Haploidentical transplantation in pediatric non-malignant diseases: A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation (GETH).

OBJECTIVE: Describe the GETH haploidentical stem cell transplantation (haplo-HSCT) activity in non-malignant disease (NMDs). METHODS: We retrospectively analyzed data from children with NMDs who underwent haplo-HSCT. RESULTS: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo-HSCT through ex vivo T cell-depleted (TCD) graft platforms or post-transplantation cyclophosphamide (PT-Cy) at 7 Spanish centers. Five cases employed unmanipulated PT-Cy haplo-HSCT, 16 employed highly purified CD34+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+ CD19+ depletion, TCRαß+ CD19+ selection or naive CD45RA+ T-cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo-HSCT, and bone marrow was the source for one PT-Cy haplo-HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1-year cumulative incidence of graft failure was 27.4%. The 1-year III-IV acute graft-versus-host disease (GvHD) and 1-year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2-year overall survival was 44.9% for PIDs, and the 2-year graft-versus-host disease-free and relapse-free survival rate was 37.6% for the other NMDs. The transplantation-related mortality at day 100 was 30.8%. CONCLUSION: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise.

Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH).

A total of 192 pediatric patients, median age 8.6 years, with high-risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PT-Cy), or ex vivo T cell-depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT-Cy for graft-vs-host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3-depleted peripheral blood stem cells (PBSCs) by either CD34+ selection, CD3+ CD19+ depletion, TCRαß+ CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo-HSCT; bone marrow was the source in 9 of 41 patients following PT-CY haplo-HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer-cell immunoglobulin-like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease-free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo-HSCT were effective and could be utilized depending on the comfort level of the center.

Measurable residual disease study through three different methods can anticipate relapse and guide early interventions in childhood acute lymphoblastic leukemia.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most common cancer among children. Measurable residual disease (MRD, previously named minimal residual disease) study can guide therapy adjustments or preemptive interventions that might avoid hematological relapse. METHODS: Clinical decision making and patient outcome were evaluated in 80 real-life childhood ALL patients, according to the results observed in 544 bone marrow samples analyzed with three MRD methods: multiparametric flow cytometry (MFC), fluorescent in-situ hybridization (FISH) on B or T-purified lymphocytes and patient-specific nested reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Estimated 5 year overall survival and event-free survival were 94% and 84.1%, respectively. A total of 12 relapses in 7 patients were associated with positive MRD detection with at least one of the three methods: MFC (p < 0.00001), FISH (p < 0.00001) and RT-PCR (p = 0.013). MRD assessment allowed the anticipation of relapse and adapted early interventions with different approaches including chemotherapy intensification, blinatumomab, HSCT and targeted therapy to halt relapse in five patients, although two of them relapsed afterwards. CONCLUSION: MFC, FISH and RT-PCR are complementary methods for MRD monitoring in pediatric ALL. Although, our data clearly show that MDR positive detection is associated with relapse, continuation of standard treatment, intensification or other early interventions were able to halt relapse in patients with different risks and genetic background. More sensitive and specific methods are warranted to enhance this approach. However, whether early treatment of MRD can improve overall survival in patients with childhood ALL needs to be evaluated in adequately controlled clinical trials.

Clinical guideline on adequacy and prescription of peritoneal dialysis.

In recent years, the meaning of adequacy in peritoneal dialysis has changed. We have witnessed a transition from an exclusive achievement of specific objectives -namely solute clearances and ultrafiltration- to a more holistic approach more focused to on the quality of life of these patients. The purpose of this document is to provide recommendations, updated and oriented to social and health environment, for the adequacy and prescription of peritoneal dialysis. The document has been divided into three main sections: adequacy, residual kidney function and prescription of continuous ambulatory peritoneal dialysis and automated peritoneal dialysis. Recently, a guide on the same topic has been published by a Committee of Experts of the International Society of Peritoneal Dialysis (ISPD 2020). In consideration of the contributions of the group of experts and the quasi-simultaneity of the two projects, references are made to this guide in the relevant sections. We have used a systematic methodology (GRADE), which specifies the level of evidence and the strength of the proposed suggestions and recommendations, facilitating future updates of the document.

Measurable residual disease study through three different methods can anticipate relapse and guide pre-emptive therapy in childhood acute myeloid leukemia.

PURPOSE: Although outcomes of children with acute myeloid leukemia (AML) have improved over the last decades, around one-third of patients relapse. Measurable (or minimal) residual disease (MRD) monitoring may guide therapy adjustments or pre-emptive treatments before overt hematological relapse. METHODS: In this study, we review 297 bone marrow samples from 20 real-life pediatric AML patients using three MRD monitoring methods: multiparametric flow cytometry (MFC), fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR). RESULTS: Patients showed a 3-year overall survival of 73% and a 3-year event-free survival of 68%. Global relapse rate was of 25%. All relapses were preceded by the reappearance of MRD detection by: (1) MFC (p = 0.001), (2) PCR and/or FISH in patients with an identifiable chromosomal translocation (p = 0.03) and/or (3) one log increase of Wilms tumor gene 1 (WT1) expression in two consecutive samples (p = 0.02). The median times from MRD detection to relapse were 26, 111, and 140 days for MFC, specific PCR and FISH, and a one log increment of WT1, respectively. CONCLUSIONS: MFC, FISH and PCR are complementary methods that can anticipate relapse of childhood AML by weeks to several months. However, in our series, pre-emptive therapies were not able to prevent disease progression. Therefore, more sensitive MRD monitoring methods that further anticipate relapse and more effective pre-emptive therapies are needed.

Treosulfan-Based Conditioning Regimen In Pediatric Hematopoietic Stem Cell Transplantation: A Retrospective Analysis on Behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC).

Increasing data on treosulfan-based conditioning regimens before hematopoietic stem cell transplantation (HSCT) demonstrate the consistent benefits of this approach, particularly regarding acute toxicity. This study aimed to describe the results of treosulfan-based conditioning regimens in children, focusing on toxicity and outcomes when used to treat both malignant and nonmalignant diseases. This retrospective observational study of pediatric patients treated in Spain with treosulfan-based conditioning regimens before HSCT was based on data collection from electronic clinical records. We studied a total of 160 treosulfan-based conditioning HSCTs to treat nonmalignant diseases (n = 117) or malignant diseases (n = 43) in 158 children and adolescents. The median patient age at HSCT was 5.1 years (interquartile range, 2 to 10 years). The most frequent diagnoses were primary immunodeficiency (n = 42; 36%) and sickle cell disease (n = 42; 36%) in the nonmalignant disease cohort and acute lymphoblastic leukemia (n = 15; 35%) in the malignant disease cohort. Engraftment occurred in 97% of the patients. The median times to neutrophil engraftment (17 days versus 14 days; P = .008) and platelet engraftment (20 days versus 15 days; P = .002) were linger in the nonmalignant cohort. The 1-year cumulative incidence of veno-occlusive disease was 7.98% (95% confidence interval [CI], 4.6% to 13.6%), with no significant differences between cohorts. The 1-year cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was higher in the malignant disease cohort (18% versus 3.2%; P = .011). Overall, the malignant cohort had both a higher total incidence (9% versus 3%; P < .001) and a higher 2-year cumulative incidence (16% versus 1.9%; P < .001) of total chronic GVHD. The 2-year cumulative transplantation-related mortality was 15%, with no difference between the 2 cohorts. The 5-year overall survival was 80% (95% CI, 72% to 86%) and was higher in the nonmalignant cohort (87% versus 61%; P = .01). The 2-year cumulative incidence of relapse was 25% in the malignant cohort. The 5-year cumulative GVHD-free, relapse-free survival rate was 60% (95% CI, 51% to 70%) and was higher in the nonmalignant cohort (72% versus 22%; P < .001). A treosulfan-based radiation-free conditioning regimen is feasible, achieving a high engraftment rate and 5-year overall survival, and is an emerging option for the first HSCT in nonmalignant diseases.

Peripheral ulcerative keratitis as presenting manifestation of systemic microscopic polyangiitis: a case report.

Microscopic polyangiitis is a rare autoimmune disease of unknown etiology, characterized by inflammation and necrosis of blood vessels. It forms a part of the antineutrophil cytoplasmic antibody-associated vasculitides-a heterogeneous group of disorders characterized by vasculitis. It is a systemic disease affecting multiple organs. The patients may present with a wide variety of symptoms. Ocular manifestations may present as its initial clinical symptoms, necessitating a multidisciplinary approach for reducing the morbidity and mortality. Early diagnosis aids in the formulation of appropriate treatment and prevention of further complications. Aggressive treatment, including surgery, is often necessary to limit structural damage and preserve visual function. We present the case of an 82-year-old woman who initially presented with peripheral ulcerative keratitis that led to the diagnosis of microscopic polyangiitis.

Haploidentical hematopoietic stem cell transplantation in pediatric and adolescent patients: A study of the Spanish hematopoietic stem cell transplantation group (GETH).

INTRODUCTION: The main advantages of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) are the immediate availability of donors, the possibility of developing cell therapy approaches with different novel transplant platforms, and the procedure's cost savings. METHODOLOGY: We retrospectively analyzed the pediatric haplo-HSCT activity of the Spanish hematopoietic stem-cell transplantation group (GETH) between 1999 and 2016, aiming to study clinical characteristics and outcomes by describing patient groups with non-malignant disease (NMD) or malignant disease (MD) and the impact of 2 different periods (1999-2009 and 2010-2016) on long-term outcomes. RESULTS: Twelve centers performed 232 haplo-HSCTs in 227 children, representing 10% of all pediatric allogeneic HSCT activity in Spain from 1999 to 2016, with a notable increase since 2013. Most haplo-HSCTs (86.7%) were performed in patients with MD; 95% received peripheral blood stem cells from donors, and 78.9% received ex vivo T-cell depleted grafts. Non-manipulated grafts using post-transplantation cyclophosphamide have been incorporated since 2012. We observed a higher percentage of graft failure in NMD versus MD (32% vs. 15.6%; p=0.029). Relapse and transplant-related mortality were the procedure's main limitations in MD and NMD, respectively. Five-year overall survival was 48.5% (SE 3.9), with no statistically significant difference when comparing the MD and NMD cohorts. Patients who received previously a HSCT the overall survival was significantly decreased. We observed no survival improvement over time. CONCLUSIONS: Although haplo-HSCT is an increasingly employed treatment option, our patients' results need improvement. We need to develop reference centers, especially for NMD whose rarity makes it difficult to gain experience.

Magnetic resonance imaging in patients with self-locating peritoneal catheters: Is it safe?

The fact that self-locating catheters have a piece of metal at the tip leads to doubt and uncertainty around performing magnetic resonance imaging (MRI) in patients with this type of catheter. We simulated a peritoneum with a weighted catheter to ascertain how the catheter behaved during MRI scans in 1.5 T and 3 T machines. We also reviewed cases in which MRI had been performed in patients with this type of catheter. In the simulation, the tip of the self-locating peritoneal catheter caused a magnetic susceptibility artefact that made it difficult to see nearby areas, but it proved to be a safe device for MRI. 14 MRI scans were performed in patients with self-locating catheters, none in the abdominal area. There were no complications in the patients or the technique after performing MRI.

Magnetic resonance imaging in patients with self-locating peritoneal catheters: Is it safe? / Resonancia magnética en pacientes con catéteres peritoneales autoposicionantes: ¿se puede?

The fact that self-locating catheters have a piece of metal at the tip leads to doubt and uncertainty around performing magnetic resonance imaging (MRI) in patients with this type of catheter. We simulated a peritoneum with a weighted catheter to ascertain how the catheter behaved during MRI scans in 1.5T and 3T machines. We also reviewed cases in which MRI had been performed in patients with this type of catheter. In the simulation, the tip of the self-locating peritoneal catheter caused a magnetic susceptibility artefact that made it difficult to see nearby areas, but it proved to be a safe device for MRI. 14 MRI scans were performed in patients with self-locating catheters, none in the abdominal area. There were no complications in the patients or the technique after performing MRI.

Impact of postoperative acute kidney failure in long-term survival after heart valve surgery.

OBJECTIVES: We investigated the impact of acute kidney failure after a heart valve procedure among patients with or without chronic kidney disease (CKD). METHODS: All patients who had undergone a surgical valve procedure between 2005 and 2017 at our institution were divided into 2 groups depending on whether they had previous history of CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2) or not. Homogeneous groups were obtained by propensity score matching. Long-term mortality was compared between the 2 groups and according to the occurrence of postoperative acute kidney failure. Level of significance was set at P-value <0.008 for multiple comparison tests. RESULTS: From the 3907 patients included to this study, 1476 (37.78%) had previous history of CKD. After adjusting for propensity score 1:1, patients with preoperative impaired renal function were at a higher risk of acute kidney failure (26.83% vs 10.16%, P < 0.001) and postoperative mortality (8.48% vs 5.17%, P = 0.001). In the follow-up, they had a poorer survival at 1, 5 and 10 years as compared to patients with normal renal function (88% vs 91.95%, 78.29% vs 81.11% and 56.13% vs 66.29%, respectively; P < 0.001). Patients without postoperative kidney failure had similar survival whether they had preoperative CKD or not [hazard ratio (HR) 1.16, 99.2% confidence interval (CI) 0.87-2.52; P = 0.142]. As compared to patients with postoperative preserved renal function, those with postoperative kidney failure had a higher long-term mortality either if they had previous kidney disease or not [(HR 2.18, 99.2% CI 1.75-2.72; P < 0.001) and (HR 1.48, 99.2% CI 1.33-1.65; P < 0.001), respectively]. Preoperative CKD was the strongest predictor of acute kidney failure (odds ratio 4.45; 95% CI 3.59-5.53; P < 0.001). CONCLUSIONS: Patients with CKD are at higher risk of postoperative adverse events and have poorer long-term outcomes. Postoperative acute kidney failure increases long-term mortality.

Recurrent postinfectious glomerulonephritis: an unusual evolution compatible with C3 glomerulopathy.

Acute endocapillary glomerulonephritis, as its name suggests, is a one-time process, which usually resolves within weeks. However, in a small percentage of patients, the disease becomes chronic. In these cases, a deregulation in the alternative complement pathway, which can be caused by mutations or autoantibodies, has been proposed as a pathophysiological mechanism. As a result, the alternative complement pathway remains active after resolution of infection. We report a patient with two episodes of acute renal failure, both times diagnosed by renal biopsy of acute endocapillary glomerulonephritis, with slow recovery after two episodes of low-serum complement C3, haematuria and proteinuria.

Peritoneal dialysis: A factor of risk or protection for posterior reversible encephalopathy syndrome? review of the literature. / Diálisis peritoneal: ¿un factor de riesgo o de protección para la encefalopatía posterior reversible (PRES)? Revisión de la literatura.

Posterior reversible encephalopathy syndrome is a clinical and radiological entity with acute or subacute neurological presentation associated with brain lesions that primarily affect the white matter of the posterior regions. It is often associated with the rapid onset of severe hypertension and/or with kidney failure (acute and chronic), but it has also been reported as a neurological complication in several medical conditions. In recent years, there has been an increase in the number of cases and related publications due to the advance of diagnostic imaging techniques. The characteristic radiological finding includes hyperintense lesions in T2- and FLAIR-weighted magnetic resonance imaging, which are often bilateral and located in the posterior cerebral regions and correspond to areas of vasogenic oedema. Little is known about the pathophysiology of posterior reversible encephalopathy syndrome. The most accepted theory, especially in cases with associated hypertension, is the loss of cerebral self-regulation which leads to the onset of vasogenic oedema. The main feature of this syndrome is the reversibility of both symptoms and cerebral lesions with an early and appropriate diagnosis. Despite the frequent association with kidney failure and severe hypertension, there are few cases reported in patients on peritoneal dialysis. This article presents a review of PRES in peritoneal dialysis patients in the published literature.

Peripheral ulcerative keratitis as presenting manifestation of systemic microscopic polyangiitis: a case report / Ceratite ulcerativa periférica como manifestação de poliangiíte microscópica sistêmica: relato de caso

ABSTRACT Microscopic polyangiitis is a rare autoimmune disease of unknown etiology, characterized by inflammation and necrosis of blood vessels. It forms a part of the antineutrophil cytoplasmic antibody-associated vasculitides-a heterogeneous group of disorders characterized by vasculitis. It is a systemic disease affecting multiple organs. The patients may present with a wide variety of symptoms. Ocular manifestations may present as its initial clinical symptoms, necessitating a multidisciplinary approach for reducing the morbidity and mortality. Early diagnosis aids in the formulation of appropriate treatment and prevention of further complications. Aggressive treatment, including surgery, is often necessary to limit structural damage and preserve visual function. We present the case of an 82-year-old woman who initially presented with peripheral ulcerative keratitis that led to the diagnosis of microscopic polyangiitis.

RESUMO A poliangeíte microscópica é uma doença autoimune rara de etiologia desconhecida, caracterizada por inflamação e necrose dos vasos sanguíneos. Faz parte das vasculites associadas a anticorpos citoplasmáticos antineutrófilos - um grupo heterogêneo de doenças caracterizadas por vasculite. É uma doença sistêmica que afeta vários órgãos. Os pacientes podem apresentar uma grande variedade de sintomas. As manifestações oculares podem apresentar-se como seus sintomas clínicos iniciais, necessitando de abordagem multidisciplinar para redução da morbimortalidade. O diagnóstico precoce ajuda na formulação do tratamento adequado e na prevenção de complicações futuras. O tratamento agressivo, incluindo cirurgia, muitas vezes é necessário para limitar o dano estrutural e preservar a função visual. Apresentamos o caso de uma mulher de 82 anos que inicialmente apresentou ceratite ulcerativa periférica que levou ao diagnóstico de poliangite microscópica.

Peritoneal dialysis catheter obstruction caused by Fallopian tube wrapping.

Peritoneal catheter malfunction is commonly related to omental wrapping, although entrapment owing to other different intraperitoneal structures is possible but rare. The authors report a case of catheter obstruction owing to fallopian tube wrapping, diagnosed and resolved by laparoscopic surgery. A brief review of this rare problem is presented.

Repairing and recovering broken peritoneal catheters.

Breakage of peritoneal catheters is an emergency of the technique that is uncommon but which requires immediate action when there is leakage of the dialysate and risk of infection. Early and adequate intervention can save broken catheters without interrupting peritoneal dialysis. We report our experience repairing damaged catheters using the Quinton® Peri-Patch repair kit (Quinton Instrument Co., Tyco Healthcare Group LP. Mansfield, MA., U.S.A.).

Measurable residual disease study through three different methods can anticipate relapse and guide early interventions in childhood acute lymphoblastic leukemia

Introduction Acute lymphoblastic leukemia (ALL) is the most common cancer among children. Measurable residual disease (MRD, previously named minimal residual disease) study can guide therapy adjustments or preemptive interventions that might avoid hematological relapse. Methods Clinical decision making and patient outcome were evaluated in 80 real-life childhood ALL patients, according to the results observed in 544 bone marrow samples analyzed with three MRD methods: multiparametric flow cytometry (MFC), fluorescent in-situ hybridization (FISH) on B or T-purified lymphocytes and patient-specific nested reverse transcription polymerase chain reaction (RT-PCR). Results Estimated 5 year overall survival and event-free survival were 94% and 84.1%, respectively. A total of 12 relapses in 7 patients were associated with positive MRD detection with at least one of the three methods: MFC (p < 0.00001), FISH (p < 0.00001) and RT-PCR (p = 0.013). MRD assessment allowed the anticipation of relapse and adapted early interventions with different approaches including chemotherapy intensification, blinatumomab, HSCT and targeted therapy to halt relapse in five patients, although two of them relapsed afterwards. Conclusion MFC, FISH and RT-PCR are complementary methods for MRD monitoring in pediatric ALL. Although, our data clearly show that MDR positive detection is associated with relapse, continuation of standard treatment, intensification or other early interventions were able to halt relapse in patients with different risks and genetic background. More sensitive and specific methods are warranted to enhance this approach. However, whether early treatment of MRD can improve overall survival in patients with childhood ALL needs to be evaluated in adequately controlled clinical trials (AU)

Measurable residual disease study through three different methods can anticipate relapse and guide pre-emptive therapy in childhood acute myeloid leukemia

Purpose Although outcomes of children with acute myeloid leukemia (AML) have improved over the last decades, around one-third of patients relapse. Measurable (or minimal) residual disease (MRD) monitoring may guide therapy adjustments or pre-emptive treatments before overt hematological relapse. Methods In this study, we review 297 bone marrow samples from 20 real-life pediatric AML patients using three MRD monitoring methods: multiparametric flow cytometry (MFC), fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR). Results Patients showed a 3-year overall survival of 73% and a 3-year event-free survival of 68%. Global relapse rate was of 25%. All relapses were preceded by the reappearance of MRD detection by: (1) MFC (p = 0.001), (2) PCR and/or FISH in patients with an identifiable chromosomal translocation (p = 0.03) and/or (3) one log increase of Wilms tumor gene 1 (WT1) expression in two consecutive samples (p = 0.02). The median times from MRD detection to relapse were 26, 111, and 140 days for MFC, specific PCR and FISH, and a one log increment of WT1, respectively. Conclusions MFC, FISH and PCR are complementary methods that can anticipate relapse of childhood AML by weeks to several months. However, in our series, pre-emptive therapies were not able to prevent disease progression. Therefore, more sensitive MRD monitoring methods that further anticipate relapse and more effective pre-emptive therapies are needed (AU)