcription levels of IL-6, COX-2, HSP-70, IDO and PD-L1 could be considered to predict and evaluate the response to steroidal therapies in PAI and their different efficacies, based on our findings on anthropometric, metabolic, and biochemical outcomes. However, further larger and controlled studies are needed to confirm our preliminary results and the relevance of this assumption

Quercetin Loaded Monolaurate Sugar Esters-Based Niosomes: Sustained Release and Mutual Antioxidant-Hepatoprotective Interplay

Flavonoids possess different interesting biological properties, including antibacterial, antiviral, anti-inflammatory and antioxidant activities. However, unfortunately, these molecules present different bottlenecks, such as low aqueous solubility, photo and oxidative degradability, high first-pass effect, poor intestinal absorption and, hence, low systemic bioavailability. A variety of delivery systems have been developed to circumvent these drawbacks, and among them, in this work niosomes have been selected to encapsulate the hepatoprotective natural flavonoid quercetin. The aim of this study was to prepare nanosized quercetin-loaded niosomes, formulated with different monolaurate sugar esters (i.e., sorbitan C12; glucose C12; trehalose C12; sucrose C12) that act as non-ionic surfactants and with cholesterol as stabilizer (1:1 and 2:1 ratio). Niosomes were characterized under the physicochemical, thermal and morphological points of view. Moreover, after the analyses of the in vitro biocompatibility and the drug-release profile, the hepatoprotective activity of the selected niosomes was evaluated in vivo, using the carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Furthermore, the levels of glutathione and glutathione peroxidase (GSH and GPX) were measured. Based on results, the best formulation selected was glucose laurate/cholesterol at molar ratio of 1:1, presenting spherical shape and a particle size (PS) of 161 ± 4.6 nm, with a drug encapsulation efficiency (EE%) as high as 83.6 ± 3.7% and sustained quercetin release. These niosomes showed higher hepatoprotective effect compared to free quercetin in vivo, measuring serum biomarker enzymes (i.e., alanine and aspartate transaminases (ALT and AST)) and serum biochemical parameters (i.e., alkaline phosphatase (ALP) and total proteins), while following the histopathological investigation. This study confirms the ability of quercetin loaded niosomes to reverse CCl4 intoxication and to carry out an antioxidant effect

Incorporation of PEGylated δ-decalactone into lipid bilayers: thermodynamic study and chimeric liposomes development

Liposomes have been on the market as drug delivery systems for over 25 years. Their success comes from the ability to carry toxic drug molecules to the appropriate site of action through passive accumulation, thus reducing their severe side effects. However, the need for enhanced circulation time and site and time specific drug delivery, turned research focus on other systems, such as polymers. In this context, novel composites that combine the flexibility of polymeric nanosystems with the properties of liposomes gained a lot of interest. In the present work a mixed/chimeric liposomal system, composed of phospholipids and block copolymers, was developed and evaluated in regards with its feasibility as a drug delivery system. These innovative nano-platforms combine advantages from both classes of biomaterials. Thermal analysis was performed in order to offers an insight into the interactions between these materials and consequently into their physicochemical characteristics. In addition, colloidal stability was assessed by monitoring z-potential and size distribution over time. Finally, their suitability as carriers for biomedical applications was evaluated by carrying out in vitro toxicity studies