Cancer and Metastasis Reviews

Integration of EMT and cellular survival instincts in reprogramming of programmed cell death to anastasis Abstract Apoptosis is a tightly controlled, coordinated cellular event responsible for inducing programmed cell death to rid the body of defective or unfit cells. Inhibition of apoptosis is, therefore, an essential process for cancer cells to harness. Genomic variants in apoptotic-controlling genes are highly prevalent in cancer and have been identified to induce pro-proliferation and pro-survival pathways, rendering cancer cells resistant to apoptosis. Traditional understanding of apoptosis defines it as an irreversible process; however, growing evidence suggests that apoptosis is a reversible process from which cells can escape, even after the activation of its most committed stages. The mechanism invoked to reverse apoptosis has been termed anastasis and poses challenges for the development and utilization of chemotherapeutic agents. Anastasis has also been identified as a mechanism by which cells can recover from apoptotic lesions and revert back to its previous functioning state. In this review, we intend to focus the attention of the reader on the comprehensive role of survival, metastasis, and epithelial mesenchymal transition (EMT), as well as DNA damage repair mechanisms in promoting anastasis. Additionally, we will emphasize the mechanistic consequences of anastasis on drug resistance and recent rational therapeutic approaches designed to combat this resistance.

What recent primary studies tell us about ovarian teratomas in children: a scoping review Abstract Our knowledge of ovarian teratomas in children is still far from complete, and much remains to be discovered. Here, we conduct a scoping review of the primary research related to ovarian teratomas in pediatric age. To our knowledge, there is no published synthesis of the literature surrounding ovarian teratomas in children using scoping review methodology. We identified 24 studies from 11 countries; 18 studies were retrospective, 3 were prospective, and 3 were experimental. There were 6 studies concerning mature teratomas, 5 concerning immature teratomas, and 13 that included both tumor types. Overall, 9 out of all the studies concerned more than 50 patients. We revealed 7 major branches of research within the topic of ovarian teratoma in pediatric population: recurrence rate/relapse and follow-up strategy, malignant potential, prognostic factors, use of sparing surgery, differences between the use of laparoscopy and laparotomy, use of chemotherapy, and additional examinations to test the character of the lesion (immature vs. mature). This scoping review has revealed a number of knowledge gaps in the evidence base for pediatric ovarian teratomas. Overall, this topic has not been extensively explored, and more research dedicated exclusively to this tumor and patient population is required.

Bariatric interventions in obesity treatment and prevention in pediatric acute lymphoblastic leukemia: a systematic review and meta-analysis Abstract Most children are surviving acute lymphoblastic leukemia (ALL) today. Yet, the emergence of cardiometabolic comorbidities in this population may impact long-term outcomes including the quality of life and lifespan. Obesity is a major driver of cardiometabolic disorders in the general population, and in ALL patients it is associated with increased risk of hypertension, dysglycemia, and febrile neutropenia when compared with lean ALL patients undergoing therapy. This systematic review aims to assess the current evidence for bariatric interventions to manage obesity in children with ALL. The primary outcome for this systematic review was the change in BMI z-score with implementation of the interventions studied. Literature searches were conducted in several databases. Ten publications addressing the study question were included in this review, and five studies were used in the meta-analysis to assess the impact of the bariatric interventions on obesity. The BMI z-score did not change significantly with the interventions. However, the quality of evidence was low, which precluded the recommendation of their use. In conclusion, prospective, rigorous, adequately powered, and high-quality longitudinal studies are urgently needed to deliver effective lifestyle interventions to children with ALL to treat and prevent obesity. These interventions, if successful, may improves cardiometabolic health outcomes and enhance the quality of life and life expectancy in children with ALL.

Oral and dental considerations in pediatric cancers Abstract Oral health care is an integral component of interprofessional collaborative care for children and adolescents diagnosed with cancer. The current review highlights the phases of cancer therapy when dental interventions and palliative care are necessary for children diagnosed with cancer. Contemporary research and review articles pertinent to the oral and dental complications during pediatric cancer therapy and late effects in pediatric cancer survivors were identified by PubMed/MEDLINE search. Best practice guidelines set forth by specialty organizations were also included. The literature search was limited to articles published in the English language. Baseline oral and dental health assessment should occur before initiation of cancer therapy to prevent debilitating complications during the immunosuppressed phase. Counseling on preventive oral health practices is imperative during cancer treatment. Ideally, all dental treatment should be completed before initiation of immunosuppressive therapy. Palliative care and treatment for mucositis, opportunistic oral infections, pain, and other oral complications associated with cancer therapy should be provided as necessary. Survivors of childhood cancers present with unique craniofacial and dental anomalies, dependent on the type of cancer treatment and age at the time of treatment. Pediatric dentists and pediatric oncology teams work collaboratively to screen for and treat dental and oral diseases. As the survival rates of childhood cancers improve, it is essential for the dental profession to provide the individualized care necessary for this vulnerable population. The oral health profession also reinforces health practices congruent with cancer prevention and cancer screening.

Mouse models of high-risk neuroblastoma Abstract Informative and realistic mouse models of high-risk neuroblastoma are central to understanding mechanisms of tumour initiation, progression, and metastasis. They also play vital roles in validating tumour drivers and drug targets, as platforms for assessment of new therapies and in the generation of drug sensitivity data that can inform treatment decisions for individual patients. This review will describe genetically engineered mouse models of specific subsets of high-risk neuroblastoma, the development of patient-derived xenograft models that more broadly represent the diversity and heterogeneity of the disease, and models of primary and metastatic disease. We discuss the research applications, advantages, and limitations of each model type, the importance of model repositories and data standards for supporting reproducible, high-quality research, and potential future directions for neuroblastoma mouse models.

Pediatric hemispheric high-grade glioma: targeting the future Abstract Pediatric high-grade gliomas (pHGGs) are a group of tumors affecting approximately 0.85 children per 100,000 annually. The general outcome for these tumors is poor with 5-year survival rates of less than 20%. It is now recognized that these tumors represent a heterogeneous group of tumors rather than one entity. Large-scale genomic analyses have led to a greater understanding of the molecular drivers of different subtypes of these tumors and have also aided in the development of subtype-specific therapies. For example, for pHGG with NTRK fusions, promising new targeted therapies are actively being explored. Herein, we review the clinico-pathologic and molecular classification of these tumors, historical treatments, current management strategies, and therapies currently under investigation.

Signaling pathways in Rhabdomyosarcoma invasion and metastasis Abstract Rhabdomyosarcoma (RMS) is an aggressive childhood mesenchymal tumor with two major molecular and histopathologic subtypes: fusion-positive (FP)RMS, characterized by the PAX3-FOXO1 fusion protein and largely of alveolar histology, and fusion-negative (FN)RMS, the majority of which exhibit embryonal tumor histology. Metastatic disease continues to be associated with poor overall survival despite intensive treatment strategies. Studies on RMS biology have provided some insight into autocrine as well as paracrine signaling pathways that contribute to invasion and metastatic propensity. Such pathways include those driven by the PAX3-FOXO1 fusion oncoprotein in FPRMS and signaling pathways such as IGF/RAS/MEK/ERK, PI3K/AKT/mTOR, cMET, FGFR4, and PDGFR in both FP and FNRMS. In addition, specific cytoskeletal proteins, G protein coupled receptors, Hedgehog, Notch, Wnt, Hippo, and p53 pathways play a role, as do specific microRNA. Paracrine factors, including secreted proteins and RMS-derived exosomes that carry cargo of protein and miRNA, have also recently emerged as potentially important players in RMS biology. This review summarizes the known factors contributing to RMS invasion and metastasis and their implications on identifying targets for treatment and a better understanding of metastatic RMS.

A systematic approach to the endocrine care of survivors of pediatric hematopoietic stem cell transplantation Abstract Hematopoietic stem cell transplantation (HSCT) is used in children to treat a variety of malignant and nonmalignant hematologic conditions and certain inborn errors of metabolism. Survivors of HSCT are markedly affected by disease and treatment toxicity. Endocrine complications are among the most commonly reported chronic health conditions in this population. In this review, we summarize the most common endocrine late effects after pediatric HSCT. We also highlight the importance of systematic and longitudinal evaluations to achieve early diagnoses and treatment for these conditions and improve the long-term health outcomes for patients who received HSCT as children.

What are the effects of exercise training in childhood cancer survivors? A systematic review Abstract This systematic review aimed to summarize evidence on the effects of physical exercise interventions in childhood cancer survivors (CCS) who had finished anticancer therapy ≥ 1 year before the study. Relevant articles were identified in the electronic databases PubMed, Web of Science, and SPORTDiscus (from inception to June 27, 2019). The PEDro scale was used to assess methodological quality. Twelve studies including 109 CCS met all inclusion criteria and were included in the systematic review. The quality of the included studies was overall low. Physical exercise improved endothelial function, reduced waist circumference, and waist-to-hip ratio and increased physical activity levels. Preliminary evidence was found regarding benefits on brain volume and structure after exercise interventions in childhood brain tumor survivors. Only two studies reported exercise-related adverse events. Physical exercise seems to be safe and effective for improving several health markers in CCS, but further high-quality research and especially randomized controlled trials are needed to confirm these results.

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. One of the major clinical challenges is adequate diagnosis and treatment of central nervous system (CNS) involvement in this disease. Intriguingly, there is little solid evidence on the mechanisms sustaining CNS disease in ALL. Here, we present and discuss recent data on this topic, which are mainly derived from preclinical model systems. We thereby highlight sites and routes of leukemic CNS infiltration, cellular features promoting infiltration and survival of leukemic cells in a presumably hostile niche, and dormancy as a potential mechanism of survival and relapse in CNS leukemia. We also focus on the impact of ALL cytogenetic subtypes on features associated with a particular CNS tropism. Finally, we speculate on new perspectives in the treatment of ALL in the CNS, including ideas on the impact of novel immunotherapies.