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Objectives: The aim of this pilot trial is evaluating the preliminary effectiveness of two in-hospital interventions in the maintenance of motor performance in children/adolescents undergoing hematopoietic stem cell transplantation (HSCT). Secondary objectives investigated the interventions' feasibility, impact on fatigue and to what degree the subjects' maintained their ankle dorsiflexion range of movement (ROM), functional mobility, muscle strength and flexibility., Methods: This trial included 5- to 18-year-old participants, affected by oncological and non-oncological diseases during hospitalisation for autologous/allogenic HSCT. The subjects were assigned to an exercise group (EG), or a counselling group based on a cluster model based on inpatient timeframe. The EG subjects performed strengthening, stretching and aerobic exercises for 30 min/5 days a week. Both groups followed rehabilitation counselling indications (RCI), 7 days a week., Results: Forty-nine participants were enrolled (median age = 12.9 years) (EG n = 36). In both groups the participants maintained their baseline motor performance and ankle ROM, and the children/adolescents and parents reduced their levels of fatigue. However, the interventions were not effective in maintaining strength., Conclusion: In maintaining the subjects' motor performance, the RCI results are significant because they pave the way for the application in clinical practice contexts where there are poor rehabilitation resources. Clinical Trials registration NCT03842735., (© 2022 John Wiley & Sons Ltd.)

Variation in clinical practice affects veno-occlusive disease management, mainly in patients who undergo allogeneic hematopoietic stem cell transplantation. Disputes about diagnostic criteria, treatment, and prophylaxis, due to the lack of high-quality data, are at the base of this variability. With the aim of limiting inconsistency in clinical care, thus improving both patient outcomes and data collection reliability, the Italian Society of Stem cell transplant (Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare) launched a collaborative effort to formulate recommendations based on integration of available evidence and expert's consensus. A systematic method, according to US National Institute of Health guidelines and Italian National System for Guidelines, was used. Twenty-nine recommendations were approved with a strong (20) or weak (9) level of agreement, while 26 were rejected. In particular, the panel pointed out the need to achieve an early diagnosis, encouraging the adoption of European Society for Blood and Marrow Transplantation criteria and the prompt use of ultrasonography. Moreover, our experts strongly recommended in favor of prophylactic use of ursodeoxycholic acid. As soon as a veno-occlusive disease diagnosis is established, treatment with defibrotide should be started for at least 21 days. A number of areas of uncertainty, particularly concerning risk stratification and use of diagnostic tools such as elastography has been identified and discussed., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

T-cell replete hematopoietic stem cell transplantation (HSCT) from a haploidentical donor followed by high doses of cyclophosphamide has been demonstrated to provide the best chances of a cure for many children in need of an allograft but who lack both a sibling and an unrelated donor. In this study we retrospectively compared the outcome of pediatric patients undergoing T-replete haploidentical HSCT (Haplo) for acute leukemia with those undergoing transplantation from unrelated HLA-matched donor (MUD) and HLA mismatched unrelated donor (MMUD) from 2012 to 2017 at our Center. Both univariable and multivariable analyses showed similar 5-year overall survival rates for MUD, MMUD, and Haplo patients: 71% (95% CI 56-86), 72% (95% CI 55-90), and 75% (95% CI 54-94), respectively (p = 0.97). Haplo patients showed reduced event-free survival rates compared to MUD and MMUD patients: 30% (95% CI 12-49) versus 70% (95% CI 55-84) versus 53% (95% CI 35-73), respectively (p = 0.007), but these data were not confirmed by a multivariable analysis. Non-relapse mortality (NRM) and relapse incidence (RI) were similar for the three groups. Therefore, our data confirm that Haplo is a suitable clinical option for pediatric patients needing HSCT when lacking both an MUD and an MMUD donor.

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., (© 2020 Wiley Periodicals LLC.)

Purpose: Reiki is a growing complementary therapy in pediatric oncology that needs evidence to become more credible among the health community. A within-subject design experiment was conducted to pilot testing the feasibility and efficacy of Reiki to provide pain relief among pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Method : Pediatric patients undergoing HSCT during the inpatient phase in the Stem Cell Transplantation Unit were eligible to participate to the pilot study. Short and medium effects were assessed investigating the increase or decrease of patient's pain during three specific time periods ("delta") of the day: morning of the Reiki session versus assessment before Reiki session (within subjects control period), assessment before Reiki session versus assessment after Reiki session (within subjects experimental period) and assessment after Reiki session versus morning the day after Reiki session (within subject follow-up period). The long-term effects were verified comparing the pain evolution in the day of the Reiki session with the following rest day. Results: The effect of 88 Reiki therapy sessions in nine patients (M age = 12; Female = 61%) was analyzed following a short, medium, and long-term perspective. Repeated-measures analysis of variance revealed a significant difference among the three periods ( F = 17,17 p < .0001): A decrease of the pain occurred in the experimental period in short and medium term, while in the follow-up period, the pain level remained stable. Conclusions: This study demonstrates the feasibility of using Reiki therapy in pediatric cancer patients undergoing HSCT. Furthermore, these findings evidence that trained pediatric oncology nurses can insert Reiki into their clinical practice as a valid instrument for diminishing suffering from cancer in childhood.

Background: Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a 7-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in 1 young adult to date., Methods: A closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft., Results: Combined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur., Conclusions: Hopefully, this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child will encourage others to adapt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies.

Here, we report a patient with Niemann-Pick disease type B, with early severe onset of disease and pulmonary involvement, treated with hematopoietic stem cell transplant (HSCT) from a bone marrow matched unrelated donor. We confirm that HSCT is feasible and potentially beneficial for patients with severe phenotype. Noteworthy, we discussed the potential usefulness of the activity of peripheral chitotriosidase for the longitudinal evaluation of HSCT success and effectiveness., (© 2017 Wiley Periodicals, Inc.)

Hematopoietic stem cell transplantation is a therapeutic strategy for several oncohematological diseases. It increases survival rates but leads to a high incidence of related effects. The objective of this paper was to examine the existing literature on physical exercise interventions among pediatric HSCT recipients to explore the most often utilized rehabilitative assessment and treatment tools. Studies published from 2002 to April 1, 2015 were selected: 10 studies were included. A previous literary review has shown that rehabilitation programs have a positive impact on quality of life. Our analysis identified some significant outcome variables and shared intervention areas., (© 2016 Wiley Periodicals, Inc.)

Post-transplant high-dose cyclophosphamide (PTCy) is a novel approach to prevent graft-versus-host disease (GVHD) and rejection in patients given haploidentical hematopoietic stem cell transplantation (HSCT). Thirty-three patients with high-risk hematologic malignancies and lacking a match-related or -unrelated donor were treated with PTCy haploidentical HSCT in 5 Italian AIEOP centers. Nineteen patients had a nonmyeloablative preparative regimen (57%), and 14 patients received a full myeloablative conditioning regimen (43%). No patients received serotherapy; GVHD prophylaxis was based on PTCy (50 mg/kg on days +3 and +4) combined with mycophenolate plus tacrolimus or cyclosporine A. Neutrophil and platelet engraftment was achieved on days +17 (range, 14 to 37) and +27 (range, 16 to 71). One patient had autologous reconstitution for anti-HLA antibodies. Acute GVHD grades II to IV and III to IV and chronic GVHD developed in 22% (95% CI, 11 to 42), 3% (95% CI, 0 to 21), and 4% (95% CI, 0 to 27) of cases, respectively. The 1-year overall survival rate was 72% (95% CI, 56 to 88), progression-free survival rate was 61% (95% CI, 43 to 80), cumulative incidence of relapse was 24% (95% CI, 13 to 44), and transplant-related mortality was 9% (95% CI, 3 to 26). The univariate analysis for risk of relapse incidence showed how 3 significant variables, mother as donor (P = .02), donor gender as female (P = .04), and patient gender as female (P = .02), were significantly associated with a lower risk of relapse. Disease progression was the main cause of death. PTCy is a safe procedure also for children and adolescents who have already received several lines of chemotherapy. Among the different diseases, a trend for better 1-year rates of overall survival was obtained for nonacute leukemia patients., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Fertility after childhood haemopoietic stem cell transplant (HSCT) is a major concern. Conditioning regimens before HSCT present a high risk (>80%) of ovarian failure. Since 2000, we have proposed cryopreservation of ovarian tissue to female patients undergoing HSCT at our centre, to preserve future fertility. After clinical and haematological evaluation, the patients underwent ovarian tissue collection by laparoscopy. The tissue was analysed by histologic examination to detect any tumour contamination and then frozen following the slow freezing procedure and cryopreserved in liquid nitrogen. From August 2000 to September 2013, 47 patients planned to receive HSCT, underwent ovarian tissue cryopreservation. The median age at diagnosis was 11.1 years and at the time of procedure it was 13 years, respectively. Twenty-four patients were not pubertal at the time of storage, whereas 23 patients had already experienced menarche. The median time between laparoscopy and HSCT was 25 days. Twenty-six out of 28 evaluable patients (93%) developed hypergonadotropic hypogonadism at a median time of 23.3 months after HSCT. One patient required autologous orthotopic transplantation that resulted in one live birth. Results show a very high rate of iatrogenic hypergonadotropic hypogonadism, highlighting the need for fertility preservation in these patients.

No predictive factors are currently available to establish patient-specific GVHD risk. A panel of six serum cytokines (TNF receptor 1, IL-2 receptor alfa (IL-2Rα), hepatocyte growth factor (HGF), monocyte chemo-attractant protein-2, IL-8, IL-12p70) were monitored at established time points (days -1, +1, +7, +14, +21, +28 and +60) in 170 paediatric hematopoietic SCT (HSCT) recipients. We found that higher concentrations of IL-2Rα on days +14 and +21 together with HGF on days +14 and +21 were significantly associated at a higher probability of both grade II-IV GVHD (on day +14 it was: 60% vs 28%, P=0.007) and grade III-IV (on day +14 it was: 40% vs 15%, P=0.001). The higher IL-8 serum concentration on day +28 was associated with a lower probability of chronic GVHD being 4% vs 29% (P=0.01) for patients with higher vs lower IL-8 serum concentration. These findings were confirmed when the analysis was restricted to the the matched unrelated donor group. In conclusion, even if the serum cytokine levels were related to several variables associated with HSCT, we identified two cytokines as predictors of GVHD II-IV and III-IV, translating into a higher TRM risk (17% vs 3%, P=0.004).

Purpose: To study the feasibility and activity of two courses of high-dose chemotherapy (HDCT) in patients with osteosarcoma in metastatic relapse., Patients and Methods: Patients with high-grade osteosarcoma in metastatic relapse (multiple metastases or solitary metastasis at intervals of less than 30 months) were eligible for study. High-dose chemotherapy consisted of carboplatin and etoposide followed by stem-cell rescue. A second course was planned 4 to 6 weeks after the first. Surgery was performed before or after HDCT., Results: Thirty-two patients were enrolled onto the study. At the end of the treatment, 25 patients were in complete remission (CR), six were alive with disease progression, and one died of toxicity. At present, 14 patients are alive with a median survival time of 23 months from study entry: four are in first CR, three are in second CR, and one is in fourth CR. Six patients are alive with disease. Eighteen patients (56%) died: 17 of disease and one of toxicity. Transplantation-related mortality was 3.1%. The relapse or progression disease rate was 84.4%. The 3-year overall survival rate is 20% and the 3-year disease-free survival rate is 12%., Conclusion: HDCT combined with surgery is feasible and can induce CR in a large portion of patients. Two points, however, need to be considered: only patients who are chemosensitive to induction treatment can obtain CR after HDCT, and the length of remission is short, because most patients relapse. Thus novel strategies are needed to maintain the remission status or to treat patients who do not respond to induction treatment.

An Italian-Scandinavian treatment and research protocol with high-dose chemotherapy and double peripheral blood stem cell (PBSC) transplantation has been designed in an attempt to improve overall results of children with metastatic osteosarcoma (OST). Six patients, aged 12-17 years, underwent PBSC mobilization with CY 4 g/m2 and VP-16 600 mg/m2 followed by G-CSF (n = 4 with recurrent disease) or ifosfamide 15 g/m2 plus G-CSF (n = 2 with synchronous metastases). The target dose of CD34+ cells for two transplant procedures was 8 x 10(6)/kg or more; conditioning regimen for both the grafts consisted of carboplatin 375 mg/m2/day for 4 days and VP16 450 mg/m2/day for 4 days. The first transplant was planned 2-4 weeks after the mobilization, the second transplant 4-6 weeks after the first graft. In three patients a single course of CY-VP16 mobilised a total number of CD34+ sufficient for two transplants; in the patient who did not obtain the target dose of CD34+ cells a bone marrow harvest was added. In the two other children high-dose ifosfamide failed to achieve the required CD34+ number: one patient underwent a single transplant procedure, one patient was successfully mobilized with doxorubicin 90 mg/m2 plus G-CSF. Patients underwent a median of two collections (range 2-4). Leukapheresis resulted in the collection of a median of 8.9 CD34+ cells/kg (range 1.3-14.8). The median time to granulocyte count recovery to more than 0.5 x 10(9)/l was 10 days (range 9-14 days) after the first graft and 11 days (range 10-12 days) after the second graft, respectively. Platelets recovered to 50 x 10(9)/l at a median of 11 (range 10-30 days) and 13 days (range 10-28) respectively after the first and the second graft. Conditioning regimen was well tolerated in all patients with mild extra haematological toxicity, also following the second transplant. Two patients grafted with metastases at diagnosis are alive and disease free 3 and 7 months from the transplant. One of the four patients transplanted for recurrent disease developed pulmonary metastases 2 months after the procedure; one patient is alive with significant reduction of tumor mass 1 month after the first transplant, one patient is alive without evidence of disease 9 months from the second transplant and one after a complete metastasectomy (tumor necrosis >90%) which followed the second transplant. With the limits of the small number of cases and the short follow-up, these preliminary results show that this approach may be promising for the treatment of patients with metastatic OST who currently are not cured by conventional-dose regimens.

Between February 1995 and August 1997, 11 children (eight males, three females) aged 4-16 years (median 7 years) underwent allogeneic PBPC transplantation for treatment of hematological disorders. Seven patients with acute leukemia (n = 5 ALL, n = 1 AML) or lymphoma (n = 1) received primary allogeneic PBPC transplantation, four patients received a second allotransplantation for graft failure (n = 1 AML, n = 1 sickle cell anemia) or disease recurrence (n = 1 ALL, n = 1 MDS). Five donors were HLA-identical siblings, five were 0-1 antigen mismatched family members and one was a matched unrelated donor. Donors received G-CSF 10-12 microg/kg/day for 3-7 days, and underwent one or two leukaphereses. The median cell yield per donor expressed per kg of recipient body weight was as follows: mononucleated cells 10.8 x 10(8)/kg (range 4.7-21.2); CD34+ cells 8.6 x 10(6)/kg (range 3.2-22); CD3+ cells 3.7 x 10(8)/kg (range 2.7-7.5). All patients achieved an ANC >0.5 x 10(9)/l after a median of 12 days (11-18). An unsupported platelet count >50 x 10(9)/l was reached 15 days (13-21) after PBPC transplantation; four patients failed to reach this threshold. Acute GVHD (aGVHD) grades II to IV occurred in eight (73%) patients: seven of them experienced grade III-IV aGVHD. Seven patients evaluable for chronic GVHD (cGVHD) were scored as absent in five, limited in one and extensive in one patient. As of September 1997, six patients (55 %) were alive between 60 and 938 days post-transplant (median follow-up 274 days); four patients with malignancy were alive in CR after primary allotransplantation, two patients were alive after a second PBPC transplant. Five patients have died with the main causes of death being aGVHD (n = 3), ARDS (n = 1), relapse of the underlying disease (n = 1). In conclusion, despite the limited number of patients, these preliminary results indicate that PBPC may be considered as an alternative to bone marrow for allografting also in children.

Human umbilical cord blood as an alternative source of hematopoietic stem cells for bone marrow reconstitution, has recently been demonstrated to yield successful HLA-matched placental blood grafts in children. It has been shown that cord blood contains sufficient progenitor cells to effect hematological reconstitution. Since then, more than 25 cord blood stem cells (CBSCs) transplants have been performed worldwide for the treatment of a variety of malignant and nonmalignant diseases. The majority of the grafts performed thus far have utilized CBSCs from HLA-identical siblings. However, much of the interest in this setting is devoted to the potential use of CBSCs for HLA-mismatched and unrelated transplants. Preliminary results suggest that allorecognition and graft-versus-host disease may be less intense in CBSCs transplants than in recipients of similarly compatible bone marrow. This review summarizes the results and potential future applications of cord blood transplantation.