COVID-19 disease in children and adolescents following allogeneic hematopoietic stem cell transplantation: A report from the Turkish pediatric bone marrow transplantation study group.

BACKGROUND: Data on the risk factors and outcomes for pediatric patients with SARS-CoV-2 infection (COVID-19) following hematopoietic stem cell transplantation (HSCT) are limited. OBJECTIVES: The study aimed to analyze the clinical signs, risk factors, and outcomes for ICU admission and mortality in a large pediatric cohort who underwent allogeneic HSCT prior to COVID-19 infection. METHOD: In this nationwide study, we retrospectively reviewed the data of 184 pediatric HSCT recipients who had COVID-19 between March 2020 and August 2022. RESULTS: The median time from HSCT to COVID-19 infection was 209.0 days (IQR, 111.7-340.8; range, 0-3845 days). The most common clinical manifestation was fever (58.7%). While most patients (78.8%) had asymptomatic/mild disease, the disease severity was moderate in 9.2% and severe and critical in 4.4% and 7.6%, respectively. The overall mortality was 10.9% (n: 20). Deaths were attributable to COVID-19 in nine (4.9%) patients. Multivariate analysis revealed that lower respiratory tract disease (LRTD) (OR, 23.20, p: .001) and lymphopenia at diagnosis (OR, 5.21, p: .006) were risk factors for ICU admission and that HSCT from a mismatched donor (OR, 54.04, p: .028), multisystem inflammatory syndrome in children (MIS-C) (OR, 31.07, p: .003), and LRTD (OR, 10.11, p: .035) were associated with a higher risk for COVID-19-related mortality. CONCLUSION: While COVID-19 is mostly asymptomatic or mild in pediatric transplant recipients, it can cause ICU admission in those with LRTD or lymphopenia at diagnosis and may be more fatal in those who are transplanted from a mismatched donor and those who develop MIS-C or LRTD.

Neurologic Status of Patients with Purine Nucleoside Phosphorylase Deficiency Before and After Hematopoetic Stem Cell Transplantation.

BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive combined immunodeficiency. The phenotype is profound T cell deficiency with variable B and NK cell functions and results in recurrent and persistent infections that typically begin in the first year of life. Neurologic findings occur in approximately two-thirds of patients. The mechanism of neurologic abnormalities is unclear. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for PNP deficiency. METHODS: We report here six patients from five unrelated families with PNP deficiency treated in two centers in Turkey. We evaluated the neurological status of patients and compared to post-transplantation period if available. Then, we performed PubMed, Google Scholar, and Researchgate searches using the terms "PNP" and "hematopoietic stem cell transplantation" to find all reported cases of PNP transplantation and compared to our cohort. RESULTS: Six patients were treated in two centers in Turkey. One patient died from post-transplant complications. The other four patients underwent successful HSCT with good immune reconstitution after transplantation (follow-up 21-48 months) and good neurological outcomes. The other patient with a new mutation is still waiting for a matching HLA donor. DISCUSSION: In PNP deficiency, clinical manifestations are variable, and this disease should be considered in the presence of many different clinical findings. Despite the comorbidities that occurred before transplantation, HSCT currently appears to be the only treatment option for this disease. HSCT not only cures immunologic disorders, but probably also improves or at least stabilizes the neurologic status of patients.

The impact of Treosulfan-based conditioning for inborn errors of immunity: Is dose monitoring crucial?

INTRODUCTION: In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan-based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre-HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes. METHODS: Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. RESULTS: Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p = .034) and slowed lymphocyte engraftment (r = .290; p = .030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not to increase risk of acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p = .021 and p = .014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR = .204, p = .022). CONCLUSION: The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group,  level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed.

Tandem high-dose chemotherapy followed by autologous stem cell transplantation: An infant with trilateral retinoblastoma.

BACKGROUND: Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Advanced RB, associated with exceedingly poor prognosis, requires more intensive multiagent chemotherapy than conventional regimens. Rescue of the bone marrow after intensive chemotherapy is achieved with stem cell transplantation. The sequential courses (tandem transplantation) of high-dose chemotherapy followed by autologous stem cell transplantation allow for even greater dose intensity in consolidation with the potential to use different active chemotherapeutics at each transplant and have proven feasible and successful in treating children with recurrent/refractory solid tumors. CASE DESCRIPTION: We report an infant with trilateral high-risk RB who received tandem high-dose chemotherapy (HDC) followed by autologous stem cell transplantation after the conventional chemotherapy. A 5-month-old female patient presented with strabismus, and the ophthalmoscopic examination showed intraocular tumoral lesions in both eyes. Magnetic resonance imaging (MRI) concluded the trilateral retinoblastoma diagnosis due to a tumoral mass in the optic chiasm. The follow-up ophthalmologic examinations and the MRI detected stable disease after six cycles of multiagent chemotherapy. CONCLUSIONS: Rescue with autologous stem cell transplantation after HDC allows for an increase in chemotherapy intensity. Tandem transplantation provides the chance to perform different chemotherapeutics at each transplant and enables an increase in the chemotherapy intensity, thus providing a positive effect on disease-free survival.

Evaluation of the risk factors for BK virus-associated hemorrhagic cystitis in pediatric bone marrow transplantation patients: Does post-transplantation cyclophosphamide increase the frequency?

BACKGROUND: BKV-HC is one of the most significant complications of HSCT. This retrospective study aimed to determine the frequency of BKV-HC in pediatric patients undergoing HSCT, detect the associated risk factors for the development of BKV-HC, and explore the effects of post-transplantation Cy use. METHODS: Three hundred twenty-seven patients (girls: 121, boys: 206) were analyzed according to sex, conditioning regimen, transplantation type, donor relatedness, stem cell source, the presence and grade of aGVHD, CMV co-existence, and Cy use. RESULTS: Multivariate analysis confirmed the prognostic importance of age (OR: 4.865), TBI use, the presence of aGVHD (OR: 2.794), CMV coinfection (OR: 2.261), and Cy use (OR: 27.353). A statistically significant difference was found between the mean BKV-HC follow-up times compared with post-transplantation Cy intake (p < .001). The BKV-HC rate increased as the number of risk factors of the patient increased. CONCLUSION: BKV-HC is an essential complication of HSCT primarily associated with Cy use, the presence of aGVHD, and donor relatedness. The present study shows that the use of Cy in the post-transplantation period further increases BKV-HC risk in pediatric patients, regardless of dose.

Primary immunodeficiencies: HSCT experiences of a single center in Turkey.

BACKGROUND: Primary immunodeficiency diseases (PID) are characterized by the occurrence of frequent infections and are caused by many genetic defects. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for the majority of PID. As a Pediatric Hematology-Oncology-Immunology Transplantation Unit, we wanted to present our HSCT experience regarding treatment of primary immunodeficiency diseases. METHODS: 58 patients were included in the study between January 2014 and June 2019. We searched 9/10 or 10/10 matched-related donor (MRD) firstly, in the absence of fully matched-related donor. We screened matched unrelated donor (MUD) from donor banks. MRD was used in 24 (41.3%) patients, MUD in 20 (34.4%) patients, and haploidentical donors in 14 (24.1%) patients. Demographic data, HSCT characteristics, and outcome were evaluated. While 16 patients had severe combined immunodeficiency (SCID), the remaining was non-SCID. RESULTS: Of the 58 patients, 38 were male and 20 were female. Median age at transplantation was 12 months (range: 2.5-172 months). Combined immunodeficiencies consisted 67.2% of patients. Mean follow-up time was 27 months (6 months-5 years). Median neutrophil, lymphocyte, and thrombocyte engraftment days were similar in comparison of both donor type and stem cell source. The most common complication was acute GvHD in 15 (25.8%) patients. In total, five patients (31%) belonging to the SCID group and 10 patients (23.8%) belonging to the non-SCID group died. Our total mortality rate was 15 (25.8%) in all patients. CONCLUSIONS: We would like to present our HSCT experiences as a pediatric immunology transplantation center. Existing severe infections before transplantation period, BCGitis, and CMV are important issues of transplantation in Turkey. However, the follow-up time is shorter than some studies, our results regarding complications and survival are similar to previous reports.

Prognostic factors for survival in children who relapsed after allogeneic hematopoietic stem cell transplantation for acute leukemia.

BACKGROUND: Post-transplant relapse has a dismal prognosis in children with acute leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Data on risk factors, treatment options, and outcomes are limited. PROCEDURE: In this retrospective multicenter study in which a questionnaire was sent to all pediatric transplant centers reporting relapse after allo-HSCT for a cohort of 938 children with acute leukemia, we analyzed 255 children with relapse of acute leukemia after their first allo-HSCT. RESULTS: The median interval from transplantation to relapse was 180 days, and the median follow-up from relapse to the last follow-up was 1844 days. The 3-year overall survival (OS) rate was 12.0%. The main cause of death was disease progression or subsequent relapse (82.6%). The majority of children received salvage treatment with curative intent without a second HSCT (67.8%), 22.0% of children underwent a second allo-HSCT, and 10.2% received palliative therapy. Isolated extramedullary relapse (hazard ratio (HR): 0.607, P = .011) and relapse earlier than 365 days post-transplantation (HR: 2.101, P < .001 for 0-180 days; HR: 1.522, P = .041 for 181-365 days) were found in multivariate analysis to be significant prognostic factors for outcome. The type of salvage therapy in chemosensitive relapse was identified as a significant prognostic factor for OS. CONCLUSION: A salvage approach with curative intent may be considered for patients with post-transplant relapse, even if they relapse in the first year post-transplantation. For sustainable remission, a second allo-HSCT may be recommended for patients who achieve complete remission after reinduction treatment.

Are the Anxiety Levels of Pediatric Hematology-Oncology Patients Different From Healthy Peers During the COVID-19 Outbreak?

The COVID-19 outbreak has caused anxiety among children with hematology-oncology disease and their families, as it has in every segment of society. In this study, we aimed to detect the anxiety levels of children with hematologic or oncologic disease and of their parents after the COVID-19 outbreak. The sample consisted of 15 patients 12 to 18 years of age receiving treatment in the Pediatric Hematology and Oncology Unit in Altinbas University Medical Faculty Bahçelievler Medikalpark Hospital and 33 parents of the same unit patients between 6 and 18 years of age, and their 35 healthy peers and their parents. The State-Trait Anxiety Inventory was applied to participant children and their parents to evaluate their general anxiety and pandemic-related anxiety levels. Children with a hematology-oncology disease and their families were compared with healthy peers and their families. No significant difference was observed for pandemic-related anxiety levels (P>0.05). Both parent groups exhibited higher anxiety levels with regard to the pandemic than did their children (P<0.05). Children with hematology-oncology disease reported significantly higher trait anxiety levels when compared with healthy peers (P=0.01). The families of children who had not received stem cell transplantation had higher state and trait anxiety scores than the families of children who had received the transplantation (P<0.05). Even though they were in the high-risk group, children with a hematology-oncology disease and their families had pandemic-related anxiety levels comparable with those of healthy peers and their families.

Comparison of Hematopoietic Stem Cell Transplantation Results in Patients with ß-Thalassemia Major from Three Different Graft Types.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the curative therapy for ß-thalassemias that induces severe life-threatening complications. The human leukocyte antigen (HLA) registries and umbilical cord blood banks have carried out diligent searches to find matched unrelated donors (MUDs) for about 70.0% of patients from 2000 onwards. The chance of finding a non-sibling fully matched family donors is higher in some ethnic groups in which consanguineous marriages are common. We have studied and compared transplant complications and outcomes in different graft types (sibling, non-sibling family and unrelated). The non-sibling matched family donor (MFD) group consisted of four mothers, three fathers, five cousins, one paternal uncle and one paternal aunt. There was no significant difference in the mean transfused CD34+ cells, engraftment, median days of neutrophil and platelet recovery were achieved (p > 0.05). The distribution of postttransplant complication did not show any significant difference between groups (p > 0.05). In univariate analysis and multivarite analyses, age, gender, Pesaro risk group (I-II vs. III) and ABO incompatibilty demonstrated a significant difference in disease free survival (p < 0.05). Furthermore, in the second step of investigating overall survival (OS), age, gender and Pesaro risk group (I-II vs. III) showed a significant difference (p < 0.05). There was no significant difference in transplant-related mortality (TRM) between groups. Non-sibling related donor transplants are important for populations where consanguineous marriages are common. Transplant groups according to graft type had similar thalassemia-free survival (TFS) and OS when using a treosulfan-based regimen in our study.

Invasive Saprochaete capitata Infection in a Patient with Autosomal Recessive CARD9 Deficiency and a Review of the Literature.

PURPOSE: Autosomal recessive (AR) CARD9 deficiency is an inherited immune disorder which results in impaired innate immunity against various fungi. Superficial and invasive fungal infections, mainly caused by Candida or Trichophyton species, are the hallmark of CARD9 deficiency. Together with the increasing number of CARD9-deficient patients reported, different pathogenic fungal species have been described such as Phialophora, Exophiala, Corynespora, Aureobasidium, and Ochroconis. Saprochaete capitata is an opportunistic infectious agent in immunocompromised patients and is a common cause of invasive fungal disease in patients with hematological malignancies. In this study, we investigated the causative genetic defect in a patient with S. capitata fungal infection which disseminated to lymph nodes and common bile duct. METHODS: The identification of the isolated yeast strain was made by direct microscopic examination and confirmed by internal transcribed spacer (ITS) sequencing. We applied whole exome sequencing to search for the disease-causing mutation. Sanger sequencing was used to validate the mutation in the patient and his parents. RESULTS: S. capitata was isolated from the biopsy specimen as the causative microorganism responsible for the invasive fungal disease in the patient. Whole exome sequencing revealed a homozygous c.883C > T, (p.Q295*) mutation in CARD9, confirmed by Sanger sequencing. CONCLUSIONS: This is the first report of invasive Saprochaete infection associated with autosomal recessive (AR) CARD9 deficiency in the literature and thereby further extends the spectrum of fungal diseases seen in these patients.

Cross-sectional study: long term follow-up care for pediatric cancer survivors in a developing country, Turkey: current status, challenges, and future perspectives

Aim: The main purpose of this study is to determine the current status of long-term follow-up (LTFU) for childhood cancer survivors and the challenges of LTFU for pediatric cancer survivors at pediatric oncology institutions in Turkey. Material and methods: A questionnaire was e-mailed to the directors of 33 pediatric oncology centers (POCs) registered in the Turkish Pediatric Oncology Group (TPOG). Of these 33 active TPOG institutions, 21 participated in the study and returned their completed questionnaires. Results: Only 1 of the 21 participating centers had a separate LTFU clinic. The remaining centers provided LTFU care for childhood cancer survivors at the pediatric oncology outpatient clinic. Of these centers, 17 (80.9%) reported difficulty in transition from the pediatric clinic to the adult clinic, 14 (66.6%) reported insufficient care providers, and 12 (57.1%) reported insufficient time and transportation problems. As neglected late effects, 16 (76.1%) centers reported psychosocial and getty job problems and 11 (52.3%) reported sexual and cognitive problems. None of the centers had their own LTFU guidelines for their daily LTFU practice Conclusion: This study was the first to gain an overview of the needs of POCs and the gaps in survivorship services in Turkey. The results from this study will help to develop a national health care system and national guidelines for pediatric cancer survivors.

A case of neuroblastoma in DICER1 syndrome: Chance finding or noncanonical causation?

DICER1 syndrome is an inherited disorder associated with at least a dozen rare, mainly pediatric-onset tumors. Its characterization remains incomplete. Some studies suggested that neuroblastoma (NB) may be involved in this syndrome. Here, we describe the case of a 14-year-old female presenting with a multinodular goiter (MNG) and a collision tumor composed of NB and cystic nephroma (CN). She is a carrier of a deleterious germline mutation in exon 23 of DICER1 and harbored different somatic mutations in the CN and MNG. However, no second hit was found in the NB, questioning its status as a DICER1-related tumor.

The Diagnostic Value of Hepatic Arterial Velocity in Venoocclusive Disease After Pediatric Hematopoietic Stem Cell Transplantation.

The aim of this study was to determine usefulness of measurements of maximal systolic velocity of the hepatic artery with Doppler ultrasonography in the diagnosis of venoocclusive disease (VOD) after hematopoietic stem cell transplantation. We prospectively obtained 5 sonograms per patient: pretransplantation, day +1, +7, +14, and +28 on 36 nonconsecutive children who underwent hematopoietic stem cell transplantation. We examined the hepatic artery, the portal, hepatic and splenic veins, the thickness of the gallbladder wall, the presence of ascites, and the liver and spleen size. The diagnosis of VOD was based on clinical and laboratory data. Patients were divided into 2 groups: those with VOD (n=18) and those without VOD (n=18). The variance of 2 groups was analyzed. Vmax of the hepatic artery had a strong correlation with clinical VOD diagnosis (P<0.001). There was no statistically significant difference in the other Doppler parameters. The results of our study showed that the measurement of Vmax of the hepatic artery can provide important support in the diagnosis of VOD and can be useful in the follow-up of treatment response.

Vitamin D Receptor (VDR) Polymorphisms in Pediatric Patients Presenting With Hodgkin's Lymphoma.

Vitamin D receptor (VDR) polymorphisms are found more commonly in some tumor types than in healthy individuals, suggesting that some polymorphisms (Cdx2, Fok1, Bsm1, Apa1, Taq1) contribute to tumor development. There is no previous report on VDR polymorphism in Hodgkin's lymphoma (HL) patients. VDR polymorphism patterns in 95 pediatric HL cases with 100 healthy controls were compared. No statistically significant difference was found between the patient group and control group in terms of Cdx2, Fok1, Bsm1, Apa1, and Taq1 polymorphisms (P>0.5). Our findings suggest that VDR polymorphisms may not play a role in HL development.

Single-center experience with sirolimus therapy for vascular malformations.

Vascular malformations (VMs) are described as congenital malformations of the vasculature derived from capillaries, veins, lymphatic vessels, arteries, or a combination of these vessels. They can cause significant morbidity resulting from soft tissue hypertrophy-related disfiguration, bony abnormalities, and even organ compromise. They are usually treated with various interventional procedures to achieve local control; however, the chance of success decreases as the anatomical distribution of the malformation widens. Unfortunately, medical treatment options have been quite limited in these patients. Sirolimus is an antiangiogenetic and antiproliferative pharmacologic agent that has been used for the management of VM in the last decade. We report 6 pediatric patients (4 with capillary lymphaticovenous malformations, 1 with lymphaticovenous malformation, and 1 with venous malformation) seen at our clinic within the last 2 years with lesions covering wide anatomical areas. After the patients had unsuccessfully undergone various treatments at various centers, they were treated at our facility with peroral sirolimus. The mean duration of treatment was 13 months, but in 3 patients, tapered dosing continues. Five patients achieved partial responses. The response to sirolimus treatment increased as the lymphatic component of the VM increased. All patients tolerated sirolimus well; side effects were acceptable. Sirolimus is a safe and effective medical treatment for widely distributed VMs with significant lymphatic components and no further local treatment option.

Successful Treatment of Macroglossia Due to Lymphatic Malformation With Sirolimus.

OBJECTIVE: To evaluate the effectiveness and safety of sirolimus therapy in a child with macroglossia due to lymphatic malformation. METHODS: Sirolimus treatment was applied to the patient with an initial dosing of 0.8 mg/m2 per dose, administered orally, twice daily at approximately 12-hour intervals. RESULTS: After 9 months of sirolimus therapy, there was a nearly complete resolution of lymphatic malformation. The last evaluation was performed 6 months after withdrawal of treatment, and the lesion had almost completely resolved. CONCLUSION: This article presents a novel approach to the treatment of lymphatic malformation of the tongue using sirolimus, which appears to be safe and effective for the management of complex cases.

Regression of symptomatic multiple cardiac rhabdomyomas associated with tuberous sclerosis complex in a newborn receiving everolimus.

UNLABELLED: Cardiac rhabdomyoma is the most common primary cardiac tumor, is considered to be a hamartoma of developing cardiac myocytes. Cardiac rhabdomyoma is associated with tuberous sclerosis complex (TSC) in 50-86% of cases. Mutations in TSC-1/TSC-2 genes result in increased mammalian target of rapamycin (mTOR) pathway activation responsible for the hamartomatous lesions of tuberous sclerosis complex. Therapy with mTOR inhibitors is currently under investigation as a treatment option for tumors associated with TSC. In this report we present a case with multiple symptomatic rhabdomyomas associated with tuberous sclerosis complex, deemed to be ineligible for surgical removal, treated with everolimus (mTOR inhibitor). CONCLUSION: As we observed in our patient, in cases with inoperable symptomatic rhabdomyomas associated with TSC, everolimus, an mTOR inhibitor, may be the treatment of choice, which should be confirmed with additional studies.

A subcutaneous paraspinal yolk sac tumor in a child.

A 3-year-old girl underwent a surgery at an external center on July 2011 for a swelling in the left lumbar paravertebral subcutaneous region. The mass was completely excised and the pathologic diagnosis was a yolk sac tumor (YST). Laboratory tests revealed a serum α-fetoprotein level of 278 IU/mL. Investigations using bone scintigraphy and magnetic resonance imaging revealed a scar tissue at the surgical site and lesions indicating metastasis at the lumbar first, second, third, and fifth vertebra. The patient was administered 5 cycles of PEB (cisplatin, etoposide, bleomycin) treatment. The serum α-fetoprotein was 3 IU/mL after the treatment. The lumbar magnetic resonance imaging and bone scintigraphy results were normal. The patient continues to be in remission since June 2012. YSTs are most commonly seen in the testis, ovary, and sacrococcygeal regions. Atypical locations have been reported with the primary lesion in the stomach, diaphragm, omentum, sino-nasal region, cranial base, lungs, vagina, and penis. Our case is probably a YST with an atypical location derived from preliminary cells left under the skin because of a migration defect.