Neurofibromatosis 1 (NF1) is caused by germline mutations in the NF1 gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of NF1 . In this study, we investigated a life‐threatening plexiform neurofibroma in a 9‐month‐old female infant with NF1. Germline mutations in two RASopathy‐associated genes were identified using whole‐exome sequencing—a de novo pathogenic variant in the NF1 gene, and a known pathogenic variant in the LZTR1 gene. Somatic analysis of the plexiform neurofibroma revealed NF1 loss of heterozygosity and a variant in GNAZ , a gene encoding a G protein‐coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1/2 activation compared to those expressing wild‐type GNAZ. Taken together, we suggest the variants in NF1 , LZRT1 and GNAZ act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non‐NF1 variants affecting the NF1 clinical phenotype and supports use of personalized, targeted therapy.

OBJECTIVE. Percutaneous imaging-guided core needle biopsies (CNBs) for cancer diagnosis in pediatric patients are gaining interest because of their availability, lower rate of complications, and high diagnostic power compared with traditional surgical biopsies. Nevertheless, their precise role in the diagnostic algorithm of pediatric oncology is still unknown. The purpose of this study was to report our accumulated 16-year experience with CNB; discuss the availability, safety, and diagnostic accuracy of the procedure and the adequacy of ancillary testing; and compare our findings with the available literature. MATERIALS AND METHODS. Pediatric ultrasound-guided CNBs performed in our hospital between November 2003 and December 2019 were retrospectively studied. Data collection included demographics, clinical and procedural parameters, complications, and final diagnosis. RESULTS. A total of 597 biopsies were performed in 531 patients (132 performed in known oncologic patients and 465 performed to establish diagnosis). The median time between the biopsy request and the procedure was 1 day. Of 432 biopsies performed in patients with malignancies, 12 (2.8%) had false-negative results. In 165 cases of benign pathologic findings, all had true-negative results. Ancillary testing was adequate in all malignant cases. Overall sensitivity, specificity, and accuracy rates were 97.2%, 100%, and 98.0%, respectively. Five biopsies (0.8%) resulted in complications, including one major bleed and one track seeding. CONCLUSION. Our experience shows that ultrasound-guided CNB for suspected malignancy in pediatric patients has a high safety profile, availability, and accuracy rate compared with surgical biopsy. Our fast-track strategy enables early initiation of designated therapy and has the potential to become the procedure of choice.

Accurate and swift tissue diagnosis is extremely important for the timely initiation of treatment in pediatric oncology. In our department, ultrasound‐guided core needle biopsy (US‐guided CNB) is used for tissue diagnosis. In 2016, we added on‐site cytology, allowing for an immediate primary diagnosis. We retrospectively reviewed our performance in terms of safety and accuracy for CNBs and on‐site cytology.

BACKGROUND:Decisions on medication treatment in children dying from cancer are often complex and may result in polypharmacy and increased medication burden. There is no information on medication burden in pediatric cancer patients at the end of life (EOL).OBJECTIVES:To characterize medication burden during the last hospitalization in children dying from cancer.METHODS:We performed a retrospective cohort study based on medical records of 90 children who died from cancer in hospital between 01 January 2010 and 30 December 2018. Demographic and clinical information were collected for the last hospitalization. We compared medication burden (number of medication orders) at hospitalization and at time of death and examined whether changes in medication burden were associated with clinical and demographic parameters.RESULTS:Median medication burden was higher in leukemia/lymphoma patients (6 orders) compared to solid (4 orders) or CNS tumor patients (4 orders, P = 0.006). Overall, the median number of prescriptions per patient did not change until death (P = 0.42), while there was a significant reduction for some medication subgroups (chemotherapy [P = 0.035], steroids [P = 0.010]).Patients dying in the ICU (n=15) had a higher medication burden at death (6 orders) than patients dying on wards (3 orders, P = 0.001). There was a trend for a reduction in medication burden in patients with "Do not resuscitate" (DNR) orders (P = 0.055).CONCLUSIONS:Polypharmacy is ubiquitous among pediatric oncology patients at EOL. Disease type and DNR status may affect medication burden and deprescribing during the last hospitalization.

Haematogenous non-contiguous metastatic spread of remote solid tumours to the heart is rare. We describe a previously healthy 5-year-old girl who presented with extensive intracardiac involvement by metastatic pelvic sarcoma.

Incorrect family name of Layth Mula-Hussain.

Medical marijuana (MM) is widespread in many medical fields, including oncology, with limited use in pediatric oncology where research is scarce and often shows conflicting results. This research focuses on alleviating side effects of anticancer treatment as an integral part of supportive and palliative care of children with cancer. We report our experience with MM treatment in 50 children, adolescents, and young adults with different types of cancer during 2010-2017. The main indications for prescriptions were nausea and vomiting, decreased mood, disturbed sleep, and pain. The medication was supplied to 30 patients via oil drops (60%) and 11 via smoking (22%), followed by vaporization, capsules, or combinations of various routes. Positive effects were reported by verbal children and parents in 80% of cases. MM was generally well tolerated with few patients reporting toxicity, with the most common adverse reactions being burning in the throat and anxiety attacks in subjects who chose to smoke the product. We conclude that MM may serve as a potentially useful complementary therapy to conventional supportive treatment of children suffering from cancer at the end of life. Further research is needed on the safety and efficacy and the consequences of prolonged use in pediatric populations.

Background: It is currently expected that about 20% of children with cancer will ultimately die. Writing advanced life directives sufficiently long before the actual death of a child ensues allows both parents and medical staff to develop optimal treatment plans in the best interests of the child. Aim of the study: The aim of the study was to evaluate factors that may influence the process of decision-making regarding Do-Not-Resuscitate (DNR) status. Methods: Retrospective single institution study. Results: Totally, 79 patients died between September 01, 2011 and August 31, 2017. Median age of the children was 10.5 years (range, 1 to 24 y). Forty-five were males. There were 37 Muslims, 27 Jews, 9 Druze, and 6 Christians. Twenty-one patients had sarcomas, 20 had CNS tumors, 10 had neuroblastoma, 17 had leukemias/lymphomas, 11 had carcinomas, and other rare tumors as well as nonmalignant diseases. No statistically significant association between all evaluated factors and DNR order status was found. Conclusions: It is possible that, other than demographic, clinical-associated, or therapy-associated factors play an important role in the process of decision-making regarding DNR. We feel that sincere communication between parents, their child (when appropriate) and medical and psychosocial staff may have a more crucial role when such decisions have to be made.

Easing physical distress is a major focus in the practice of palliative care in a child with malignancy throughout the disease course from diagnosis to cure and survivorship or death. Physical suffering is a main contributor to global suffering of the ill child, his parents, other family members, and also other persons involved. Physical suffering is multifactorial and stems from many causes, mainly the disease itself, side effects of anticancer treatment and its consequences, as well as various painful procedures. Physical distress reflects the body organ(s) involved in the disease, and therefore symptoms and, mainly, pain may vary widely in form, intensity, location, and its ability to interfere with the child’s daily activity and life. Common types of physical distress are fatigue, pain, respiratory problems such as shortness of breath, gastrointestinal discomfort due to functional and mechanical obstruction, mucositis, and damage to central and peripheral nervous systems with accompanying alterations in conscience, seizures, and motor dysfunctions. Timely recognition of the various signs and symptoms of physical distress allows the physician and other members of medical team to convey appropriate treatment to the suffering child with cancer. Easing the physical distress should be of paramount concern for all those involved in the management of pediatric oncologic patient at all levels of care: primary pediatrician in the community clinic, pediatric oncologist in the hospital ward, or specialist in pediatric palliative care both in hospital and in hospice service. Proper and timely delivered pediatric palliative care directed at the easing of physical distress of pediatric cancer patient also greatly facilitates easing of both psychological distress and preserving the dignity of the child and the rest of his/her family members. In this chapter we will describe in a detailed manner the use of various techniques for easing the pain and other forms of physical suffering using various pharmacological and non-pharmacological techniques. The pharmacological techniques will include intravenous, enteral, or topical drugs along with implementation of minimally invasive procedures such as various nerve blockades and insertion of epidural and other catheters to deliver site-specific or regional treatment. Non-pharmacological techniques will include procedures to ease physical distress such as pleurocentesis and paracentesis as well as ventilatory support with high-flow nasal cannula and noninvasive positive pressure ventilation. Management of symptoms related to the central nervous system as seizures, depressed levels of consciousness, and symptoms originating from dysfunction of pelvic organs (neurogenic bladder and rectum) is also discussed. Spinal cord compression, almost the only emergency condition encountered in children with cancer during the last phases of their lives, needs special attention, and therefore its diagnosis and management are also reflected in this chapter. Although detailed discussion of palliative sedation as a mean of last resort in the management of unbearable suffering is beyond the scope of this chapter, its role in the easing of physical distress is shortly mentioned.

ObjectiveWhen patients feel spiritually supported by staff, we find increased use of hospice and reduced use of aggressive treatments at end of life, yet substantial barriers to staff spiritual care provision still exist. We aimed to study these barriers in a new cultural context and analyzed a new subgroup with unrealized potential for improved spiritual care provision: those who are positively inclined toward spiritual care yet do not themselves provide it.MethodWe distributed the Religion and Spirituality in Cancer Care Study via the Middle East Cancer Consortium to physicians and nurses caring for advanced cancer patients. Survey items included how often spiritual care should be provided, how often respondents themselves provide it, and perceived barriers to spiritual care provision.ResultWe had 770 respondents (40% physicians, 60% nurses) from 14 Middle Eastern countries. The results showed that 82% of respondents think staff should provide spiritual care at least occasionally, but 44% provide spiritual care less often than they think they should. In multivariable analysis of respondents who valued spiritual care yet did not themselves provide it to their most recent patients, predictors included low personal sense of being spiritual (p < 0.001) and not having received training (p = 0.02; only 22% received training). How developed a country is negatively predicted spiritual care provision (p < 0.001). Self-perceived barriers were quite similar across cultures.Significance of resultsDespite relatively high levels of spiritual care provision, we see a gap between desirability and actual provision. Seeing oneself as not spiritual or only slightly spiritual is a key factor demonstrably associated with not providing spiritual care. Efforts to increase spiritual care provision should target those in favor of spiritual care provision, promoting training that helps participants consider their own spirituality and the role that it plays in their personal and professional lives.

BackgroundPalliative medicine is a growing field in Israel, and its training program is still in process. The current study aimed to evaluate students' attitudes regarding a course in palliative care established in a division of oncology.MethodSome 45 medical students in their 5th to 6th years participated in a one-week course on palliative care. At the end of each training week, students were asked to complete a questionnaire, evaluating their attitudes regarding different aspects of the program content, such as its importance and relevance to their training as physicians, as well as the contribution of specific parts of the program to their knowledge regarding palliative care.ResultsThe overall satisfaction of the 45 students was high. The most contributory parts of the course were the multidisciplinary team and the complementary and alternative medicine. Participating in the staff meetings and accompanying physicians in their daily work were scored as the least contributory parts.Significance of resultsThis preliminary study demonstrated students' overall high satisfaction with the newly established palliative care course and their need for more practical skills. Future studies should investigate and evaluate educational programs in palliative care in order to establish suitable training for medical students.

Cancer is a leading cause of death in adolescents and young adults (AYAs) Wiener et al. (Pediatr Blood Cancer 60(5):715-718, 2013). Though most AYAs will survive, cancer will become incurable in 10-40 % Schrijvers and Meijnder (Cancer Treat Rev 33(7):616-621, 2007). Although the general philosophies of palliative care apply to AYAs, developmental considerations are unique to this group (Ferrari et al. J Clin Oncol Off J Am Soc Clin Oncol 28(32):4850-4857, 2010); Wein et al. J Clin Oncol Off J Am Soc Clin Oncol 28(32):4819-4824, 2010). The interaction of psychosocial, emotional, physical, and existential issues is essential to consider (Wein et al. J Clin Oncol Off J Am Soc Clin Oncol 28(32):4819-4824, 2010). The gaps in care experienced on both sides of the healthcare system between pediatric and adult medicine can be particularly impactful when delivering palliative care. The benefit of a multidisciplinary palliative care approach is widely appreciated as is the need to begin the process early in order to develop a trusting relationship (Wiener et al. Pediatr Blood Cancer 60(5):715-718, 2013; Baker et al. Pediatr Clin N Am 55(1):223-250, 2008; Ferris et al. J Clin Oncol Off J Am Soc Clin Oncol 27(18):30523058). Honest communication which supports autonomy is essential in discussions of their goals, worries, risks versus benefits of treatment, and advanced care planning (Clark and Fasciano Am J Hosp Palliat Care 32(1):101-111, 2015; Christenson et al. J Pediatr Health Care Off Publ Natl Assoc Pediatr Nurse Assoc Pract 24(5):286-291, 2010; Linebarger et al. Pediatr Clin N Am 61(4):785-796, 2014).

Autoimmune lymphoproliferative syndrome (ALPS) is typically caused by mutations in genes of the extrinsic FAS mediated apoptotic pathway, but for about 30% of ALPS-like patients the genetic diagnosis is lacking. We analyzed 30 children with ALPS-like disease of unknown cause and identified two dominant gain-of-function mutations of the Signal Transducer And Activator Of Transcription 3 (STAT3, p.R278H, p.M394T) leading to increased transcriptional activity. Hyperactivity of STAT3, a known repressor of FAS, was associated with decreased FAS-mediated apoptosis, mimicking ALPS caused by FAS mutations. Expression of BCL2 family proteins, further targets of STAT3 and regulators of the intrinsic apoptotic pathway, was disturbed. Cells with hyperactive STAT3 were consequently more resistant to intrinsic apoptotic stimuli and STAT3 inhibition alleviated this effect. Importantly, STAT3-mutant cells were more sensitive to death induced by the BCL2-inhibitor ABT-737 indicating a dependence on anti-apoptotic BCL2 proteins and potential novel therapeutic options.

Malignant mesothelioma is an uncommon tumor that usually arises in the pleural cavity of adults with a history of asbestos exposure. Less frequently, it appears in the peritoneum or other mesothelial surfaces. Deciduoid mesothelioma is a rare subtype that has been found at both sites. Of the 3 reported cases in children, 2 originated in the mesenterium and 1 in the pleura. We describe a 4th case of pediatric, malignant, deciduoid mesothelioma and a third case in the mesenteric cavity. The patient was an 8-year-old girl who presented with abdominal pain and fullness. Workup revealed extensive involvement of the abdomen by a serosa-based tumor. The clinical and pathologic findings are described, and the pertinent literature is reviewed.