Second malignant neoplasms within 5 years from first primary diagnosis in pediatric oncology patients in Canada: a population-based retrospective cohort study.

Introduction: From the advancement of treatment of pediatric cancer diagnosis, the five-year survival rate has increased significantly. However, the adverse consequence of improved survival rate is the second malignant neoplasm. Although previous studies provided information on the incidence and risk of SMN in long term survivors of childhood cancer, there is still scarce information known for short term (< 5 years) prognosis. This study aims to assess the incidence, characteristics, management, and outcome of children who develop SMN malignancies within 5 years of diagnosis of their initial cancer. Method: This is a retrospective cohort study of early Second Malignant Neoplasms (SMN) in pediatric oncology patients. The Cancer in Young People - Canada (CYP-C) national pediatric cancer registry was used and reviewed pediatric patients diagnosed with their first cancer from 2000-2015. Results: A total of 20,272 pediatric patients with a diagnosis of a first malignancy were analyzed. Of them, 0.7% were diagnosed with a SMN within the first 5 years following their first cancer diagnosis. Development of a SMN impacted survival, shown by an inferior survival rate in the SMN cohort (79.1%) after three years compared to that of the non-SMN cohort (89.7%). Several possible risk factors have been identified in the study including the use of epipodophyllotoxins, exposure to radiation, and hematopoietic stem cell 169 transplant. Discussion: This is the first national study assessing the incidence, 170 characteristics, risk factors and outcome of early SMN in Canadian children 171 from age 0-15 from 2000-2015.

Advances in pediatric gliomas: from molecular characterization to personalized treatments.

Pediatric gliomas, consisting of both pediatric low-grade (pLGG) and high-grade gliomas (pHGG), are the most frequently occurring brain tumors in children. Over the last decade, several milestone advancements in treatments have been achieved as a result of stronger understanding of the molecular biology behind these tumors. This review provides an overview of pLGG and pHGG highlighting their clinical presentation, molecular characteristics, and latest advancements in therapeutic treatments.  Conclusion: The increasing understanding of the molecular biology characterizing pediatric low and high grade gliomas has revolutionized treatment options for these patients, especially in pLGG. The implementation of next generation sequencing techniques for these tumors is crucial in obtaining less toxic and more efficacious treatments. What is Known: • Pediatric Gliomas are the most common brain tumour in children. They are responsible for significant morbidity and mortality in this population. What is New: • Over the last two decades, there has been a significant increase in our global understanding of the molecular background of pediatric low and high grade gliomas. • The implementation of next generation sequencing techniques for these tumors is crucial in obtaining less toxic and more efficacious treatments, with the ultimate goal of improving both the survival and the quality of life of these patients.

Very Long-term Survivorship in Pediatric DIPG: Case Report and Review of the Literature.

Diffuse intrinsic pontine gliomas are lethal tumors with a prognosis generally less than 1 year. Few cases of survivors of 5 years or more have been reported. This case report highlights the journey of a 9.5-year survivor who underwent 3 rounds of focal radiotherapy; she experienced 6 years of progression-free survival following the first round but ultimately succumbed to her disease. An autopsy revealed a favorable IDH1 mutation and the absence of H3K27M. This case reiterates the importance of extensive molecular analyses in diffuse intrinsic pontine gliomas and explores the potential benefit of re-irradiation in patients with positive responses and long periods of remission.

Recurrent primary intracranial sarcoma, DICER1-mutant in a pediatric patient with DICER1 syndrome: the importance of molecular testing.

Pediatric intracranial sarcomas are rare, aggressive tumors with a poor prognosis in general. Here we report the case of a child who was initially diagnosed with a primary intracranial sarcoma, DICER1-mutant; subsequent genetic analyses confirmed a pathogenic germline DICER1 mutation. She received multimodal standard treatments consisting of surgery, radiotherapy and chemotherapy. The tumor recurred 2.5 years later within the surgical cavity. Following the gross tumor resection of this new lesion, the same multimodal standard approach was used. From a molecular perspective, evidence of hyperactivation of the MAPK-kinase pathway with a pathogenic KRAS mutation at both diagnosis and recurrence was present. The patient is currently in remission, 18 months post-end of treatment.

Bevacizumab in the Treatment of Refractory Brain Edema in High-grade Glioma.

We report the case of a 14-year-old boy with a steroid-dependent refractory tumor whose longstanding dexamethasone treatment was successfully discontinued after a course of bevacizumab. The use of bevacizumab despite the absence of clear evidence of radionecrosis allowed a significant decrease in the amount of the brain edema.

Myeloproliferative Neoplasm Driven by ETV6-ABL1 in an Adolescent with Recent History of Burkitt Leukemia.

ETV6-ABL1 gene fusion is a rare genetic rearrangement in a variety of malignancies, including myeloproliferative neoplasms (MPN), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). Here, we report the case of a 16-year-old male diagnosed with a MPN, 7 months post-completion of treatment for Burkitt leukaemia. RNA sequencing analysis confirmed the presence of an ETV6-ABL1 fusion transcript, with an intact, in-frame ABL tyrosine-kinase domain. Of note, secondary ETV6-ABL1-rearranged neoplastic diseases have not been reported to date. The patient was started on a tyrosine kinase inhibitor (TKI; imatinib) and, subsequently, underwent a 10/10 matched unrelated haematopoietic stem cell transplant. He is disease-free five years post-transplant. Definitive evidence of the prognostic influence of the ETV6-ABL1 fusion in haematological neoplasms is lacking; however, overall data suggest that it is a poor prognostic factor, particularly in patients with ALL and AML. The presence of this ETV6-ABL1 fusion should be more routinely investigated, especially in patients with a CML-like picture. More routine use of whole-genome and RNA sequencing analyses in clinical diagnostic care, in conjunction with conventional cytogenetics, will facilitate these investigations.

COVID-19, Coronavirus Vaccines, and Possible Association with Lipschütz Vulvar Ulcer: A Systematic Review.

Lipschütz genital ulcer is a self-limited, non-sexually acquired disorder characterized by the sudden onset of a few ulcers. A primary Epstein-Barr virus infection is currently considered the most recognized cause. Recent reports document cases temporally related with coronavirus disease 2019 (COVID-19) or immunization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We carried out a review of the literature to investigate the possible association between COVID-19 or the immunization against SARS-CoV-2 and genital ulcer. The pre-registered study (CRD42023376260) was undertaken following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Excerpta Medica, the National Library of Medicine, and Web of Sciences were searched. Inclusion criteria encompassed instances of acute Lipschütz ulcer episodes that were temporally linked to either COVID-19 or a vaccination against SARS-CoV-2. Eighteen articles were retained. They provided information on 33 patients 15 (14-24) years of age (median and interquartile range), who experienced a total of 39 episodes of Lipschütz ulcer temporally associated with COVID-19 (N = 18) or an immunization against SARS-CoV-2 (N = 21). The possible concomitant existence of an acute Epstein-Barr virus infection was excluded in 30 of the 39 episodes. The clinical presentation and the disease duration were similar in episodes temporally associated with COVID-19 and in those associated with an immunization against SARS-CoV-2. In conclusion, COVID-19 and immunization against SARS-CoV-2 add to Epstein-Barr virus as plausible triggers of Lipschütz genital ulcer.

Splenic rupture or infarction associated with Epstein-Barr virus infectious mononucleosis: a systematic literature review.

BACKGROUND: Epstein-Barr virus (EBV), also known as human herpesvirus 4, is one of the most common pathogenic viruses in humans. EBV mononucleosis always involves the spleen and as such it predisposes to splenic rupture, often without a trauma, and splenic infarction. Nowadays the goal of management is to preserve the spleen, thereby eliminating the risk of post-splenectomy infections. METHODS: To characterise these complications and their management, we performed a systematic review (PROSPERO CRD42022370268) following PRISMA guidelines in three databases: Excerpta Medica, the United States National Library of Medicine, and Web of Science. Articles listed in Google Scholar were also considered. Eligible articles were those describing splenic rupture or infarction in subjects with Epstein-Barr virus mononucleosis. RESULTS: In the literature, we found 171 articles published since 1970, documenting 186 cases with splenic rupture and 29 with infarction. Both conditions predominantly occurred in males, 60% and 70% respectively. Splenic rupture was preceded by a trauma in 17 (9.1%) cases. Approximately 80% (n = 139) of cases occurred within three weeks of the onset of mononucleosis symptoms. A correlation was found between the World Society of Emergency Surgery splenic rupture score, which was retrospectively calculated, and surgical management: splenectomy in 84% (n = 44) of cases with a severe score and in 58% (n = 70) of cases with a moderate or minor score (p = 0.001). The mortality rate of splenic rupture was 4.8% (n = 9). In splenic infarction, an underlying haematological condition was observed in 21% (n = 6) of cases. The treatment of splenic infarction was always conservative without any fatal outcomes. CONCLUSIONS: Similarly to traumatic splenic rupture, splenic preservation is increasingly common in the management of mononucleosis-associated cases as well. This complication is still occasionally fatal. Splenic infarction often occurs in subjects with a pre-existing haematological condition.

An Adolescent With Intermittent Claudication.

ABSTRACT: Intermittent claudication is very uncommon in children and adolescents. We describe the case of a 14-year-old adolescent girl experiencing left calf pain for a year that occurs during running and becomes unbearable after around 2 km. She was ultimately diagnosed with extrinsic compression of the popliteal artery caused by an osteocartilaginous exostosis (osteochondroma) originating from the fibula.

Non-rhabdomyosarcoma soft tissue sarcomas diagnosed in patients at a young age. An overview of clinical, pathological, and molecular findings.

OBJECTIVE: Disease spectrum in pediatric sarcoma differs substantially from adults. We report a cohort of very young children with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) detailing their molecular features, treatment, and outcome. METHODS: We report features of consecutive children (age <2 years) with NRSTS (2000-2017). Archival pathological material was re-reviewed, with additional molecular techniques applied where indicated. RESULTS: Twenty-nine patients (16 females, 55%) were identified (median age 6 months; range 0-23). Most common diagnoses included infantile fibrosarcoma (IFS, n = 14, 48%), malignant rhabdoid tumor (MRT, n = 4, 14%), and undifferentiated sarcoma (n = 4, 14%). Twenty-seven of 29 (93%) had tumor molecular characterization to confirm diagnosis. Clinical presentation included a swelling/mass (n = 23, 79%). Disease extent was localized (n = 20, 69%), locoregional (n = 6, 21%), or metastatic (n = 3, 10%). Seventeen of 29 (59%) who underwent surgery achieved complete resection (R0). Other treatments included conventional chemotherapy (n = 26, 90%), molecularly targeted therapies (n = 3, 10%), and radiation (n = 5, 17%). At last follow-up (median 3 years; range 0.3-16.4), 23 (79%) were alive, disease-free and six (21%) had died of disease. All patients with IFS were alive and all those with MRT died. A cancer predisposition syndrome (CPS) was confirmed in three of 10 (30%) genetically tested patients. CONCLUSION: We recommend tumor molecular characterization in all young patients including evaluation for CPS to optimize treatment options and prognostication.

Hodgkin Lymphoma in an Adolescent With Isolated Bone Marrow and Bone Involvement: A Case Report and a Review of the Literature.

BACKGROUND: Primary presentation of Hodgkin lymphoma (HL) with bone and/or bone marrow involvement is a rare entity. Diagnostic criteria, treatment approaches, and follow-up strategies for these patients have not been standardized. OBSERVATION: We report a unique case of bone and bone marrow HL in an adolescent male without lymph node involvement. CONCLUSIONS: It is important to keep HL in the differential diagnosis of isolated and multifocal bone lesions. Evidence is needed to define the best management of these patients.

Causes of death in pediatric neuro-oncology: the sickkids experience from 2000 to 2017.

PURPOSE: Primary benign and malignant central nervous system (CNS) tumors are the most frequent solid tumors in the pediatric age and represent the leading cause of death by cancer in children in high income countries. However, information regarding specific causes of death in this population is still limited. The objective of this work was to investigate mortality in a large cohort of children diagnosed at our institution. METHODS: We identified patients consecutively diagnosed with CNS tumor and treated at a Tertiary Care Canadian Children's Hospital between January 2000 and December 2017. Patient charts were reviewed and different variables such as tumor diagnosis, location, gender, age at diagnosis, age at death and cause of death collected. RESULTS: Of 1274 patients, 306 (24%) succumbed to their disease. Mortality rate varied significantly according to tumor subtype, ranging from 3.1% in low grade glioma (LGG) to 97.8% in diffuse intrinsic pontine glioma (DIPG). While high grade gliomas (HGG) and DIPG represented only 6.3 and 7.1% of total diagnoses respectively, together they accounted for 49.3% of total deaths (n = 151). Median time from diagnosis to death was 15 months (4 days to 15 years) and shortest for DIPG (11 months). Two hundred and ninety patients (94.8%) died as a result of the primary disease, 4 of treatment-related toxicity, two patients' deaths were unrelated to the primary disease (idiopathic encephalopathy and domestic fire) whereas 10 patients succumbed to a secondary malignancy. Of note, four of these ten patients had a confirmed underlying cancer predisposition syndrome. CONCLUSION: Disease progression is the main cause of death in children with brain tumor, while treatment related mortality is low in this series. Research should continue to focus on improving treatment strategies for patients whose prognosis remains dismal.

Primary immunodeficiencies and their associated risk of malignancies in children: an overview.

Primary immunodeficiency disorders represent a heterogeneous spectrum of diseases, predisposing to recurrent infections, allergy, and autoimmunity. While an association between primary immunodeficiency disorders and increased risk of cancer has been suggested since the 1970s, renewed attention has been given to this topic in the last decade, largely in light of the availability of large registries as well as advances in next generation sequencing. In this narrative review, we will give an insight of the primary immunodeficiencies that are commonly responsible for the greater number of cancers in the primary immunodeficiency disorders population. We will describe clinical presentations, underlying genetic lesions (if known), molecular mechanisms for carcinogenesis, as well as some management considerations. We will also comment on the future directions and challenges related to this topic.Conclusion: The awareness of the association between several primary immunodeficiencies and cancer is crucial to provide the best care for these patients.What is Known: • Patients with primary immunodeficiency have an increased risk of malignancy. The type of malignancy is highly dependent on the specific primary immunodeficiency disorder.What is New: • Survival in patients with primary immunodeficiency disorders has been improving, and conversely also their lifetime risk of malignancy. • International collaboration and multinational registries are needed to improve our knowledge and therapeutic strategies.

Bevacizumab for NF2-associated vestibular schwannomas of childhood and adolescence.

Seventeen children at six institutions with neurofibromatosis type 2 (NF2)-related vestibular schwannomas received bevacizumab. Eight of the 13 patients with initial hearing loss (61%) showed objective hearing improvement within six months of treatment. No patients showed hearing deterioration during therapy; however, only two patients showed objective radiological response. Seven of eight patients had tumor progression or worsening hearing loss upon cessation of treatment. Bevacizumab was well tolerated with no patients discontinuing therapy. Bevacizumab appears to postpone hearing loss in childhood NF2-associated vestibular schwannomas, but responses are not durable, suggesting that either longer maintenance therapy or new strategies are required.

Sirolimus Treatment of an Infant With Intrathoracic Kaposiform Hemangioendothelioma Complicated by Life-threatening Pleural and Pericardial Effusions.

Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that may be associated with Kasabach-Merritt Phenomenon (KMP), which is a consumptive coagulopathy with potentially life-threatening thrombocytopenia. Management of KHE and KMP is challenging, and currently, there are no standardized validated treatment protocols. Mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of KHE. We describe a term male who presented as a diagnostic dilemma with life-threatening pleural and pericardial effusions and severe thrombocytopenia. After extensive work-up the etiology for his condition was determined to be KHE with KMP. The patient was commenced on sirolimus and responded well to therapy with resolution of KMP.

Lymphocyte subset at time of Epstein-Barr viremia post-allogeneic hematopoietic stem cell transplantation in children may predict development of post-transplant lymphoproliferative disease: CD8:CD20 ratio as a sensitive predictor.

EBV-associated PTLD following allogeneic HSCT is a serious complication associated with significant mortality. In this retrospective study, we evaluated whether lymphocyte subset numbers and CD8:CD20 ratio at time of EBV viremia in children undergoing allogeneic HSCT could predict development of PTLD. Absolute lymphocyte count, lymphocyte subsets, and CD8:CD20 ratio at the time of EBV viremia were analyzed. Patients who were treated preemptively with rituximab for high blood EBV viral load were excluded. Out of 266 patients transplanted during the study period, 26 patients were included in the analysis. Patients were divided into two cohorts; cohort 1 included patients with EBV-associated PTLD (n = 5; four with proven, one with probable PTLD). Cohort 2 included patients with EBV viremia without PTLD (n = 21). Lymphocyte recovery was slower in the PTLD group. CD8:CD20 ratio was significantly lower in the PTLD group (median 0.15) compared to the non-PTLD group (median 2.4, P = .012). Using the ROC curve and 1 as the cutoff value, CD8:CD20 ratios were analyzed. In the PTLD group, 4/5 patients (80%) had a ratio <1 whereas in the non-PTLD group, all 21 patients had a ratio >1. Sensitivity and specificity were 80% and 100%, respectively. Negative and PPVs were 95% and 100%, respectively. Profoundly low T-cell count and CD8:CD20 ratio may be used to predict development of PTLD in the context of EBV viremia in children post-allogeneic HSCT. Further studies are needed to validate this finding.

MYCN Amplified Relapse Following Resolution of MYCN Nonamplified 4S Neuroblastoma With Placental Involvement: A Case Report and Review of the Literature.

Congenital neuroblastoma with placental involvement is exceptionally rare, but mortality is high. Detailed examination of placenta including MYCN amplification and segmental chromosomal aberrations should be performed in all suspected cases, as it is noninvasive and readily available. Maternal dissemination has not been reported. In this manuscript, we describe an infant with placental diagnosis of MYCN nonamplified congenital neuroblastoma. This is the first report of a recurrence of congenital 4S neuroblastoma following resolution in which MYCN amplification is only detected in the recurrence. Germline sequencing using a large comprehensive cancer panel did not reveal variants in candidate cancer predisposition genes.