Publications by authors named "Franca Fagioli"

232 Publications

Front-Line Window Therapy with Temozolomide and Irinotecan in Patients with Primary Disseminated Multifocal Ewing Sarcoma: Results of the ISG/AIEOP EW-2 Study.

Cancers (Basel) 2021 Jun 18;13(12). Epub 2021 Jun 18.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milan, Italy.

Purpose: The main objective was to evaluate the activity and tolerability of TEMIRI as a front-line treatment in primary disseminated Ewing sarcoma (PDMES) using the RECIST 1.1 criteria. The secondary objectives included the assessment of toxicity and the performance status/symptom changes.

Methods: Between 2012 and 2018, patients with PDMES received two courses of temozolomide 100 mg/sqm/day + irinotecan 50 mg/sqm/day for 5 days every 3 weeks as an amendment to the Italian Sarcoma Group/Associazione Italiana EmatoIogia ed Oncologia Pediatrica (ISG/AIEOP) EW-2 protocol (EUDRACT#2009-012353-37, Vers. 1.02).

Results: Thirty-four patients were enrolled. The median age at diagnosis was 19 years (range 3-55). After TEMIRI, the RECIST response was as follows: a partial response in 20 (59%) patients, stable disease in 11 (32%), and disease progression in 3 (9%). The ECOG/Lansky score was improved in 25/34 (73.5%) cases, and a reduction or disappearance of pain was observed in 31/34 patients (91%). The incidence of grade 3-4 toxicity was 3%. The 3-year event-free survival (EFS) and overall survival (OS) were 21% (95% CI 6-35%) and 36% (95% CI: 18-54%), respectively.

Conclusion: the smooth handling and encouraging activity demonstrated by up-front TEMIRI did not change the EFS in PDMES, so this result suggests the need for the further evaluation of the efficacy of TEMIRI in combination with conventional treatments in non-metastatic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13123046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234176PMC
June 2021

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study.

Cancers (Basel) 2021 Jun 3;13(11). Epub 2021 Jun 3.

Paediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy.

Purpose: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI).

Methods: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for <14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed.

Results: After WLI, grade 1-2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1-79.3), 61.2% (48.4-71.7) and 70.5% (56.3-80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis.

Conclusions: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13112789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199967PMC
June 2021

Wilms tumour occurring in a patient with osteopathia striata with cranial sclerosis: A still unsolved biological question.

Pediatr Blood Cancer 2021 Sep 24;68(9):e29132. Epub 2021 May 24.

Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29132DOI Listing
September 2021

Outcomes of Unmanipulated Haploidentical Transplantation Using Post-Transplant Cyclophosphamide (PT-Cy) in Pediatric Patients With Acute Lymphoblastic Leukemia.

Transplant Cell Ther 2021 05 21;27(5):424.e1-424.e9. Epub 2021 Jan 21.

Pediatric Hematology, Oncology and Stem Cell Transplantation Department, University of Regensburg, Regensburg, Germany.

HLA-haploidentical transplantation (haplo-HCT) using post-transplantation-cyclophosphamide (PT-Cy) is a feasible procedure in children with malignancies. However, large studies on Haplo-HCT with PT-Cy for childhood acute lymphoblastic leukemia (ALL) are lacking. We analyzed haplo-HCT outcomes in 180 children with ALL. Median age was 9 years, and median follow-up was 2.7 years. Disease status was CR1 for 24%, CR2 for 45%, CR+3 for 12%, and active disease for 19%. All patients received PT-Cy day +3 and +4. Bone marrow (BM) was the stem cell source in 115 patients (64%). Cumulative incidence of 42-day engraftment was 88.9%. Cumulative incidence of day-100 acute graft-versus-host disease (GVHD) grade II-IV was 28%, and 2-year chronic GVHD was 21.9%. At 2 years, cumulative incidence of nonrelapse mortality (NRM) was 19.6%. Cumulative incidence was 41.9% for relapse and 25% for patients in CR1. Estimated 2-year leukemia free survival was 65%, 44%, and 18.8% for patients transplanted in CR1, CR2, CR3+ and 3% at 1 year for active disease. In multivariable analysis for patients in CR1 and CR2, disease status (CR2 [hazard ratio {HR} = 2.19; P = .04]), age at HCT older than 13 (HR = 2.07; P = .03) and use of peripheral blood stem cell (PBSC) (HR = 1.98; P = .04) were independent factors associated with decreased overall survival. Use of PBSC was also associated with higher NRM (HR = 3.13; P = .04). Haplo-HCT with PT-Cy is an option for children with ALL, namely those transplanted in CR1 and CR2. Age and disease status remain the most important factors for outcomes. BM cells as a graft source is associated with improved survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.01.016DOI Listing
May 2021

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti.

Transplant Cell Ther 2021 05 16;27(5):406.e1-406.e11. Epub 2021 Feb 16.

Stem Cell Transplant and Cellular Therapies Unit, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.

HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2020.11.021DOI Listing
May 2021

Artificial Intelligence in Bulk and Single-Cell RNA-Sequencing Data to Foster Precision Oncology.

Int J Mol Sci 2021 Apr 27;22(9). Epub 2021 Apr 27.

Cancer Genomics and Bioinformatics Unit, IIGM-Italian Institute for Genomic Medicine, c/o IRCCS, Str. Prov.le 142, km 3.95, 10060 Candiolo, TO, Italy.

Artificial intelligence, or the discipline of developing computational algorithms able to perform tasks that requires human intelligence, offers the opportunity to improve our idea and delivery of precision medicine. Here, we provide an overview of artificial intelligence approaches for the analysis of large-scale RNA-sequencing datasets in cancer. We present the major solutions to disentangle inter- and intra-tumor heterogeneity of transcriptome profiles for an effective improvement of patient management. We outline the contributions of learning algorithms to the needs of cancer genomics, from identifying rare cancer subtypes to personalizing therapeutic treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22094563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123853PMC
April 2021

Childhood cancer in Italy: background, goals, and achievements of the Italian Paediatric Hematology Oncology Association (AIEOP).

Tumori 2021 Apr 20:3008916211007934. Epub 2021 Apr 20.

Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, University of Torino, Piemonte, Italy.

This article reviews the primary goals and achievements of the Italian Association for Pediatric Hematology-Oncology (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP]), a national cooperative group that has been working for children and adolescents with cancer in Italy since 1975.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/03008916211007934DOI Listing
April 2021

CD56, HLA-DR, and CD45 recognize a subtype of childhood AML harboring CBFA2T3-GLIS2 fusion transcript.

Cytometry A 2021 Apr 2. Epub 2021 Apr 2.

Pediatric Hemato Oncology, Maternal and Child Health Department, University of Padua, Padua, Italy.

The presence of CBFA2T3-GLIS2 fusion gene has been identified in childhood Acute Myeloid Leukemia (AML). In view of the genomic studies indicating a distinct gene expression profile, we evaluated the role of immunophenotyping in characterizing a rare subtype of AML-CBFA2T3-GLIS2 rearranged. Immunophenotypic data were obtained by studying a cohort of 20 pediatric CBFA2T3-GLIS2-AML and 77 AML patients not carrying the fusion transcript. Enrolled cases were included in the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) AML trials and immunophenotypes were compared using different statistical approaches. By multiple computational procedures, we identified two main core antigens responsible for the identification of the CBFA2T3-GLIS2-AML. CD56 showed the highest performance in single marker evaluation (AUC = 0.89) and granted the most accurate prediction when used in combination with HLA-DR (AUC = 0.97) displaying a 93% sensitivity and 99% specificity. We also observed a weak-to-negative CD45 expression, being exceptional in AML. We here provide evidence that the combination of HLA-DR negativity and intense bright CD56 expression detects a rare and aggressive pediatric AML genetic lesion improving the diagnosis performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cyto.a.24339DOI Listing
April 2021

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Governs GVHD and Immunosuppression Need, Reducing Late Toxicities in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

J Clin Med 2021 Mar 11;10(6). Epub 2021 Mar 11.

Pediatric Onco-Hematology, Stem Cell Transplantation, and Cellular Therapy Division, Turin Metropolitan Transplant Center, A.O.U. Citta'della Salute e della Scienza di Torino, Ospedale Infantile Regina Margherita, 10126 Turin, Italy.

Combined direct antineoplastic activity and the long-lasting immunological effects of allogeneic hematopoietic cell transplant (HCT) can cure many hematological malignancies, but broad adoption requires non-relapse mortality (NRM) rates and graft-versus-host disease (GVHD) control. Recently, posttransplant cyclophosphamide (PTCy) given after a bone marrow transplant significantly reduced GVHD-incidence, while PTCy given with tacrolimus/mofetil mycophenolate (T/MMF) showed activity following allogeneic peripheral blood stem cell transplantation (alloPBSCT). Here, we report the experience of a larger cohort (85 consecutive patients) and expanded follow-up period (03/2011-12/2019) with high-risk hematological malignancies who received alloPBSCT from Human-Leukocyte-Antigens HLA-matched unrelated/related donors. GVHD-prophylaxis was PTCy 50 mg/kg (days+3 and +4) combined with T/MMF (day+5 forward). All patients stopped MMF on day+28 with day+110 = median tacrolimus discontinuation. Cumulative incidences were 12% for acute and 7% for chronic GVHD- and no GVHD-attributed deaths. For surviving patients, the 12, 24, and 36-month probabilities of being off immunosuppression were 92, 96, and 96%, respectively. After a 36-month median follow-up, NRM was 4%; median event-free survival (EFS) and overall survival (OS) had yet to occur. One- and two-year chronic GVHD-EFS results were 57% (95% CI, 46-68%) and 53% (95% CI, 45-61%), respectively, with limited late infections and long-term organ toxicities. Disease relapse caused the most treatment failures (38% at 2 years), but low transplant toxicity allowed many patients (14/37, 38%) to receive donor lymphocyte infusions as a post-relapse strategy. We confirmed that PTCy+T/MMF treatment effectively prevented acute and chronic GVHD and limited NRM to unprecedented low rates without loss of disease control efficacy in an expanded patient cohort. This trial is registered at U.S. National Library of Medicine as #NCT02300571.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10061173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998305PMC
March 2021

Clinical research and burnout syndrome in Italy - only a physicians' affair?

Trials 2021 Mar 12;22(1):205. Epub 2021 Mar 12.

Unità di Ricerca e Sviluppo Clinico SC Oncoematologia Pediatrica, AOU Città della Salute e della Scienza, Presidio Ospedaliero Infantile Regina Margherita, Piazza Polonia 94, 10126, Turin, Italy.

Background: The burnout phenomenon has been extensively investigated among health care professionals, particularly focusing on physicians and nurses. However, literature concerning burnout in clinical research is poor and often neglects the other professional categories involved.

Methods: In March 2019, all members of Italian Group of Clinical Research Coordinator were invited to participate to a web survey, consisting of three sections: general information and workload; Maslach Burnout Inventory (MBI) test; subjective perception of oneself's work stress and possible causes.

Results: The majority of respondents felt a form of distress. The main source was contract type (31.2%), followed by workload (20.5%) and lack of skills recognition (17.8%). Results from MBI test confirmed the interviewees' subjective perception: an intermediate level of emotional exhaustion (19.1 points) and a very high sense of reduced professional achievement (26.8 points) were observed. Both depersonalization and sense of reduced professional achievement showed weak to moderate correlations with emotional exhaustion. Emotional exhaustion was associated with contract type with high significance.

Conclusion: It is necessary to act on those qualitative factors that are greatly increasing the level of perceived stress, jeopardizing the quality of clinical research coordinators work and significantly amplifying the phenomenon of migration towards the private sector.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-021-05158-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953807PMC
March 2021

Haplo-identical or mismatched unrelated donor hematopoietic cell transplantation for Fanconi anemia: Results from the Severe Aplastic Anemia Working Party of the EBMT.

Am J Hematol 2021 05 4;96(5):571-579. Epub 2021 Mar 4.

French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint Louis Hospital and University Paris Diderot, Paris, France.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p = .22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p = .046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p = .005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.26135DOI Listing
May 2021

Precision Medicine in Osteosarcoma: MATCH Trial and Beyond.

Cells 2021 Jan 31;10(2). Epub 2021 Jan 31.

Paediatric Onco-Haematology Division, Regina Margherita Children's Hospital, City of Health and Science of Turin, 10126 Turin, Italy.

Osteosarcoma (OS) is a rare bone malignant tumour with a poor prognosis in the case of recurrence. So far, there is no agreement on the best systemic therapy for relapsed OS. The availability of next generation sequencing techniques has recently revolutionized clinical research. The sequencing of the tumour and its matched normal counterpart has the potential to reveal a wide landscape of genetic alterations with significant implications for clinical practice. The knowledge that the genomic profile of a patient's tumour can be precisely mapped and matched to a targeted therapy in real time has improved the development of precision medicine trials (PMTs). PMTs aiming at determining the effectiveness of targeted therapies could be advantageous for patients with a tumour refractory to standard therapies. Development of PMTs for relapsed OS is largely encouraging and is in its initial phase. Assessing OS features, such as its rarity, its age distribution, the technical issues related to the bone tissue origin, and its complex genomic landscape, represents a real challenge for PMTs development. In this light, a multidisciplinary approach is required to fully exploit the potential of precision medicine for OS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10020281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911557PMC
January 2021

Management of Hepatitis-B Virus Infection in Immunocompromised Children: A Single Center Experience.

J Pediatr Gastroenterol Nutr 2021 04;72(4):597-602

Pediatric Onco-Hematology, Stem Cell Transplantation and Cell Therapy Division, Regina Margherita Children's Hospital.

Objectives: The aims of the study was to expand the pediatric experience on hepatitis-B virus (HBV) reactivation, a known complication in patients with hematologic malignancies or on immunosuppression.

Methods: Retrospective appraisal of HBV therapy/prophylaxis in immunocompromised children, studied from April 2006 to March 2020.

Results: Eighteen HBV-positive patients, 5 girls, median age 11.1 (4.1--17.9) years were included. Seventeen of 18 were immunosuppressed at HBV-infection diagnosis. Seventeen were at high risk of reactivation, 1 at moderate risk. Five of 18 had acute hepatitis B as first infection or reactivation, 6 had HBeAg-positive infection, 1 an HBeAg-negative infection and 6 HBsAg-negative infection. Median follow-up was 2.7 (0.7--12.5) years. No HBV-related mortality was observed. Prophylaxis had to be repeated in 1. Lamivudine was used in 6/12 viremic patients and HBV-DNA negativization obtained in 2/6 (33%). Tenofovir-DF was used in 2/12 and entecavir in 4/12: 100% attained HBV-DNA negativization. Therapy had to be switched from tenofovir-DF to entecavir in 1 patient because of renal impairment. Virological breakthroughs were observed in 1 lamivudine-treated patient, leading to a hepatitis flare; 1 patient on entecavir had a hepatitis flare at immunoreconstitution. Mortality was 33% in the HBsAg-positive group. Seven prophylactic treatments were administered to 6 patients with HBsAg-negative infection: tenofovir-DF in 2 HBV-DNA-positive, lamivudine in 5 HBV-DNA-negative, without reverse HBsAg seroconversion, morbidity or mortality.

Conclusions: There is a residual risk of acute hepatitis B in immunocompromised children, mortality rate was substantial, potentially related to the delays in commencing chemotherapy caused by liver dysfunction. Tenofovir-DF or entecavir are the drugs of choice for HBV treatment in immunocompromised children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000003042DOI Listing
April 2021

A multi-target lateral flow immunoassay enabling the specific and sensitive detection of total antibodies to SARS COV-2.

Talanta 2021 Feb 5;223(Pt 1):121737. Epub 2020 Oct 5.

Department of Chemistry, University of Turin, Torino, Italy. Electronic address:

A rapid test for detecting total immunoglobulins directed towards the nucleocapsid protein (N) of severe acute syndrome coronavirus 2 (SARS CoV-2) was developed, based on a multi-target lateral flow immunoassay comprising two test lines. Both test lines bound to several classes of immunoglobulins (G, M, and A). Specific anti-SARS immunoglobulins were revealed by a colorimetric probe formed by N and gold nanoparticles. Targeting the total antibodies response to infection enabled achieving 100% diagnostic specificity (95.75-100, C.I. 95%, n = 85 healthy and with other infections individuals) and 94.6% sensitivity (84.9-98.9, C.I. 95%, n = 62 SARS CoV-2 infected subjects) as early as 7 days post confirmation of positivity. Agreeing results with a reference serological ELISA were achieved, except for the earlier detection capability of the rapid test. Follow up of the three seroconverting patients endorsed the hypothesis of the random rise of the different immunoglobulins and strengthened the 'total antibodies' approach for the trustworthy detection of serological response to SARS CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.talanta.2020.121737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534878PMC
February 2021

Use of letermovir in off-label indications: Infectious Diseases Working Party of European Society of Blood and Marrow Transplantation retrospective study.

Bone Marrow Transplant 2021 05 7;56(5):1171-1179. Epub 2020 Dec 7.

Department for Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden.

Letermovir (LMV) is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV-seropositive patients. Due to its favorable safety profile, LMV brings potential for use in other clinical situations, outside the approved indication. The objective of the study was to analyze the efficacy and safety of the use of LMV in off-label indications in EBMT centers. A total of 49 patients were reported including 44 adults and 5 children. LMV was administered for: secondary prophylaxis (37 adults, 3 children), primary prophylaxis (2 children), pre-emptive treatment (5 adults), and therapy of CMV disease (2 adults; pneumonia, colitis). Cyclosporine was concomitantly used in 26 patients. Overall, LMV was used for a median 112 days (range: 10-473). Cumulative incidence of breakthrough infections during secondary prophylaxis was 10.1% (95% CI = 3.1-21.9). Prophylactic treatment with LMV resulted in 94.9% (95% CI = 81.0-98.7), and 81.9% (95% CI = 65.7-90.9) probability of, respectively, 60 and 120-day survival without CMV infection in patients receiving secondary prophylaxis. During therapy of CMV infection/disease, probability of 60 and 120-day overall survival was 100% and 71.4% (95% CI = 25.8-92.0), respectively. No breakthrough infection occurred in children on LMV prophylaxis. Adverse events were reported in 15/49 (30.4%) patients: the most common being nausea/vomiting (22.4%). In conclusion, the efficacy of the use of LMV as secondary prophylaxis was high, and the preliminary experience with the use of LMV for the treatment of patients with refractory CMV infection/disease was positive. Our data showed that higher dose or prolonged therapy did not result in increased rate of adverse events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01166-wDOI Listing
May 2021

CD34+ selected peripheral blood Stem Cell Boost (SCB) for Poor Graft Function (PGF) or mixed chimerism in pediatric patients, after hematopoietic stem cell transplantation: Results of a retrospective multicenter study.

Pediatr Transplant 2021 Aug 3;25(5):e13909. Epub 2020 Nov 3.

Pediatric Onco-Hematology, Regina Margherita Children Hospital, City of Health and Science, University of Turin, Turin, Italy.

Background: PGF is historically associated with high morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods: In this study, we report our multicenter experience on stem cell boost (SCB) for PGF, or incomplete donor engraftment, in 16 pediatric patients. Donors were HLA-matched siblings (n = 4), unrelated donors (n = 11), or haploidentical family members (n = 1). Ten patients had two-lineage cytopenia, 5 had one-lineage cytopenia, and 1 had poor immunological reconstitution together with a low percentage of donor cell engraftment. A median of 6.6x10 selected CD34+/Kg was infused after 194 days from allo-HSCT (48-607).

Results: In 4 out of 5 patients, one-lineage cytopenia was resolved, while among the 10 patients with two-lineage cytopenia, 4 resolved both cytopenia, 5 resolved one-lineage, and one did not respond. All patients reverted their mixed chimera to full donor chimera. OS was 56%, transplant-related mortality (TRM) 32%, and RI 12%. The main causes of failure were related to infections with 4 out of 7 deaths caused by this.

Conclusions: SCB may rescue over 50% of patients with PGF after allo-HSCT. An earlier treatment may reduce the infectious complications and improve survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13909DOI Listing
August 2021

Impact of COVID-19 in paediatric early-phase cancer clinical trials in Europe: A report from the Innovative Therapies for Children with Cancer (ITCC) consortium.

Eur J Cancer 2020 12 9;141:82-91. Epub 2020 Oct 9.

Center for Child Health Research, Tampere University and Department of Pediatrics, Tampere University Hospital, Tampere, Finland, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Introduction: Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC).

Methods: A survey was sent to all ITCC-accredited early-phase clinical trial hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1st March and 30th April 2020.

Results: Thirty-one of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared with that in 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. In addition, 26% of sites had restrictions on performing trial assessments because of local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organisational and structural changes.

Conclusion: The study reveals a profound disruption of paediatric cancer early-phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546235PMC
December 2020

[Bureaucracy gives way to science. What good the pandemic has left.]

Recenti Prog Med 2020 10;111(10):565-567

SC Oncoematologia Pediatrica, AOU Città della Salute e della Scienza, Presidio Ospedaliero Infantile Regina Margherita, Torino - Dipartimento di Scienze della Sanità Pubblica e Pediatriche, Università di Torino.

The CoViD-19 pandemic has pointed out the the need for an efficient, timely, ethically correct clinical research, in order to find rapid and reliable responses to health challenges. The guidelines published by the Agenzia Italiana del Farmaco during the pandemic have shown that some useful changes for simplifying and speeding-up clinical research in Italy are feasible, while maintaining high levels of quality. In this perspective, a reflection is a must: perhaps we are ready to detach ourselves from that image of a slow and bureaucratic country now widespread in Europe. Perhaps the pandemic has left us something good. Maybe we are really able of working much better, even in non-emergency conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1701/3453.34414DOI Listing
October 2020

Successfully treated severe COVID-19 and invasive aspergillosis in early hematopoietic cell transplantation setting.

Transpl Infect Dis 2021 04 29;23(2):e13470. Epub 2020 Sep 29.

Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, University of Turin, Turin, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tid.13470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537000PMC
April 2021

The Italian consensus conference on the role of rehabilitation for children and adolescents with leukemia, central nervous system, and bone tumors, part 1: Review of the conference and presentation of consensus statements on rehabilitative evaluation of motor aspects.

Pediatr Blood Cancer 2020 12 17;67(12):e28681. Epub 2020 Sep 17.

Pediatric Oncohematology, Stem Cell Transplantation and Cell Therapy Division, A.O.U. Città della Salute e della Scienza-Regina Margherita Children's Hospital, Turin, Italy.

Because of increasing survival rates in pediatric oncology, attention is focusing on cancer and its treatment-related side effects. Rehabilitation may reduce their impact. However, the literature does not provide strong evidence regarding rehabilitation pathways. Therefore, the Italian Association of Pediatric Hematology and Oncology organized a consensus conference on the role of rehabilitation of motor impairments in children/adolescents affected by leukemia, central nervous system, and bone tumors to define recommendations for daily practice. The grading of recommendation assessment, developing and evaluation (GRADE) method was used in order to formulate questions, select outcomes, evaluate evidence, and create recommendations. This paper includes the results on the rehabilitation assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28681DOI Listing
December 2020

Effects of treatments on gonadal function in long-term survivors of pediatric hematologic malignancies: A cohort study.

Pediatr Blood Cancer 2020 12 12;67(12):e28709. Epub 2020 Sep 12.

Transition Unit for Childhood Cancer Survivors, "Città della Salute e della Scienza" Hospital, Torino, Italy.

Background: Potentially gonadotoxic protocols are currently used for the treatment of childhood hematologic malignancies. This study aims to evaluate the prevalence of gonadal dysfunction and the most important associated risk factors in a cohort of hematologic malignancy survivors.

Procedure: We considered all patients referred to our long-term follow-up clinic for childhood cancer survivors, between November 2001 and December 2017. Inclusion criteria were: (a) previous diagnosis of hematologic malignancy; (b) age at hematologic malignancy diagnosis < 18 years; (c) at least five years after the end of anticancer treatments; (d) at least one evaluation of gonadal function after the 18th birthday. Patients diagnosed before January 1, 1990, were excluded.

Results: Three hundred twenty-seven survivors (males = 196) were included. Isolated spermatogenesis damage was found in 58/196 (29.6%) of males, whereas 18/196 (9.2%) had Leydig cell failure. In females, 35/131 (26.7%) experienced premature ovarian insufficiency. In both sexes, abdominopelvic irradiation and hematopoietic stem cell transplantation were strongly associated with the risk of gonadal dysfunction. For every 1000 mg/m increase in cyclophosphamide-equivalent dose exposure, the risk of spermatogenesis damage increased 1.52-fold and that of Leydig cell failure increased 1.34-fold, whereas the risk of premature ovarian insufficiency increased 1.80-fold. About 30% of those males who developed Leydig cell failure did so more than five years after the end of treatments.

Conclusions: Gonadal dysfunction is still a significant late effect of therapies for pediatric hematologic malignancies. In males, the reevaluation of Leydig cell function may be useful even several years after the exposure to gonadotoxic treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28709DOI Listing
December 2020

CSPG4-Specific CAR.CIK Lymphocytes as a Novel Therapy for the Treatment of Multiple Soft-Tissue Sarcoma Histotypes.

Clin Cancer Res 2020 12 8;26(23):6321-6334. Epub 2020 Sep 8.

Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.

Purpose: No effective therapy is available for unresectable soft-tissue sarcomas (STS). This unmet clinical need prompted us to test whether chondroitin sulfate proteoglycan 4 (CSPG4)-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CAR.CIK) are effective in eliminating tumor cells derived from multiple STS histotypes and in immunodeficient mice.

Experimental Design: The experimental platform included patient-derived CAR.CIK and cell lines established from multiple STS histotypes. CAR.CIK were transduced with a retroviral vector encoding second-generation CSPG4-specific CAR (CSPG4-CAR) with 4-1BB costimulation. The functional activity of CSPG4-CAR.CIK was explored , in two- and three-dimensional STS cultures, and in three STS xenograft models.

Results: CSPG4-CAR.CIK were efficiently generated from patients with STS. CSPG4 was highly expressed in multiple STS histotypes by analysis and on all 16 STS cell lines tested by flow cytometry. CSPG4-CAR.CIK displayed superior cytolytic activity against multiple STS histotypes as compared with paired unmodified control CIK. CSPG4-CAR.CIK also showed strong antitumor activity against STS spheroids; this effect was associated with tumor recruitment, infiltration, and matrix penetration. CSPG4-CAR.CIK significantly delayed or reversed tumor growth in three STS xenograft models (leiomyosarcoma, undifferentiated pleomorphic sarcoma, and fibrosarcoma). Tumor growth inhibition persisted for up to 2 weeks following the last administration of CSPG4-CAR.CIK.

Conclusions: This study has shown that CSPG4-CAR.CIK effectively targets multiple STS histotypes and in immunodeficient mice. These results provide a strong rationale to translate the novel strategy we have developed into a clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-0357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710537PMC
December 2020

Steroid-refractory acute graft-versus-host disease graded III-IV in pediatric patients. A mono-institutional experience with a long-term follow-up.

Pediatr Transplant 2020 11 26;24(7):e13806. Epub 2020 Aug 26.

Pediatric Onco-Hematology, City of Health and Science, Regina Margherita Children Hospital, University of Turin, Turin, Italy.

aGvHD remains a major obstacle to successful HSCT. We report our experience on steroid-refractory aGvHD III and IV from 1989 to 2017. Ninety patients with aGvHD III or IV were stratified according to the HSCT year: 1989-1998, 1999-2007, and 2008-2017 and to aGvHD extension (GvHD III vs IV) and finally the probability of OS, RI, and TRM was calculated accordingly. aGvHD III patients had a substantial improvement over time: day 100 OS raised from 64% (95% CI 39-89) in the first cohort to 100% in the latest (P = .022), and it was mainly due to a reduction of TRM (it was 28% [95% CI 12-65] in the first cohort to 0% in the latest (P = .01). The aGvHD IV patients did not present a significant improvement. Day 100 OS was 42% (95% CI 16-68) in the first group and 54% (95% CI 25-83) in the year 2008-2017 (P = NS), and the day-100 TRM was very similar (it was 57% [95% CI 36-90] in the first cohort and 45% [95% CI 23-89] in the latest (P = NS). We report significant improvements in OS and TRM in patients diagnosed with grade III aGvHD. Patients with the most severe aGvHD appear to have no or fewer benefits on long-term outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13806DOI Listing
November 2020

Inactivated Platelet Lysate Supports the Proliferation and Immunomodulant Characteristics of Mesenchymal Stromal Cells in GMP Culture Conditions.

Biomedicines 2020 Jul 17;8(7). Epub 2020 Jul 17.

Department of Public Health and Paediatrics, The University of Turin, Piazza Polonia 94, 10126 Torino, Italy.

Mesenchymal stromal cells (MSCs) isolated from bone marrow (BM-MSCs) are considered advanced therapy medicinal products (ATMPs) and need to be produced according to good manufacturing practice (GMP) in their clinical use. Human platelet lysate (HPL) is a good GMP-compliant alternative to animal serum, and we have demonstrated that after pathogen inactivation with psoralen, it was safer and more efficient to use psoralen in the production of MSCs following GMP guidelines. In this study, the MSCs cultivated in fetal bovine serum (FBS-MSC) or inactivated HPL (iHPL-MSC) were compared for their immunomodulatory properties. We studied the effects of MSCs on (1) the proliferation of total lymphocytes (Ly) and on naïve T Ly subsets induced to differentiate in Th1 versus Th2 Ly; (2) the immunophenotype of different T-cell subsets; (3) and the cytokine release to verify Th1, Th2, and Th17 polarization. These were analyzed by using an in vitro co-culture system. We observed that iHPL-MSCs showed the same immunomodulatory properties observed in the FBS-MSC co-cultures. Furthermore, a more efficient effect on the increase of naïve T- cells and in the Th1 cytokine release from iHPL was observed. This study confirms that iHPL, used as a medium supplement, may be considered a good alternative to FBS for a GMP-compliant MSC expansion, and also to preserve their immunomodulatory proprieties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines8070220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400095PMC
July 2020

Acute lymphoblastic leukemia onset in a 3-year-old child with COVID-19.

Pediatr Blood Cancer 2020 11 24;67(11):e28423. Epub 2020 Jul 24.

Department of Pediatric Onco-Hematology, Regina Margherita Children's Hospital, Turin, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404518PMC
November 2020

Phase II results from a phase I/II study to assess the safety and efficacy of weekly nab-paclitaxel in paediatric patients with recurrent or refractory solid tumours: A collaboration with the European Innovative Therapies for Children with Cancer Network.

Eur J Cancer 2020 08 15;135:89-97. Epub 2020 Jun 15.

Gustave Roussy, Villejuif, France.

Background: The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study.

Patients And Methods: Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle. The primary end-point was the overall response rate (ORR; complete response [CR] + partial response [PR]). Secondary end-points included duration of response, disease control rate (DCR; CR + PR + stable disease [SD]), progression-free survival, 1-year overall survival, safety and pharmacokinetics.

Results: Forty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia [50%] and anaemia [48%]), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive.

Conclusions: In this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed.

Trial Registration: NCT01962103 and EudraCT 2013-000144-26.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.04.031DOI Listing
August 2020

Effects of a high-intensity psychosocial intervention among child-parent units in pediatric oncology.

Tumori 2020 Oct 16;106(5):362-368. Epub 2020 Jun 16.

Pediatric Oncology Division, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, Turin, Italy.

Aim: To compare the efficacy of a high-intensity psychosocial intervention with standardized usual care in countering psychosocial complexity among child-parent units in a pediatric oncology setting.

Methods: Two hundred pediatric oncology patients and their parents were recruited from Italian hospitals. A total of 81 child-parent units were assigned to the high-intensity psychosocial intervention and 119 child-parent units to standardized usual care. Psychosocial factors were assessed before and 1 year after intervention to measure efficacy.

Results: More improvements over time were observed in the high-intensity intervention group of child-parent units compared to the standard intervention group.

Conclusion: An intensive, structured, and tailored high-intensity intervention positively affects the psychosocial factors of child-parent units. Patients and families should have access to intensive psychosocial support throughout the cancer trajectory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0300891620926226DOI Listing
October 2020

How paediatric psycho-oncology is changing during the COVID-19 epidemic in Italy: New approaches.

Psychooncology 2020 09 6;29(9):1384-1386. Epub 2020 Jul 6.

Pediatric Oncology Division, Regina Margherita Children's Hospital, AOU Città della Salute e della Scienza di Torino, Turin, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pon.5444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323114PMC
September 2020

Transplantation Induces Profound Changes in the Transcriptional Asset of Hematopoietic Stem Cells: Identification of Specific Signatures Using Machine Learning Techniques.

J Clin Med 2020 Jun 1;9(6). Epub 2020 Jun 1.

Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy.

During the phase of proliferation needed for hematopoietic reconstitution following transplantation, hematopoietic stem/progenitor cells (HSPC) must express genes involved in stem cell self-renewal. We investigated the expression of genes relevant for self-renewal and expansion of HSPC (operationally defined as CD34+ cells) in steady state and after transplantation. Specifically, we evaluated the expression of ninety-one genes that were analyzed by real-time PCR in CD34+ cells isolated from (i) 12 samples from umbilical cord blood (UCB); (ii) 15 samples from bone marrow healthy donors; (iii) 13 samples from bone marrow after umbilical cord blood transplant (UCBT); and (iv) 29 samples from patients after transplantation with adult hematopoietic cells. The results show that transplanted CD34+ cells from adult cells acquire an asset very different from transplanted CD34+ cells from cord blood. Multivariate machine learning analysis (MMLA) showed that four specific gene signatures can be obtained by comparing the four types of CD34+ cells. In several, but not all cases, transplanted HSPC from UCB overexpress reprogramming genes. However, these remarkable changes do not alter the commitment to hematopoietic lineage. Overall, these results reveal undisclosed aspects of transplantation biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9061670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355574PMC
June 2020
-->