Abstract 4101
The only curative option for adult patients with refractory or relapsed ALL is allogeneic haematopoietic stem cell transplant (allo-HSCT), which can offer a 28-34% long term survival in ...transplanted patients. However the actual feasibility of allo-HSCT is only 20-30% in unselected patients because of the low rate (30-50%) of complete remission (CR) achieved with salvage regimens (Tavernier, 2007- Thomas, 1999), the high rate of early relapse (Martino, 1999) and the difficulties in finding a suitable donor before progression (Davies, 1996). Hence, relapsed ALL can be actually cured in less than 10% of unselected adult patients. Using a second line treatment capable of obtaining a higher proportion of CR of longer duration may improve the dismal overall prognosis of patients. We report on the efficacy and toxicity profile of the combination of 6-metilprednisolone, mitoxantrone, etoposide and high-dose cytarabine (MECp), a salvage regimen containing cytostatic drugs to which patients had not been exposed during first line therapy, except for cytarabine at lower doses.
Between October 2000 and May 2009, 18 refractory/relapsed ALL patients were treated at our Institution with MECp regimen, consisting of a single course of etoposide 80mg/mq/die iv, cytarabine 1000mg/mq/die iv for 6 hours and mitoxantrone 6mg/mq/die iv 9 hours after cytarabine infusion for 6 days associated to metilprednisolone 50 mg/mq/die for 21 days, subsequently tapered to zero over one week. Three patients received an experimental sequential pulsed chemotherapy program in a multiinstitutional setting. At diagnosis, all patients had been treated according to the NILG-ALL 00/09 program (Bassan, Blood 2009). Four had been refractory to induction therapy and 14 had relapsed after a median of 12 months (range 3-43), 11 while on consolidation/maintenance, one after allo-HSCT, two after 3 and 12 months from the end of maintenance. There were 10 males and 8 females with a median age of 28 (range 17-64). ALL lineage was B in 9 cases (4 pro-B, 4 common, 1 pre B), T in 8 (5 pro-T, 3 cortical-TIII) and biphenotypic in 1. Molecular studies showed MLL/AF4 rearrangement in 3 and bcr/abl rearrangement in 3 cases, all before tyrosine-kinase inhibitors were available. Karyotypic abnormalities were present in 10 of 16 evaluable cases. Patients were treated in single/double bed rooms with reverse isolation. In 3 cases treatment duration was reduced to 4 days.
CR was obtained in 13 of 18 patient (72,2%), independently of immunophenotype and time to relapse. CR rate was 100% in all ten patients with karyotypic abnormalities. Three patients (16%) died in aplasia during treatment, 2 of septic shock and 1 of unexplained shock. Two patients (T-ALL) were resistant. Recovery of neutrophils (>0,5×109/L) and platelets (>20×109/L) required a median of 22 days (range 17-37) and 28 days (range 21-45) from the start of therapy, respectively. Infections were documented in 9 of 18 (50%), being fatal in 2 (11%). Non-haematologic toxicity, mainly mucositis, was negligible. The median duration of CR was 5 months (range 2-5) which allowed 9 of 13 CR patients (69%) to undergo allo-HSCT (7 MUD, 1 HLA-identical sibling and 1 cord blood) after a median of 4 months (range 2-7) from CR. Reason for not being transplanted was failure of donor search in 4 patients who relapsed a median of 4 months. Causes of death included progressive disease in 7 patients, in 3 cases after HSCT, and transplant-related toxicity in 3 patients. The median survival of patients achieving CR was 13 months (range 7-33) and overall survival of the entire cohort was 8 months (range 1-33m).
With MECp, a combination of drugs not used during previous first-line therapy, a higher CR rate (72%) than commonly reported could be obtained, with acceptable toxicity. CR duration was long enough to allow 44,4% of patients to receive a non-family donor allo-HSCT, which is presently the best, yet still unsatisfactory, treatment option for adult patients with refractory/relapsed ALL.
No relevant conflicts of interest to declare.
COVID-19 associated pulmonary aspergillosis (CAPA) is common and linked with high fatality rates. To assess the impact on the incidence and outcome of CAPA of an antifungal prophylaxis (AFP) we ...compared two cohorts of COVID-19 patients admitted to intensive care units (ICU) in Brescia, Italy, from January to August 2021.
The study cohort included all mechanically ventilated patients observed between April 2021 and August 2021 with SARS-CoV-2-pneumonia, who received AFP with oral posaconazole (200 mg every 6 h) and nebulized liposomal amphotericin B (50 mg every 2 weeks) from ICU admission to 7 days after discharge or, if applicable, until tracheostomy removal. The control cohort included COVID-19 patients admitted to the same ICU between January and March 2021 who did not receive any AFP. Subjects with CAPA at ICU admission were excluded.
We included 270 patients, of whom 64 (23.7%) received AFP. In patients in the study group, CAPA-related mortality was significantly reduced (29% vs. 48% p = 0.04), as well as the incidence of CAPA (3.1% vs 12.1%, p = 0.03). Patients who developed CAPA were older (mean of 70-y-old vs 63-y-old, p < 0.001). One subject discontinued posaconazole due to an adverse reaction. Among the 46 patients who received it, only one patient reached an effective plasma concentration of posaconazole.
AFP was associated with reduced incidence and mortality from CAPA and was well tolerated in patients with severe COVID-19. Posaconazole concentrations below the efficacy threshold in almost all patients may be attributable to drug interactions and prompt further studies to define its clinical significance.
The development of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematological diseases. However, approximately 60% of patients relapse after CAR-T cell therapy, ...and no clear cause for this failure has been identified. The objective of the Bio-CAR-T BS study (ClinicalTrials.gov: NCT05366569) is to improve our understanding of the lymphocyte harvest to maximize the quality of the CAR-T cell product. Of the 14 patients enrolled, 11 were diagnosed with DLBCL, 2 with PMBCL, and 1 with ALL. Five of 11 DLBCL patients met the criteria for “pre-emptive” Lymphocytes-apheresis (being at high risk of second relapse), and 6 were included in the standard-of-care Lymphocytes-apheresis group. Previous autologous stem cell transplantation (ASCT) and age were significantly different between the two groups. At the time of Lymphocyte-apheresis, patients in the “pre-emptive” group had more “fit” lymphocytes (higher CD4+/CD8+ ratio; higher naïve T cells levels) compared with standard group, probably due to the impact of ASCT. At the same time, also being older than 60 years results in a more “exhausted” lymphocyte profile. Overall, “pre-emptive” Ly-apheresis in DLBCL patients at high risk of relapse appears to be feasible and may allow the timely collection of “fit” lymphocytes for CAR-T cell manufacturing.
A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia.
A prospective series of 100 consecutive patients ...admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response.
The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24–72 h and 10 days after tocilizumab administration.
Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 IQR 0–2), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died.
All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10.
In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement.
The discovery of Helicobacter pylori infection in the stomach could be considered as one of the most important events of modern gastroenterology. Understanding of the natural history of many ...disorders of the upper gastrointestinal tract, including chronic gastritis, peptic ulcer disease, gastric cancer and MALT lymphoma, was altered by this discovery. Interestingly, epidemiological studies have also revealed a correlation between H. pylori infection and some diseases localized outside the stomach, especially those characterized by persistent and low-grade systemic inflammation. Of note, H. pylori has an important role in iron deficiency anaemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency. Moreover, the association of this bacterial pathogen with many other diseases, including hepatobiliary, pancreatic, cardiovascular and neurodegenerative disorders is currently under investigation. In this Review, we summarize the results of the most important studies performed to date surrounding the association of H. pylori infection with extragastric diseases, as well as the strength of the evidence. We also provide information concerning bacterial-host interactions and the mechanisms implicated in the pathogenesis of each of these extragastric diseases.
This paper aims to verify the effectiveness of a process of superficial protection based on nanotechnologies produced by 4Ward360 and specifically developed for aeronautical applications on composite ...material aircraft. The Dardo aircraft, a composite VLA category manufactured by CFM Air, was taken as a reference case and two application/investigation areas were identified. The potential anticorrosive behavior of the nanotechnology treatment was investigated when applied to the metal joints of the aircraft, such as the wing–fuselage attachments usually made of Al-2024-T3 aluminum alloy. Furthermore, the potential increased effectiveness in cleaning was investigated as another possible application concerning the parts made of composite material both solid and in a sandwich configuration and the plexiglass parts of the canopy.
While gastric cancer is a well established angiogenesis driven tumor, no data has been published regarding angiogenesis stimulated by mast cells (MCs) positive for tryptase in bone metastases from ...gastric cancer patients (BMGCP). It is well established that MCs play a role in immune responses and more recently it was demonstrated that MCs have been involved in tumor angiogenesis. We analyzed infiltrating MCs and neovascularization in BMGCP diagnosed by histology. A series of 15 stage T3-4N2-3M1 (by AJCC for Gastric Cancer Staging 7th Edition) BMGCP from bone biopsies were selected. Tumour tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of MCs density positive to tryptase (MCDPT), MCs area positive to tryptase (MCAPT), microvascular density (MVD) and endothelial area (EA). A significant correlation between MCDPT, MCAPT, MVD and EA groups to each other was found by Pearson and t-test analysis (r ranged from 0.68 to 0.82; p-value ranged from 0.00 to 0.02). Our very preliminary data suggest that infiltrating MCs positive for tryptase may play a role in BMGCP angiogenesis, and could be further evaluated as a novel target of anti-angiogenic therapy.
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