Kristin Zelley

Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens

Haemophagocytic lymphohistiocytosis (HLH) is a life threatening complication of Epstein–Barr virus (EBV) infection. The anti‐CD20 antibody rituximab depletes B cells, leading to improved outcomes for patients with EBV‐associated B‐lymphoproliferative disorders. To gather data on the use of rituximab in EBV‐HLH, we performed a retrospective investigation involving 42 EBV‐HLH patients who had received treatment with rituximab‐containing regimens. On average, patients received 3 rituximab infusions (range 1–10) at a median dose of 375 mg/m2. In all patients, rituximab was administered with other HLH‐directed medications, including steroids, etoposide and/or ciclosporin. Rituximab‐containing regimens appeared well tolerated and improved clinical status in 43% of patients. Examination of laboratory data obtained prior to and within 2–4 weeks after the first rituximab dose revealed significant reductions in EBV load (median load pre‐rituximab: 114 200 copies/ml, median post‐rituximab: 225 copies/ml, P = 0·0001) and serum ferritin levels (median ferritin pre‐rituximab: 4260 μg/l, median post‐rituximab: 1149 μg/l, P = 0·001). Thus, when combined with conventional HLH‐directed therapies, rituximab improves symptoms, reduces viral load and diminishes inflammation. These data support the incorporation of rituximab into future prospective clinical trials for patients with EBV‐HLH.

Clinical Features of Three Girls With Mosaic Genome-Wide Paternal Uniparental Isodisomy

Here we describe three subjects with mosaic genome‐wide paternal uniparental isodisomy (GWpUPD) each of whom presented initially with overgrowth, hemihyperplasia (HH), and hyperinsulinism (HI). Due to the severity of findings and the presence of additional features, SNP array testing was performed, which demonstrated mosaic GWpUPD. Comparing these individuals to 10 other live‐born subjects reported in the literature, the predominant phenotype is that of pUPD11 and notable for a very high incidence of tumor development. Our subjects developed non‐metastatic tumors of the adrenal gland, kidney, and/or liver. All three subjects had pancreatic hyperplasia resulting in HI. Notably, our subjects to date display minimal features of other diseases associated with paternal UPD loci. Both children who survived the neonatal period have displayed near‐normal cognitive development, likely due to a favorable tissue distribution of the mosaicism. To understand the range of UPD mosaicism levels, we studied multiple tissues using SNP array analysis and detected levels of 5–95%, roughly correlating with the extent of tissue involvement. Given the rapidity of tumor growth and the difficulty distinguishing malignant and benign tumors in these GWpUPD subjects, we have utilized increased frequency of ultrasound (US) and alpha‐fetoprotein (AFP) screening in the first years of life. Because of a later age of onset of additional tumors, continued tumor surveillance into adolescence may need to be considered in these rare patients.

Diagnostic Performance of Whole-Body MRI as a Tool for Cancer Screening in Children With Genetic Cancer-Predisposing Conditions

OBJECTIVE Children with cancer-predisposing conditions are at increased risk to develop and die of cancer. Limited data exist on the utility of whole-body MRI as a cancer screening tool in children. In this study, we examined the diagnostic performance of whole-body MRI as a mechanism of tumor surveillance for children at increased genetic risk for cancer. MATERIALS AND METHODS Twenty-four children (six boys and 18 girls) with a mean age of 11.2 years (range, 2.1-18.2 years) underwent 50 unenhanced whole-body MRI examinations over a 5-year period. Scans were retrospectively reviewed and assessed for image quality; sequences performed; and the presence of osseous, soft-tissue, or solid organ abnormalities. Findings suggestive of a malignancy were stratified by risk as low (< 20% chance for cancer), moderate (20-80%), or high (> 80%). MRI findings were correlated with medical records, biopsy results, or additional follow-up imaging; biopsy and follow-up were considered as the reference standards. RESULTS Forty-eight of 50 (96%) examinations were of very good quality. Nine findings suspicious for malignancy were identified, including two high-risk, two moderate-risk, and five low-risk lesions. One high-risk lesion was proven by biopsy to be a papillary thyroid carcinoma, with the remaining lesions deemed nonmalignant. The sensitivity of whole-body MRI was 100%; specificity, 94%; positive predictive value, 25%; and negative predictive value (NPV), 100%. CONCLUSION Unenhanced whole-body MRI is safe and produces excellent images. The high sensitivity, specificity, and NPV make whole-body MRI a valuable cancer screening tool in children with a genetic predisposition for cancer.

Parent decision-making around the genetic testing of children for germline TP53 mutations

Li‐Fraumeni syndrome is a rare genetic cancer predisposition syndrome caused by germline TP53 mutations. Up to 20% of mutation carriers develop cancer during childhood. The benefits of TP53 mutation testing of children are a matter of debate and knowledge of parent decision‐making around such testing is limited. The current study examined how parents make decisions regarding TP53 testing for their children.

Predisposition to pediatric and hematologic cancers: a moving target.

Our understanding of hereditary cancer syndromes in children, adolescents, and young adults continues to grow. In addition, we now recognize the wide variation in tumor spectrum found within each specific cancer predisposition syndrome including the risk for hematologic malignancies. An increased understanding of the genetic mutations, biologic consequences, tumor risk, and clinical management of these syndromes will improve patient outcome. In this article, we illustrate the diversity of molecular mechanisms by which these disorders develop in both children and adults with a focus on Li-Fraumeni syndrome, hereditary paraganglioma syndrome, DICER1 syndrome, and multiple endocrine neoplasia syndrome. This is followed by a detailed discussion of adult-onset tumors that can occur in the pediatric population including basal cell carcinoma, colorectal cancer, medullary thyroid cancer, and adrenal cortical carcinoma, and the underlying hereditary cancer syndromes that these tumors could indicate. Finally, the topic of leukemia predisposition syndromes is explored with a specific focus on the different categories of syndromes associated with leukemia risk (genetic instability/DNA repair syndromes, cell cycle/differentiation, bone marrow failure syndromes, telomere maintenance, immunodeficiency syndromes, and transcription factors/pure familial leukemia syndromes). Throughout this article, special attention is made to clinical recognition of these syndromes, genetic testing, and management with early tumor surveillance and screening.

Bilateral Pheochromocytomas, Hemihyperplasia, and Subtle Somatic Mosaicism: The Importance of Detecting Low-Level Uniparental Disomy

We report on a patient with early onset pediatric bilateral pheochromocytomas caused by mosaic chromosome 11p15 paternal uniparental isodisomy (UPD). Hemihyperplasia of the arm was diagnosed in a 4‐month‐old female and clinical methylation testing for 11p15 in the blood was normal, with a reported detection threshold for mosaicism of 20%. She was subsequently diagnosed at 18 months with bilateral pheochromocytomas. Single‐nucleotide polymorphism (SNP) array analysis of pheochromocytoma tissue demonstrated mosaic deletions of 8p12pter, 21q21.1qter, 22q11.23qter; commonly seen in pheochromocytomas. In addition, mosaic 11p15.3pter homozygosity was noted. Molecular testing for other causes of pheochromocytomas was normal, suggesting that 11p15 homozygosity was the primary event. Subsequent SNP array analysis of skin fibroblasts from the hyperplastic side demonstrated 5% mosaic paternal UPD for 11p15. We have subsequently used SNP array analysis to identify four patients with subtle hemihyperplasia with low‐level mosaic UPD that was not detected by methylation analysis. Given the increased sensitivity of SNP array analysis to detect UPD along with the increased incidence of tumorigenesis in these UPD patients, we suggest that it has high utility in the clinical work‐up of hemihyperplasia. The present case also suggests that 11p15 paternal UPD may be an under‐detected mechanism of sporadic pheochromocytoma in the pediatric population. Furthermore, a review of the literature suggests that patients with 11p15 paternal UPD may present after 8 years of age with pheochromocytoma and raises the possibility that ultrasound screening could be considered beyond 8 years of age in this subset of hemihyperplasia and Beckwith–Wiedemann syndrome patients.

Identification, management, and evaluation of children with cancer-predisposition syndromes.

A substantial proportion of childhood cancers are attributable to an underlying genetic syndrome or inherited susceptibility. Recognition of affected children allows for appropriate cancer risk assessment, genetic counseling, and testing. Identification of individuals who are at increased risk to develop cancers during childhood can guide cancer surveillance and clinical management, which may improve outcomes for both the patient and other at-risk relatives. The information provided through this article will focus on the current complexities involved in the evaluation and management of children with cancer-predisposing genetic conditions and highlight remaining questions for discussion.

Genetic Counselor Recommendations for Cancer Predisposition Evaluation and Surveillance in the Pediatric Oncology Patient

As the understanding of the genetic etiology of childhood cancers increases, the need for the involvement of experts familiar with the provision of genetic counseling for this population is paramount. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in pediatric cancer predisposition met to establish surveillance guidelines for children with cancer predisposition. Identifying for whom, when, why, and how these cancer predisposition surveillance guidelines should be implemented is essential. Genetic counselors invited to this workshop provide a genetic counseling framework for oncology professionals in this article. Points of entry and recommendations regarding the provision and timing of the initial and subsequent genetic counseling sessions are addressed. The genetic counseling and testing processes are reviewed, and the psychologic impact related to surveillance is explored. Pediatric cancer genetics will continue to grow and evolve as a field, and genetic counseling services will be vital to ensure appropriate identification and management of at-risk children moving forward. Clin Cancer Res; 23(13); e91–e97. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk

In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83–e90. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Tumor Screening in Beckwith-Wiedemann Syndrome: Parental Perspectives

Children with Beckwith-Wiedemann Syndrome (BWS) and Isolated Hemihypertrophy (IHH) are at an increased risk for developing tumors. Tumor screening in this population is currently being reassessed by several groups and the effect on patients and patient-families has been argued both as a reason to screen and not to screen. Parental perspectives on this topic have never been systematically addressed for the BWS population. Here, we conducted a parent-based survey to evaluate knowledge and attitudes toward tumor screening in patients affected by BWS/IHH. A total of 261 surveys were completed. Overall, parents reported that screening decreased their worry and did not feel that screening increased worry or created a burden. This effect was observed across various demographic variables and other factors examined. Almost all significant differences observed could be attributed to parental knowledge of tumor risk. Parents who correctly identified their child’s tumor risk were more likely to agree with stratified screening recommendations according to BWS type and risk, and were less likely to feel worried if recommendations were changed. These results highlight the need to educate families about their child’s genetic type and tumor risk in order to facilitate an informed decision about tumor screening.