Neutropenic patients with persistent fever despite antibiotic therapy are managed with empirical or pre-emptive antifungal therapy. The aim of the present study was to evaluate the current clinical ...use and efficacy of these two approaches in patients with high risk hematologic conditions.
An electronic medical record system, the "Hema e-Chart", was designed and implemented to collect information prospectively on infectious complications, particularly on invasive fungal diseases, in patients with hematologic malignancies treated with chemotherapy and/or autologous or allogenic hemopoietic stem cell transplantation. The patients were enrolled from Hematology units distributed widely across Italy.
Three hundred and ninety-seven adults with hematologic malignancies treated with chemotherapy with persistent fever and suspected invasive fungal disease were evaluable for the study (190 treated had been treated with empirical antifungal therapy and 207 with preemptive antifungal therapy). There was a significantly lower incidence of proven/probable invasive fungal diseases in patients treated with empirical antifungal therapy (n=14, 7.4%) than in patients treated with pre-emptive therapy (n=49, 23.7%) (P<0.001). The rate of deaths attributable to invasive fungal diseases was significantly lower in subjects treated with empirical antifungal therapy (1 case; 7.1%) than in subjects treated with pre-emptive therapy (11 cases; 22.5%) (P=0.002).
These data indicate that empirical antifungal treatment decreased the incidence of invasive fungal disease and of attributable mortality with respect to a pre-emptive antifungal approach in neutropenic febrile patients with hematologic malignancies. (ClinicalTrials.gov Identifier: NCT01069887).
Patients with venous thromboembolism (VTE) should receive a decision on the duration of anticoagulant treatment (AT) that is often not easy to make. Sixteen Italian clinical centers included patients ...with recent VTE in the START2-POST-VTE register and reported the decisions taken on duration of AT in each patient and the reasons for them. At the moment of this report, 472 (66.9%) of the 705 patients included in the registry were told to stop AT in 59.3% and to extend it in 40.7% of patients. Anticoagulant treatment lasted ≥3 months in >90% of patients and was extended in patients with proximal deep vein thrombosis because considered at high risk of recurrence or had thrombophilic abnormalities. d-dimer testing, assessment of residual thrombus, and patient preference were also indicated among the criteria influencing the decision. In conclusion, Italian doctors stuck to the minimum 3 months AT after VTE, while the secondary or unprovoked nature of the event was not seen as the prevalent factor influencing AT duration which instead was the result of a complex and multifactorial evaluation of each patient.
The multiple myeloma (MM) treatment has changed over the last years due to the introduction of novel drugs. Despite improvements in the MM outcome, MM remains an incurable disease. Daratumumab is a ...human IgGK monoclonal antibody targeting CD38 with tumor activity associated with immunomodulatory mechanism. In combination with standard of care regimens, including bortezomib (Vd) or lenalidomide (Rd), daratumumab prolonged progression‐free survival (PFS) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) and in new diagnosis MM. We report the data of the MM GIMEMA Lazio group in 171 heavily treated pts who received daratumumab, lenalidomide and dexamethasone (DRd) or daratumumab, velcade and dexamethasone (DVd). The overall response rate was 80%, and the overall survival (OS) and PFS were 84% and 77%, respectively. In addition, pts treated with DRd showed a better median PFS compared to pts treated with DVd, at 12 and 24 months, respectively. The most common hematologic treatment‐emergent adverse events (TAEs) were neutropenia, thrombocytopenia, and anemia. The most common nonhematologic TAEs were peripheral sensory neuropathy and infections. Our data confirmed that DRd or DVd therapy is effective and safe in RRMM pts, and our real‐life analysis could support the physicians regarding the choice of optimal therapy in this setting of pts.
Tumors with microsatellite instability (MSI) are caused by a defective DNA mismatch repair system that leads to the accumulation of mutations within microsatellite regions. Indels in microsatellites ...of coding genes can result in the synthesis of frameshift peptides (FSP). FSPs are tumor-specific neoantigens shared across patients with MSI. In this study, we developed a neoantigen-based vaccine for the treatment of MSI tumors. Genetic sequences from 320 MSI tumor biopsies and matched healthy tissues in The Cancer Genome Atlas database were analyzed to select shared FSPs. Two hundred nine FSPs were selected and cloned into nonhuman Great Ape Adenoviral and Modified Vaccinia Ankara vectors to generate a viral-vectored vaccine, referred to as Nous-209. Sequencing tumor biopsies of 20 independent patients with MSI colorectal cancer revealed that a median number of 31 FSPs out of the 209 encoded by the vaccine was detected both in DNA and mRNA extracted from each tumor biopsy. A relevant number of peptides encoded by the vaccine were predicted to bind patient HLA haplotypes. Vaccine immunogenicity was demonstrated in mice with potent and broad induction of FSP-specific CD8 and CD4 T-cell responses. Moreover, a vaccine-encoded FSP was processed
by human antigen-presenting cells and was subsequently able to activate human CD8 T cells. Nous-209 is an "off-the-shelf" cancer vaccine encoding many neoantigens shared across sporadic and hereditary MSI tumors. These results indicate that Nous-209 can induce the optimal breadth of immune responses that might achieve clinical benefit to treat and prevent MSI tumors. SIGNIFICANCE: These findings demonstrate the feasibility of an "off-the-shelf" vaccine for treatment and prevention of tumors harboring frameshift mutations and neoantigenic peptides as a result of microsatellite instability.
Abstract
Background
We evaluated the incidence of proven/probable invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP) in a ‘real-life’ setting of patients with AML receiving ...intensive consolidation therapy.
Methods
Cases of IA, observed during consolidation in adult/paediatric patients with AML between 2011 and 2015, were retrospectively collected in a multicentre Italian study.
Results
Of 2588 patients, 56 (2.2%) developed IA 43 probable (1.7%) and 13 proven (0.5%). IA was diagnosed in 34 of 1137 (2.9%) patients receiving no AP and in 22 of 1451 (1.5%) who were given AP (P = 0.01). Number-needed-to-treat calculation indicates that, on average, 71 patients should have received AP (instead of no AP) for one additional patient to not have IA. Initial antifungal therapy was ‘pre-emptive’ in 36 (64%) patients and ‘targeted’ in 20 (36%) patients. A good response to first-line therapy was observed in 26 (46%) patients, mainly those who received AP 16 of 22 (73%) versus 10 of 34 (29%); P = 0.001. The overall mortality rate and the mortality rate attributable to IA by day 120 were 16% and 9%, respectively. In multivariate analysis, age ≥60 years (OR = 12.46, 95% CI = 1.13–136.73; P = 0.03) and high-dose cytarabine treatment (OR = 10.56, 95% CI = 1.95–116.74; P = 0.04) independently affected outcome.
Conclusions
In our experience, AP appears to prevent IA from occurring during consolidation. However, although the incidence of IA was low, mortality was not negligible among older patients. Further prospective studies should be carried out particularly in elderly patients treated with high-dose cytarabine to confirm our data and to identify subsets of individuals who may require AP.
Introduction.During last years, a reduction in invasive aspergillosis (IA) incidence and mortality was observed in acute myeloid leukemia (AML) patients undergoing to induction phase of treatment. ...Instead, the incidence of IA and the attributable mortality rate (AMR) during the consolidation has not been recently evaluated. It is also uncertain whether posaconazole prophylaxis during induction chemotherapy affects IA on consolidation phase.
Design and Methods. The aim of our study was to evaluate incidence and mortality for IA in AML patients during the consolidation phase. All cases of proven/probable IA observed during consolidation chemotherapy in adult and pediatric patients with AML, who received conventional chemotherapy, between 2011 and 2015 were retrospectively collected in a multicenter study involving 38 Italian hematologic centers. All relevant clinical data were collected in CRFs.
Results. A total of 2556 of AML patients in consolidation phase were registered. A total of 52 patients (2%) developed an IA 13 proven (0,5%) and 39 probable (1.5%). Male/female ratio was 33/19, median age was 57 yrs (range 5-79). As a consolidation, all these patients received high/intermediate doses cytarabine, in combination with an anthracycline in 30. Only 21 of 52 (40%) were on antifungal prophylaxis at the time of IA diagnosis: posaconazole in 5 (24%), fluconazole in 6 (28%), itraconazole in 5 (24%), liposomal amphotericin B (L-AmB) in 4 (19%) and voriconazole in 1 (5%). In 2 of 52 IA was a reactivation of an infection diagnosed during induction (Fig.).
Empiric antifungal therapy was initiated in 33 cases (65%) (mainly L-AmB: 24/33, 73%), while the remaining 19 (35%) received a pre-emptive/targeted approach. Fourteen cases switched from L-AmB to voriconazole, so that the most frequently targeted antifungal therapy was voriconazole (29/52, 55%). The median duration of antifungal treatment was 89 days (range 12-700). The overall mortality at day 120 was 19% (10/52), but the AMR was only 3.2% (5/52).
During induction, many patients (85%) received posaconazole as antifungal prophylaxis while the remaining 15% received other antifungals. (Fig.) During consolidation, antifungal prophylaxis was performed in about 50% of the patients. The most commonly used drug was fluconazole. In consideration of the hypothesized long-lasting activity of posaconazole, we also performed an analysis of incidence of IA during consolidation taking into whether or not the patients received posaconazole during induction. Considering the overall population of AMLs treated in consolidation no statistical differences were observed between those receiving in induction posaconazole or other prophylaxis, even if a lower percentage of patients in posaconazole arm developed an IA. (Fig.)
Conclusion. Our study shows that the incidence of IA during the consolidation in patients with AML is low but not absent. Similarly, also the AMR is low, likely due to advances in diagnosis and antifungal therapy. It is still a matter of discussion whether or not prophylaxis is needed in this subset of patients, since these are in remission and often candidates for transplantation. Finally, the long-lasting benefits of posaconazole is not confirmed but it might be correlated to the few cases of IA observed.
Display omitted
No relevant conflicts of interest to declare.
OBJECTIVES
Aim of this prospective study was to evaluate the risk of invasive fungal infection (IFI) in patients (pts) with acute promyelocytic leukemia (APL) and to compare APL pts with patients ...affected by non promyelocytic acute myeloid leukemia (npAML) in order to evaluate factors potentially linked to IFI in these two subsets of acute myeloid leukemia.
PATIENTS AND METHODS
From January 2010 to April 2012 all pts with newly diagnosed AML were registered in 33 Italian participating centers. A minimum follow up of 90 days after 1st induction chemotherapy was requested for all pts. A prolonged follow up until June 2014 was made only for APL. Data were collected about age, gender, AML subtype, treatment and also about post chemotherapy risk factors for IFI (duration of neutropenia, mucosal damages, vomiting, diarrhea, presence of medical devices), antifungal prophylaxis, onset of IFI, level of certainty (possible/probable/proven), and antifungal treatment. Only for APL the survey was prolonged for at least 3 months in order to analyze if these pts have an IFI risk during other than first induction phases.
RESULTS
1,192 consecutive newly diagnosed adult AML pts (npAML:1,086/APL:106) were enrolled in the study.
Among npAML pts, those receiving low dose chemotherapy and/or palliative treatment were excluded from the analysis; in the remaining 881 pts 214 cases (24%) of IFI were recorded.
Considering APL, 3 pts were excluded from the analysis due to early death (1 pt) or bad performance status (2 pts). The remaining 103 pts received APL treatment according to local protocols: all trans retinoic acid (ATRA) plus chemotherapy (90 pts) or ATRA plus arsenic trioxide (ATO)(13 pts). Only 8 (8%) APL pts developed an IFI after the induction phase: 1 proven, 3 probable and 4 possible IFI. All cases were caused by molds. All APL were followed for a median follow up of 36 months (range 3-54). During this time only 2 other cases of IFI were observed: 1 possible IFI during consolidation at 16 weeks from APL diagnosis and 1 probable aspergillosis in a rare case of APL relapse at 132 weeks from APL diagnosis. All the IFI occurred in pts treated with ATRA plus chemotherapy.
IFI was fatal in only 1 case (cerebral aspergillosis), all the other pts recovered after antifungal treatment.
A comparison between npAML and APL was made in order to analyze the risk of IFI within 90 days after induction treatment among these 2 groups of patients (see table). A significantly lower number of overall IFI and systemic antifungal treatment was observed in the APL group, in spite of the fact that systemic anti mold prophylaxis was significantly less frequently utilized. Table 1Comparison between APL and npAML in induction phaseAPLnpAMLpNumber of pts103881Mean age51550.01m/f50/53448/433N.S.Performance status (WHO)0-1>1. 76 27. 284 597. <0.0001Central venous catheter52 (50%)687 (78%)<0.0001Neutropenia (<1000/mm3)103 (100%)874 (99%)N.S.Mean duration of neutropenia (<1000/mm3)23 days25 days0.1Mean duration of deep neutropenia (<500/mm3)17.5 days24 days0.04Antifungal prophylaxis94 (91%)837 (95%)N.S.Topical antifungal prophylaxis17 (17%)60 (7%)0.0005Drug in prophylaxisfluconazoleitraconazoleposaconazoleother.33 (32%)13 (12%)38 (37%)1 (1%).168 (19%)117 (13%)513 (58%)23 (3%).0.002N.S. <0.0001IFIsall casesproven/probable.8 (8%)4 (4%).214 (24%)77 (9%).0.00010.08moldsall casesproven/probable.8 (8%)4 (4%).191 (22%)55 (6%).0.0006N.S.yeastsall cases.0.23 (3%). <0.0001Antifungal treatmentMean duration11 (11%)17 days275 (31%)14 days<0.0001 N.S.Overall mortality at 30 days8 (8%)110 (12%)N.S.Mortality due to IFI at 30 days1 (1%)25 (3%)N.S.
Comparing APL among them in order to identify parameters that could be correlated to IFI presentation, no significant factors were identified.
DISCUSSION
In our prospective study we specifically analyzed the incidence and the type of IFI in APL during a prolonged follow-up. Only 10 cases of IFI were documented and in most cases (6 pts) the infection was only possible. Comparing APL to npAML a lower incidence of overall IFI was observed despite less use of mold active drugs as prophylaxis. It could be attributed to the different chemotherapy (less aggressive in APL) and to lower duration of deep neutropenia. No yeast infection was observed in APL. On the basis of this study, APLs may be considered at low risk of IFI so probably the use of a mold active antifungal prophylaxis could be omitted.
No relevant conflicts of interest to declare.
Congenital syphilis in Italy: a multicentre study Tridapalli, Elisabetta; Capretti, Maria Grazia; Reggiani, Maria Letizia Bacchi ...
Archives of disease in childhood. Fetal and neonatal edition,
05/2012, Letnik:
97, Številka:
3
Journal Article
Recenzirano
To study the prevalence of congenital syphilis and its risk factors in Italy.
Prospective study from 1 July 2006 to 30 June 2007. Data on mother-child pairs were collected for every syphilis ...seropositive mother.
Maternal syphilis seroprevalence at delivery was 0.17%. 207 infants were born to 203 syphilis seropositive mothers. In 25 newborns it was possible to diagnose congenital syphilis (20/100,000 live births). Maternal risk factors included age <20 years, no antenatal care and no adequate treatment. The infected babies were more often preterm or weighed <2000 g at birth.
Many syphilis seropositive mothers were foreign born but the risk of an infected newborn was not higher in foreign-born than in Italian seropositive women. The significant factors were lack of antenatal screening and inadequate maternal treatment.
Syphilis is a re-emerging infection in Italy. Prevention strategies should include antenatal serological tests for all pregnant women and treatment for infected mothers.
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