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  • 1
    In: Journal of Translational Medicine, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2020-10-21)
    Abstract: Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P  = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P   〈  0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).
    Type of Medium: Online Resource
    ISSN: 1479-5876
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2118570-0
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  • 2
    In: Journal of Translational Medicine, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2021-12)
    Type of Medium: Online Resource
    ISSN: 1479-5876
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2118570-0
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  • 3
    In: JAMA Internal Medicine, American Medical Association (AMA), Vol. 180, No. 10 ( 2020-10-01), p. 1345-
    Type of Medium: Online Resource
    ISSN: 2168-6106
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2020
    detail.hit.zdb_id: 2699338-7
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  • 4
    In: The Lancet Haematology, Elsevier BV, Vol. 7, No. 12 ( 2020-12), p. e861-e873
    Type of Medium: Online Resource
    ISSN: 2352-3026
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2802056-X
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  • 5
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 5398-5398
    Abstract: Six Italian scuba divers, three men and three women, lived permanently for 14 days at a depth of 8 – 10 metres under the sea level breathing a mixture with the same composition of the air at a pressure ranging between 1,8–2 ATA (Hyperoxic Air-HOA), under the control of a physician’s team. This experience called Abyss project: the “underwater home” was born as a Guinness record attempt, but it had been also surrounded by scientific attention giving the opportunity to collect scientific data. The effect of long-term diving on blood in professional and recreational-professional scuba divers has not been studied. Oxygen is the main regulator of Epo production through the activation or degradation of HIF-1α, the most important transcriptional factor of Epo gene. Hypoxia favours HIF-1α activation, on the contrary hyperoxia favours its degradation. In this case, the excess of Reactive Oxygen Species (ROS), play a crucial role. In the six subjects of Abyss Project, we evaluated S-Epo (Immunoturbidimetric method-Immulite Medical System), CBC and differential (ADVIA 120 Automated Hematology System-Bayer Diagnostics), Reticulocyte count (absolute and perceptual) (Beckman Coulter LH 750-IL Instruments).and the most important hemato-chemical parameters with this timing: before immersion (TIME 0), 7 days (TIME 1), 14 days (TIME 2) after beginning the dive, two hours (TIME 3) and 24 hours (TIME 4) after the resurface. The aim of our study was to investigate if erythropoiesis is affected by a so long diving. Hgb, as far as the hematochemical parameters did not change while Ht, s-Epo, O/P ratio absolute and perceptual reticulocyte counts decline progressively from TIME 0 until TIME 3. At Time 4 (24 hours after the resurface) a rise of Epo production was observed. No significant variation of renal function was registered, According to Repeated Measures ANOVA test, these results are statistically significant (see the Table). We retain that the different results of Hgb and Ht reflect a variation of hydration state. Similar results were obtained previously by other Authors (Balestra C et al J Appl Physiol 2006) although in different experimental conditions and for shorter exposition. Their experiment was conducted in two steps: hyperoxia (100% O2, two hours, with a “nonrebreather” mask) in normobarysm; hyperoxia in hyperbarysm (100% O2, 2,5 ATA, 1,5 hours, in hyperbaric chamber). They observed the rise of s-Epo only 24 hours after the exposition to normobarism, not after the exposition to hyperbarism. This phenomenon was called “normobaric oxygen paradox”. Our results confirm that the s-Epo production is affected by the exposition to hyperbarism. It could be hypothesize that the Oxygen dissolved in the plasma influences the s-Epo production, moving the equilibrium between reduction and oxidation towards the last. In fact, no relevant variation of the Hgb Oxygen transport was observed. The reverse of this equilibrium should determine the rise of s-Epo 24 hours after the resurface. Taking in account our results and those of Balestra, it seem that Oxygen pressure, more than O2 concentration, is crucial for the “normobaric oxygen paradox”. Finally, although Hgb did not change, some signs of impairment of erythropoiesis are already present. In fact, absolute and perceptual reticulocyte counts decline from Time 0 to time 4. Taking into account the timing of erythropoiesis, it is predictable that anemia would be a clinical problem if the exposition continued. In fact, erythropoiesis could suffer from the Epo reduction and also from the enhancement of the apoptosis. The last effect could be produced either by the Epo reduction, either by a direct effect of hyperoxia as demonstrated in vitro (Ganguly BJ Apoptosis 2002). T Hgb g/dl Ht Ret% Ret 10^9/l s-Epo mU/ml 0 14,03±1,25 41,32±2,81 1,19±0,35 56,40±22,09 11,58±3,09 1 13,72±1,39 40,03±3,37 1,08±0,50 50,72±26,16 6,28±3,20 2 13,33±1,80 38,83±4,35 0,72±0,23 32,58±12,82 4,23±1,59 3 13,40±1,43 39,77±3,38 0,67±0,17 30,18±8,90 4,50±1,73 4 13,67±1,35 39,82±3,43 0,71±0,28 32,96±13,44 14,02±5.05 P n.s. & lt;0.0001 & lt;0.0001 & lt;0.0001 & lt;0.0001
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    In: Annals of Intensive Care, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-12)
    Abstract: A Covid-19 outbreak developed in Lombardy, Veneto and Emilia-Romagna (Italy) at the end of February 2020. Fear of an imminent saturation of available ICU beds generated the notion that rationing of intensive care resources could have been necessary. Results In order to evaluate the impact of Covid-19 on the ICU capacity to manage critically ill patients, we performed a retrospective analysis of the first 2 weeks of the outbreak (February 24–March 8). Data were collected from regional registries and from a case report form sent to participating sites. ICU beds increased from 1545 to 1989 (28.7%), and patients receiving respiratory support outside the ICU increased from 4 (0.6%) to 260 (37.0%). Patients receiving respiratory support outside the ICU were significantly older [65 vs. 77 years], had more cerebrovascular (5.8 vs. 13.1%) and renal (5.3 vs. 10.0%) comorbidities and less obesity (31.4 vs. 15.5%) than patients admitted to the ICU. PaO 2 /FiO 2 ratio, respiratory rate and arterial pH were higher [165 vs. 244; 20 vs. 24 breath/min; 7.40 vs. 7.46] and PaCO 2 and base excess were lower [34 vs. 42 mmHg; 0.60 vs. 1.30] in patients receiving respiratory support outside the ICU than in patients admitted to the ICU, respectively. Conclusions Increase in ICU beds and use of out-of-ICU respiratory support allowed effective management of the first 14 days of the Covid-19 outbreak, avoiding resource rationing.
    Type of Medium: Online Resource
    ISSN: 2110-5820
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2617094-2
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  • 7
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4604-4604
    Abstract: Gentuzumab Ozogamicin (GO) is an anti-CD33 antibody linked to the cytotoxic antibiotic calicheamycin and it is effective as single agent in the treatment of poor risk acute myeloid leukemia (AML) patients. In 3 Italian Hematology Departments from September 2003 to December 2004, we treated 26 AML patients, both untreated (12 cases) and resistant (14 cases) with the following protocol: rhG-CSF(5 μg/kg, on days 0 through 8), Aracytin as continuous perfusion (100 mg/m2 on days 4 through 8) followed by GO (6 mg/m2 iv over 2 hours on day 9) (G-GOA). Inclusion criteria were: 1) CD33+ de novo or secondary AML (except M3 AML; 2) Primary refractory AML or relapse of AML in patients between 61 and 80 years; 3) Untreated patients 〉70 years or not eligible for aggressive chemotherapy. There were 13 male and 13 female with a median age of 69 years (range 58–77). FAB classification was 5 M0, 5 M1, 7 M2, 2 M4, 1 M5, 6 AML post-MDS. Ten patients presented a secondary AML. The median duration of first complete remission (CR) of 9 patients with relapsed AML was 48 weeks (range 8–76). Cytogenetic study was performed in all patients; karyotype was intermediate in 13 cases, unfavourable in 7 cases. In 6 patients no metaphases were observed. All patients performed the CD33+ evaluation on BM, the median percentage of CD33 positive blasts was 90% (range 25%–95%). Fourteen patients (56%) achieved a CR and 1 patient had CR with delayed platelet recovery (CRp) with an overall response (OR) of 58% (7 untreated AML and 8 resistant patients). One patient obtained a partial remission with only a transient hematologic improvement, characterized by a peripheral increase of all hematological parameters and by a 50% reduction of the bone marrow blast count. Five patients (19%) resulted refractory to treatment and 5 patients died during the aplasia period post induction treatment. The most common adverse event was myelosuppression, as expected. Median durations of neutropenia and thrombocytopenia in patients reaching CR were 19 days (range 15–62) and 16 days (range 10–37) respectively. No VOD was recorded. Six patients (23%) developed documented infection (including pulmonary aspergillosis in 3 cases). Notably, in 2 cases we observed a grade III/IV bleeding consisting in CNS haemorrhage. Two patients died while in CR, 1 due to bladder cancer relapse and 1 to ischemic stroke. Seven patients (27%) relapsed; the median CR duration was 20 weeks (range 8–41+). At March 2005 10 patients (38%) were alive of whom 6 are still in CR (27%). The median overall survival was 17,5 weeks (1–60 weeks). On the basis of our results the G-GOA protocol could be considered an useful approach for poor risk elderly AML also in consideration of the low reported side effects. We did not observe any case of VOD, which characterized other trials using GO at higher dosage. Unfortunately the CR duration was brief. Probably it could be improved with the addition of more aggressive consolidation schedule (i.e. Intermediate doses of Ara-C).
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2928-2928
    Abstract: Abstract 2928 Introduction. The recent development of a safe and efficient once daily oral iron chelator (Deferasirox, ExjadeÒ) made possible regular chelation therapy in transfusion dependent MDS patients. However in this category of patients the reported clinical experience is limited to selected populations. For this reason the GIMEMA group developed a phase IIIb prospective trial to test safety and efficacy of Deferasirox in a large population of patients comparable to general MDS population. Methods. One hundred and fifty-nine transfusion dependent IPSS low-intermediate1 risk MDS patients were enrolled. Analysis has been performed on 123 patients who had completed the planned year of treatment. Baseline characteristics were the following (data are expressed as median with upper and lower quartile unless specifically indicated): median age was 72 years (range 24 – 87); 48 were IPSS low risk and 75 Intermediate1; duration of transfusion dependency before treatment was 20 months (12-36) corresponding to 38 (22-70) packed red blood cells transfusions received. Baseline serum ferritin was 2000 ng/ml (1471-3000). Baseline Charlson and CIRS comorbity scores were 1 (0-1) and 0.2 (0.1-0.4), respectively. Patients started treatment with the standard 20 mg/kg Deferasirox dose but dose adjustments on clinical indications were allowed. Results. 61 patients (49%) prematurely interrupted the study (drop out), 62 (51%) patients completed the planned year of treatment. In logistic model for drop out rate high Charlson co-morbidity score showed a trend as significant risk factors (p=0.06). Drops out were related to: ten patients (8%) had progression to acute leukemia during the study; twenty patients (16%) experienced MDS related clinical problem (three had cardiac failure, seven had severe infectious diseases, four had severe bleeding, three died at home, three presented others MDS related problems); five patients underwent hemopoietic stem cell transplantation and thirteen discontinued treatment for unrelated problems. Drug related toxicity was drop out cause in 13 patients (11% of the entire population). Main causes of toxicity related drops out were increase of creatinine and gastro-intestinal disturbance. Out of 123 patients analyzed for adverse events only 4 (3%) presented grade 3–4 drug related adverse events. Severe adverse events with suspected relationship with study drug were diarrhea and increase of liver enzymes. Serum ferritin was monthly recorded in the 62 patients who completed the protocol with a statistically significant decrement during the 12 months follow up: median baseline value 2000 ng/ml (interquartile range 1471–3000), median final value 1550 ng/ml (interquartile range 775–2200) P 〈 0.001, Friedman test analyzing the entire study period. Analysis of quality of life is ongoing. One patient showed a complete erythroid response to Deferasirox treatment acquiring transfusion independence that is still ongoing after 18 months. Discussion. Preliminary results from the GIMEMA MDS0306 study confirmed feasibility of Deferasirox therapy in transfusion dependent MDS patients. Drop out rate, toxicity related drop out and severe side effects were similar to those reported in other trials even if the present population presented clinical characteristics of more advanced disease and age. The rate of progression is coherent with prolonged disease story. Serum ferritin behavior confirms Deferasirox efficacy. The serum ferritin reduction was more evident in the more heavily overloaded population indicating successful iron depletion in this group of patients as clinically requested. ClinicalTrial.gov identifier NCT00469560. Disclosures: Angelucci: Novartis: Honoraria. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 4945-4945
    Abstract: Bendamustine is an purine analog alkylating agent with marked efficacy in haematological malignancies either when given as monotherapy or in combination with rituximab. The efficacy and safety of this drug was investigated in heavily pretreated patients (pts) with hematological malignancies. A total of 44 patients (median age 63 years ranging from 22–87) from 6 Italian centers treated with bendamustine alone or in combination with rituximab were analyzed in this retrospective study. The diagnoses were multiple myeloma (n=2), chronic lymphocytic leukemia or small lymphocytic lymphoma (n=19), diffuse large B cell lymphoma (n=7), follicular lymphoma (n=8), mantle cell lymphoma (n=4), marginal zone lymphoma (n=2), Hodgkin’s disease (n=1) and peripheral T cell lymphoma (n=1). All pts received bendamustine 60–90 mg/m2 at day 1+2, alone or in combination with rituximab 375 mg/m2 (n=35) at day 1 of each cycle given every 21 or 28 days. The pts were heavily pretreated with a median of 3 previous treatments (range 1–8); 37 pts had previously received rituximab and 9 pts had undergone autologous transplantation. Prior to receiving bendamustine, 14 pts had relapsed disease, 7 had refractory disease and 23 were progressing during therapy. The median number of bendamustine cycles was 3 (range 1–8); 11 pts were still on treatment at the time of this analysis. Patients who completed therapy with at least 1 cycle of chemotherapy were evaluated for response and toxicity; pts in continuous therapy were evaluated for toxicity only. Of 33 pts evaluable for response 7 pts achieved a CR (21%) and 14 a PR (42%) resulting in an ORR of 64%. The remaining 12 pts were non-responders. No differences in the results were observed between groups with different bendamustine doses or scheduling. The best results were obtained in 10 evaluable pts with indolent lymphoma (4 CR, 6 PR) and in 9 pts with chronic lymphocytic leukemia (1 CR, 6 PR). Two evaluable pts with mantle cell lymphoma obtained a response (1 CR, 1 PR). By contrast, only 1 pt with diffuse large B cell lymphoma of 6 patients evaluable for response obtained a CR: the other 5 were non-responders. No pt with myeloma, Hodgkin’s disease or T cell lymphoma achieved a response. After a median follow-up of 4 months, 80% of pts were alive. During 150 treatment cycles, 2 pts experienced grade 4 thrombocytopenia and 1 experienced grade 4 neutropenia; non-hematological toxicity was mild. In conclusion, this retrospective analysis shows that treatment with bendamustine, alone or in combination with rituximab, is a safe and effective regimen in heavily pretreated pts. The best results were obtained in indolent lymphoma: the data in mantle cell lymphoma were also encouraging. No lack of efficacy can be inferred in pts with diffuse large B cell lymphoma, due to the refractory nature of their disease and the advanced age of this particular group (median age 76 years ranging from 67–87).
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1662-1662
    Abstract: Abstract 1662 Poster Board I-688 Introduction Bendamustine is an alkylating agent with a nitrogen mustard group and a purine like benzimidazol group. Recently this drug was introduced in Italy. We analized all pts treated in sixteen haematological Italian centers with Bendamustine alone or in combination with anti-CD20 antibody. Patients and methods On an intention to treat basis pts who have received at least one complete cycle were evaluable for response and toxicity. The treatments consisted of: Bendamustine 60-90 mg/m2 days 1,2 alone or in combination with Rituximab 375 mg/m2 day 0, every 21 or 28 days. 173 pts were analized, median age was 67 (range 31-87), 114 were male, 63 chronic lymphatic leukaemia 41 indolent non-follicular lymphoma, 26 diffuse large B cell lymphoma, 26 follicular lymphoma, 15 mantle cell lymphoma, 2 Peripheral T cell lymphoma. Pts were heavily pretreated, the median number of previous treatments was 3,5 (range 1-8), 121 pts have experienced more than three chemotherapy schemes. One hundred and twenty-seven pts were previously treated with Rituximab and 24 performed an autologous peripheral blood stem cell transplantation. The Bendamustine pre-treatment condition was: 70 relapsed pts, 40 with refractory disease and 63 with a progressive disease after partial response. The median number of Bendamustine cycles was 4.3 (range 1-11). Results All patients were evaluable for response: 48 pts (28%) obtained a complete remission, 78 (45%) a partial response or stable disease with an overall response rate of 73% and 47 were non responders. According to histotype we observed that 10/15 pts (67%) with mantle cell lymphoma obtained a response (6 CR;4 PR), 37/41 (9 CR; 28 PR) indolent non follicular lymphoma and 25/26 (96%) follicular lymphoma obtained a response (12 CR;13 PR), 46/63 CLL obtained a response and 8/26 (31%) DLBCL obtained a response to therapy (4 CR;4 PR), none of the two T lymphoma pts responded to therapy. With a median period of observation of 12 months (1-46) 121 (70%) pts are alive and 83 pts are in complete remission or with stable disease without any other treatment. The overall survival was 82%, 72%, 68% and 27% respectively for indolent, CLL, mantle cell and diffuse large B cell lymphoma. The progression free survival was 31%, 27%, 15% and 10% respectively for indolent, CLL, mantle cell and diffuse large B cell lymphoma. Fifthy-two pts died, 47 for progressive disease, 11 due to infection and sepsis (6%) and 2 due to other causes not related with therapy or disease. In this group of heavily pretreated pts 760 cycles were performed. The extrahematological toxicity was mild the most important problem were infections (Herpes Zooster, pneumonia, enteritis) reported in 16 pts, hepatic in 4 and cardiologic in 2 pts. The hematological toxicity was trombocytopenia grade 3-4 in 20 pts (12%), neutropenia grade 3-4 in 40 pts (23%) and anemia grade 3-4 in 19 pts (11%). Discussion In conclusion this retrospective study shows that treatment with Bendamustine alone or in combination with Rituximab is a safe and efficacy regimen in a subset of pluriresistent patients. This data shows also that the best results could be obtained in indolent lymphoma and CLL incouraging data in mantle cell lymphoma are reported. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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