Neonatal outcomes and follow-up of children born to women with pregnancy-associated cancer: a prospective observational study.

BACKGROUND: During the last decade, there has been a growing number of cases of children born from pregnancy-associated cancer (PAC), however there are currently insufficient data on the follow up to be observed in this category of newborns. Objective of the study was to evaluate the neonatal outcomes of infants born to mother with PAC, the potential adverse effect of chemotherapy during pregnancy and the risk of metastasis to the fetus. METHODS: Maternal clinical data and neonatal outcomes of child born to mothers diagnosed with PAC were collected; infants were divided into those were and were not exposed to chemotherapy during fetal life and their outcomes were compered. RESULTS: A total of 37 newborn infants from 36 women with PAC were analyzed. Preterm delivery occurred in 83.8% of the cases. No significant differences in neonatal outcomes were found between infants who were and were not exposed to chemotherapy during pregnancy. The median follow-up period was 12 months. CONCLUSIONS: PAC treatment during the second or third trimester does not seem to be dangerous for the fetus, however infants born from PAC must be carefully evaluated for to rule out the consequences of chemotherapy and exclude the presence of metastasis. Long-term follow-up, especially in children exposed to chemotherapy, should be encouraged to obtain relevant data on long-term toxicity.

Transplacental Passage and Fetal Effects of Antineoplastic Treatment during Pregnancy.

The incidence of PAC is relatively infrequent among pregnant women. However, it has gradually increased in recent years, becoming a challenging area for clinicians that should take into account in the same way maternal benefits and fetal potential risks correlated to the antineoplastic treatment. None of the antineoplastic drugs is completely risk-free during the pregnancy, the timing of exposure and transplacental transfer properties influence the toxicity of the fetus. Despite the lack of guidelines about the management of PAC, several studies have described the use and the potential fetal and neonatal adverse events of antineoplastic drugs during pregnancy. We provide a review of the available literature about the transplacental passage and fetal effects of chemotherapy and targeted agents, to guide the clinicians in the most appropriate choices for the management of PAC.

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study.

Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3-26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14-26) versus 10 (3-17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual, pituitary and neurological dysfunction. Despite an excellent overall survival, PFS rates are poor in OPGs with DS. These patients invariably present visual, neurological or endocrine sequelae. Therefore, functional outcomes and quality-of-life measures should be considered in prospective trials involving patients with OPGs, aiming to identify "high-risk" patients and to better individualize treatment.

Hematological disorders in children with Down syndrome.

INTRODUCTION: Hematological abnormalities are common in children with down syndrome (DS), mainly during childhood. AREAS COVERED: DS newborns can develop hematological benign conditions that resolve spontaneously within 1 -2 months. However, about 10% of them can present transient abnormal myelopoiesis (TAM), characterized by the presence of circulating blasts. About 80% of DS neonates with TAM undergo spontaneous resolution of both clinical and laboratory abnormalities within 3-6 months after birth. However, some newborns with TAM may develop acute myeloid leukemia associated with DS (ML-DS), usually after an interval without signs of leukemia. GATA1 mutations are stable molecular markers that may monitor the presence of minimal residual disease (MRD) after TAM resolution. Moreover, DS children have a 10-20-fold increased risk of developing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The predisposition to develop leukemia occurs both in children with complete trisomy 21 and in those with mosaic trisomy, suggesting an important role of chromosome 21 in leukemogenesis. EXPERT OPINION: In contrast to the excellent prognosis of ML-DS obtained likewise with low doses of chemotherapy, DS-ALL patients show worse outcomes than non-DS children, therefore advances and risk-stratified treatment adjustments are mandatory for this particular set of patients.

Vincristine-Induced Peripheral Neuropathy (VIPN) in Pediatric Tumors: Mechanisms, Risk Factors, Strategies of Prevention and Treatment.

Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug-drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer.

Management of Oral Mucositis in Children With Malignant Solid Tumors.

INTRODUCTION: In recent years, the use of intensive regimens for the treatment of pediatric cancer has led to a marked improvement in patient survival. However, these treatments are associated with an increase in toxic effects. Among these side effects, mucositis (inflammation of the oral cavity) significantly affect the success of treatment. The aim of this study was to assess the prevalence of mucositis in a pediatric population with solid tumor and undergoing chemotherapy, identify the risk factors that influence its occurrence, and verify the usefulness of pain rating scales. METHODS: We registered episodes of mucositis which occurred in a sample of 84 consecutive children with solid tumors between 1 January, 2012 and 30 April, 2018. The World Health Organization (WHO) oral mucositis grading scale and the modified Wong-Baker FACES Pain Rating Scale (WBS) were used to assess the severity of each episode. Moreover, data on the treatments used and blood count results were collected. RESULTS: The prevalence of mucositis in our population was 50%, without statistically significant difference according to sex and a higher prevalence observed in patients aged >10 years. The presence of neutropenia, higher number of cycles of chemotherapy, and co-existence of lymphomas and sarcomas were identified as factors favoring the occurrence of mucositis. The WBS showed results superimposed on the WHO oral mucositis grading scale in choosing the intensity and duration of mucositis treatment. CONCLUSION: Oral mucositis is a common complication of chemotherapy against childhood malignancies. The WHO oral mucositis scale is a valuable tool for assessing its severity in pediatric patients. Furthermore, WBS can be used as an assessment tool to establish the therapy to be adopted for patients in whom direct evaluation of the oral cavity is not possible.

Opioid transdermal delivery system: a useful method for pain management in children.

Transdermal delivery system (TDDS) is a non-invasive and less expensive method for drug delivery. Despite its feasibility, only a restricted group of drugs can be delivered by TDDS, because of the little permeability of skin. Moreover, TDDS is limited to lipophilic drugs with small molecular masses and it is not indicated for peptides, macromolecules and hydrophilic drugs. Among opioids, fentanyl and buprenorphine are suitable for transdermal administration only for chronic pain management (not for acute pain). However, opioid TDDS still remains off-label for chronic pain management in children. In this review, we describe the main features of the adhesive TDDS and the main characteristics of pediatric skin and the differences from the adult one. Moreover, we focus on fentanyl and buprenorphine patches and their non-invasive mechanism of action, and on the main aspects that make them suitable for pain management among the pediatric population.

Narrative review of intrathecal drug delivery (IDD): indications, devices and potential complications.

The management of chronic refractory pain (non-neoplastic and cancer-related pain) remains a therapeutic challenge. The continuous intrathecal (IT) administration of drugs may play an important role in the possible management options. Intrathecal drug delivery devices (IDDDs) may be effective for patients with refractory chronic pain. Therefore, they may be adopted for non-oncologic pain in patients with compression fractures, spondylolisthesis, spondylosis, back surgery failure syndrome and spinal stenosis. Oncologic patients can benefit from these treatments in a variable way according to tumor characteristics, prognosis, periprocedural imaging and risk of disease progression. In this review, we describe the most commonly used drugs (opioids and non-opioids), their pharmacokinetic and pharmacodynamic features and indications of use. The most used drugs are morphine, hydromorphone, fentanyl, methadone, bupivacaine, clonidine, and ketamine. Patient evaluation before the device implantation should be based on clinical examination, medical records assessment and psychometric evaluation. The infusion pumps available on the market are both non-programmable (with continuous IT deliver of drugs) and programmable (with variable deliver of drugs according to their flow rate). Moreover, we describe the procedure of implantation and the potential complications of IT drug delivery (such as bleeding, infection, loss of cerebrospinal fluid, wound seroma, loss of catheter pump propellant).

Managing children with brain tumors during the COVID-19 era: Don't stop the care!

The COVID-19 pandemic has substantially stressed health care systems globally, subsequently reducing cancer care services and delaying treatments. Pediatric populations infected by COVID-19 have shown mild clinical symptoms compared to adults, perhaps due to decreased susceptibility. Several scientific societies and governments have released information on the management of patients with cancer, wherein they warn against exposure to SARS-CoV-2 infection and suggest continuing treatment. To determine the best diagnostic and therapeutic approach, multidisciplinary tumor boards should convene regularly, including through conference calls and telematics platforms. A prompt diagnostic workup may reduce children's suffering and prevent loss of confidence in the health care system among parents. Moreover, ensuring adequate support and information regarding measures for preventing SARS-CoV-2 infection in pediatric patients and their families is essential for avoiding panic and excessive stress, allowing early reporting of any suspected symptoms of cancer and, in turn, facilitating early diagnosis and prompt modulation of treatment.

Cisplatin-induced nephrotoxicity in children: what is the best protective strategy?

INTRODUCTION: Platinum compounds, which are considerably effective for the treatment of childhood malignancies, have significantly contributed to the increase in long-term survival of children with cancer. Unfortunately, children receiving cisplatin-based chemotherapy have been known to be at risk for severe disabling adverse effects, such as nephrotoxicity. METHODS: A literature research of the MEDLINE PubMed database was conducted to identify articles published between 1980 and 2019 reviewing "Cisplatin AND mannitol." RESULTS: The primary pharmacodynamics and clinical characteristics of cisplatin were described, focusing on its renal toxic effects and potential preventive strategies, in order to improve clinical outcomes among children with cancer aged 1 to 14 years. Currently, selecting either hydration alone or hydration plus mannitol for preventing nephrotoxicity has been controversial considering the lack of guidelines to provide treatment recommendations both among adults and children. CONCLUSIONS: Appropriate knowledge regarding the pharmacokinetics and toxicological profile of cisplatin may help physicians prevent renal toxicity. Unfortunately, published data regarding the nephroprotective utility of adding mannitol appear to be inconclusive. As such, appropriate hydration remains the main fundamental strategy for reducing the risk of cisplatin-induced nephrotoxicity. Considering the increasing number of children safely cured of their tumours, it is imperative that those treated with cisplatin receive the most appropriate nephroprotective strategy for reducing the negative impact of platinum compounds on quality of life.

Temozolomide and oral etoposide in children with recurrent malignant brain tumors.

Despite advances in the treatment of brain tumors, the prognosis of children with recurrent malignant brain tumors remains poor. Etoposide (VP-16), an inhibitor of nuclear enzyme deoxyribonucleic acid (DNA)-topoisomerase II, has shown activity in brain tumors. Its efficacy appears schedule dependent but, to date, the most effective schedule of administration has not been well defined. Temozolomide (TMZ), like VP-16, penetrates the blood-brain barrier and has activity against malignant brain tumors. This novel alkylating agent is rapidly absorbed and is highly bioavailable after oral administration. The antitumor activity of TMZ has been shown to be schedule dependent. Based on the evidence of different mechanisms of cytotoxicity, TMZ and VP-16 have been utilized in combination in patients with malignant brain tumors. This review evaluates the results derived from the combination use of TMZ and oral VP-16. The reported data suggest potential activity of oral VP-16 and TMZ alone or in combination. Further clinical trials are needed to explore and confirm their promising activity in relapsed brain neoplasms.

Gynecological cancer among adolescents and young adults (AYA).

Adolescents and young adults (AYA) patients with cancer show specific biological, sociodemographic and behavioral features, with lower survival rates than younger group. Gynecologic malignancies that occur among AYA requires a multidisciplinary management and a tailored model of care, in order to enhance the early diagnosis, the adherence to the treatment, the enrollment in clinical trials, the rate of survival and the quality of life (QoL). In this article, we review the main gynecological tumors that may occur in AYA, with a focus on the clinical signs at the diagnosis and the modality of treatment. In addition, we proposed a model of multidisciplinary and personalized care for AYA with gynecological tumors, which can help the clinicians to manage the specific gynecologic concerns, such as ovarian failure, contraception, fertility, late psychosocial effects.

Assessment and Management of Platinum-Related Ototoxicity in Children Treated for Cancer.

Platinum compounds are a group of chemotherapeutic agents included in many pediatric and adult oncologic treatment protocols. The main platinum compounds are cisplatin, carboplatin, and oxaliplatin. Their use in clinical practice has greatly improved long-term survival of pediatric patients, but they also cause some toxic effects: ototoxicity, myelosuppression, nephrotoxicity, and neurotoxicity. Hearing damage is one of the main toxic effects of platinum compounds, and it derives from the degeneration of hair cells of the ear, which, not having self-renewal capacity, cannot reconstitute themselves. Hearing loss from platinum exposure is typically bilateral, sensorineural, and permanent, and it is caused by the same mechanisms with which platinum acts on neoplastic cells. According to available data from the literature, the optimal timing for the audiological test during and after treatment with platinum compounds is not well defined. Moreover, no substances capable of preventing the onset of hearing loss have been identified.

Multifocal infantile haemangiomatosis with hepatic involvement: two cases and treatment management.

Infantile haemangiomas (IHs) are the most common benign tumours of childhood; despite the benign histology, prognosis depends on severity of visceral involvement, with a mortality rate ranging from 50 to 90%. In this paper, we describe two infants with multifocal infantile haemangiomatosis and hepatic involvement. This condition should receive appropriate management as it can be potentially lethal due to the high risk of systemic complications such as cardiac or fulminant hepatic failure and abdominal compartment syndrome. Both cases presented with liver involvement, but only the infant who had an excellent response to propranolol is still alive. A review of current therapeutic approaches is also presented even though there are, at present, no uniform guidelines for treatment, despite the relative frequency of infantile haemangiomatosis and the potential severe complications.

Neonatal pharmacology and clinical implications.

During the neonatal period, there is physiological immaturity of organs, systems and metabolic pathways that influences the pharmacokinetics and pharmacodynamics of administered drugs, the dosage of which should be constantly amended, considering the progressive increase in weight and the maturation of the elimination pathways. In this article, we analyse the main pharmacokinetic aspects (absorption, distribution, metabolism and excretion) that exist during the neonatal period, to offer a description of the physiological background for variability in pharmacological dosing.

Improving the Brain Delivery of Chemotherapeutic Drugs in Childhood Brain Tumors.

The central nervous system (CNS) may be considered as a sanctuary site, protected from systemic chemotherapy by the meninges, the cerebrospinal fluid (CSF) and the blood-brain barrier (BBB). Consequently, parenchymal and CSF exposure of most antineoplastic agents following intravenous (IV) administration is lower than systemic exposure. In this review, we describe the different strategies developed to improve delivery of antineoplastic agents into the brain in primary and metastatic CNS tumors. We observed that several methods, such as BBB disruption (BBBD), intra-arterial (IA) and intracavitary chemotherapy, are not routinely used because of their invasiveness and potentially serious adverse effects. Conversely, intrathecal (IT) chemotherapy has been safely and widely practiced in the treatment of pediatric primary and metastatic tumors, replacing the neurotoxic cranial irradiation for the treatment of childhood lymphoma and acute lymphoblastic leukemia (ALL). IT chemotherapy may be achieved through lumbar puncture (LP) or across the Ommaya intraventricular reservoir, which are both described in this review. Additionally, we overviewed pharmacokinetics and toxic aspects of the main IT antineoplastic drugs employed for primary or metastatic childhood CNS tumors (such as methotrexate, cytosine arabinoside, hydrocortisone), with a concise focus on new and less used IT antineoplastic agents.

Intranasal therapy with opioids for children and adolescents with cancer: results from clinical studies.

Opioids are essential for the treatment of pain, which is a serious symptom for children and adolescents affected by cancer. Intranasal opioids may be very useful for the treatment of breakthrough pain in children and adolescents with cancer, for their little invasiveness, ease of administration, rapid onset of action, and high bioavailability. Intranasal drug delivery may be influenced by anatomical and physiological factors (nasal mucosa absorption area, mucociliary clearance, enzymatic activity, anatomical anomalies, chronic or inflammatory alterations of nasal mucosa), drug-related factors (molecular weight, solubility), and delivery device. Fentanyl is a lipophilic opioid commonly proposed for intranasal use among pediatric patients, but no studies have been conducted yet about intranasal use of other available opioids for management of pediatric cancer pain. In this review, we analyze several elements which may influence absorption of intranasal opioids in children and adolescents, with a focus on pharmacokinetics and therapeutic aspects of each opioid currently available for intranasal use.

Relapsed papillary urothelial neoplasm of low malignant potential (PUNLMP) of the young age: a case report and a review of the literature.

BACKGROUND: Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP) are exceptionally rare in the first decade of life (mostly if multifocal) and there is a lack of standardized recommendations for the pediatric age. CASE PRESENTATION: We describe the case of a 9-year-old boy with a diagnosis of PUNLMP, who underwent to cystoscopic lesion removal and later to endoscopic lesion removal and intra-bladder Mitomycin-c (MMC) instillations for relapsed disease. Follow-up investigations at five years showed disease negativity. CONCLUSIONS: Intra-bladder MMC instillation may allow obtaining the complete remission with bladder-sparing for paediatric patients with a high-risk relapsed PUNLMP.