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Allison F O’Neill,1 Raul C Ribeiro,2 Emilia M Pinto,3 Michael R Clay,4 Gerard P Zambetti,3 Brent A Orr,3 Christopher B Weldon,5 Carlos Rodriguez-Galindo2,6 1Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA; 2Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA; 3Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA; 4Department of Pathology, Children’s Hospital Colorado, Denver, CO, USA; 5Department of Surgery, Boston Children’s Hospital, Boston, MA, USA; 6Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USACorrespondence: Allison F O’Neill, Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue – DA3111, Boston, MA, 02215, USA, Email Allison_oneill@dfci.harvard.eduAbstract: Adrenocortical tumors (ACTs) are infrequent neoplasms in children and adolescents and are typically associated with clinical symptoms reflective of androgen overproduction. Pediatric ACTs typically occur in the context of a germline TP53 mutation, can be cured when diagnosed at an early stage, but are difficult to treat when advanced or associated with concurrent TP53 and ATRX alterations. Recent work has demonstrated DNA methylation patterns suggestive of prognostic significance. While current treatment standards rely heavily upon surgical resection, chemotherapy, and hormonal modulation, small cohort studies suggest promise for multi-tyrosine kinases targeting anti-angiogenic pathways or immunomodulatory therapies. Future work will focus on novel risk stratification algorithms and combination therapies intended to mitigate toxicity for patients with perceived low-risk disease while intensifying therapy or accelerating discoveries aimed at improving survival for patients with difficult-to-treat disease.Keywords: adrenocortical, pediatric, management, discovery, carcinoma, tumors

Background/Aims: The Clock Drawing Test (CDT) assesses cognition focusing on executive function and praxis in contrast to the more language-based Mini-Mental State Exam. The CDT may allow early identification of cognitive decline. Methods: A systematic review of the literature was used to identify studies that had used the CDT to predict future cognitive impairment. Results: Five studies were found with the CDT as a predictor. The data were too disparate for meta-analytic techniques. Conclusion: The CDT may be a useful tool to identify decline before more traditional screening tests; however, further studies are needed as the data are sparse and heterogeneous. [ABSTRACT FROM AUTHOR]

Aim: To estimate the frequency of pericardial effusion/cardiac tamponade associated with the use of neonatal percutaneous long lines (PLLs) over the past five years.Method: A retrospective nationwide postal survey, of all neonatal and special care units in the United Kingdom.Results: Eighty two cases of pericardial effusion/cardiac tamponade were reported from the five year period, during which we estimate that 46 000 PLLs were inserted. The calculated frequency of pericardial effusion/cardiac tamponade occurring with PLLs was 1.8/1000 lines. There were 30 deaths, giving a fatality rate after pericardial effusion of 0.7/1000 lines.Conclusions: Pericardial effusion/cardiac tamponade is a serious but infrequent complication of PLL use. [ABSTRACT FROM AUTHOR]

Pediatric adrenocortical tumors (ACTs), rare conditions with uncertain prognoses, have high incidence in southern and southeastern Brazil. Pediatric ACTs are highly heterogeneous, so establishing prognostic markers for these tumors is challenging. We have conducted transcriptomic analysis on 14 pediatric ACT samples and compared cases with favorable and unfavorable clinical outcomes to identify prognostically significant genes. This comparison showed 1257 differentially expressed genes in favorable and unfavorable cases. Among these genes, 15 out of 60 hub genes were significantly associated with five-year event-free survival (EFS), and 10 had significant diagnostic value for predicting ACT outcomes in an independent microarray dataset of pediatric adrenocortical carcinomas (GSE76019). Overexpression of N4BP2, HSPB6, JUN, APBB1IP, STK17B, CSNK1D, and KDM3A was associated with poorer EFS, whereas lower expression of ISCU, PTPR, PRKAB2, CD48, PRF1, ITGAL, KLK15, and HIST1H3J was associated with worse outcomes. Collectively, these findings underscore the prognostic significance of these hub genes and suggest that they play a potential role in pediatric ACT progression and are useful predictors of clinical outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Justicia pectoralis Jacq. is traditionally applied in folk medicine in Brazil and in several Latin American countries. The leaves are used in tea form, especially in the treatment of respiratory disorders, acting as an expectorant. It also has activity in gastrointestinal disorders, and it is anti-inflammatory, antioxidant, sedative, and estrogenic, among others., Aims: To investigate the gastroprotective activity of the methanol extract of the leaves of Justicia pectoralis Jacq. (MEJP) in different experimental models of gastric ulcers., Materials and Methods: The adult leaves of Justicia pectoralis Jacq. were collected and cultivated in beds, with an approximate spacing of 40 × 40 cm, organic fertilization, irrigation with potable water and without shelter from light. The MEJP was prepared from the dried and pulverized leaves and concentrated under reduced pressure in a rotary evaporator. For the experimental model of gastric ulcer, Swiss male albino mice were used. The inputs used in the experiment were MEJP at three different concentrations (250, 500 and 1000 mg/kg p.o.), cimetidine (50 mg/kg p.o.), indomethacin (50 mg/kg s.c.) and vehicle (10 mL/kg p.o.)., Results: MEJP (250, 500 and 1000 mg/kg p.o.) demonstrated gastroprotective activity, with levels of protection of 45.65%, 44.80% and 40.22%, respectively, compared to the control (vehicle). Compared with cimetidine (48.29%), MEJP showed similar gastroprotective activity., Conclusions: This study demonstrated the gastroprotective activity of MEJP and contributes to validate the traditional use the species for gastric disorders and provides a pharmacological basis for its clinical potential.

The germline TP53 p.R337H mutation is reported as the most common germline TP53 variant. It exists at a remarkably high frequency in the population of southeast Brazil as founder mutation in two distinct haplotypes with the most frequent co-segregating with the p.E134∗ variant of the XAF1 tumor suppressor and an increased cancer risk. Founder mutations demonstrate linkage disequilibrium with neighboring genetic polymorphic markers that can be used to identify the founder variant in different geographic regions and diverse populations. We report here a shared haplotype among Brazilian, Portuguese, and Spanish families and the existence of three additional distinct TP53 p.R337H alleles. Mitochondrial DNA sequencing and Y-STR profiling of Brazilian carriers of the founder TP53 p.R337H allele reveal an excess of Native American haplogroups in maternal lineages and exclusively European haplogroups in paternal lineages, consistent with communities established through male European settlers with extensive intermarriage with Indigenous women. The identification of founder and independent TP53 p.R337H alleles underlines the importance for considering the haplotype as a functional unit and the additive effects of constitutive polymorphisms and associated variants in modifier genes that can influence the cancer phenotype., Competing Interests: Declaration of interests K.B. reports an immediate family member on the scientific advisory board of Emendo Biotherapeutics, Karyopharm Therapeutics, Imago BioSciences, and DarwinHealth; is co-founder of Isabl Technologies; and has equity interest in Imago BioSciences, Emendo Biotherapeutics, and Isabl Technologies., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant., (© 2023 Pinto et al.; Published by Cold Spring Harbor Laboratory Press.)

Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition., (© 2023. The Author(s).)

Objective: The purpose of this study was to systematically review the evidence on inflammatory biomarkers as analytic predictors of non-specific low back pain (NsLBP). Low back pain (LBP) is the number one cause of disability globally, posing a major health problem that causes an enormous social and economic burden, and there is an increasing interest on the importance of biomarkers in quantifying and even emerge as potential therapeutic tools to LBP., Methods: A systematic search was conducted on July 2022 in Cochrane Library, MEDLINE and Web of Science for all the available literature. Cross-sectional, longitudinal cohort or case-control studies that evaluated the relationship between inflammatory biomarkers collected from blood samples and low back pain in humans were considered eligible for inclusion, as well as prospective and retrospective studies., Results: The systematic database search resulted in a total of 4016 records, of which 15 articles were included for synthesis. Sample size comprised a total of 14,555 patients with LBP (acute LBP (n = 2073); chronic LBP (n = 12482)) and 494 controls. Most studies found a positive correlation between classic pro-inflammatory biomarkers and NsLBP, namely C-reactive protein (CRP), interleukin 1 (IL-1) and IL-1β, interleukin 6 (IL-6) and tumour necrosis factor α (TNF-α). On the other hand, anti-inflammatory biomarker interleukin 10 (IL-10) demonstrated a negative association with NsLBP. Four studies have made direct comparisons between ALBP and CLBP groups regarding their inflammatory biomarkers profile., Conclusions: This systematic review found evidence of increased levels of pro-inflammatory biomarkers CRP, IL-6 and TNF-α and decreased levels of anti-inflammatory biomarker IL-10 in patients with LBP. Hs-CRP was not correlated with LBP. There is insufficient evidence to associate these findings with the degree of pain severity or the activity status of the lumbar pain over time., (© 2023. The Author(s).)

Background and Aim: Using simulators in high education enables practical training by repetition in circumstances close to reality reducing the stress of both animal and operator. The limited resources of veterinary schools, the increase in the number of students in lecture halls, and the low availability of animals for teaching due to welfare regulations, reduce teaching opportunities with live animals being simulator as the better alternative. This study aimed to assess the efficacy of a low-cost handmade simulator (SIMCA-COW) in eight veterinary students inexperienced in palpation, ultrasonography evaluation, and artificial insemination in cows., Materials and Methods: Two sets of exercises were carried out: structure localization by rectal palpation and ultrasonography were evaluated by the inexpert veterinary students in the SIMCA-COW simulator. Also, evaluated the length of time to insert the insemination catheter through the cervix in the inert simulator during four sessions., Results: All the students were able to palpate both structures and to locate the body and both uterine horns by ultrasonography. Cervix and follicles were located by 5/8 (62.5%) students and 3/8 (37.5%) students found the corpus luteum by ultrasonography. A reduction in time span between the first and fourth intrauterine insemination attempts was observed (8.26 ± 2.7 vs. 3.69 ± 1.7; mean ± standard error; p < 0.05)., Conclusion: The simulator validated in this study (SIMCA-COW) allows training and learning by repetition, saving the limitations found in live animal practice., Competing Interests: The authors declare that they have no competing interests., (Copyright: © da Silva and Pinto.)

Background: The Fontan circulation challenges the lymphatic system. Increasing production of lymphatic fluid and impeding lymphatic return, increased venous pressure may cause lymphatic dilatation and decrease lymphatic contractility. In-vitro studies have reported a lymphatic diameter-tension curve, with increasing passive stretch affecting the intrinsic contractile properties of each thoracic duct segment. We aimed to describe thoracic duct occlusion pressure and asses if thoracic duct dilation impairs contractility in individuals with a Fontan circulation and lymphatic failure., Methods: Central venous pressure and thoracic duct measurements were retrospectively collected from 31 individuals with a Fontan circulation. Thoracic duct occlusion pressure was assessed during a period of external manual compression and used as an indicator of lymphatic vessel contractility. Measurements of pressure were correlated with measurements of the thoracic duct diameter in images obtained by dynamic contrast-enhanced MR lymphangiography., Results: The average central venous pressure and average pressure of the thoracic duct were 17 mm Hg. During manual occlusion, the thoracic duct pressure significantly increased to 32 mm Hg. The average thoracic duct diameter was 3.3 mm. Thoracic duct diameter correlated closely with the central venous pressure. The rise in pressure following manual occlusion showed an inverse correlation with the diameter of the thoracic duct., Conclusion: Higher central venous pressures are associated with increasing diameters of the thoracic duct. When challenged by manual occlusion, dilated thoracic ducts display a decreased ability to increase pressure. Dilatation and a resulting decreased contractility may partly explain the challenged lymphatic system in individuals with a Fontan circulation.

Two major concerns associated with cancer development in Paraná state, South Brazil, are environmental pollution and the germline TP53 p.R337H variant found in 0.27−0.30% of the population. We assessed breast cancer (BC) risk in rural (C1 and C2) and industrialized (C3) subregions, previously classified by geochemistry, agricultural productivity, and population density. C2 presents lower organochloride levels in rivers and lower agricultural outputs than C1, and lower levels of chlorine anions in rivers and lower industrial activities than C3. TP53 p.R337H status was assessed in 4658 women aged >30 years from C1, C2, and C3, subsequent to a genetic screening (Group 1, longitudinal study). BC risk in this group was 4.58 times higher among TP53 p.R337H carriers. BC prevalence and risk were significantly lower in C2 compared to that in C3. Mortality rate and risk associated with BC in women aged >30 years (n = 8181 deceased women; Group 2) were also lower in C2 than those in C3 and C1. These results suggest that environmental factors modulate BC risk and outcome in carriers and noncarriers.

Study Design: Systematic review., Objective: This work aimed to compare the Hounsfield units (HU) value obtained from computed tomography and the t score of dual-energy x-ray absorptiometry (DXA) in the prediction of the lumbar spine bone mineral density (BMD)., Summary of Background Data: Several reports have found a correlation between HU and BMD values based on DXA. Using HUs to infer bone quality has a thorough clinical relevance as it could triage patients at risk for osteoporotic and fragility fractures or modify surgical indications., Methods: A systematic review in Cochrane Library, Medline, Scopus and Web of Science was performed, using the following query: "hounsfield units" AND ("osteoporosis" OR "spine" OR "bone mineral density" OR "dual x-ray absorptiometry"). We included 18 cohort studies that compared HU value obtained from computed tomography and t score of DXA for predicting regional BMD., Results: A total of 18 studies were included, enrolling 5307 patients. The HU measurement was most frequently made at L1 (N = 3; 18.8%). The mean HU values differentiated based on BMD measured through DXA were reported in seven studies, with values from 54.7 to 130 for osteoporotic, 78.8 to 146 for osteopenic, and from 120.8 to 230 in normal patients. Eight studies identified thresholds for diagnosing osteoporosis through receiver-operating characteristic (ROC) curves, with values ranging from 0.66 to 0.96. Medium HU values reported as diagnostic of osteoporosis ranged between 110 and 150, after exclusion of the two papers presenting outlier values. We infer an HU interval value of 90.9 to 138.7 (95% CI, P  < 0.001) for the diagnosis osteoporosis., Conclusions: Present data evidence favorable results regarding the possibility of establishing a threshold value for osteoporosis diagnosis from CT measurements of HU. Prospective large-scale studies are needed to more robustly infer the possibility of quantifying BMD based on CT as a screening test and infer a prognostic value of the CT-based evaluation.Level of Evidence: 2., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Increased TERT mRNA is associated with disease relapse in favorable histology Wilms tumor (WT). This study sought to understand the mechanism of increased TERT expression by determining the association between TERT and WT1 and N-MYC, two proteins important in Wilms tumor pathogenesis that have been shown to regulate TERT expression. Three out of 45 (6.7%) WTs and the corresponding patient-derived xenografts harbored canonical gain-of-function mutations in the TERT promoter. This study identified near ubiquitous hypermethylation of the TERT promoter region in WT compared to normal kidney. WTs with biallelic inactivating mutations in WT1 (7/45, 15.6%) were found to have lower TERT expression by RNA-seq and qRT-PCR and lower telomerase activity determined by the telomerase repeat amplification protocol. Anaplastic histology and increased percentage of blastema were positively correlated with higher TERT expression and telomerase activity. In vitro shRNA knockdown of WT1 resulted in decreased expression of TERT , reduced colony formation, and decreased proliferation of WiT49, an anaplastic WT cell line with wild-type WT1 . CRISPR-Cas9-mediated knockout of WT1 resulted in decreased expression of telomere-related gene pathways. However, an inducible Wt1 -knockout mouse model showed no relationship between Wt1 knockout and Tert expression in normal murine nephrogenesis, suggesting that WT1 and TERT are coupled in transformed cells but not in normal kidney tissues. N-MYC overexpression resulted in increased TERT promoter activity and TERT transcription. Thus, multiple mechanisms of TERT activation are involved in WT and are associated with anaplastic histology and increased blastema. This study is novel because it identifies potential mechanisms of TERT activation in Wilms tumor that could be of therapeutic interests.

Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that affects patients across the age spectrum. Although the overall survival in patients with ACC is poor, there is significant heterogeneity in terms of outcomes, presentation, and underlying genetic drivers., Evidence Acquisition: This review is based on the evidence collected from primary research studies, expert reviews, and published guidelines. The studies were identified through PubMed search with key words "adrenocortical carcinoma," "prognosis," "pathology," and "genetics." The PubMed search was complemented by authors' expertise, research, and clinical experience in the field of ACC., Evidence Synthesis: Identification of biomarkers has been critical to gain better insight into tumor behavior and to guide therapeutic approach to patients. Tumor stage, resection status, and Ki67 are pathological tumor characteristics that have been identified as prognosticators in patients with ACC. Cortisol excess also correlates with worse prognosis. Clinical and histopathological characteristics help stratify patient outcomes, yet still up to 25% of patients have a different outcome than predicted. To bridge this gap, comprehensive genomic profiling studies have characterized additional profiles that correlate with clinical outcomes. In addition, studies of clinically applicable molecular markers are under way to further stratify outcomes in patients with ACC tumors., Conclusions: Clinical predictors in combination with pathological markers play a critical role in the approach to patients with ACC. Recent advances in genetic prognosticators will help extend the stratification of these tumors and contribute to a personalized therapeutic approach to patients with ACC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Germline TP53 splicing variants are uncommon, and their clinical relevance is unknown. However, splice-altering variants at exon 4-intron 4 junctions are relatively enriched in pediatric adrenocortical tumors (ACT). Nevertheless, family histories of cancer compatible with classic Li-Fraumeni syndrome are rarely seen in these patients. We used conventional and in silico assays to determine protein stability, splicing, and transcriptional activity of 10 TP53 variants at exon 4-intron 4 junctions and analyzed their clinical correlates. We reviewed public databases that report the impact of TP53 variants in human cancer and examined individual reports, focusing on family history of cancer. TP53 exon 4-intron 4 junction germline variants were identified in 9 of 75 pediatric ACTs enrolled in the International Pediatric Adrenocortical Tumor Registry and Children's Oncology Group ARAR0332 study. An additional eight independent TP53 variants involving exon 4 splicing were identified in the Pediatric Cancer Genome Project ( n = 5,213). These variants resulted in improper expression due to ineffective splicing, protein instability, altered subcellular localization, and loss of function. Clinical case review of carriers of TP53 exon 4-intron 4 junction variants revealed a high incidence of pediatric ACTs and atypical tumor types not consistent with classic Li-Fraumeni syndrome. Germline variants involving TP53 exon 4-intron 4 junctions are frequent in ACT and rare in other pediatric tumors. The collective impact of these germline TP53 variants on the fidelity of splicing, protein structure, and function must be considered in evaluating cancer susceptibility. IMPLICATIONS: Taken together, the data indicate that splice variants at TP53 codon 125 and surrounding bases differentially impacted p53 gene expression and function., (©2021 American Association for Cancer Research.)

Objectives: To characterize hepatic to systemic lymphatic connections in patients with systemic lymphatic disease using intra-hepatic lymphangiography and to compare outcomes after lymphatic intervention., Methods: In this retrospective study, patients with intra-hepatic lymphangiography from May 2014 - April 2019 at our institution were included. Imaging review was performed and hepatic lymphatic connections and flow patterns were characterized. Clinical data were reviewed and comparisons between patients undergoing lymphatic intervention with or without abnormal hepatic lymphatics were performed., Results: During the study period, 105 patients underwent intra-hepatic lymphangiography. Primary clinical presentation included ascites (19/105), chylothorax (27/105), plastic bronchitis (PB) (17/105), and protein losing enteropathy (PLE) (42/105). Five categories of hepatic lymphatic connections and flow patterns were identified (%): normal (25%, 26/105), hepatoperitoneal (12%, 13/105), hepatopulmonary (10.5%, 11/105), hepatomesenteric (7.5%, 8/105), and hepatoduodenal (41%, 43/105) with four patients having more than one abnormal pattern. A comparison between clinical presentation and imaging category revealed an increased likelihood of having ascites with hepatoperitoneal (p < .0001), chylothorax/PB with hepatopulmonary (p = .01), and PLE with hepatoduodenal (p < .001) connections. Seventy-six patients had a lymphatic intervention, 24% with normal, and 76% with abnormal liver lymphatics. There was no difference in length of hospital stay or mortality between the two groups, but there was a prolonged time to symptom resolution (p = .006) and persistent symptoms after 6 months (5% vs 44%, p = .002) in the group with abnormal liver lymphatics., Conclusion: We identified five liver lymphatic imaging categories with a substantial correlation to presenting lymphatic disease. Abnormal imaging patterns correlated with increased morbidity. Evaluation of liver lymphatics should be considered in patients with a systemic lymphatic disease if central lymphatic imaging is normal., Key Points: • We identified five liver lymphatic imaging patterns: normal, hepatoperitoneal, hepatomesenteric, hepatopulmonary, and hepatoduodenal. • Imaging patterns were correlated with disease presentation (normal - chylothorax/PB, hepatoperitoneal - ascites/chylothorax, hepatopulmonary - chylothorax/PB, hepatoduodenal - PLE). • Abnormal imaging patterns correlated with increased morbidity., (© 2021. The Author(s).)

Pediatric adrenocortical tumors (ACTs) are rare and heterogeneous. Approximately 50% of children with ACT carry a germline TP53 variant; however, the genetic underpinning of remaining cases has not been elucidated. In patients having germline TP53 variants, loss of maternal chromosome 11 and duplication of the paternal copy [paternal uniparental disomy, (UPD)] occurs early in tumorigenesis and explains the overexpression of IGF2 , the hallmark of pediatric ACT. Beckwith-Wiedemann syndrome (BWS) is also associated with overexpression of IGF2 due to disruption of the 11p15 loci, including segmental UPD. Here, we report six children with ACT with wild type TP53 and germline paternal 11p15 UPD. Median age of five girls and one boy was 3.2 years (range 0.5-11 years). Two patients met the criteria for BWS before diagnosis of ACT. However, ACT was the first and only manifestation of paternal 11p15 UPD in four children. Tumor weight ranged from 21.5 g to 550 g. Despite poor prognostic features at presentation, such as pulmonary metastasis, bilateral adrenal involvement, and large tumors, all patients are alive 8-21 years after cancer diagnosis. Our observations suggest that children with ACT and wild type TP53 , irrespective of their age, should be screened for germline abnormalities in chromosome 11p15., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pinto, Rodriguez-Galindo, Lam, Ruiz, Zambetti and Ribeiro.)

Adjacent segment pathology (ASP) is a major cause of disability, and the recognition of the surgical risk factors associated with the development of this condition is essential for its prevention.Different surgical approaches, from decompression without fusion to non-instrumented and instrumented fusion, have distinct contributions to the development of ASP.Although motion-preservation procedures could reduce the prevalence of ASP, these are also associated with a higher percentage of complications.Several risk factors associated with previous surgery, namely the chosen surgical approach and anatomical dissection, the choice of interbody fusion, the increment and length of the fusion, and the restoration of sagittal alignment, may influence the development of ASP. Cite this article: EFORT Open Rev 2021;6:966-972. DOI: 10.1302/2058-5241.6.210050., Competing Interests: ICMJE Conflict of interest statement: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The author(s).)

Purpose: Adrenocortical carcinoma (ACC) is a rare aggressive pediatric malignancy with distinct biology. Its treatment follows the principles developed for adults; pediatric-specific studies are scarce., Patients and Methods: Prospective single-arm risk-stratified interventional study. Study objectives were (1) to describe the outcome of patients with stage I ACC treated with adrenalectomy alone; (2) to describe the outcome of stage II patients (completely resected > 200 cc or > 100 g) treated with adrenalectomy and retroperitoneal lymph node dissection; and (3) to describe the outcome of patients with stage III or IV treated with mitotane and chemotherapy., Results: Between September 2006 and May 2013, 78 patients (77 eligible, 51 females) were enrolled. The 5-year event-free survival estimates for stages I (24 patients), II (15 patients), III (24 patients), and IV (14 patients) were 86.2%, 53.3%, 81%, and 7.1%, respectively. The corresponding 5-year overall survival estimates were 95.2%, 78.8%, 94.7%, and 15.6%, respectively. On univariate analysis, age, stage, presence of virilization, Cushing syndrome, or hypertension, germline TP53 status, and presence of a somatic ATRX mutation were associated with outcome. On multivariable analysis, only stage and age were significantly associated with outcome. The probabilities of mitotane and chemotherapy feasibility events were 10.5% and 31.6%, respectively., Conclusion: Outcome for children with stage I ACC is excellent with surgery. Outcome for patients with stage II disease is inferior despite retroperitoneal lymph node dissection. Patients with stage III ACC have an excellent outcome combining surgery and chemotherapy. Patients with stage IV ACC are older and have a poor outcome; new treatments should be explored for this high-risk group. The combination of mitotane and chemotherapy as prescribed in ARAR0332 resulted in significant toxicity; one third of patients with advanced disease could not complete the scheduled treatment., Competing Interests: Mark D. KrailoConsulting or Advisory Role: Merck Sharp & DohmeTravel, Accommodations, Expenses: Merck Sharp & Dohme Emilia M. PintoPatents, Royalties, Other Intellectual Property: Genotyping assays to identify mutations in XAF1 pending to St Jude Children's Research Hospital Farzana PashankarConsulting or Advisory Role: Novartis David MalkinConsulting or Advisory Role: Bayer Jonathan D. WassermanConsulting or Advisory Role: Bayer Gerard ZambettiResearch Funding: Johnson & JohnsonPatents, Royalties, Other Intellectual Property: MCL1 antibody license (Rockland Labs) to St Jude Children's Research Hospital. I receive small royalty on an annual basis, Patent pending for Genotyping assays to identify mutations in XAF1 Provisional application #62/659,427; Foreign filing April 18, 2019 Alberto S. PappoHonoraria: Bayer, RocheConsulting or Advisory Role: Merck, Loxo/Bayer, EUSA Pharma, DebbioNo other potential conflicts of interest were reported.

Objectives: Individual risk factors for the development of adjacent segment pathology (ASP) need to be investigated and identified to address possible modifiable factors in advance and improve outcomes and reduce medical costs. This study aimed to review the literature regarding patient-related risk factors and sagittal alignment parameters associated with ASP development., Methods: The authors performed an extensive review of the literature addressing the objectives mentioned earlier., Results: Certain patient factors such as age, gender, obesity, preexisting degeneration, osteoporosis, postmenopausal state, rheumatoid arthritis, and facet tropism may contribute to adjacent segment degeneration. Genetic influences, such as polymorphisms of the vitamin D receptor and collagen IX genes, can also be a potential cause for disc degeneration with consequent deterioration of the motion segment.The influence of sagittal imbalances, particularly after lumbar fusion, is a significant parameter to be taken into account as an independent risk factor for ASP development., Conclusions: Patient-specific risk factors, such as age, gender, obesity, preexisting degeneration, and genetic features increase the likelihood of developing ASP. On the other hand, sagittal alignment plays a significant role in the development of this condition., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The TP53-R337H founder mutation exists at a high frequency throughout southern Brazil and represents one of the most common germline TP53 mutations reported to date. It was identified in pediatric adrenocortical tumors in families with a low incidence of cancer. The R337H mutation has since been found in association with early-onset breast cancers and Li-Fraumeni syndrome (LFS). To study this variability in tumor susceptibility, we generated a knockin mutant p53 mouse model (R334H). Endogenous murine p53-R334H protein was naturally expressed at high levels in multiple tissues and was functionally compromised in a tissue- and stress-specific manner. Mutant p53-R334H mice developed tumors with long latency and incomplete penetrance, consistent with many human carriers being at a low but elevated risk for cancer. These findings suggest the involvement of additional cooperating genetic alterations when TP53-R337H occurs in the context of LFS, which has important implications for genetic counseling and long-term clinical follow-up. SIGNIFICANCE: A p53-R334H knockin mouse serves as an important model for studying the most common inherited germline TP53 mutation (R337H) that is associated with variable tumor susceptibility., (©2021 American Association for Cancer Research.)

The p53 tumor suppressor transcriptionally regulates a myriad of genes involved in cell cycle control, DNA repair, cell survival, and cell metabolism and represents one of the most well-studied inhibitors of tumorigenesis. Since the discovery of TP53 in 1979, somatic mutations have been shown to be extremely common; more than 50% of human cancers carry loss-of-function mutations in TP53. Inherited or germline TP53 mutations are rare and are involved in complex hereditary cancer predisposition disorders, and affected family members can develop diverse tumor types and multiple primary cancers at young ages. In Brazil, a fascinating history of p53 and cancer predisposition began in the year 2000 with identification of the TP53 p.R337H mutation in close association with the development of adrenocortical tumors. In these past 20 years, much has been learned about the genetics and biochemistry of this mutation, which is widespread in Brazil because of a founder effect. This review highlights the contributions of TP53 p.R337H research over the last 20 years, the findings of which have sparked passionate debate among researchers worldwide, to understanding cancer predisposition in Brazilian individuals and families., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53 . The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3 , and LCN15 ) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE: TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk., (©2020 American Association for Cancer Research.)

Cancer risk is highly variable in carriers of the common TP53- R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma ( P = 0.003) and subsequent malignancies ( P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1 -E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1- E134* and TP53- R337H mutations leads to a more aggressive cancer phenotype than TP53- R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Childhood adrenocortical tumors (ACTs) are rare, representing ∼0.2% of all pediatric malignancies and having an incidence of 0.2-0.3 new cases per million per year in the United States, but incidences are remarkably higher in Southern Brazil. At diagnosis, most children show signs and symptoms of virilization, Cushing syndrome, or both. Less than 10% of patients with ACT exhibit no endocrine syndrome at presentation, although some show abnormal concentrations of adrenal cortex hormones. Pediatric ACT is commonly associated with constitutional genetic and/or epigenetic alterations, represented by germline TP53 mutations or chromosome 11p abnormalities. Complete tumor resection is required to achieve cure. The role of chemotherapy is not established, although definitive responses to several anticancer drugs are documented. For patients undergoing complete tumor resection, favorable prognostic factors include young age, small tumor size, virilization, and adenoma histology. Prospective studies are necessary to further elucidate the pathogenesis of ACT and improve patient outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Li-Fraumeni syndrome (LFS), caused by the germline mutations in the TP53 gene, leads to significant lifetime risk to cancer in the central nervous system. Recognition of LFS, and elucidating its underlying cause has had a remarkable effect on our knowledge of the biology of brain tumors and represents a significant opportunity for cancer surveillance and screening. In this review, we discuss the historical context of the LFS with an emphasis on the clinicopathologic implications in clincal diagnosis, germline testing, and clinical management of brain tumor patients.

Background: Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist., Methods: We analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits., Results: A SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression., Conclusions: These results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC.

Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith-Wiedemann syndrome).

The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we establish 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid -/- mice that capture the biological heterogeneity of Wilms tumor (WT). Among these 45 total WTPDX, 6 from patients with diffuse anaplastic tumors, 9 from patients who experienced disease relapse, and 13 from patients with bilateral disease are included. Early passage WTPDX show evidence of clonal selection, clonal evolution and enrichment of blastemal gene expression. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes.

Purpose: Pediatric adrenocortical carcinomas (ACCs) are aggressive; the overall survival of patients with ACCs is 40%-50%. Appropriate staging and histologic classification are crucial because children with incomplete resections, metastases, or relapsed disease have a dismal prognosis. The clinical course of pediatric adrenocortical tumors (ACTs) is difficult to predict using the current classification schemas, which rely on subjective microscopic and gross macroscopic variables. Recent advances in adult ACT studies have revealed distinct DNA methylation patterns with prognostic significance that have not been systematically interrogated in the pediatric population., Patients and Methods: We performed DNA methylation analyses on 48 newly diagnosed ACTs from the International Pediatric Adrenocortical Tumor Registry and 12 pediatric adrenal controls to evaluate for distinct methylation groups. Pediatric methylation data were also compared systematically with the adult ACC cohort from The Cancer Genome Atlas (TCGA)., Results: Two pediatric ACT methylation groups were identified and showed differences in selected clinicopathologic and outcome characteristics. The A1 group was enriched for CTNNB1 variants and unfavorable outcome. The A2 group was enriched for TP53 germline variants, younger age at onset, and favorable outcome. Pediatric ACT methylation groups were maintained when International Pediatric Adrenocortical Tumor Registry cohort data were combined with TCGA cohort data. The CpG-island hypermethylator phenotype characterizing the TCGA cohort was not identified in the pediatric patients. When methylome findings were combined with independent histopathologic review using the Wieneke criteria, a high-risk population was identified with uniform fatal outcome., Conclusion: Our results indicate DNA methylation analysis can enhance current diagnostic algorithms. A combination of methylation and histologic classification produced the strongest prediction model and may prove useful in future risk-adapted therapeutic trials., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Emilia M. PintoPatents, Royalties, Other Intellectual Property: Genotyping assays to identify mutations in xaf1 pending to St Jude Children's Research HospitalGerard P. ZambettiResearch Funding: Johnson & Johnson Patents, Royalties, Other Intellectual Property: Mcl1 antibody license (Rockland Labs) to St Jude Children's Research Hospital. I receive small royalty on an annual basis patent pending for genotyping assays to identify mutations in XAF1 Provisional application #62/659,427; foreign filing April 18, 2019 No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

Adrenocortical carcinoma (ACC) is an uncommon and heterogeneous disease and may present differently in children and adults. Management of ACC is dependent on disease stage and complete surgical resection is the only potentially curative treatment. The first and most extensively used adrenocortical cancer cell line, as model system to examine mechanisms controlling normal and pathologic function of adrenal cortex, was initially isolated in 1980. Although NCI-H295 maintained steroid capabilities and adrenocortical characteristics, the lack of new cell lines and animal models of ACC has hampered the progress and development of new therapies. In this review we provide description of cellular and patient-derived tumor xenograft (PDTX) models of ACC generated for the elucidation of the underlying pathogenic mechanisms and preclinical functional studies for this aggressive disease.

Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by heterozygous germline mutations in the TP53 gene. Although more than 200 missense and null TP53 mutations are well established as disease-causing, little is known about the pathogenicity and cancer risks associated with small in-frame deletions. This leads to challenges in variant classification and subsequent difficulty making a molecular diagnosis. We report the genetic testing process for a pediatric patient diagnosed with an undifferentiated high-grade brain tumor following his mother's diagnosis of early-onset bilateral breast cancer. Sequential testing revealed that both harbored a heterozygous three-nucleotide deletion in exon 7 of TP53 (c.764&#95;766delTCA; I255del), which was classified as a variant of uncertain significance. Because the maternal family history was void of any other LFS spectrum tumors, additional information was needed to effectively classify the variant. Targeted TP53 testing of the patient's maternal grandparents confirmed that neither carried the variant; this new de novo data upgraded the variant classification to likely pathogenic. To assess the impact of this mutation on the encoded p53 protein, additional in vitro analyses were performed. Structural modeling predicted that the deletion of isoleucine at codon 255 would disrupt the architecture of the DNA-binding domain, suggesting that it might negatively impact p53 function. Consistent with this notion, the I255del mutant protein exhibited significantly impaired transcriptional activity and greatly reduced growth suppressive properties, similar to more well-characterized LFS-associated p53 mutants. This report illustrates the importance of seeking additional evidence to assign proper pathogenicity classification, which enables optimal genetic counseling and medical management of individuals with LFS and their at-risk relatives., (© 2019 Quinn et al.; Published by Cold Spring Harbor Laboratory Press.)

Background The Fontan operation is performed for surgical palliation of single ventricle physiology. This operation is usually preceded by a superior cavopulmonary connection (SCPC); lymphatic abnormalities after SCPC may be demonstrated at MRI and prior to the Fontan operation. Purpose To determine if the degree of neck and thoracic lymphatic abnormalities at T2-weighted MRI in patients after superior cavopulmonary connection (SCPC) correlated with surgical outcomes from the Fontan procedure. Materials and Methods Patients for whom SCPC was performed for palliation of single ventricle disease who underwent chest MRI between July 2012 and May 2015 at a single institution were retrospectively reviewed. T2-weighted images were scored as lymphatic type 1 (little or no T2 mediastinal and supraclavicular signal) to type 4 (T2 signal into both the mediastinum and the lung parenchyma). Fontan takedown, duration of post-Fontan hospitalization and pleural effusion, postoperative plastic bronchitis, need for transplant, and mortality were tabulated. The relationship between lymphatic type and clinical outcomes was evaluated by using analysis of variance (ANOVA), the Kruskal-Wallis H test, and the Fisher exact test. Results A total of 83 patients (mean age, 7.9 years ± 2.6) were evaluated. Among these 83 patients, 53 (64%) were classified with type 1 or 2 lymphatic abnormalities, 17 (20%) with type 3, and 12 (16%) with type 4. The rate of failure of Fontan completion was higher in patients with type 4 than in type 1 or 2 (54% vs 2%, respectively; P = .004). Need for cardiac transplant (one of 13 [8%]) and death (three of 13 [23%]) occurred only in type 4. Median postoperative length of stay was longer for patients with type 4 than for those with types 1 or 2 (29 days vs 9 days, respectively; P < .01). Conclusion Greater MRI-based severity of lymphatic abnormalities in patients prior to planned Fontan procedure was associated with failure of Fontan completion and longer postoperative stay. © RSNA, 2019 Online supplemental material is available for this article.

Caffeine is widely present in food and drinks, such as teas and coffees, being also part of some currently commercialized medicines, but despite its enhancement on several functions of human body, its exceeding use can promote many health problems. In order to develop new fast approaches for the caffeine sensing, graphite-epoxy composite electrodes (GECE) were used as substrate, being modified by different diazonium salts, synthetized as their tetraflouroborate salts. An analytical method for caffeine quantification was developed, using sware wave voltammetry (SWV) in Britton-Robinson buffer pH 2.0. Detection limits for bare electrode and 4-benzenesulfonic modified electrode were observed circa 145  µ mol·L -1 and 1.3  µ mol·L -1 , respectively. The results have shown that the modification shifts the oxidation peaks to lower potential. Kinetics of the reaction limited by diffusion was more expressive when caffeine was added to the solution, resulting in decreases of impedance, characterized by lower R ct . All results for caffeine determination were compared to a reference chromatographic procedure (HPLC), showing no statistical difference. Analytical parameters for validation were suitably determined according to local legislation, leading to a linear behaviour from 5 to 150  µ mol·L -1 ; precision of 4.09% was evaluated based on the RDC 166/17, and accuracy was evaluated in comparison with the reference method, with recovery of 98.37 ± 2.58%.

Multifocal synchronous or metachronous atypical teratoid rhabdoid tumors (ATRTs) and non-central nervous system malignant rhabdoid tumors (extra-CNS MRTs) are rare cancers. We reviewed the clinical and radiologic characteristics of affected patients seen at our institution. Genotyping and analysis of copy number abnormalities (CNAs) in SMARCB1 were performed in germline and tumor samples. Tumor samples underwent genome-wide DNA methylation and CNA analysis. The median age at diagnosis of 21 patients was 0.6 years. Two-thirds of ATRTs and extra-CNS MRTs were diagnosed synchronously. Although kidney tumors predominated, including two patients with bilateral involvement, at least 30% of cases lacked renal involvement. Histopathologic review confirmed MRTs in all cases and INI1 expression loss in all tumors tested. Fourteen (78%) of 18 patients tested had heterozygous germline SMARCB1 abnormalities. At least one allelic SMARCB1 abnormality was confirmed in 81 and 88% of ATRTs and extra-CNS MRTs, respectively. Unsupervised hierarchical clustering analysis of DNA methylation in 27 tumors and comparison with a reference group of 150 ATRTs classified the CNS tumors (n = 14) as sonic hedgehog (64%), tyrosinase (21%), and MYC (14%). The MYC subgroup accounted for 85% of 13 extra-CNS MRTs. Of 16 paired ATRTs and extra-CNS MRTs, the tumors in seven of eight patients showed a different pattern of genome-wide DNA methylation and/or CNAs suggestive of non-clonal origin. CNS and extra-CNS tumors had an identical SMARCB1 amplification (n = 1) or very similar DNA methylation pattern (n = 1) suggestive of clonal origin. All patients died of tumor progression. The clinical and molecular characteristics of multifocal ATRTs and extra-CNS MRTs are heterogeneous with most patients harboring a cancer predisposition. Although independent tumor origin was confirmed in most cases, metastatic spread was also documented. The recognition of their distinct molecular characteristics is critical in selecting new biologic therapies against these deadly cancers.

Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. β-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 LI were associated with prognosis. Ki-67 LI and age remained significantly associated with PFS after adjusting for stage and tumor weight. Three-year PFS for 27 patients with Ki-67 LI ≥ 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI < 15% (log-rank P = .002), and the rate of relapse increased by 24% with each 1-year increase in age at diagnosis (hazard ratio, 1.24; P = .0057). Conclusion Clinicopathologic features and outcomes of children with ACTs without germline TP53 mutations overlapped those reported for children with germline TP53 mutations. Our findings highlight the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACTs. Ki-67 LI is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs.

Purpose: Histologic markers that differentiate benign and malignant pediatric adrenocortical tumors are lacking. Previous studies have implicated an association of MHC class II expression with adrenocortical tumor prognosis. Here, we determined the expression of MHC class II as well as the cell of origin of these immunologic markers in pediatric adrenocortical tumor. The impact of MHC class II gene expression on outcome was determined in a cohort of uniformly treated children with adrenocortical carcinomas., Experimental Design: We analyzed the expression of MHC class II and a selected cluster of differentiation genes in 63 pediatric adrenocortical tumors by Affymetrix Human U133 Plus 2.0 or HT HG-U133+PM gene chip analyses. Cells expressing MHC class II were identified by morphologic and immunohistochemical assays., Results: MHC class II expression was significantly greater in adrenocortical adenomas than in carcinomas (P = 4.8 ×10 -6 ) and was associated with a higher progression-free survival (PFS) estimate (P = 0.003). Specifically, HLA-DPA1 expression was most significantly associated with PFS after adjustment for tumor weight and stage. HLA-DPA1 was predominantly expressed by hematopoietic infiltrating cells and undetectable in tumor cells in 23 of 26 cases (88%)., Conclusions: MHC class II expression, which is produced by tumor-infiltrating immune cells, is an indicator of disease aggressiveness in pediatric adrenocortical tumor. Our results suggest that immune responses modulate adrenocortical tumorigenesis and may allow the refinement of risk stratification and treatment for this disease. Clin Cancer Res; 22(24); 6247-55. ©2016 AACR., (©2016 American Association for Cancer Research.)

Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Most cases (91%) show loss of heterozygosity (LOH) of chromosome 11p, with uniform selection against the maternal chromosome. IGF2 on chromosome 11p is overexpressed in 100% of the tumours. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 28 ACTs (76%). Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumour-driver events. Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p. A dismal outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities, including massive structural variations and frequent background mutations. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in paediatric ACT and outline a hypothetical model of paediatric adrenocortical tumorigenesis.

Laron syndrome (LS) is a genetic disorder caused by mutations in the growth hormone receptor (GHR) gene. The most frequent GHR mutation is E180splice (rs121909360), which was initially found in an inbred population of Spanish descent in Ecuador and subsequently in Israel, Brazil, Chile, and the United States. The aim of the present study is to determine if the E180splice mutation arose from a common origin. We studied 22 patients with LS from Ecuador, Israel (of Moroccan origin), Brazil, Chile, and the United States (of Mexican origin) who were homozygous for the E180splice mutation and compared them to control individuals for markers surrounding the GHR, intragenic polymorphisms, and Y-chromosome STR. An identical haplotype was found in all but one of the subjects carrying the E180splice mutation: D5S665: 150/150; D5S2082: 192/192; D5S2087: 246/246; rs6179 G/G; and rs6180 C/C. One patient differed from the others only at D5S2082 (168/192). This haplotype is rare (~1%) in control individuals and confirmed that the E180splice-associated haplotype was not derived from independent origins but represented recombination from a common ancestor. The analysis of paternal lineage markers showed that 50% belong to haplogroup R1b (found in Portugal and Spain) and 40% to haplogroups J and E (typical in the Middle East and in Eastern European Jews). The germline E180Splice mutation appears to have originated from a single common ancestor. The presence of Y-chromosome markers associated with Sephardic populations in persons harboring the E180splice mutation provides genetic evidence in support of the historical tracking of the exodus of this specific population., (© 2014 Wiley Periodicals, Inc.)

Objective: To investigate the influence of (CA)n repeats in the insulin-like growth factor 1 gene and a variable number of tandem repeats of the insulin gene on birth size in children who are small or adequate-sized for gestational age and to correlate these polymorphisms with serum insulin-like growth factor 1 levels and insulin sensitivity in children who are small for gestational age, with and without catch-up growth., Patients and Methods: We evaluated 439 infants: 297 that were adequate-sized for gestational age and 142 that were small for gestational age (66 with and 76 without catch-up). The number of (CA)n repeat in the insulin-like growth factor 1 gene and a variable number of tandem repeats in the insulin gene were analyzed using GENESCAN software and polymerase chain reaction followed by enzymatic digestion, respectively. Clinical and laboratory data were obtained from all patients., Results: The height, body mass index, paternal height, target height and insulin-like growth factor 1 serum levels were higher in children who were small for gestational age with catch-up. There was no difference in the allelic and genotypic distributions of both polymorphisms between the adequate-sized and small infants or among small infants with and without catch-up. Similarly, the polymorphisms were not associated with clinical or laboratory variables., Conclusion: Polymorphisms of the (CA)n repeats of the insulin-like growth factor 1 gene and a variable number of tandem repeats of the insulin gene, separately or in combination, did not influence pre- or postnatal growth, insulin-like growth factor 1 serum levels or insulin resistance.

Purpose: Pediatric adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy. Conventional chemotherapeutic agents have shown limited utility and are largely ineffective in treating children with advanced ACC. The lack of cell lines and animal models of pediatric ACC has hampered the development of new therapies. Here we report the establishment of the first pediatric ACC xenograft model and the characterization of its sensitivity to selected chemotherapeutic agents., Experimental Design: A tumor from an 11-year-old boy with previously untreated ACC was established as a subcutaneous xenograft in immunocompromised CB17 scid(-/-) mice. The patient harbored a germline TP53 G245C mutation, and the primary tumor showed loss of heterozygosity with retention of the mutated TP53 allele. Histopathology, DNA fingerprinting, gene expression profiling, and biochemical analyses of the xenograft were conducted and compared with the primary tumor and normal adrenal cortex. The second endpoint was to assess the preliminary antitumor activity of selected chemotherapeutic agents., Results: The xenograft maintained the histopathologic and molecular features of the primary tumor. Screening the xenograft for drug responsiveness showed that cisplatin had a potent antitumor effect. However, etoposide, doxorubicin, and a panel of other common cancer drugs had little or no antitumor activity, with the exception of topotecan, which was found to significantly inhibit tumor growth. Consistent with these preclinical findings, topotecan as a single agent in a child with relapsed ACC resulted in disease stabilization., Conclusion: Our study established a novel TP53-associated pediatric ACC xenograft and identified topotecan as a potentially effective agent for treating children with this disease., (©2013 AACR.)

Adrenocortical tumor (ACT), a rare tumor with a heterogeneous presentation, incompletely understood pathogenesis, and generally poor prognosis, occurs in 1-2 people per million and is even more uncommon in the pediatric population. Such rare cancers are a challenge to clinical practice. Exchange of experience, information, and data on rare cancers is lacking, and outcomes for these rare cancers could be improved through the establishment of an international registry. The establishment of the International Pediatric Adrenocortical Tumor Registry (IPACTR) in 1990 by the St. Jude Children's Research Hospital International Outreach Program offered a new opportunity to collect clinical and laboratory features, treatment practices, and outcome data for children with ACT, research this disease, and systematically investigate how to improve patient outcomes. These efforts will improve the availability of information for both patients and the medical community., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)