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1.
Neurooncol Adv ; 3(1): vdab160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34901858

RESUMO

Background: Immunotherapeutic early-phase clinical trials (ieCTs) increasingly adopt large expansion cohorts exploring novel agents across different tumor types. High-grade glioma (HGG) patients are usually excluded from these trials. Methods: Data of patients with recurrent HGGs treated within multicohort ieCTs between February 2014 and August 2019 (experimental group, EG) at our Phase I Unit were retrospectively reviewed and compared to a matched control group (CG) of patients treated with standard therapies. We retrospectively evaluated clinical, laboratory, and molecular parameters through univariate and multivariate analysis. A prospective characterization of circulating leukocyte subpopulations was performed in the latest twenty patients enrolled in the EG, with a statistical significance cutoff of P < .1. Results: Thirty HGG patients were treated into six ieCTs. Fifteen patients received monotherapies (anti-PD-1, anti-CSF-1R, anti-TGFß, anti-cereblon), fifteen patients combination regimens (anti-PD-L1 + anti-CD38, anti-PD-1 + anti-CSF-1R). In the EG, median progression-free survival and overall survival (OS) from treatment initiation were 1.8 and 8.6 months; twelve patients survived more than 12 months, and two of them more than 6 years. Univariate analysis identified O 6-methylguanine DNA methyltransferase (MGMT) promoter methylation and total protein value at six weeks as significantly correlated with a better outcome. Decreased circulating neutrophils and increased conventional dendritic cells levels lead to significantly better OS. Conclusions: A subgroup of EG patients achieved remarkably durable disease control. MGMT promoter methylation identifies patients who benefit more from immunotherapy. Monitoring dynamic changes of innate immune cell populations may help to predict clinical outcomes.

2.
Transplant Cell Ther ; 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34954296

RESUMO

BACKGROUND: Risk factors for cytomegalovirus (CMV) reactivation and the impact of CMV reactivation on patients' outcomes have been extensively investigated after matched related or unrelated donor transplants, but little is known in the setting of haploidentical stem cell transplant (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy), where recipients are supposed to be more severely immune-compromised. METHODS: We retrospectively analyzed a cohort of 554 consecutive patients undergoing Haplo-SCT with PT-Cy at 3 different centers. RESULTS: Early CMV reactivation, taking place within the first 120 days after transplant, occurred in 242 patients for an estimated cumulative incidence of 44%. Out of those patients, 74 (30%) had recurrent CMV and 20 (8%) CMV disease. By multivariable analysis, positive recipient CMV serostatus (Hazard ratio [HR] > 2.5, p<0.001), disease histology (lymphoid vs myeloid: HR 0.66, p=0.003) and increasing recipient age (HR 1.01, p=0.015) were independent predictors of CMV reactivation. At four months landmark analysis, CMV reactivation was associated with higher 1-year and 5-year cumulative incidence of non-relapse mortality (NRM) relative to patients without reactivation: 13% vs 5% and 22% vs 9%, respectively (p<0.001). By multivariable analysis, CMV reactivation was an independent negative predictor of non-relapse mortality (NRM) (HR 2.69, p<0.001) and was close to statistical significance for overall survival (OS) (HR: 1.38, p=0.062). CONCLUSIONS: Our results suggest that CMV reactivation plays an important role at determining NRM. Because patient CMV serostatus is the main predictor of CMV reactivation, it should be considered when evaluating strategies for preventing CMV reactivation.

3.
Cancers (Basel) ; 13(22)2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34830823

RESUMO

Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC immune class (based on intratumoral tertiary lymphoid structures, and glutamine synthase, CD3, and CD79 expression); and (ii) the relationship between HIRAE onset and subsequent treatment outcomes. Fifty-eight patients were included-20 (34%) received ICIs alone, and 38 (66%) received ICIs plus targeted agents as first- or further-line treatment. After a median time of 0.9 months (range, 0.4-2.7), nine patients (15.5%) developed grade ≥ 3 hepatitis, which was significantly associated with higher baseline ALT levels (p = 0.037), and an infectious HCC etiology (p = 0.023). ICIs were safely resumed in six out of nine patients. Time to treatment failure (TTF) was not significantly different in patients developing grade ≥ 3 hepatitis vs. lower grades (3.25 vs. 3.91 months, respectively; p = 0.81). Biomarker surrogates for the HCC immune class were not detected in patients developing grade ≥ 3 hepatitis. Grade ≥ 3 hepatitis has a benign course that does not preclude safe ICI reintroduction, without any detrimental effect on TTF.

4.
Cancer ; 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34706060

RESUMO

BACKGROUND: Angiogenesis has an important role in thymic epithelial tumors (TETs). Regorafenib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor ß (PDGFR-ß), and fibroblast growth factor receptors (FGFRs). This study explored the activity of regorafenib as monotherapy in patients with advanced or recurrent B2-B3 thymoma (T) and thymic carcinoma (TC) previously treated with platinum-containing chemotherapy. METHODS: A Fleming single-arm, single-stage, phase 2 trial to evaluate the activity of regorafenib (160 mg once a day by mouth for 3 weeks on/1 week off) was planned. The study was designed to reject the null hypothesis of an 8-week progression-free survival (PFS) rate ≤25% with a type I error of 0.10 and a statistical power of 80% at the alternative hypothesis of an 8-week PFS rate of ≥50% (≥8 of 19 evaluable patients progression-free at 2 months). RESULTS: From June 2016 to November 2017, 19 patients were enrolled (11T/8TC). We observed partial response (PR) in 1 patient (1T) (5.3%), stable disease (SD) in 14 patients (9T/5TC) (73.7%), and progressive disease in 2 patients (1T/1TC) (10.5%), with a disease control rate of 78.9%. According to Choi-criteria, 13 patients (68.4%) achieved PR, and 2 patients SD (10.5%). The median PFS was 9.6 months whereas median overall survival was 33.8 months. The 8-week PFS rate was 78.9% (15 of 19 patients). Grade 3-4 treatment-related adverse events were observed in 10 patients (52.6%). CONCLUSIONS: The primary end point of this study was reached. The high rate of PR (Choi-criteria) suggests antitumor activity of regorafenib in TETs. On the basis of survival outcomes, the efficacy of regorafenib should be further evaluated in larger studies.

5.
Curr Probl Cancer ; : 100787, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34489119

RESUMO

Molecular characterization of non-small-cell lung cancer (NSCLC) is essential to define the correct therapeutic algorithm in metastatic disease. Approximately 90% of epidermal growth factor receptor (EGFR) mutations are usually associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The remaining 10% defines a small, extremely heterogeneous subgroup of mutations, with a varied profile of sensitivity and response to target therapies.This retrospective observational study includes 47 patients affected by metastatic NSCLC harboring uncommon EGFR mutations (single or compound mutation). Patients were treated with EGFR-targeting TKIs or platinum-based chemotherapy as first-line treatment.Median OS resulted longer in the compound mutation group when compared to single rare mutations (33.6 vs 12 months; P = 0.473); a similar result was observed for PFS (16 vs 7.6 months; P = 0.281), although statistical significance was not reached. ORR, PFS and OS resulted similar for patients treated with first-line EGFR TKIs or chemotherapy. No difference in terms of PFS and OS was found according to the TKI administered.Compound mutations seem to be a good prognostic indicator for OS; they are also predictive of response to 1st and 2nd generation EGFR TKIs, as well as exon 19 insertions and mutations in codon 719 of exon 18. For mutations in exon 18 (not in codon 719) and exon 20 insertions, chemotherapy seems the most effective available option. The addition of immunotherapy to chemotherapy could change this approach in the next future.

6.
Transplant Cell Ther ; 27(11): 912.e1-912.e6, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34403790

RESUMO

Busulfan (Bu) is an alkylating agent routinely used for conditioning regimens before allogeneic stem cell transplantation (allo-SCT). Bu shows wide pharmacokinetic (PK) variability among patients. Patients can have a higher systemic exposure (expressed as area under the curve [AUC]) with an increased risk of toxicity or a lower AUC with a higher probability of graft rejection and/or disease relapse. After i.v. administration, an optimal Bu therapeutic window (AUC target of 16,000 to 24,000 µM·minute) has been identified. The use of PK-guided Bu dosing leads to improved overall survival (OS) and progression-free survival (PFS) compared with fixed-dose administration in a variety of hematologic diseases. The aim of this study was to evaluate the outcomes and feasibility of a reduced-toxicity conditioning (RTC) regimen comprising thiotepa, Bu, and fludarabine (TBF) with therapeutic drug monitoring of Bu in patients with hematologic disorders. We report on 41 adult patients with myeloid or lymphoid malignancies who underwent an allo-SCT with a PK-guided Bu-based RTC regimen between January 2019 and October 2020. Patients received a total Bu dose to achieve a target AUC of 16,000 µM·minute in combination with Flu and thiotepa. The median time to absolute neutrophil count recovery and transfusion-independent platelet count recovery was 23 days (range, 15 to 42 days) and 29 days (range, 14 to 97 days), respectively. The cumulative incidence (CI) of nonrelapse mortality was 7% at 100 days and 13% at 1 year. Grade 3 liver toxicity was observed in 6 patients. One patient developed sinusoidal obstruction syndrome at day +27. Grade 3 mucositis occurred in 18 patients. Looking at grade ≥3 infections, the CI was 29% at 30 days, 34% at 60 days, 44% at 100 days, and 56% at 1 year. The 180-day CI of grade II-IV acute graft-versus-host disease (GVHD) was 15%, and the 1-year CI of overall chronic GVHD was 20%. With a median follow-up of alive patients of 14.4 months (range, 3.2 to 24 months), the CI of relapse at 1 year was 6%. The 1-year PFS was 81%, and 1-year OS was 84%. In conclusion, these data support the efficacy of PK-guided Bu dose in the context of a TBF conditioning regimen and the feasibility of therapeutic dosage monitoring of i.v. Bu for patients with hematologic diseases. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

7.
Diabetes Ther ; 12(9): 2557-2569, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34383261

RESUMO

INTRODUCTION: Studies on the durability of an intensive, structured education protocol on best insulin injection practice are missing for people with type 2 diabetes mellitus (T2DM). The aim of this study was to assess the durability of an intensive, structured education-based rehabilitation protocol on best insulin injection practice in well-trained subjects from our previous intensive, multimedia intervention study registered as the ISTERP-1 study. A total of 158 subjects with T2DM from the well-trained group of the 6-month-long ISTERP-1 study, all of whom had successfully attained lower glucose levels compared to baseline levels with lower daily insulin doses and with less frequent and severe hypoglycemic episodes, participated in the present investigation involving an additional 6-month follow-up period, called the ISTERP-2 study. METHODS: Participants were randomized into an intervention group and a control group, depending on whether they were provided or not provided with further education refresher courses for 6 months. At the end of the 6 months, the two groups were compared in terms of injection habits, daily insulin dose requirement, number of severe or symptomatic hypoglycemic events, and glycated hemoglobin (HbA1c) levels. RESULTS: Despite being virtually superimposable at baseline, the two groups behaved quite differently during the follow-up. The within-group analysis of observed parameters showed that the subjects in the intervention group maintained and even improved the good behavioral results learned during the ISTERP-1 study by further reducing both the rate of injection technique errors (p < 0.001) and size of lipohypertrophic lesions at injection sites (p < 0.02). Conversely, those in the control group progressively abandoned best practice, except for the use of ice-cold insulin and, consequently, had significantly higher HbA1c levels and daily insulin dose requirements at the end of the follow-up than at baseline (p < 0.05). In addition, as expected from all the above, the rate of hypoglycemic episodes also decreased in the intervention group (p < 0.05), resulting in a significant difference between groups after 6 months (p < 0.02). CONCLUSION: Our data provide evidence that intensive, structured education refresher courses have no outstanding durability, so that repeated refresher courses, at least at 6-month intervals, are needed to have positive effects on people with T2DM, contributing not only to prevention but also to long-term rehabilitation. TRIAL REGISTRATION: Trial Registration no. 118 bis/15.04.2018.

8.
Ann Hematol ; 100(10): 2547-2556, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34327561

RESUMO

We investigated the feasibility and activity of an intensified dose-dense ABVD (dd-ABVD) regimen in patients with early-stage unfavorable Hodgkin lymphoma (HL). This prospective, multicenter, phase II study enrolled 96 patients with newly diagnosed, unfavorable stage I or II classical HL. The patients received four cycles of dd-ABVD followed by radiotherapy. Interim PET (PET-2) was mandatory after two courses. Primary endpoints were the evaluation of dd-ABVD feasibility and activity (incidence of PET-2 negativity). The feasibility endpoint was achieved with 48/52 (92.3%) patients receiving > 85% of the programmed dose. The mean dose intensity in the overall patient population (n = 96) was 93.7%, and the median duration of dd-ABVD was 85 days (range, 14-115) versus an expected duration of 84 days. PET-2 was available for 92/96 (95.8%) patients, of whom 79 were PET-2 negative (85.9%). In total, 90 (93.8%) patients showed complete response at the end of treatment. With a follow-up of 80.9 months (3.3-103.2), the median progression-free survival (PFS) and overall survival (OS) were not reached. At 84 months, PFS and OS rates were 88.4% and 95.7%, respectively. No evidence for a difference in PFS or OS was observed for PET-2-negative and PET-2-positive patients. Infections were documented in 8.3% and febrile neutropenia in 6.2% of cases. Four patients died: one had alveolitis at cycle 3, one death was unrelated to treatment, and two died from a secondary cancer. dd-ABVD is feasible and demonstrates activity in early-stage unfavorable HL. The predictive role of PET-2 positivity in early-stage unfavorable HL remains controversial. The study was registered in the EudraCT (reference number, 2011-003,191-36) and the ClinicalTrials.gov (reference number, NCT02247869) databases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Bleomicina/uso terapêutico , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/uso terapêutico , Adulto Jovem
9.
Wound Manag Prev ; 67(4): 16-22, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34283799

RESUMO

BACKGROUND: Chronic wounds require frequent assessment, minor procedures, and dressing changes. Discomfort, anxiety, and stress are commonly reported during treatment procedures. PURPOSE: To examine the effect of music during treatment on post-wound care treatment anxiety levels and blood pressure measurements in patients with chronic wounds. METHODS: This randomized controlled trial was conducted in a wound care center within a nonprofit academic medical center with a before-and-after intervention measurement. A total of 222 consecutive patients were randomly allocated to either an intervention group (n = 112; classical music was played during treatment) or a control group (n = 110; no music was played during treatment) at their scheduled routine outpatient visits. The State-Trait Anxiety Inventory (STAI) was administered and blood pressure measurements were obtained automatically by machine before and after the intervention. Pretreatment and posttreatment scores were compared using the paired t-test in SPSS 25. RESULTS: Patient age and sex did not differ between the intervention and control groups and pretreatment and posttreatment STAI scores; blood pressure measurements were almost identitical in the control group. In the intervention group, statistically significant differences between the pretreatment and posttreatment STAI scores (M = 45.94 and 40.83), systolic blood pressure measurements (M = 141.94 and 135.72), and diastolic blood pressure measurements (M = 70.93 and 66.23) were observed (P < .001). CONCLUSION: In this study, playing classical music in the treatment room during wound care interventions resulted in a significant decrease in patient anxiety scores and blood pressure measurements.

10.
Dig Liver Dis ; 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34219044

RESUMO

BACKGROUND: It is unclear whether invasive intraductal papillary mucinous neoplasm (IPMN) has different clinical and prognostic characteristics, beyond histological factors, when compared to pancreatic ductal adenocarcinoma (PDAC). AIMS: compare prognostic features of resected PDAC and invasive IPMN METHODS: A retrospective study of patients resected for PDAC or invasive IPMN realized at Humanitas Cancer Center's Pancreatic Surgery Unit, Milan, Italy, between 2010 and 2016. Data recorded included patient demographics, onset symptoms, preoperative health status, tumor features, histology and surgical characteristics. Overall survival was estimated using Kaplan-Meier and prognostic factors for survival were assessed by multivariate Cox regression. RESULTS: A total of 332 patients were included (PDAC, n = 289; invasive IPMN, n = 43). Patients with invasive IPMN had better overall survival than PDAC patients (median: 76.6 versus 25.6 months; 5-year OS rate: 65.4% vs. 14.2%; p < 0.001). PDAC histology was associated with a significantly higher risk of death than IPMN (hazard ratio 1.815, 95% CI: 1.02, 3.24; p = 0.044). Survival was also worse with PDAC in early-stage disease (IA-IB-IIA, N0). In multivariate analysis, independent predictors of worse survival included perineural invasion, preoperative ASA physical status ≥3 and pain at diagnosis. CONCLUSIONS: Patients with IPMN had a better prognosis than PDAC patients, regardless of disease stage.

11.
Blood ; 138(21): 2093-2105, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34125889

RESUMO

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

12.
Br J Cancer ; 125(3): 358-365, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33976367

RESUMO

BACKGROUND: The impact of active cancer in COVID-19 patients is poorly defined; however, most studies showed a poorer outcome in cancer patients compared to the general population. METHODS: We analysed clinical data from 557 consecutive COVID-19 patients. Uni-multivariable analysis was performed to identify prognostic factors of COVID-19 survival; propensity score matching was used to estimate the impact of cancer. RESULTS: Of 557 consecutive COVID-19 patients, 46 had active cancer (8%). Comorbidities included diabetes (n = 137, 25%), hypertension (n = 284, 51%), coronary artery disease (n = 114, 20%) and dyslipidaemia (n = 122, 22%). Oncologic patients were older (mean age 71 vs 65, p = 0.012), more often smokers (20% vs 8%, p = 0.009), with higher neutrophil-to-lymphocyte ratio (13.3 vs 8.2, p = 0.046). Fatality rate was 50% (CI 95%: 34.9;65.1) in cancer patients and 20.2% (CI 95%: 16.8;23.9) in the non-oncologic population. Multivariable analysis showed active cancer (HRactive: 2.26, p = 0.001), age (HRage>65years: 1.08, p < 0.001), as well as lactate dehydrogenase (HRLDH>248mU/mL: 2.42, p = 0.007), PaO2/FiO2 (HRcontinuous: 1.00, p < 0.001), procalcitonin (HRPCT>0.5ng/mL: 2.21, p < 0.001), coronary artery disease (HRyes: 1.67, p = 0.010), cigarette smoking (HRyes: 1.65, p = 0.041) to be independent statistically significant predictors of outcome. Propensity score matching showed a 1.92× risk of death in active cancer patients compared to non-oncologic patients (p = 0.013), adjusted for ICU-related bias. We observed a median OS of 14 days for cancer patients vs 35 days for other patients. CONCLUSION: A near-doubled death rate between cancer and non-cancer COVID-19 patients was reported. Active cancer has a negative impact on clinical outcome regardless of pre-existing clinical comorbidities.


Assuntos
COVID-19/mortalidade , Neoplasias/mortalidade , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos
13.
Transplant Cell Ther ; 27(4): 328.e1-328.e6, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33836877

RESUMO

Allogeneic stem cell transplantation from haploidentical donors using unmanipulated bone marrow and posttransplantation cyclophosphamide has been largely employed to cure high-risk lymphomas. However, the increased incidence of relapse associated with the use of a nonmyeloablative conditioning regimen is still considered a concerning issue. The aim of our study was to prospectively evaluate the efficacy and feasibility of a reduced-intensity conditioning regimen, including thiotepa, cyclophosphamide, and fludarabine, in high-risk lymphoma patients. This was a prospective multicenter study. We enrolled 49 patients, of whom 47 were evaluable. Graft source (bone marrow) and graft-versus-host disease (GVHD) prophylaxis were the same for all patients. The primary endpoint was the proportion of patients free of disease progression at 1 year. The primary endpoint was met, as 29 out of 47 patients were alive and free of disease at 1 year (1-year progression-free survival, 60%). Forty-five recipients engrafted and achieved full donor chimerism at day 100. The cumulative incidences (CIs) of ANC engraftment at 30 days and platelet engraftment at 60 days were 89% and 83%, respectively. Two patients experienced graft failure. The CIs of day 100 grades 2 to 4 acute GVHD and 2-year moderate-to-severe chronic GVHD were 26% and 16%, respectively. With a median follow-up of 47.5 months (range, 22 to 74), the 4-year progression-free survival and overall survival were 54% and 64%, respectively. The 4-year CI of relapse was 28%, and the 4-year nonrelapse mortality was 15%. Thiotepa-based reduced-intensity conditioning was well tolerated with encouraging survival in a cohort of patients with poor-prognosis lymphoma. Both the incidence of relapse and nonrelapse mortality were acceptable.


Assuntos
Transplante de Medula Óssea , Linfoma , Ciclofosfamida/uso terapêutico , Humanos , Linfoma/terapia , Recidiva Local de Neoplasia , Prognóstico , Estudos Prospectivos
14.
Transplant Cell Ther ; 27(6): 478.e1-478.e5, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33819481

RESUMO

Allogeneic stem cell transplantation from haploidentical donor using post-transplantation cyclophosphamide has been used to cure hematological diseases. Because of slow immunological reconstitution, there is an increased incidence of viral infection. The aim of our study was to prospectively evaluate the efficacy and the feasibility of a CD45RA+ depleted donor lymphocytes infusion (DLI) in terms of reduction of viral infection early after haploidentical transplantation. This a prospective single-center study. We enrolled 23 patients, of whom 19 were evaluable. Graft-versus-host disease (GVHD) prophylaxis was the same for all patients. The primary endpoint was 100-day cumulative incidence of viral infections. The primary endpoint was met, because the 100-day cumulative incidence of viral infection was 32%. The median time from transplantation to first CD45RA+ depleted DLI was 55 days (range, 46-63). 28% of patients had cytomegalovirus reactivation, no patients reactivated human herpesvirus-6; 1 patient developed BK virus related hemorrhagic cystitis. Most of the patients received the planned 3 infusions. Only 1 patient had development of grade 2 acute GVHD, and 2 patients had moderate chronic GVHD. All evaluable patients were off immunosuppressive therapy at last follow-up. The median follow-up was 12 months (range, 3-23), the 1-year overall survival and progression-free survival were 79% and 75%, respectively; the 100-day and 1-year non-relapse mortality were 5% and 12%, respectively. CD45RA+ depleted DLI are feasible in patients treated with haploidentical transplantation. The toxic profile is good with a low risk for development of both acute and chronic GVHD.


Assuntos
Neoplasias Hematológicas , Transplante Haploidêntico , Ciclofosfamida/uso terapêutico , Estudos de Viabilidade , Neoplasias Hematológicas/terapia , Humanos , Linfócitos , Estudos Prospectivos
15.
Leukemia ; 35(9): 2672-2683, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33658659

RESUMO

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doença de Hodgkin/terapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Recidiva Local de Neoplasia/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Terapia de Salvação , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Adulto Jovem
16.
Breast ; 57: 80-85, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33780903

RESUMO

BACKGROUND: Few data are available about real-life cardiotoxicity associated with s.c. versus i.v. trastuzumab treatment of early-stage, HER2-positive breast cancer, and little is known about its predisposing factors. PATIENTS AND METHODS: We retrospectively reviewed data of 363 adult patients treated with adjuvant trastuzumab for HER2-positive breast cancer. Univariate statistical analysis was performed, and a multivariable logistic model was developed to identify independent risk factors of cardiac toxicity. RESULTS: Within 5 years, the overall incidence of events meeting our criteria was 11.8%, and an early discontinuation of trastuzumab was recorded in 20 patients (5.5%). No cases of congestive heart failure occurred, neither multiple events per patient were observed. A total of 184 patients received i.v. and 179 received s.c. trastuzumab. Compared with the s.c. formulation, a higher cardiotoxicity rate for the i.v. administration (15.2% vs 8.4%) was found, and particularly in those patients with cardiovascular risk factors (19.3% vs 8.7%), at the univariate and multivariate analyses. Although more patients with prior anthracycline-based chemotherapy experienced cardiac events, the association of this therapy with cardiac events was not significant. The incidence of cardiac events was not influenced by anthropometric data (e.g. body mass index) or a diagnosis of diabetes mellitus. 5-year event-free survival was 91.7% in the overall population; event-free survival rates were similar between the s.c. and the i.v. groups. CONCLUSION: Our study shows a more favorable safety profile of s.c. versus i.v trastuzumab administration. The use of s.c. trastuzumab could be advisable in at-risk patients.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/epidemiologia , Coração/efeitos dos fármacos , Receptor ErbB-2 , Trastuzumab/efeitos adversos , Função Ventricular Esquerda/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/análise , Estudos Retrospectivos , Trastuzumab/uso terapêutico
17.
Thorac Cancer ; 12(9): 1271-1278, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33704917

RESUMO

BACKGROUND: Significant efforts have been made to investigate the molecular pathways involved in thymic carcinogenesis. However, genetic findings have still not impacted clinical practice. The aim of this exploratory trial was to evaluate the immunoscore and molecular profile of a series of thymic carcinomas (TCs), correlating this data with clinical outcome. METHODS: Formalin-fixed, paraffin-embedded (FFPE) TC tissues were retrieved from our center archive. The immunoscore was evaluated according to Angell and Gallon. DNA was extracted from FFPE tumor samples and, when available, from adjacent histologically normal tissues. Next-generation sequencing (NGS) was performed targeting hotspot regions of 50 oncogenes and tumor suppressor genes. RESULTS: A series of 15 TCs were analyzed. After a median follow-up of 82.4 months, the median overall survival was 104.7 months. The immunoscore was >2 in 5/15 patients (33%). Among the investigated genes, absence of mutations was observed in 5/15 patients (33%), whereas three variants in 1/15 (6%) patient, two variants in 4/15 (26%) patients, and one variant in 5/15 patients (33%) were found. The most recurrently mutated genes were FGFR3 (five mutations) and CDKN2A (three mutations, two of which were nonsense). Patients with CDKN2A loss showed a statistically significantly worse survival (P = 0.0013), whereas patients with FGFR3 mutations showed a statistically significantly better survival (P = 0.048). CONCLUSIONS: This study adds data to the few existing reports on the mutational landscape of TCs, providing the first comprehensive analysis to date. Here, we confirm the low rate of mutations in TCs and suggest FGFR3 and CDKN2A mutations as intriguing potential therapeutic targets.

19.
Recenti Prog Med ; 112(1): 81-88, 2021 Jan.
Artigo em Italiano | MEDLINE | ID: mdl-33512363

RESUMO

INTRODUCTION: Into blood relatives of patients affected by breast cancer, the prevalence of pancreatic ductal adenocarcinoma (PDAC) seems to be elevated. BRCA1/2 mutations as other VUS (variants of uncertain significance) could be responsible. METHODS: We retrospectively revised dataset of Pancreatic Surgery Unit of Humanitas Clinical and Research Center - IRCCS and identified patients who underwent resection for PDAC between 2010 and 2018. We evaluated neoplastic family history and remote pathological history, particularly for breast and prostate tumors. The characteristics of family history were described. Overall survival (OS) and progression free survival (PFS) were calculated for different identified groups. RESULTS: 483 PDAC have been analyzed; 57% had a family history positive for neoplasia; 25% at least showed a blood relative affected by one of these type of cancers: PDAC, breast and prostate, of which 88% was a first degree relative (FDR). One hundred and six patients (22%) had a previous neoplasia, of which 8% a breast cancer and 4% a prostate one. Into this group of patients, 54% had a family history positive for neoplasia and 23% consisted of either a pancreatic neoplasm, or breast tumor or prostate cancer; 71% was a FDR. With a median follow-up of 54.9 months (range 0.066-120), the median survival was 22,8 months. Both OS than PFS weren't statistically significant, considering family history and remote pathological history. CONCLUSIONS: There appears to be a high prevalence of breast and prostate cancer in family members and patients with PDAC. PDAC patients have the prognosis of the pancreatic cancer, not influenced by a previous treated neoplasia.

20.
Trends Biotechnol ; 39(8): 811-823, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33419585

RESUMO

Chronic kidney disease (CKD) typically appears alongside other comorbidities, highlighting an underlying complex pathophysiology that is thought to be vastly modulated by the bidirectional gut-kidney crosstalk. By combining advances in tissue engineering, biofabrication, microfluidics, and biosensors, microphysiological systems (MPSs) have emerged as promising approaches for emulating the in vitro interconnection of multiple organs, while addressing the limitations of animal models. Mimicking the (patho)physiological states of the gut-kidney axis in vitro requires an MPS that can simulate not only this direct bidirectional crosstalk but also the contributions of other physiological participants such as the liver and the immune system. We discuss recent developments in the field that could potentially lead to in vitro modeling of the gut-kidney axis in CKD.


Assuntos
Intestinos , Rim , Modelos Biológicos , Animais , Humanos , Sistema Imunitário/fisiologia , Intestinos/fisiologia , Rim/fisiologia , Fígado/fisiologia , Microfluídica , Engenharia Tecidual
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