Background: Children with hematologic malignancies, especially those who receive intensive chemotherapy, are at high risk for invasive mold infections (IMI) that confer substantial mortality. Randomized controlled trials support the use of anti-fungal prophylaxis with anti-mold activity as an optimal strategy for risk reduction in this population, but studies outlining the practical application of evidence-based recommendations are lacking. Procedure: We conducted a 15-year, single-institution retrospective review of children with hematologic malignancies treated with chemotherapy to determine the incidence of proven or probable IMI diagnosed between 2006 and 2020 and to identify the host and disease factors associated with IMI risk. We then compared the incidence and type of IMI and related factors before and after 2016 implementation of an evidence-based, risk-adapted anti-fungal prophylaxis algorithm that broadened coverage to include molds in patients at highest risk for IMI. Multivariable linear regression was used to determine factors related to IMI risk. Results: We identified 61 cases of proven or probable IMI in 1,456 patients diagnosed with hematologic malignancies during the study period (4.2%). Implementation of an anti-fungal prophylaxis algorithm reduced the IMI incidence in this population from 4.8% to 2.9%. After multivariable analysis, both Hispanic ethnicity and cancer diagnosis prior to 2016 were significantly associated with risk for IMI. Conclusion: An evidence-based, risk-adapted approach to anti-fungal prophylaxis for children with hematologic malignancies is an effective strategy to reduce incidence of IMI.
Objective: 7-50% of children with medulloblastoma (MB) develop postoperative cerebellar mutism syndrome (pCMS). pCMS has a short-term negative impact on intelligence, but results on long-term outcomes are contradictory. The aim of this study was to assess long-term effects of pCMS in MB patients on aspects of intelligence (IQ) and its perioperative risk factors. Methods: In this single centre retrospective cohort study, 31 children with MB were included of which 14 had pCMS. Peri-operative risk factors included brainstem invasion, vermis incision, pre-and post-operative hydrocephalus, tumor size, duration and severity of pCMS, neurological symptoms on day 10 after surgery, mean body temperature (BT) on days 1-4 post surgery, and age at resection. Age appropriate Wechsler Intelligence tests were assessed within a structured follow up programme. Results: No significant differences in IQ scores were found between pCMS and non pCMS groups. The pCMS group had a clinically relevant difference of 10 points when compared to age norms on verbal IQ (VIQ). Bilateral pyramidal and swallowing problems were risk factors for lower performance in this group. In the overall group, tumor size, younger age at surgery, and raised mean BT on days 1-4 post-surgery were negatively correlated with aspects of IQ. Conclusions: We found a clinically significant reduction of VIQ in the pCMS patient group. pCMS patients with a larger tumor size, younger age at surgery, a higher mean BT in the first days after surgery, bilateral pyramidal symptoms, and swallowing problems 10 days post-surgery are more at risk for VIQ deficits at long-term.
Unusual ovarian leukemic relapse in a girl with history of B cell lymphoblastic leukemiaACH Fung, KKY WongTo the editor:Extramedullary leukemic recurrence mostly occurs in the central nervous system and occasionally in the skin.  Here, we report an unusual case of a girl with relapsed lymphoblastic leukemia involving the ovary, presenting as a large pelvic mass.A 10-year-old girl with history of B cell lymphoblastic leukaemia treatment and in remission 1 year ago presented to oncology clinic with an enlarging pelvic mass for 2 months. Magnetic resonance imaging revealed a large lobulated solid heterogeneous pelvic mass (measuring 12cm in greatest dimension) with mass effect on pelvic organs (Figure 1a). Bone marrow aspirate at conventional site confirmed absence of lymphoblastic cells, which would have suggested leukaemia relapse. In view of the suspicion of a second primary tumour in the ovary with complication, exploratory laparotomy and left salpingo-oophorectomy were performed (Figure 1b). Histology showed diffuse infiltration of the ovary by B cell lymphoblastic leukaemia. Hematoxylin and eosin staining showed sheets of lymphoid cells with irregular nuclei. The tumour cells are positive for TdT, CD19, CD79a and CD34. (Figure 1c) She was well after operation. In view of extramedullary relapse, bone marrow aspirate was repeated after operation at anterior iliac spine which confirmed bone marrow relapse. She received treatment according to high risk protocol of CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children .Acute lymphoblastic leukaemia (ALL) is responsible for one-third of childhood malignancy. Despite efforts in the treatment of ALL, 15-20% of patients developed relapse with highest risk immediately after cessation of treatment and diminishes with time.  Extramedullary involvement constitutes 2-5% of all relapses with the majority in the central nervous system. It seldom involves other sites, such as the eye, kidney, and omentum. Ovarian leukemic relapse is rarely reported in children with scarce case reports in the literature [4, 5] It is insidious and not usually detected until symptoms arise. Patient most commonly presents with lower abdominal pain or a palpable large abdominal mass.  Timely detection is important as it often coincides with marrow recurrence. Routine surveillance pelvic sonography is recommended for timely detection of pelvic extramedullary relapse. In patients with background of leukaemia presenting with an ovarian mass, a higher level of suspicion needs to be kept. In the absence of evidence in bone marrow relapse at conventional site, repeat marrow aspirate at another site would be warranted since this affect the choice of management. Previous reports shown that mainly chemotherapy had a beneficial effect, while neither local radiation nor extensive surgical resection of the leukaemic mass had any obvious effect on overall outcome . Operation could have been avoided if marrow relapse is confirmed at the time of ovarian mass detection. However, surgical excision was reported to have role in situation when bone marrow had good response but no signs of regression of ovarian mass. Reference1. Kim, J.W., et al., Ovarian and multiple lymph nodes recurrence of acute lymphoblastic leukemia: a case report and review of literature. Pediatr Surg Int, 2008. 24 (11): p. 1269-73.2. CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children .https://ClinicalTrials.gov/show/NCT04224571.3. Berretta, R., et al., Isolated ovarian relapse of pre-B acute lymphoblastic leukemia: a case report. J Pediatr Adolesc Gynecol, 2009.22 (4): p. e65-8.4. Kantekure, K., et al., A unique case of relapsed B-acute lymphoblastic leukemia/lymphoma as an isolated omental mass. Case Rep Hematol, 2014. 2014 : p. 425163.5. Sava, C.N., et al., Unusual extramedullary relapses in a case of common B-cell acute lymphoblastic leukemia. Case report and review of literature. Rom J Morphol Embryol, 2019. 60 (1): p. 249-254.6. Turial, S., et al., Ovarian tumours: late extramedullary recurrence of acute leukaemia. Eur J Pediatr Surg, 2009.19 (3): p. 184-6.7. Lane, D.M. and R.L. Birdwell, Ovarian leukemia detected by pelvic sonography. A case report. Cancer, 1986. 58 (10): p. 2338-42.8. Pais, R.C., et al., Ovarian tumors in relapsing acute lymphoblastic leukemia: a review of 23 cases. J Pediatr Surg, 1991.26 (1): p. 70-4.9. Till, H., O. Muensterer, and U. Graubner, Laparoscopic adnexectomy of a persistent ovarian tumor in a girl with acute lymphoblastic leukemia relapse. Pediatr Hematol Oncol, 2003.20 (5): p. 417-20.
Purpose: Craniospinal irradiation (CSI) has historically treated the entire vertebral body (VB) in growing children. Vertebral body sparing proton craniospinal irradiation (VBSpCSI) is a technique which spares the majority of the VB from significant irradiation. This retrospective study reviews the acute toxicity of VBSpCSI compared to photon CSI. Methods: Pediatric CSI patients treated between 2008 and 2018 were evaluated. Patients were stratified to the VBSpCSI cohort or the photon cohort and analyzed for acute toxicity profile during treatment and disease-free survival (DFS). Statistical analysis was performed using Kaplan-Meier log rank analysis for DFS and Fisher’s exact test for toxicity. Results: Twenty-five patients received VBSpCSI and 13 patients received photon CSI. Mean patient age at treatment was 7.5y (range 2 to 16). The cohorts were well-matched with respect to gender, age, and CSI dose. Two-year DFS was similar between cohorts (81% VBSpCSI vs 61% photon, p=0.18). Patients receiving VBSpCSI had lower rates of grade 2+ GI toxicity (24% vs 76.5%, p=0.005), grade 2+ nausea (24% vs 61.5%, p=0.035), and any-grade esophagitis (0% vs 38%, p=0.0026). Patients treated with VBSpCSI had lower red blood cell transfusion rates (21.7% vs 60%, p=0.049) and grade 4+ lymphopenia (33.3% vs 77.8%, p=0.046). Conclusions: VBSpCSI in children is a volumetric de-escalation from traditional volumes which irradiate the entire vertebral body. Based on our results, VBSpCSI was associated with less acute gastrointestinal and hematologic toxicity. The study adds to the growing body of evidence supporting the use of protons over photons for pediatric CSI.
Congenital lymphatic leak may develop in patients with maldeveloped lymphatics and result in life-threatening fluid and electrolyte imbalance, protein deficiency and immunodeficiency. Rapid diagnosis and therapy are necessary to prevent these complications; however, the field lacks clinical trials to support standardized diagnostic treatment guidelines. We present our current multidisciplinary approach to the diagnosis and management of congenital lymphatic leak including chylous pleural effusion and ascites. Depending on the rate of lymphatic leak, therapy can range from observation with nutritional modifications to surgical and interventional procedures aimed to reduce lymphatic drainage. Modalities to image central and peripheral lymphatics have advanced considerably. Genetic variants and subsequent targets that drive lymphatic maldevelopment have expanded the repertoire of possible pharmacotherapeutic options.
Background: Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy has been established as a novel treatment approach for peritoneal sarcomatosis. Despite promising clinical reports, there is still a lack of knowledge regarding optimal drug usage and local effects. Therefore, we intended to establish a murine animal model for further evaluation. Procedure: Alveolar rhabdomyosarcoma cells were xenotransplanted into NOD/LtSz-scid IL2Rγnullmice (n=100). The mice received a continuous intraperitoneal lavage with isotonic saline solution as control- or with cisplatin (30 or 60 mg/m2) as treatment group for 60 minutes at 37 or 42 °C (6 subgroups, each n=16). Tumor spread was documented by an adapted peritoneal cancer index and MRI (n=4). Tumor and tissue samples, harvested at the end of the perfusion, were evaluated regarding morphology, proliferation and apoptosis (H&E-, Ki-67-, Cleaved Caspase 3-staining, TUNEL-assay). Results: Extensive peritoneal sarcomatosis in over 91% of the cases was observed. HIPEC was feasible without acute side effects. Ki-67 staining revealed concentration- or temperature-dependent effects of cisplatin-based HIPEC on the tumors. While Cleaved Caspase-3 showed only sporadic apoptotic effects. TUNEL-assay detected concentration- or temperature-dependent apoptotic effects at the outer tumor surface. MRI scans confirmed the observed tumor dissemination. Conclusion: This is the first animal model for evaluation of HIPEC in pediatric RMS in mice. Cisplatin-based HIPEC had early effects on the proliferation whereas circumscribed apoptotic effects could be detected at the tumor surface. This model allows further insights on the possible efficiency of HIPEC in RMS. Further studies using other drug combinations and treatment will follow.
A 13-year-old healthy girl presented with dizziness and palpitations, found to have a left atrial mass. An 8 cm tumor was removed. Pathology confirmed leiomyosarcoma, Grade 3 with positive margins. She was treated with ifosfamide and doxorubicin prior to radiation with concurrent ifosfamide alone. She was treated to 66 Gy in 33 fractions to the operative bed. Prospectively graded toxicities included Gr 2 esophagitis and Gr 1 anorexia, dermatitis and fatigue. She completed a total of 6 cycles of ifosfamide. One year after treatment she had no evidence of disease with normal ECHO and no cardiac, pulmonary or esophageal symptoms.
Introduction - Treatment abandonment contributes significantly to poor survival of children with cancer in low-middle-income countries (LMICs). In order to inform an approach to this problem at our Cancer Unit, we investigated why caregivers withdraw their children from treatment. Methods – In a qualitative study, in-depth interviews were conducted with caregivers of children who had abandoned cancer treatment at the Paediatric Cancer Unit (PCU) of Mbarara Regional Referral Hospital (MRRH) in South Western Uganda, between May 2017 and September 2020. Recorded in-depth interviews with caregivers were transcribed and analyzed to identify themes of caregiver self-reported reasons for treatment abandonment. Results - Seventy-seven out of 343 (22.4%) children treated for cancer at MRRH abandoned treatment during the study period; 20 contactable and consenting caregivers participated in the study. The median age of children’s caregivers was 37 years and most (65%) were mothers. At the time of this study, eight (40%) children were alive and 5 (62.5%) were males; with a median age of 6.5 years. Financial difficulties, other obligations, the child falsely appearing cured, preference for alternative treatments, belief that cancer was incurable, fear that the child’s death was imminent and chemotherapy side-effects were the caregivers’ reasons for treatment abandonment. Conclusions and Recommendation – Treatment abandonment among children with cancer in Uganda is, most times, as a result of difficult conditions beyond the caregivers’ control and needs to be approached with empathy and support.
Background Previous studies have explored post-hematopoietic cell transplant (HCT) outcomes by race in adults; however, pediatric data addressing this topic are scarce. Procedure This retrospective registry study included 238 White (W) and 57 Black (B) children with hematologic malignancies (HM) receiving first allogeneic HCT between 2010 and 2019 in one of five Florida pediatric HCT centers. Results We found no differences between W and B children by transplant characteristics, other than donor type. There was a significant difference in use of HLA-mismatched donors (HLA-MMD) (53% W, 71% B, p=0.01). When comparing HLA-MMD use to fully HLA-matched donors, B had RR of 1.47 [95% CI 0.7-3] of receiving a mismatched unrelated donor (MMUD), RR of 2.34 [95% CI 1.2-4.4] of receiving a mismatched related donor (MMRD), and a RR of 1.9 [95% CI 0.99-3.6] of receiving a mismatched cord blood donor (MMCBD) HCT, respectively. There was no significant difference in the incidence of aGVHD (48% W, 35% B), p=0.1 or cGVHD (19% W 28% B, p=0.1), or primary cause of death. Overall 24-month survival was 61% [95% CI 54-68%] for W, and 60% [95% CI 38-68] for B children, log-rank p=0.72. While HLA matching improved survival in W children, the number of B children receiving HLA-matched HCT was too small to identify the impact of HLA matching on survival. Conclusions In this contemporary cohort of children with HM we found that B children were more likely to receive HLA-MMD transplants, but this did not adversely affect survival or GVHD rates.
Background – Loss of bone mineral is a common concomitant of the treatment of acute lymphoblastic leukemia (ALL) due mainly to chemotherapy, especially with corticosteroids. Osteopenia/osteoporosis may persist long into survivorship. Measurement of bone mineral density (BMD) by dual energy X-ray absorptiometry is limited to two-dimensionality and cannot distinguish trabecular from cortical bone. Methods – A sample of 74 subjects, more than 10 years from diagnosis, underwent peripheral quantitative computed tomography (pQCT) at metaphyseal (trabecular bone) and diaphyseal (cortical bone) sites in the radius and tibia. pQCT provides three-dimensional assessment of bone geometry, density and architecture. Results – Similarities of average values in multiple metrics with those in healthy subjects obscured deficits in both trabecular and cortical bone, as well as bone strength, revealed by Z scores using an ethnically comparable sample of healthy individuals. Connectivity, a measure of bone architecture and a surrogate measure of bone strength, was lower in females than males. Survivors of standard risk ALL had greater connectivity in and more compact trabecular bone than high risk survivors who had received more intensive osteotoxic chemotherapy. There were no statistically significant differences in any of the metrics at any of the sites between subjects who had or had not a history of fracture, cranial irradiation or use of a bisphosphonate. Conclusions – These long-term survivors of ALL have somehat compromised bone health, but data in comparable healthy populations are limited. Longitudinal studies in larger and more ethnically diverse cohorts will provide greater insight into bone health in this vulnerable population.
Some vascular anomalies can present with challenging hematologic aberrations. Kaposiform hemangioendothelioma (KHE) may be complicated with Kasabach-Merritt phenomenon (KMP) and stagnant blood flow in slow flow malformations can promote activation and consumption of coagulation factors which results in bleeding and clotting known as localized intravascular coagulopathy (LIC). These patients can experience significant morbidity secondary to pain due to thrombosis and are at higher risk of hematologic complications during surgical procedures. No standard of care has been established to prevent or manage these complications. This review focuses on the management of coagulopathy in children and adults with vascular anomalies.
BACKGROUND: Workplace burnout can result in negative consequences for clinicians and patients. We assessed burnout prevalence and sources among pediatric hematology/oncology inpatient nurses, ambulatory nurses, physicians (MDs), and advanced practice providers (APPs) by evaluating effects of job demands and involvement in patient safety events (PSEs). METHODS: A cross-sectional survey (Maslach Burnout Inventory) measured emotional exhaustion, depersonalization, and reduced personal accomplishment. The NASA Task Load Index measured mental demand, physical demand, temporal demand, effort, and frustration. Relative weights analyses estimated the unique contributions of tasks and PSEs on burnout. Post-hoc analyses evaluated open-response comments for burnout factors. RESULTS: Burnout prevalence was 33%, 20%, 34% and 33% in inpatient nurses, ambulatory nurses, and MD, and APPs respectively (N=481, response rate 69%). Reduced personal accomplishment was significantly higher in inpatient nurses than MDs & APPs. Job frustration was the most significant predictor of burnout across all four cohorts. Other significant predictors of burnout included temporal demand (nursing groups & MDs) effort (inpatient nurses & MDs) and PSE involvement (ambulatory nurses). Open-response comments identified time constraints, lack of administrator support, insufficient institutional support for self-care, and inadequate staffing and/or turnover as sources of frustration. CONCLUSIONS: All four clinician groups reported substantial levels of burnout, and job demands predicted burnout. The body of knowledge on job stress and workplace burnout supports targeting organizational-level sources, versus individual-level factors, as the most effective prevention and reduction strategy. This study elaborates on this evidence by identifying structural drivers of burnout within a multidisciplinary context of pediatric hematology/oncology clinicians.
Vascular anomalies are a group of disorders divided into two distinct subtypes: vascular tumors and vascular malformations. Vascular tumors are proliferative in nature, while malformations are non-proliferative. Simple, localized vascular malformations refer to a group of malformations that are localized to a single area of involvement. These simple malformations include capillary, lymphatic, venous, and arteriovenous malformations. The pediatric hematologist and oncologist is becoming increasingly involved in the diagnosis and management of these disorders. This review presents four cases as a means to discuss the diagnosis, clinical and imaging features, and management strategies of simple, localized vascular malformations.
Background: Outcome of children with bladder-prostate rhabdomyosarcoma has improved with multimodal therapies, including surgery and/or radiotherapy for local treatment. Our aim was to report the long-term urological complications after a conservative approach combining conservative surgery and brachytherapy. Patients and methods: Eighty-six patients, free of disease, were retrospectively reviewed. Symptoms related to urinary tract obstruction, incontinence, infection and lithiasis were reported and graded according to CTCAE classification. Only symptomatic patients underwent urodynamic studies. Risk factors for complications were analyzed. Results: There were 76 males and 10 females. The median follow-up was 6.3 years (18 months-24 years). Complications occurred after a median follow up 5 years (0-21). Twenty-two patients had long-term urological complications. Urinary tract obstruction was found in 15 patients, urinary incontinence in 14 patients. Recurrent urinary tract infection and urinary lithiasis were found in 5 patients respectively. Beyond symptom, 3 etiologies were identified: bladder dysfunction in 15 patients, urethral stenosis in 6 and uretero-vesical junction stenosis in 5. Posterior bladder wall dissection used in large prostatic tumors, operation at age less than 2 years and partial prostatectomy were identified as risk factors for these complications. Conclusion: The conservative surgical approach combined with brachytherapy for BPRMS leads to long-term urological complications in 22% of patients free of their disease. Optimizing brachytherapy doses for young children and establishing a clear and long term follow-up protocol, could help to reduce these complications.
Background: Medulloblastoma is the most common malignant brain tumor in children. We aim to determine the survival in children with medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 to 2013 in Peru, a low-middle income country at the time of this analysis. We also describe the barriers and factors influencing outcomes. Methods: Between 1997-2013, data from 103 children older than 3 years with medulloblastoma were analyzed. Two groups of treatment were identified 1997 – 2008 and 2009 – 2013. Event-free (EFS) and overall survival (OS) were obtained using Kaplan-Meier method and prognostic factors by univariate analysis (log-rank test). A survey was created to identify factors that may have influenced outcome. Results: Eighty-nine patients were included; median age was 8.1 years (range: 2.9-13.9 years). Surgical resection was complete in 39 patients. The five-year OS was 63% (95% CI: 53 – 74%) while EFS was 59% (95% CI: 49 – 71%). The variables adversely affecting survival were: anaplastic histology [compared to desmoplastic; OS: HR=3.5, p=0.03; EFS: HR=3.4, p=0.03], metastasis [OS: HR=3.4, p=0.01; EFS: HR=4.4, p=0.003], and treatment post-2008 [OS: HR=2.5, p=0.01; EFS: HR=2.5; p=0.01]. Conclusions: Outcomes for Medulloblastoma at INEN are low compared with high- income countries (HIC). Univariate analysis demonstrated that histological sub-type, metastasis at diagnosis, and treatment post-2008 all negatively affected outcomes in our study. The importance of multidisciplinary teamwork in the care of children with pediatric brain tumors as well as partnerships with loco-regional groups and colleagues in HIC is vastly beneficial.
Background: Primary and secondary malignant tumors of the spine are relatively uncommon in the pediatric population but are associated with high morbidity and significantly decreased quality of life due to pain. Local management of these tumors is often challenging due to the importance of maintaining vertebral mechanical integrity as well as the spinal growth potential. Typically, surgery and/or radiation therapy have been used in the primary management of these tumors. However, treatment options become more limited when there is relapse or refractory disease, with re-resection or additional radiotherapy often not being viable therapies. The purpose of this study was to assess the feasibility of percutaneous vertebroplasty as a palliative treatment for intractable pain secondary to malignant tumors affecting the spine. Procedure: A retrospective review of all cases of vertebroplasty performed at a single institution between 2003 and 2020. Results: A total of 11 vertebral levels were treated in 3 children with relapsed cancers (two with alveolar rhabdomyosarcoma, and one with Wilms tumor). All three had clinical benefit with sustained significant improvement in their pain. Conclusions: Vertebroplasty is a currently underutilized modality that might provide excellent pain palliation in cases of relapsed cancer in the spine. Future prospective studies of its use in pediatric oncology are needed.