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All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) represent the standard of care for low-intermediate risk acute promyelocytic leukaemia (APL). Leucocytosis during induction with ATRA-ATO represents a common complication with an incidence of up to 60%. To identify predictive factors for this complication, we studied a cohort of 65 low-intermediate risk APL patients treated with ATRA-ATO in three highly specialized Italian centres. Overall, 39/65 (60%) patients developed leucocytosis, with a peak in leucocyte count being most frequent in the second week from diagnosis. All cases were successfully managed with hydroxyurea. Predictive factors for leucocytosis in univariate analysis were lower platelet counts (odds ratio [OR] 0.98, 0.97-1.00, p = 0.018), lower fibrinogen levels (OR 0.36, 0.17-0.66, p = 0.003), higher bone marrow blast infiltration (OR 1.03, 1.01-1.07, p = 0.021) and CD117 expression by flow (OR 1.04, 1.01-1.08, p = 0.012). Multivariate analysis confirmed lower levels of fibrinogen at diagnosis as the strongest predictive factor for the development of leucocytosis (OR 0.36, 0.15-0.72, p = 0.009). Differentiation syndrome (DS) occurred only in patients developing leucocytosis showing a strict correlation with rising leucocytes counts (16/39 vs. 0/26, p < 0.001). In addition, other treatment-related complications including QTc prolongation, cardiac events, liver, and haematological toxicities were significantly more frequent in patients experiencing leucocytosis (22/39 vs. 3/26, p < 0.001). In conclusion, APL patients undergoing ATRA-ATO therapy with lower fibrinogen levels and platelet counts at diagnosis and with a massive bone marrow blast infiltrate should be carefully monitored for the development of leucocytosis during induction. DS and other treatment-related complications seem to occur almost exclusively in patients developing leucocytosis, who should necessarily receive DS prophylaxis and more intensive monitoring and supportive therapy to prevent treatment complications., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: In the last decade, TKIs improved the overall survival (OS) of chronic myeloid leukemia (CML) patients who achieved a deep and sustained molecular response (DMR, defined as stable MR4 and MR4.5). Those patients may attempt therapy discontinuation. In our analysis, we report the differences in eligibility criteria due to time of response and different TKI used as frontline treatment analyzed in a large cohort of CP-CML patients., Methods: Data were exported by LabNet CML, a network founded by GIMEMA in 2014. The network standardized and harmonized the molecular methodology among 51 laboratories distributed all over Italy for the diagnosis and molecular residual disease (MRD) monitoring., Results: Out of 1777 patients analyzed, 774 had all evaluable timepoints (3, 6, and 12 months). At 3 months, 40 patients obtained ≥MR4: of them 14 (3.6%) with imatinib, 8 (5.8%) with dasatinib, and 18 (7.4%) with nilotinib (P = .093); at 6 months, 146 patients were in MR4: 42 (11%) with imatinib, 38 (28%) with dasatinib, and 66 (27%) with nilotinib (P < .001). At 12 months, 231 patients achieved a DMR: 85 (22%) with imatinib, 55 (40%) with dasatinib and 91 (38%) with nilotinib (P < .001). Achieving at least ≥MR2 at 3 months, was predictive of a DMR at any timepoint of observation: with imatinib 67% versus 30% of patients with 2 years was significant for patients who at 3 months had ≥MR2 (18% vs. 9.9% of pts with

We analyzed 140 patients with a median age of 51 years; 21% had WBC ≥ 100 × 10 9 /L, and 52% had an NPM1 co-mutation. Until 2018, 101 patients received chemotherapy; thereafter, 39 received 3+7+midostaurin. The overall CR rate was 64%, higher in NPM1 mutant patients (73%). Univariate analysis showed that NPM1 mutation ( p = 0.032) and WBC < 100 × 10 9 /L ( p = 0.013) positively influenced the response, with a trend for FLT3i administration ( p = 0.052). Multivariate analysis confirmed WBC count as an independent prognostic factor ( p = 0.017). In CR1, 41/90 patients underwent allogeneic and 18 autologous transplantation. The median EFS was 1.1 vs. 1.6 years in autografted and allografted patients, respectively ( p = 0.9). The one-year non-relapse mortality was 0.00% for autologous and 28% for allogeneic transplants ( p = 0.007); CIR at 1 and 3 years was higher in autologous transplants (39% vs. 15% and 57% vs. 21%, p = 0.004). The median survival was not reached in the FLT3i group. Overall, 69 patients received stem cell transplantation (18 autologous, 51 allogeneic). Post-transplant FLT3i was resumed in eight patients, all alive after a median of 65 months. Allogeneic transplantation is crucial in FLT3-mutated AML, but the next challenge will be to identify which patients can benefit from transplants in CR1 and in which to intensify post-transplant therapy.

The introduction of pediatric-inspired regimens in adult Philadelphia-negative acute lymphoblastic leukemia (Ph-ALL) has significantly improved patients' prognosis. Within the Campus ALL network we analyzed the outcome of adult Ph-ALL patients treated according to the GIMEMA LAL1913 protocol outside the clinical trial, to compare the real-life data with the study results. We included 421 consecutive patients, with a median age of 42 years. The complete remission (CR) rate after the first course of chemotherapy was 94% and a measurable residual disease (MRD) negativity after the third course was achieved in 72% of patients. The 3-year overall survival (OS) and disease-free survival (DFS) were 67% and 57%, respectively. In a multivariate analysis, MRD positivity negatively influenced DFS. In a time-dependent analysis including only very high risk (VHR) and MRD positive cases, transplanted (HSCT) patients had a significantly better DFS than non-HSCT ones (P=0.0017). During induction, grade ≥2 pegaspargase-related hepato-toxicity was observed in 25% of patients (vs 12% in the GIMEMA LAL1913 trial, P=0.0003). In this large real-life cohort of Ph-ALL, we confirmed the very high CR rate and a superimposable OS and DFS compared to the GIMEMA LAL1913 clinical trial: CR rate after C1 94% vs 85%, P=0.0004; 3-year OS 67% vs 67%, P=0.94; 3-year DFS 57% vs 63%, P=0.17. HSCT confirms its important role in VHR and MRD-positive patients. The rate of pegaspargase-related toxicity was significantly higher in the real-life setting, emphasizing the importance of dose adjustment in the presence of risk factors to avoid excessive toxicity.

Toscana Virus (TosV) was firstly isolated from phlebotomine in our Institute about fifty years ago. Later, in 1984-1985, TosV infection, although asymptomatic in most cases, was shown to cause disease in humans, mainly fever and meningitis. By means of genetic analysis of part of M segment, we describe 3 new viral isolates obtained directly from cerebrospinal fluid or sera samples of patients diagnosed with TosV infection in July 2020 in Tuscany region. Phylogenesis was used to propose the clustering of TosV lineage A strains in 3 main groups, whereas deep mutational analysis based on 12 amino acid positions, allowed the identification of 9 putative strains. We discuss deep mutational analysis as a method to identify molecular signature of host adaptation and/or pathogenesis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Claudio argentini reports a relationship with istituto superiore di sanità that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Arboviruses are pathogens transmitted mainly by mosquitoes, ticks, and sandflies [...].

Background: Childhood Hodgkin lymphoma (HL) is an eminently curable disease. Good outcomes can be achieved even in resource-limited settings, and the focus is increasingly on limiting long-term toxicity. Contemporary treatment incorporates a risk-stratified, response-adapted approach using multiagent chemotherapy with/without low-dose radiotherapy. Many developing countries continue to use ABVD-based regimens due to limited acute toxicity, cost, and ease of delivery., Objective: We herein report the outcomes of childhood HL diagnosed and treated in an Iraqi single centre over 16 years., Methods: Children ≤14 years old with biopsy-proven HL were enrolled. Most patients received ABVD chemotherapy or COPP/ABV when Dacarbazine was unavailable. Radiotherapy was not available., Results: Three hundred-three children were consecutively newly diagnosed with HL; 284 were considered eligible for the retrospective analysis (treatment refusals 9; deaths before therapy 5; initially diagnosed of non-Hodgkin lymphoma 5). ABVD scheme was administered to 184 children (65%), COPP/ABV to 83 (29%), and other schemes to the remaining 17 patients. Complete response (CR) was achieved in 277 (98%); 4 (1.4%) showed disease progression, and 1 had stable disease. Four patients in CR abandoned therapy and were in CR at the time of analysis, 2 died from infection. Relapse occurred in 42 patients (15%). The 15-year OS and EFS are 89.7% and 70.3%, respectively., Conclusion: In this single Centre, over 16 years, almost 90% of children suffering from HL survive, despite the numerous limitations in diagnostic procedures, shortage of chemotherapy, no radiotherapy facilities, absence of effective second-line treatments, and finally, therapy abandonment for social and financial reasons., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Aims: To evaluate whether antibodies specific for the vaccinia virus (VV) are still detectable after at least 45 years from immunization. To confirm that VV-specific antibodies are endowed with the capacity to neutralize Mpox virus (MPXV) in vitro. To test a possible role of polyclonal non-specific activation in the maintenance of immunologic memory., Methods: Sera were collected from the following groups: smallpox-vaccinated individuals with or without latent tuberculosis infection (LTBI), unvaccinated donors, and convalescent individuals after MPXV infection. Supernatant of VV- or MPXV-infected Vero cells were inactivated and used as antigens in ELISA or in Western blot (WB) analyses. An MPXV plaque reduction neutralization test (PRNT) was optimized and performed on study samples. VV- and PPD-specific memory T cells were measured by flow cytometry., Results: None of the smallpox unvaccinated donors tested positive in ELISA or WB analysis and their sera were unable to neutralize MPXV in vitro. Sera from all the individuals convalescing from an MPXV infection tested positive for anti-VV or MPXV IgG with high titers and showed MPXV in vitro neutralization capacity. Sera from most of the vaccinated individuals showed IgG anti-VV and anti-MPXV at high titers. WB analyses showed that positive sera from vaccinated or convalescent individuals recognized both VV and MPXV antigens. Higher VV-specific IgG titer and specific T cells were observed in LTBI individuals., Conclusions: ELISA and WB performed using supernatant of VV- or MPXV-infected cells are suitable to identify individuals vaccinated against smallpox at more than 45 years from immunization and individuals convalescing from a recent MPXV infection. ELISA and WB results show a good correlation with PRNT. Data confirm that a smallpox vaccination induces a long-lasting memory in terms of specific IgG and that antibodies raised against VV may neutralize MPXV in vitro. Finally, higher titers of VV-specific antibodies and higher frequency of VV-specific memory T cells in LTBI individuals suggest a role of polyclonal non-specific activation in the maintenance of immunologic memory.

The frequency of locally transmitted dengue virus (DENV) infections has increased in Europe in recent years, facilitated by the invasive mosquito species Aedes albopictus , which is well established in a large area of Europe. In Italy, the first indigenous dengue outbreak was reported in August 2020 with 11 locally acquired cases in the Veneto region (northeast Italy), caused by a DENV-1 viral strain closely related to a previously described strain circulating in Singapore and China. In this study, we evaluated the vector competence of two Italian populations of Ae. albopictus compared to an Ae. aegypti lab colony. We performed experimental infections using a DENV-1 strain that is phylogenetically close to the strain responsible for the 2020 Italian autochthonous outbreak. Our results showed that local Ae. albopictus is susceptible to infection and is able to transmit the virus, confirming the relevant risk of possible outbreaks starting from an imported case.

Dengue (DENV) and Zika (ZIKV) viruses are mosquito-borne human pathogens. In Italy, the presence of the competent vector Aedes albopictus increases the risk of autochthonous transmission, and a national plan for arboviruses prevention, surveillance, and response (PNA 2020-2025) is in place. The results of laboratory diagnosis of both viruses by the National Reference Laboratory for arboviruses (NRLA) from November 2015 to November 2022 are presented. Samples from 655 suspected cases were tested by both molecular and serological assays. Virus and antibody kinetics, cross-reactivity, and diagnostic performance of IgM ELISA systems were analysed. Of 524 cases tested for DENV, 146 were classified as confirmed, 7 as probable, while 371 were excluded. Of 619 cases tested for ZIKV, 44 were classified as confirmed, while 492 were excluded. All cases were imported. Overall, 75.3% (110/146) of DENV and 50% (22/44) of ZIKV cases were confirmed through direct virus detection methods. High percentages of cross reactivity were observed between the two viruses. The median lag time from symptoms onset to sample collection was 7 days for both DENV molecular (range 0-20) and NS1 ELISA (range 0-48) tests, with high percentages of positivity also after 7 days (39% and 67%, respectively). For ZIKV, the median lag time was 5 days (range 0-22), with 16% positivity after 7 days. Diagnostic performance was assessed with negative predictive values ranging from 92% to 95% for the anti-DENV systems, and of 97% for the ZIKV one. Lower positive predictive values were seen in the tested population (DENV: 55% to 91%, ZIKV: 50%). DENV and ZIKV diagnosis by molecular test is the gold standard, but sample collection time is a limitation. Serological tests, including Plaque Reduction Neutralization Test, are thus necessary. Co-circulation and cross-reactivity between the two viruses increase diagnostic difficulty. Continuous evaluation of diagnostic strategies is essential to improve laboratory testing.

There is an urgent need to identify efficient antiviral compounds to combat existing and emerging RNA virus infections, particularly those related to seasonal and pandemic influenza outbreaks. While inhibitors of the influenza viral integral membrane proton channel protein (M2), neuraminidase (NA), and cap-dependent endonuclease are available, circulating influenza viruses acquire resistance over time. Thus, the need for the development of additional anti-influenza drugs with novel mechanisms of action exists. In the present study, a cell-based screening assay and a small molecule library were used to screen for activities that antagonized influenza A non-structural protein 1 (NS1), a highly conserved, multifunctional accessory protein that inhibits the type I interferon response against influenza. Two potential anti-influenza agents, compounds 157 and 164 , were identified with anti-NS1 activity, resulting in the reduction of A/PR/8/34(H1N1) influenza A virus replication and the restoration of IFN-β expression in human lung epithelial A549 cells. A 3D pharmacophore modeling study of the active compounds provided a glimpse of the structural motifs that may contribute to anti-influenza virus activity. This screening approach is amenable to a broader analysis of small molecule compounds to inhibit other viral targets.

Type I interferon (IFN-I) evasion by Dengue virus (DENV) is key in DENV pathogenesis. The non-structural protein 5 (NS5) antagonizes IFN-I response through the degradation of the signal transducer and activator of transcription 2 (STAT2). We developed a K562 cell-based platform, for high throughput screening of compounds potentially counteracting the NS5-mediated antagonism of IFN-I signaling. Upon a screening with a library of 1220 approved drugs, 3 compounds previously linked to DENV inhibition (Apigenin, Chrysin, and Luteolin) were identified. Luteolin and Apigenin determined a significant inhibition of DENV2 replication in Huh7 cells and the restoration of STAT2 phosphorylation in both cell systems. Apigenin and Luteolin were able to stimulate STAT2 even in the absence of infection. Despite the "promiscuous" and "pan-assay-interfering" nature of Luteolin, Apigenin promotes STAT2 Tyr 689 phosphorylation and activation, highlighting the importance of screening for compounds able to interact with host factors, to counteract viral proteins capable of dampening innate immune responses., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Several flaviviruses such as Hepatitis C virus, West Nile virus, Dengue virus and Japanese Encephalitis virus exploit the raft platform to enter host cells whereas the involvement of lipid rafts in Zika virus-host cell interaction has not yet been demonstrated. Zika virus disease is caused by a flavivirus transmitted by Aedes spp. Mosquitoes, although other mechanisms such as blood transfusion, sexual and maternal-fetal transmission have been demonstrated. Symptoms are generally mild, such as fever, rash, joint pain and conjunctivitis, but neurological complications, including Guillain-Barré syndrome, have been associated to this viral infection. During pregnancy, it can cause microcephaly and other congenital abnormalities in the fetus, as well as pregnancy complications, representing a serious health threat. In this study, we show for the first time that Zika virus employs cell membrane lipid rafts as a portal of entry into Vero cells. We previously demonstrated that the antifungal drug Amphotericin B (AmphB) hampers a microbe-host cell interaction through the disruption of lipid raft architecture. Here, we found that Amphotericin B by the same mechanism of action inhibits both Zika virus cell entry and replication. These data encourage further studies on the off-label use of Amphotericin B in Zika virus infections as a new and alternate antiviral therapy.

We report the molecular evidence of dengue virus (DENV) and chikungunya virus (CHIKV) infection in symptomatic individuals in Cameroon and Gabon, respectively. Arthropod-borne viruses (arboviruses) are distributed in the tropical or subtropical regions, with DENV having the highest burden. The morbidity and mortality related to arboviral diseases raise the concern of timely and efficient surveillance and care. Our aim was to assess the circulation of arboviruses [DENV, CHIKV, Zika virus (ZIKV)] among febrile patients in Dschang (West Cameroon) and Kyé-ossi (South Cameroon, border with Gabon and Equatorial Guinea). Dried blood spots were collected from 601 consenting febrile patients, and 194 Plasmodium spp.-negative samples were tested for the molecular detection of cases of DENV, CHIKV and ZIKV infection. Overall, no case of ZIKV infection was found, whereas one case of DENV infection and one case of CHIKV infection were detected in Dschang and Kyé-ossi, respectively, with the CHIKV-infected patient being resident in Gabon. Our findings suggest the need to establish an active surveillance of arbovirus transmission in Cameroon and bordering countries., Competing Interests: The authors declare that there are no conflicts of interest., (© 2022 The Authors.)