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• We conducted a prospective trial of haploidentical hematopoietic stem cell transplantation for nonmalignant diseases. • Post-transplantation cyclophosphamide and low-dose antithymocyte globulin were used as graft-versus-host disease (GVHD) prophylaxis. • All 6 patients achieved engraftment, and none developed severe GVHD. • All patients had sustained full donor chimerism without chronic GVHD. Allogeneic hematopoietic stem cell transplantation (HSCT) is performed as a curative treatment for children with nonmalignant diseases, such as bone marrow failure syndromes and primary immunodeficiencies. Because graft-versus-host-disease (GVHD) is a major factor affecting survival probability and quality of life after HSCT, the availability of HLA-matched donors restricts the application of HSCT. Recently, HSCT with post-transplantation cyclophosphamide (PTCy) has emerged as a potent method to prevent GVHD after HSCT from HLA-haploidentical donors, and some studies have suggested the safety of PTCy-HSCT for nonmalignant diseases. We conducted a prospective clinical trial aiming to help confirm the safety of HSCT and further reduction of GVHD using a combination of PTCy and low-dose antithymocyte globulin (ATG) from HLA-mismatched related donors for children with nonmalignant diseases. Six patients underwent HSCT and achieved engraftment at a median of 14.5 days, and no patient developed severe acute GVHD. All patients had sustained donor chimerism without developing chronic GVHD at the last follow-up. In conclusion, HSCT with PTCy and low-dose ATG from an HLA-mismatched related donor were feasible to control GVHD for nonmalignant diseases in the children involved in our study. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. [ABSTRACT FROM AUTHOR]

• Unlicensed umbilical cord blood units can be safely and effectively used for hematopoietic cell transplantation (HCT) in adult and pediatric patients. • Unlicensed umbilical cord blood expands access to racially/ethnically diverse patients in need of HCT. • Further studies are required to compared licensed and unlicensed umbilical cord blood HCT. Umbilical cord blood (UCB) transplantation (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access to transplantation for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the US Food and Drug Administration required that unrelated UCBT be performed using either licensed UCB or unlicensed UCB under the Investigational New Drug (IND) program. The National Marrow Donor Program manages an IND under which 2456 patients (1499 adults and 957 children, 564 with malignant diseases and 393 with nonmalignant diseases) underwent single or double UCBT between October 2011 and December 2016. The median patient age was 31 years (range, <1 to 81 years), and 50% of children and 36% of adults were non-Caucasian. The median time to neutrophil engraftment (ie, absolute neutrophil count ≥500/mm3) was 22 days for adults, 20 days for pediatric patients with malignant diseases, and 19 days for pediatric patients with nonmalignant diseases, with corresponding rates of engraftment at 42 days of 89%, 88%, and 90%. In these 3 groups of patients, the incidence of acute graft-versus-host disease (GVHD) grade II-IV was 35%, 32%, and 24%; the incidence of chronic GVHD was 24%, 26%, and 24%; and 1-year overall survival (OS) was 57%, 71%, and 79%, respectively. In multivariate analysis, younger age, lower Hematopoietic Cell Transplantation-Specific Comorbidity Index, early-stage chemotherapy-sensitive disease, and higher performance score were predictive of improved OS for adults. In a subset analysis of children with malignancies undergoing single UCBT, the use of either licensed UCB (n = 48) or unlicensed UCB (n = 382) was associated with similar engraftment and survival. The use of unlicensed UCB units is safe and effective and provides an important graft source for a diverse population. [ABSTRACT FROM AUTHOR]

It is recognized that chimerism following hematopoietic stem cell transplantation (HSCT) is a dynamic process. The aims of this study were to describe the evolution of chimerism in children with nonmalignant diseases who underwent allogeneic HSCT, and to analyze the risk factors influencing chimerism status. A total of 101 HSCTs were performed in 85 patients with nonmalignant diseases. The donor was unrelated in 62.4% of HSCTs. Reduced-intensity conditioning (RIC) regimen was administered in 48.5% of patients. Acute graft-versus-host disease (aGVHD) occurred in 51.7% and chronic GVHD (cGVHD) in 39.7% of patients. Analysis of chimerism was performed through amplification of 9 specific short tandem repeats by polymerase chain reaction at engraftment and 1, 6, and 12 months after HSCT. Upon first evaluation, complete chimerism (CC) was detected in 34.7% and mixed chimerism (MC) in 55.4%, whereas graft failure occurred in 9.9% of patients. Severe aGVHD was associated with CC ( P  = .031). The last chimerism evaluation showed CC in 72.1%, stable MC in 12.8%, and progressive MC in 3.5%. CC was associated with a higher incidence of aGVHD ( P  = .016) and cGVHD ( P  = .022), whereas the RIC regimen was associated with graft failure ( P  = .026). One- and 3-year overall survival (OS) was 87.4% and 80.5%, respectively, with a lower OS at 3 years in patients with CC compared with those with MC ( P  = .008). aGVHD and cGVHD represent factors favoring CC, thus close, careful follow-up of chimerism is recommended in patients affected by nonmalignant disease. [ABSTRACT FROM AUTHOR]

Mixed donor chimerism is increasingly common in the pediatric hematopoietic stem cell transplantation (HSCT) setting because of the increased use of reduced-intensity preparative regimens for nonmalignant diseases. Donor lymphocyte infusion (DLI) is potentially useful in the treatment of mixed donor chimerism, but little are data available on the use of DLI in this setting. We conducted a retrospective review of 27 pediatric patients who received DLI for mixed donor chimerism between January 2006 and December 2010 after receiving a preparative regimen of alemtuzumab, fludarabine, and melphalan. Twenty-one patients (78%) were alive at a median of 35 months post-transplant. Seven patients (26%) sustained full donor chimerism after DLI only at a median of 35 months post-HSCT. Nine patients (33%) continued with mixed donor chimerism (median, 38% [range, 18% to 70%]) at a median of 37 months after DLI only. Five patients underwent unconditioned stem cell boosts or second conditioned transplants after no improvement in donor chimerism was seen following DLI. Donor source appeared to contribute to outcomes after DLI; patients with mismatched unrelated donors had earlier first decline in chimerism and timing of first DLI, a higher response rate to DLI, and an increased rate of graft-versus-host disease (GVHD). There was no response to DLI in patients with matched sibling donors. Ten patients, all with improvement in chimerism after DLI, developed acute GVHD after DLI, with 3 having grade III GVHD. Three patients developed chronic GVHD after DLI. These data illustrate the potential efficacy of DLI in the treatment of mixed donor chimerism after a reduced-intensity preparative regimen. [ABSTRACT FROM AUTHOR]

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a valuable alternative for children with nonmalignant disease and ex vivo negative selection of TCR-αβ + cells is an emerging graft manipulation option that carries several potential advantages in terms of reduced risk of graft-versus-host disease (GvHD) and improved immune reconstitution. We report all consecutive patients with a diagnosis of nonmalignant disease who received a TCR-αβ + and CD19 + depleted haplo-HSCT at "IRCCS Istituto Giannina Gaslini" from 2013 to 2019; the conditioning regimen was myeloablative or non-myeloablative, depending on underlying disease; all patients received antithymocyte globulin and rituximab. No post-transplantation GvHD prophylaxis was given in presence of a TCR-αβ + cell dose in the graft lower than the threshold of 1 × 10 5 /kg of the recipient's weight. Among 20 HSCTs, engraftment occurred in 17 (85%) after a median of 14 and 12 days from graft infusion for neutrophils and platelets, respectively. Primary graft failure was diagnosed in 3 (15%) patients, and 2 (10%) experienced secondary rejection; all of these patients underwent a second HSCT. The cumulative incidence of a-GvHD and c-GvHD was 15% (2 = grade 1, 1 = grade 4) at 90 days and 5% (1 = grade 1) at 7 months, respectively. Cytomegalovirus reactivation requiring pre-emptive treatment was observed in 9 patients (45%). One patient developed a JC virus-related progressive multifocal leukoencephalopathy, successfully managed with donor-derived virus-specific T-cell infusions. A complete immunological recovery was reached in most patients within 6 months. After a median follow-up of 4 years, 18 patients are alive, with a cumulative survival probability of 90%. Haplo-HSCT after ex vivo TCR-αβ + /CD19 + negative selection may be considered a good option for children with nonmalignant diseases because it ensures a high engraftment rate with an acceptable risk of graft failure, very low incidence of significant GvHD, and good immune reconstitution with low frequency of severe virus-related disease. However, the control of viral infection/reactivation should be kept high to promptly provide pre-emptive treatments and approaches of antiviral adoptive immunotherapy., Competing Interests: Conflict of interest statement There are no conflicts of interest to report. Authorship statement: SG contributed to data collection, material preparation, analysis of results, and wrote the manuscript. SG, MF, and EL contributed equally to the study conception and to the patient's management. FB performed all statistical analyses. MR and MF contributed to donor selection and management. MP and FS managed the graft manipulation. MM, FP, GD, BC and MR contributed to data collection and to the clinical management of patients. All authors contributed to the manuscript revision and approved its final version., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Abstract: In an attempt to abrogate the deleterious effects of graft-versus-host disease (GVHD), allogeneic transplantation for nonmalignant diseases was performed using high-dose CD34-cell infusion, partial T cell depletion, and no posttransplantation GVHD prophylaxis. Between 1998 and 2004, 16 patients with matched related donors were treated. Median age was 1.5 years (range, 5 months-18 years). The conditioning regimen consisted of busulphan 16 mg/kg, cyclophosphamide 200 mg/kg, antithymocyte globulin (ATG) 25 mg/kg, and fludarabine 200 mg/m2. No GVHD prophylaxis was given. High doses of CD34 cells, positively selected by immunomagnetic beads, were infused at a median dose of 10.7 × 106 CD34/kg (range, 7.4-50 × 106). A total of 1 × 105/kg T cells were given. All patients engrafted, with no graft rejections. All were alive and well at a median of 37 months posttransplantation (range, 18-89 months). Only 1 patient developed chronic GVHD. No episodes of severe infection occurred during or after transplantation. Immunologic reconstitution with CD3/CD4 T cells > 200/μL was observed at a median of 117 days and that with naive T cells (CD4/CD45RA) at a median of 188 days posttransplantation. Our findings suggest that allogeneic transplantation from a matched family donor for nonmalignant disorders can be successfully performed using high doses of CD34 cells, moderate T cell depletion, and no posttransplantation immunosuppression. [Copyright &y& Elsevier]

Allogeneic stem cell transplantation (SCT) can cure several nonmalignant diseases in children. However, patients frequently have significant morbidity before transplantation and there is a high transplant-related mortality. Nonmyeloablative SCT might achieve the same goals but with less toxicity. Six pediatric patients with nonmalignant diseases underwent nonmyeloablative SCT from different stem cell sources. All patients were conditioned with fludarabine/melphalan with additional anti-thymocyte globulin for haploidentical grafts and prophylaxis for graft-versus-host disease (GVHD) consisting of tacrolimus and methotrexate with additional prednisolone for haploidentical grafts. Hematopoietic stem cells were neither T-cell depleted nor purged. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning. Five of the six are alive and in complete disease resolution at a median of 19 months (range, 7–53 months) after SCT. One patient died of bacteremia before engraftment. Three patients achieved complete donor chimerism. Two patients remained stable mixed chimerism. Short-term toxicities were minimal. Acute and chronic GVHD were not seen. In summary, the fludarabine-based nonmyeloablative regimen followed by SCT provides a good approach for children with nonmalignant diseases. Even patients with severe organ dysfunctions had adequate engraftment with acceptable toxicities.Bone Marrow Transplantation (2006) 38, 665–669. doi:10.1038/sj.bmt.1705511; published online 2 October 2006 [ABSTRACT FROM AUTHOR]

Integrated care pathways (ICPs) are multiprofessional documents designed to enable the implementation of evidence-based care and support the practical delivery of clinical governance. However, the implementation of care pathways is resource intensive and few evaluations have been conducted with respect to these areas or to the efficacy of care pathways to change practice and improve outcomes in care. This project sought to address these issues and the report outlines the approach taken by a palliative care team in South Wales, UK, to implement a care pathway for the dying throughout a district general hospital and six community hospitals. Dying can be a complex area of care and changing practice can be challenging, therefore a PRINCE Project management approach was taken and a full-time project nurse employed for the life of the project. This paper describes the strategies used to approach implementing a care pathway and provides a template for other teams who may embark on similar projects. At the end of the project, the care pathway was successfully implemented and provided demonstrable outcomes of care for those dying from cancer and nonmalignant diseases. Strikingly, a large number of patients dying from nonmalignant disease were cared for via the pathway, which was not expected. [ABSTRACT FROM AUTHOR]

Summary:Transplantation of allogeneic stem cells is currently the only curative treatment for some nonmalignant pediatric diseases. We investigated whether transplantation of purified CD34+ stem cells prevents acute and chronic GvHD and reduces transplant-related mortality. A total of 25 pediatric patients with nonmalignant diseases underwent allogeneic transplantation from 26 donors (matched related n=4, matched or partially matched unrelated n=14, mismatched related n=8). All grafts were purified peripheral-blood CD34+ stem cells mobilized with G-CSF. Patients received a median of 12.9 × 106 CD34+ progenitor cells with a median of 6.1 × 103 contaminating T-lymphocytes per kilogram of body weight. No post transplant immunosuppressive drugs were given for prophylaxis of GvHD. Engraftment was seen in 21 patients. Three patients engrafted after a second transplant and one patient failed to engraft. Two patients had autologous reconstitution 1.5 years post transplant and one of them was successfully retransplanted. No acute GvHD >grade II was seen, and only two patients developed limited, chronic GvHD. In all, 22 patients (88%) are alive with a median follow-up of 3.7 years. In total, 19 patients (76%) are free of disease or of progression. Transplantation of highly purified peripheral-blood CD34+ stem cells is associated with low toxicity in patients with nonmalignant diseases.Bone Marrow Transplantation (2004) 33, 25-32. doi:10.1038/sj.bmt.1704303 [ABSTRACT FROM AUTHOR]

Purpose: To overcome the lack of written guidelines for radiation therapy (RT) of benign diseases, the German Working Group on Radiotherapy of Benign Diseases initiated a consensus process in 1999 to warrant continuous quality assurance and outcome research in this field.Methods: An expert panel was convened to define key issues and develop written guidelines for RT of benign diseases. Pertinent information and data from published literature were reviewed, and data of most importance were identified. In addition, a patterns of care study was conducted to obtain a nationwide survey on the current status and treatment standards.Results: From the data gathered, the expert panel prepared a first consensus statement that was open to propositions and comments from all participating institutions. After completion of the multicenter discussion, a final written consensus statement was compiled, discussed, and finally agreed on during a national conference of radiation therapists. For each individual nonmalignant disease, the accepted RT concepts were documented. Finally, specific evaluation tools and recommendations for follow-up examinations were defined.Conclusions: For the first time, written consensus guidelines for RT of nonmalignant diseases have been developed by the interaction of all institutions involved. These guidelines may serve as a starting point for quality assessment, prospective clinical trials, and outcome research. [Copyright &y& Elsevier]

Objective Few reports have analyzed the diagnostic process of carcinoma of unknown primary site (CUP) or have focused on the frequency of nonmalignant lesions among patients with suspected malignant diseases. The aim of this study was to investigate the incidence and characteristics of nonmalignant diseases that tend to be mistaken for malignant diseases. Patients We retrospectively analyzed the medical records of patients with suspected CUP who were referred to the National Cancer Center Hospital (Tokyo, Japan) between April 2007 and December 2014. All patients underwent a thorough history and physical examination as well as radiological and ultrasonography imaging tests for the CUP diagnostic work up. Results Among 830 patients with suspected CUP, 46 were diagnosed with nonmalignant diseases, and 780 were diagnosed with a malignant neoplasm (409 neoplasms with detected primary site and 371 CUP neoplasms). Four patients discontinued the diagnostic workup because they refused further examinations or had a poor general status. The final diagnosis of the 46 patients with nonmalignant disease comprised 10 benign tumors, 10 benign diseases, and 26 with no evidence of disease. The nonmalignant tumors comprised three hemangiomas, two schwannomas, two uterine myomas, two pseudomyxoma peritonei, one lymphangioma, one meningioma, and one poroma. Conclusion The incidence of nonmalignant diseases among patients with suspected CUP was 46 out of 830 patients in our institution. It is important to perform a thorough pathological examination in the CUP diagnostic workup. To confirm a diagnosis, some patients may need to visit specialized institutions, especially those with liver and bone lesions.

Background: Donor mixed chimerism (MC) is an increasing problem after hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases., Procedure: In this study, a self-administered questionnaire was used to retrospectively compare efficacy and safety in 49 patients undergoing second HSCT (n = 13) or donor lymphocyte infusion (DLI; n = 36) as treatment for MC., Results: The response rate to DLI of patients with secondary graft failure (GF) (25.0%) was significantly lower than that of patients without secondary GF (81.3%; P = 0.041). Among patients undergoing DLI, the rates of successful response were significantly higher in patients having at least 30% donor chimerism (94.1%) than in patients having less than 30% donor chimerism (61.1%; P = 0.041). Furthermore, the rates of successful response were significantly higher in patients receiving larger first or maximum doses of DLI. Sixteen (50.0%) of 32 patients without secondary GF attained complete chimerism after DLI. The cumulative incidence of grade II-IV acute graft-versus-host disease and cytopenia was 37.6 and 26.1%, respectively., Conclusions: DLI yields promising response rates in most patients with higher donor chimerism levels, whereas second HSCT is more likely to benefit patients with lower donor chimerism levels., (© 2016 Wiley Periodicals, Inc.)