Results of a long-term, prospective study on complications of central venous catheter in pediatric patients with hematologic-oncologic diseases.

BACKGROUND: Central venous catheter (CVC)-related complications remain a significant cause of morbidity in pediatric hematology-oncology. We prospectively surveyed the incidence of CVC-related complications in children with hematologic-oncologic diseases. PROCEDURE: Five-hundred-eighty-one CVCs were inserted in 421 patients from January 2010 to June 2022 (153,731 CVC days observation; follow-up data up to December 31, 2022). RESULTS: Overall, 671 complications were recorded (4.365/1000 CVC days): 49.7% malfunctions (1.88/1000 CVC days, 4.8% of CVC early removals), 23.9% bacteremia (0.90/1000, 15.1%), 19.6% mechanical complications (0.74/1000, 70.2%), 20.1% localized infections (0.76/1000, 17.1%), 0.5% thrombosis (0.02/1000, 33.3%). At multivariate analysis, risk factors for malfunction were Broviac-Hickman type of CVC (hazard ratio [HR] 2.5) or Port-a-cath (HR 3.4) or Proline (HR 4.3), p < .0001; for bacteremia double-lumen CVC (HR 3.2, p < .0001); for mechanical complications age at CVC insertion under median (HR 4.5, p < .0001) and Broviac-Hickman (HR 1.6) or Proline (HR 2.7), p = .01; finally for localized infections Broviac-Hickman (HR 2.9) or Proline (HR 4.4), p = .0001. The 2-year cumulative incidence of premature removal was 23.5%, and risk factors were age at CVC insertion under median (HR 2.4, p < .0001), Broviac-Hickman (HR 2.3) or Proline (HR 4.2), p < .0001. CONCLUSIONS: Premature removal occurs in approximately 20%-25% of long-term CVCs. A surveillance program has a fundamental role in identifying the risk factors for CVC complications and the areas of intervention to improve CVC management.

Refractory Anaplastic Large Cell Lymphoma Rescued by the Combination of the Second-Generation ALK Inhibitor Brigatinib, High-dose Chemotherapy and Allogeneic Stem Cell Transplantation: A Case Report and Review of the Literature.

The treatment of pediatric patients with refractory or relapsed anaplastic large cell lymphoma (ALCL) is still a major challenge. In addition to conventional chemotherapy and stem cell transplantation, new therapeutic options such as anti-CD30 drugs and anaplastic lymphoma kinase (ALK) inhibitors have been recently introduced in this setting. Among ALK inhibitors, only the first-generation molecule crizotinib is approved for pediatric use, while second-generation molecules, such as brigatinib, are still under investigation. Here we report the case of a 13-year-old boy diagnosed with stage IV ALCL, refractory to first-line conventional chemotherapy and second-line therapy with the anti CD30 antibody-drug conjugate brentuximab-vedotin, who finally achieved remission after a combination of conventional high-dose chemotherapy and the second-generation ALK inhibitor brigatinib. The latter was chosen for its ability to penetrate through the blood-brain barrier, due to the persistent involvement of the patient's cerebral nervous system. The remission was then consolidated with an allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor using myeloablative conditioning with total body irradiation. At 24 months after HSCT, the patient is in complete remission, alive and well. An updated review regarding the use of ALK inhibitors in ALCL patients is provided.

Characteristics and Outcomes of Bloodstream Infections in a Tertiary-Care Pediatric Hematology-Oncology Unit: A 10-Year Study.

Bloodstream infections (BSIs) after chemotherapy or hematopoietic stem cell transplantation (HSCT) are a leading cause of morbidity and mortality. Data on 154 BSIs that occurred in 111 onco-hematological patients (57 hematological malignancies, 28 solid tumors, and 26 non-malignant hematological diseases) were retrospectively collected and analyzed. Monomicrobial Gram-positive (GP), Gram-negative (GN), and fungal BSIs accounted for 50% (77/154), 38.3% (59/144), and 3.2% (5/154) of all episodes. Polymicrobial infections were 7.8% (12/154), while mixed bacterial-fungal infections were 0.6% (1/154). The most frequent GN isolates were Escherichia coli (46.9%), followed by Pseudomonas aeruginosa (21.9%), Klebsiella species (18.8%), and Enterobacter species (6.3%). Overall, 18.8% (12/64) of GN organisms were multidrug-resistant (seven Escherichia coli, three Klebsiella pneumoniae, and two Enterobacter cloacae), whereas GP resistance to glycopeptides was observed in 1% (1/97). Initial empirical antibiotic therapy was deemed inappropriate in 12.3% of BSIs (19/154). The 30-day mortality was 7.1% (11/154), while the bacteremia-attributable mortality was 3.9% (6/154). In multivariate analysis, septic shock was significantly associated with 30-day mortality (p = 0.0001). Attentive analysis of epidemiology and continuous microbiological surveillance are essential for the appropriate treatment of bacterial infections in pediatric onco-hematological patients.

Long-term and quality of survival in patients treated for acute lymphoblastic leukemia during the pediatric age.

Long-term survival for acute lymphoblastic leukemia (ALL) in children improved over the last three decades up to 80-90% of affected patients. Consequently, the quality of life of survivors has become increasingly important. This study analyses the clinical features and outcome of 119 children with ALL, focusing on the quality of long-term survival in a subset of 22 patients over 18 years of age. Among this group, the 10-year event-free survival and overall survival were 83.1% (C.I. 74.0-89.2) and 88.4% (C.I. 80.9-93.1), respectively. Treatment related long-term medical complications were reported only in 2 patients (9.1%). Secondary school was completed successfully in 20 of 22 patients (89.9%). The remaining 2 patients were still attending at the time of the analysis. In conclusion, current treatment for ALL is well tolerated and does not compromise significantly the quality of life of survivors.

Female adolescents and young women previously treated for pediatric malignancies: assessment of ovarian reserve and gonadotoxicity risk stratification for early identification of patients at increased infertility risk.

OBJECTIVES: Childhood and adolescent cancer survivors (CACSs) are at risk of adverse reproductive outcomes. Assessment of follicle-stimulating hormone (FSH) levels is the most common test used to diagnose premature ovarian insufficiency (POI) whereas anti-m|llerian hormone (AMH) and antral follicle count (AFC) have been proposed as ovarian reserve markers. We assessed the correlation between these markers and treatment gonadotoxicity risk (GR) in CACSs. METHODS: A total of 55 female CACSs were enrolled. GR was graded as low, medium, or high according to classifications based on disease and treatments and on cyclophosphamide equivalent dose score. FSH, AMH, and AFC were determined. POI was defined by amenorrhea and FSH>30 IU/L. For remaining patients, diminished ovarian reserve (DOR) was defined by AMH<5th centile. FSH and AFC cut-offs proposed in the literature as DOR markers were also considered (FSH>10 IU/L or >95th centile; AFC<8 or <5th centile). RESULTS: Ovarian reserve results to be compromised in 23 (41.8%) patients: 14 with DOR and 9 with an established POI. Results showed GR classifications to be a good predictor of ovarian reserve, with significantly lower AMH and AFC in the high-risk groups. AFC resulted to be directly correlated with AMH (r=0.75, p<0.001). CONCLUSIONS: In CACSs, GR classifications correlate with post-treatment AMH and AFC. These are useful tools in the early identification of young patients with DOR, who may benefit from reproductive and fertility preservation counseling. Further studies are needed to determine the rate and time of progression from DOR to POI in this population.

The Diagnostic Pitfalls of Mucormycosis.

BACKGROUND: Invasive mucormycosis is a very aggressive fungal disease among immunocompromised pediatric patients caused by saprophytic fungi that belong to the order of the Mucorales. CASE REPORT: We describe a case of of Lichtheimia corymbifera infection in a 15-year-old child with B-cell-Non-Hodgkin Lymphoma (B-NHL) involving lung, kidney and thyroid that initially was diagnosed as probable aspergillosis delaying the effective therapy for mucormycosis. CONCLUSIONS: This case showed that also the intensive chemotherapy for B-NHL may represent a risk factor for mucormycosis infection. Liposomal amphotericin B and surgery remain the key tools for the successful treatment of this aggressive disease.

Acute Cervical Longitudinally Extensive Transverse Myelitis in a Child With Lipopolysaccharide-Responsive-Beige-Like-Anchor-Protein (LRBA) Deficiency: A New Complication of a Rare Disease.

Lipopolysaccharide responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disorder (PID) that can cause a common variable immunodeficiency (CVID)-like disease. The typical features of the disease are autoimmunity, chronic diarrhea, and hypogammaglobulinemia. Neurological complications are also reported in patients affected by LRBA deficiency. We describe a 7-year old female with an acute cervical longitudinally extensive transverse myelitis (LETM) as a feature of LRBA deficiency. This is the first case of LETM associated with LRBA deficiency described in literature.

The Impact of Chemotherapy after Pediatric Malignancy on Humoral Immunity to Vaccine-Preventable Diseases.

BACKGROUND/AIM: The antibody titer of vaccine-preventable diseases in pediatric patients who underwent chemotherapy was assessed in order to evaluate the seroprotection after treatment and the feasibility and the efficacy of a policy of revaccination. METHODS: Serum antibody titers of 55 patients for hepatitis B (HBV), rubella, varicella-zoster (VZV), measles, mumps, polio viruses, Clostridium tetani (C. tetani) and Streptococcus pneumoniae (S. pneumoniae) were analysed.Results: After chemotherapy, a lack of protective antibody titers against HBV, rubella, VZV, measles, mumps, polio viruses, C. tetani, and S. pneumoniae was found in 53%, 45%, 46%, 46%, 43%, 21-26%, 88% and 55% of patients, respectively. In 49 of 55 patients who were tested both before and after chemotherapy for at least a pathogen, the loss of immunity for HBV, rubella, VZV, measles, mumps, polio viruses and C. tetani was respectively 39%, 43%, 38%, 42%, 32%, 33%, and 80%. A low number of B-lymphocytes was associated with the loss of immunity against measles (p=0.04) whereas a high number of CD8+ T-lymphocytes was associated with the loss of immunity against VZV (p=0.03). A single booster of vaccine dose resulted in a seroprotection for HBV, rubella, VZV, measles, mumps, polio viruses, C. tetani and S. pneumoniae in 67%, 83%, 80%, 67%, 33%, 100%, 88% and 67% of patients, respectively. CONCLUSIONS: We confirm that seroprotection for vaccine-preventable diseases is affected by treatment for pediatric malignancy. A single booster dose of vaccine might be a practical way to restore vaccine immunity in patients after chemotherapy.

Chronic Graft-Versus-Host-Disease-Related Polymyositis: a 17-Months-Old Child with a Rare and Late Complication of Haematopoietic Stem Cell Transplantation.

BACKGROUND: Chronic graft versus host disease (cGVHD) occurs in 20-30% of paediatric patients receiving haemopoietic stem cell transplantation (HSCT). Neuromuscular disorders such as polymyositis are considered a rare and distinctive but non-diagnostic manifestation of cGVHD and, in the absence of other characteristic signs and symptoms, biopsy is highly recommended to exclude other causes. CASE REPORT: We report a case of a 17-months-old child affected by hemophagocytic lymphohistiocytosis who underwent a matched unrelated donor haematopoietic stem cell transplantation (HSCT). She developed severe cGVHD-related polymyositis that was successfully treated with high-dose steroid therapy, rituximab and sirolimus. CONCLUSIONS: This is the first case of cGVHD-related-polymyositis described in a pediatric patient which was successfully treated with rituximab.

Pure Red Cell Aplasia (PRCA) and Cerebellar Hypoplasia as Atypical Features of Polyglandular Autoimmune Syndrome Type I (APS-1): Two Sisters With the Same AIRE Mutation but Different Phenotypes.

The polyglandular autoimmune syndrome type I is a rare hereditary autosomal recessive disease. We describe a child with the classic triad of the disease and her sister with pure red cell aplasia and cerebellar hypoplasia. The latter received two haematopoietic stem cell transplantations, complicated by an acute disseminated encephalomyelitis.

Pediatric intracranial ependymoma: correlating signs and symptoms at recurrence with outcome in the second prospective AIEOP protocol follow-up.

PURPOSE: The aims of patients' radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear. METHODS: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months. RESULTS: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5-104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients. CONCLUSIONS: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI.

Successful Management of Kaposiform Hemangioendothelioma with Long-Term Sirolimus Treatment: a Case Report and Review of the Literature.

BACKGROUND: Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumour of the infancy and the first decade of life. It is locally aggressive and potentially life threatening when associated with consumptive coagulopathy, known as Kasabach-Merritt syndrome (KMS). No consensus or guideline for the therapy has been reached because of the lack of prospective trials, and the different standard care suggestions are based on retrospective case series. CASE REPORT: We report the case of a 9-month-old male with KHE and KMS in which the initial response, obtained with prednisone and vincristine, was subsequently consolidated and strengthened by long-term treatment with sirolimus, a mTOR inhibitor. A summary of the published data is presented as well. CONCLUSIONS: The inhibition of mTOR pathway represents the most important therapeutic innovation introduced in the last few years for KHE. Our case shows the effectiveness and good tolerance of long-term therapy with sirolimus.

Venoocclusive disease due to chemotherapy for pediatric acute lymphoblastic leukemia is associated with increased levels of plasminogen-activator inhibitor-1.

We describe three cases of sinusoidal obstruction syndrome/venoocclusive disease (SOS) in pediatric patients with acute lymphoblastic leukemia (ALL). All three episodes occurred during or just after the induction or reinduction phase of treatment based on prednisone/dexamethasone, vincristine, daunorubicin, and pegylated-l-asparaginase. SOS episodes were categorized as mild/moderate and resolved in 7, 10, and 16 days using supportive measures or defibrotide therapy. In all three episodes, the clinical diagnosis of SOS was associated with a significant increase in plasminogen-activator inhibitor-1 (PAI-1) that reduced with patient clinical improvement. PAI-1 warrants study as a diagnostic marker for SOS in ALL.

ALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation.

Adenosine deaminase 2 (ADA2) deficiency is an auto-inflammatory disease due to mutations in cat eye syndrome chromosome region candidate 1 (CECR1) gene, currently named ADA2. The disease has a wide clinical spectrum encompassing early-onset vasculopathy (targeting skin, gut and central nervous system), recurrent fever, immunodeficiency and bone marrow dysfunction. Different therapeutic options have been proposed in literature, but only steroids and anti-cytokine monoclonal antibodies (such as tumor necrosis factor inhibitor) proved to be effective. If a suitable donor is available, hematopoietic stem cell transplantation (HSCT) could be curative. Here we describe a case of ADA2 deficiency in a 4-year-old Caucasian girl. The patient was initially classified as autoimmune neutropenia and then she evolved toward an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. The diagnosis of ALPS became uncertain due to atypical clinical features and normal FAS-induced apoptosis test. She was treated with G-CSF first and subsequently with immunosuppressive drugs without improvement. Only HSCT from a 9/10 HLA-matched unrelated donor, following myeloablative conditioning, completely solved the clinical signs related to ADA2 deficiency. Early diagnosis in cases presenting with hematological manifestations, rather than classical vasculopathy, allows the patients to promptly undergo HSCT and avoid more severe evolution. Finally, in similar cases highly suspicious for genetic disease, it is desirable to obtain molecular diagnosis before performing HSCT, since it can influence the transplant procedure. However, if HSCT has to be performed without delay for clinical indication, related donors should be excluded to avoid the risk of relapse or partial benefit due to a hereditary genetic defect.

Biliary tract rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Associazione Italiana Ematologia Oncologia Pediatrica.

INTRODUCTION: Rhabdomyosarcoma is a soft tissue malignant musculoskeletal tumor frequent in children. Biliary duct localization is extremely rare, but it is the most common cause of malignant obstructive jaundice in pediatric patients. METHODS: This report describes a series of 10 patients under 18 years of age with biliary tract rhabdomyosarcoma who were enrolled, from 1979 to 2004, in 3 consecutive Italian pediatric cooperative protocols that had been drawn up by the Soft Tissue Sarcoma Committee of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). RESULTS: Considering initial and delayed surgery, tumor resection was achieved in 7 cases, 3 complete with free margins (2 liver transplants) and 4 with microscopic residual disease. Chemotherapy was given to all patients and radiotherapy to 3. At present, 5 patients survive in complete remission 90-200 months after diagnosis while 4 died of disease progression or relapse and 1 of liver transplant-related complications. CONCLUSIONS: Better outcomes in this series were associated with the feasibility of conservative surgery due to the favorable location of the tumor, in particular in the common bile duct. Chemotherapy and radiotherapy might obviate the need for demolitive surgery or liver transplant, which were linked to worse outcomes in our series.

Bone marrow features in Pearson syndrome with neonatal onset: A case report and review of the literature.

Pearson syndrome (PS) is a rare mitochondrial disorder that usually presents with transfusion-dependent macrocytic anemia, exocrine pancreatic dysfunction, and lactic acidosis. Typical bone marrow (BM) features are vacuolization in hematopoietic progenitors, hypocellularity, and ringed sideroblasts. At the neonatal age, PS may have a variable clinical onset. Moreover, there is little information about BM features at this age and the timing of their presentation. We report a neonatal case of PS that presented with refractory anemia and atypical BM features. We reviewed the BM findings in neonatal-onset PS cases to stress the importance and limitations of BM evaluation at this age.

Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma.

BACKGROUND: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). METHODS: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. RESULTS: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. CONCLUSIONS: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

The Use of Splenectomy to Manage Platelet Transfusion Refractoriness due to Anti-Human Leukocyte Antibodies in Allogeneic Stem Cell Transplantation.

In patients undergoing hematopoietic stem cell transplantation (HSCT), refractoriness to platelet transfusion has been associated with graft failure, delayed engraftment, early mortality and decreased overall survival. Therapeutic strategies include plasma exchange, immunoglobulins, rituximab, and splenectomy. We describe here three patients with refractoriness to platelet transfusion due to anti-human leukocyte antibodies who were splenectomized before HSCT (two cases) and after HSCT (one case) due to the lack of efficacy of other therapies. Splenectomy was uneventful. All three patients achieved a full donor engraftment. We suggest that splenectomy is feasible and effective in HSCT patients to reduce the risk of graft failure or delayed engraftment.