Search

Germline pathogenic variants in cancer susceptibility genes are identified in up to 18% of all children with cancer. Because pediatric cancer predisposition syndromes (CPS) themselves are rare and underrecognized, there are limited data to guide the diagnosis and management of affected children and at-risk relatives. Furthermore, the care of affected children requires distinct considerations given the early onset of cancers, lifelong risks of additional cancers, and potential late effects of therapy. Herein, we discuss efforts to leverage existing infrastructure, organize experts, and develop a new consortium to optimize care and advance research for children with CPS. A 2016 workshop organized by the American Association for Cancer Research united many experts in childhood cancer predisposition and resulted in publication of multiple consensus guidelines for tumor surveillance. More recently, several of these authors established the Consortium for Childhood Cancer Predisposition (C3P), a multi-institutional collaboration that provides a structure for systematic research in cancer predisposition, screening, and prevention in children. The Consortium intends to work with other cooperative groups to merge longitudinal data from children with CPS throughout the continuum of the cancer risk period, as well as cancer treatment and survivorship care, to optimize overall outcomes.

Supplementary Figures S1-S4 from A Functional Screen Identifies miR-34a as a Candidate Neuroblastoma Tumor Suppressor Gene

IC50 for resistant cell lines as compared to IC50 of parental cell line

Purpose: Currently, Experimental Design: SN38, the active metabolite of irinotecan (CPT-11), is a potent therapeutic agent that is readily encapsulated in polymeric nanoparticles. Tocopherol oxyacetate (TOA) is a hydrophobic mitocan that was linked to SN38 to significantly increase hydrophobicity and enhance nanoparticle retention. We treated neuroblastomas with SN38-TOA nanoparticles and compared the efficacy with the parent prodrug CPT-11 using a mouse xenograft model.Results: Nanoparticle treatment induced prolonged event-free survival (EFS) in most mice, compared with CPT-11. This was shown for both SH-SY5Y and IMR-32 neuroblastoma xenografts. Enhanced efficacy was likely due to increased and sustained drug levels of SN38 in the tumor compared with conventional CPT-11 delivery. Interestingly, when recurrent CPT-11–treated tumors were re-treated with SN38-TOA nanoparticles, the tumors transformed from undifferentiated neuroblastomas to maturing ganglioneuroblastomas. Furthermore, these tumors were infiltrated with Schwann cells of mouse origin, which may have contributed to the differentiated histology.Conclusions: Nanoparticle delivery of SN38-TOA produced increased drug delivery and prolonged EFS compared to conventional delivery of CPT-11. Also, lower total dose and drug entrapment in nanoparticles during circulation should decrease toxicity. We propose that nanoparticle-based delivery of a rationally designed prodrug is an attractive approach to enhance chemotherapeutic efficacy in pediatric and adult tumors. Clin Cancer Res; 24(11); 2585–93. ©2018 AACR.

PDF file - 2.5MB

Supplemental Figure Legends

SN22 and SN38 pharmacokinetics

Supp Figure S1 Figure S1. SRB assay assessing efficacy of free SN-38 and SN38-TOA NP. A, Growth inhibition by SN38-TOA NPs is statistically significant for 4 nM at 72-h (p=0.0002), and 2 nM and 4 nM at 96-h (p0.0001) and 96-h (p>0.0001), and 1 nM at 96-h (p=0.0007). FD = free drug. NP = nanoparticles.

Purpose: Neuroblastoma is an embryonal tumor with contrasting clinical courses. Despite elaborate stratification strategies, precise clinical risk assessment still remains a challenge. The purpose of this study was to develop a PCR-based predictor model to improve clinical risk assessment of patients with neuroblastoma.Experimental Design: The model was developed using real-time PCR gene expression data from 96 samples and tested on separate expression data sets obtained from real-time PCR and microarray studies comprising 362 patients.Results: On the basis of our prior study of differentially expressed genes in favorable and unfavorable neuroblastoma subgroups, we identified three genes, CHD5, PAFAH1B1, and NME1, strongly associated with patient outcome. The expression pattern of these genes was used to develop a PCR-based single-score predictor model. The model discriminated patients into two groups with significantly different clinical outcome [set 1: 5-year overall survival (OS): 0.93 ± 0.03 vs. 0.53 ± 0.06, 5-year event-free survival (EFS): 0.85 ± 0.04 vs. 0.042 ± 0.06, both P < 0.001; set 2 OS: 0.97 ± 0.02 vs. 0.61 ± 0.1, P = 0.005, EFS: 0.91 ± 0.8 vs. 0.56 ± 0.1, P = 0.005; and set 3 OS: 0.99 ± 0.01 vs. 0.56 ± 0.06, EFS: 0.96 ± 0.02 vs. 0.43 ± 0.05, both P < 0.001]. Multivariate analysis showed that the model was an independent marker for survival (P < 0.001, for all). In comparison with accepted risk stratification systems, the model robustly classified patients in the total cohort and in different clinically relevant risk subgroups.Conclusion: We propose for the first time in neuroblastoma, a technically simple PCR-based predictor model that could help refine current risk stratification systems. Clin Cancer Res; 18(7); 2012–23. ©2012 AACR.

XLS file - 61K

PDF file - 24K

Blood counts

Liver function tests

Camptothecins are potent topoisomerase I inhibitors used to treat high-risk pediatric solid tumors, but they often show poor efficacy due to intrinsic or acquired chemoresistance. Here, we developed a multivalent, polymer-based prodrug of a structurally optimized camptothecin (SN22) designed to overcome key chemoresistance mechanisms. The ability of SN22 vs. SN38 (the active form of irinotecan/CPT-11) to overcome efflux pump-driven drug resistance was tested. Tumor uptake and biodistribution of SN22 as a polymer-based prodrug (PEG-[SN22]4) compared with SN38 was determined. The therapeutic efficacy of PEG-[SN22]4 to CPT-11 was compared in: (i) spontaneous neuroblastomas (NB) in transgenic TH-MYCN mice; (ii) orthotopic xenografts of a drug-resistant NB line SK-N-BE(2)C (mutated TP53); (iii) flank xenografts of a drug-resistant NB-PDX; and (iv) xenografts of Ewing sarcoma and rhabdomyosarcoma. Unlike SN38, SN22 inhibited NB cell growth regardless of ABCG2 expression levels. SN22 prodrug delivery resulted in sustained intratumoral drug concentrations, dramatically higher than those of SN38 at all time points. CPT-11/SN38 treatment had only marginal effects on tumors in transgenic mice, but PEG-[SN22]4 treatment caused complete tumor regression lasting over 6 months (tumor free at necropsy). PEG-[SN22]4 also markedly extended survival of mice with drug-resistant, orthotopic NB and it caused long-term (6+ months) remissions in 80% to 100% of NB and sarcoma xenografts. SN22 administered as a multivalent polymeric prodrug resulted in increased and protracted tumor drug exposure compared with CPT-11, leading to long-term “cures” in NB models of intrinsic or acquired drug resistance, and models of high-risk sarcomas, warranting its further development for clinical trials.Significance:SN22 is an effective and curative multivalent macromolecular agent in multiple solid tumor mouse models, overcoming common mechanisms of drug resistance with the potential to elicit fewer toxicities than most cancer therapeutics.

Supplementary Table 2 from Integrative Genomics Identifies Distinct Molecular Classes of Neuroblastoma and Shows That Multiple Genes Are Targeted by Regional Alterations in DNA Copy Number

Neuroblastoma is remarkable for its clinical heterogeneity and is characterized by genomic alterations that are strongly correlated with tumor behavior. The specific genes that influence neuroblastoma biology and are targeted by genomic alterations remain largely unknown. We quantified mRNA expression in a highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors using an oligonucleotide-based microarray. Genomic copy number status at the prognostically relevant loci 1p36, 2p24 (MYCN), 11q23, and 17q23 was determined by PCR and was aberrant in 26, 20, 40, and 38 cases, respectively. In addition, 72 diagnostic neuroblastoma primary tumors assayed in a different laboratory were used as an independent validation set. Unsupervised hierarchical clustering showed that gene expression was highly correlated with genomic alterations and clinical markers of tumor behavior. The vast majority of samples with MYCN amplification and 1p36 loss of heterozygosity (LOH) clustered together on a terminal node of the sample dendrogram, whereas the majority of samples with 11q deletion clustered separately and both of these were largely distinct from the copy number neutral group of tumors. Genes involved in neurodevelopment were broadly overrepresented in the more benign tumors, whereas genes involved in RNA processing and cellular proliferation were highly represented in the most malignant cases. By combining transcriptomic and genomic data, we showed that LOH at 1p and 11q was associated with significantly decreased expression of 122 (61%) and 88 (27%) of the genes mapping to 1p35-36 and all of 11q, respectively, suggesting that multiple genes may be targeted by LOH events. A total of 71 of the 1p35-36 genes were also differentially expressed in the independent validation data set, providing a prioritized list of candidate neuroblastoma suppressor genes. Taken together, these data are consistent with the hypotheses that the neuroblastoma transcriptome is a sensitive marker of underlying tumor biology and that chromosomal deletion events in this cancer likely target multiple genes through alteration in mRNA dosage. Lead positional candidates for neuroblastoma suppressor genes can be inferred from these data, but the potential multiplicity of transcripts involved has significant implications for ongoing gene discovery strategies. (Cancer Res 2006; 66(12): 6050-62)

Supplementary Table 3 from Integrative Genomics Identifies Distinct Molecular Classes of Neuroblastoma and Shows That Multiple Genes Are Targeted by Regional Alterations in DNA Copy Number

Supplementary Table 1 from Integrative Genomics Identifies Distinct Molecular Classes of Neuroblastoma and Shows That Multiple Genes Are Targeted by Regional Alterations in DNA Copy Number

We report here on the recent upgrade of the TwinSol radioactive nuclear beam (RNB) facility at the University of Notre Dame. The new TriSol system includes a magnetic dipole to provide a second beamline and a third solenoid which acts to reduce the size of the radioactive beam on target., submitted to Nuclear Instruments and Methods A

Juvenile polyposis syndrome (JPS) is a clinically diagnosed hamartomatous polyposis syndrome that increases the risk of gastrointestinal cancer. Approximately 40%–50% of JPS is caused by a germline disease-causing variant (DCV) in the SMAD4 or BMPR1A genes. The aim of this study was to characterize the phenotype of DCV-negative JPS and compare it with DCV-positive JPS. Herein, we analyzed a cohort of 145 individuals with JPS from nine institutions, including both pediatric and adult centers. Data analyzed included age at diagnosis, family history, cancer history, need for colectomy/gastrectomy, and polyp number and location. Compared with DCV-positive JPS, DCV-negative JPS was associated with younger age at diagnosis (P < 0.001), lower likelihood of having a family history of JPS (P < 0.001), and a lower risk of colectomy (P = 0.032). None of the DCV-negative individuals had gastric or duodenal polyps, and polyp burden decreased after the first decade compared with DCV-positive JPS. Subgroup analysis between SMAD4 and BMPR1A carriers showed that SMAD4 carriers were more likely to have a family history of JPS and required gastrectomy. Taken together, these data provide the largest phenotypic characterization of individuals with DCV-negative JPS to date, showing that this group has distinct differences compared with JPS due to a SMAD4 or BMPR1A variant. Better understanding of phenotype and cancer risk associated with JPS both with and without a DCV may ultimately allow for individualized management of polyposis and cancer risk. Prevention Relevance: Juvenile Polyposis Syndrome (JPS) is a gastrointestinal cancer predisposition syndrome requiring lifelong surveillance, however there is limited data comparing individuals with and without a germline disease-causing variant in SMAD4 or BMPR1A. Herein we show that individuals with JPS without an underlying disease-causing variant have distinct phenotypic differences including lack of upper gastrointestinal polyps and lower rates of a family history of JPS, suggesting that a different approach to management may be appropriate in this population.

Camptothecins are potent topoisomerase I inhibitors used to treat high-risk pediatric solid tumors, but they often show poor efficacy due to intrinsic or acquired chemoresistance. Here, we developed a multivalent, polymer-based prodrug of a structurally optimized camptothecin (SN22) designed to overcome key chemoresistance mechanisms. The ability of SN22 vs. SN38 (the active form of irinotecan/CPT-11) to overcome efflux pump-driven drug resistance was tested. Tumor uptake and biodistribution of SN22 as a polymer-based prodrug (PEG-[SN22]4) compared with SN38 was determined. The therapeutic efficacy of PEG-[SN22]4 to CPT-11 was compared in: (i) spontaneous neuroblastomas (NB) in transgenic TH-MYCN mice; (ii) orthotopic xenografts of a drug-resistant NB line SK-N-BE(2)C (mutated TP53); (iii) flank xenografts of a drug-resistant NB-PDX; and (iv) xenografts of Ewing sarcoma and rhabdomyosarcoma. Unlike SN38, SN22 inhibited NB cell growth regardless of ABCG2 expression levels. SN22 prodrug delivery resulted in sustained intratumoral drug concentrations, dramatically higher than those of SN38 at all time points. CPT-11/SN38 treatment had only marginal effects on tumors in transgenic mice, but PEG-[SN22]4 treatment caused complete tumor regression lasting over 6 months (tumor free at necropsy). PEG-[SN22]4 also markedly extended survival of mice with drug-resistant, orthotopic NB and it caused long-term (6+ months) remissions in 80% to 100% of NB and sarcoma xenografts. SN22 administered as a multivalent polymeric prodrug resulted in increased and protracted tumor drug exposure compared with CPT-11, leading to long-term “cures” in NB models of intrinsic or acquired drug resistance, and models of high-risk sarcomas, warranting its further development for clinical trials. Significance: SN22 is an effective and curative multivalent macromolecular agent in multiple solid tumor mouse models, overcoming common mechanisms of drug resistance with the potential to elicit fewer toxicities than most cancer therapeutics.

Purpose In a previous study, we demonstrated that the combination of fenretinide with lenalidomide, administered by a novel nanomicellar formulation (FLM), provided a strong antitumor effect in a neuroblastoma TrkB-expressing tumor. In this study, we tested the nanomicellar combination in an MYCN amplified neuroblastoma xenograft to assess its efficacy in different tumor genotypes and evaluate the interactions of the nanomicelles with the tumor cells. Experimental design FLM was administered to mice bearing human NLF xenografts to evaluate its efficacy in comparison with the nanomicelles containing fenretinide alone (FM). Confocal laser-scanning fluorescence microscopy images of the NLF cells treated with FLM and FM allowed us to estimate the nanomicelle ability to transport the encapsulated drugs inside the tumor cells. Flow cytometric analysis of the cells from treated tumors was performed to assess the effect of treatment on GD2 expression and NK cell infiltration. Results FLM and FM decreased the growth of NLF xenografts at comparable extents during the treatment period. Afterwards, FLM induced a progressive tumor regression without regrowth, while FM treatment was followed by regrowth within 15-20 days after the end of treatment. Both FLM and FM were able to penetrate the tumor cells transporting the encapsulated drugs. FLM transported higher amount of fenretinide inside the cells. Also, FLM treatment strongly increased GD2 expression in treated tumors and slightly decreased the NK infiltration compared to FM. Conclusion FLM treatment induced a superior antitumor response than FM in NLF xenografts, presumably due to the combined effects of fenretinide cytotoxicity and lenalidomide antiangiogenic activity. The ability of FLM to penetrate tumor cells, transporting the encapsulated drugs, substantially improved the therapeutic efficiency of this system. Moreover, the enhancement of GD2 expression in FLM treated tumors offers the possibility to further increase the antitumor effect by the use of anti-GD2 CAR-T cells and anti-GD2 antibodies in combination with FLM in multimodal therapies.

Context Assessments of the duration of concussion recovery have primarily been limited to sport-related concussions and male contact sports. Furthermore, whereas durations of symptoms and return-to-activity (RTA) protocols encompass total recovery, the trajectory of each duration has not been examined separately. Objective To identify individual (eg, demographics, medical history), initial concussion injury (eg, symptoms), and external (eg, site) factors associated with symptom duration and RTA-protocol duration after concussion. Design Cohort study. Setting Three US military service academies. Patients or Other Participants A total of 10 604 cadets at participating US military service academies enrolled in the study and completed a baseline evaluation and up to 5 postinjury evaluations. A total of 726 cadets (451 men, 275 women) sustained concussions during the study period. Main Outcome Measure(s) Number of days from injury (1) until the participant became asymptomatic and (2) to complete the RTA protocol. Results Varsity athlete cadets took less time than nonvarsity cadets to become asymptomatic (hazard ratio [HR] = 1.75, 95% confidence interval = 1.38, 2.23). Cadets who reported less symptom severity on the Sport Concussion Assessment Tool, third edition (SCAT3), within 48 hours of concussion had 1.45 to 3.77 times shorter symptom-recovery durations than those with more symptom severity. Similar to symptom duration, varsity status was associated with a shorter RTA-protocol duration (HR = 1.74, 95% confidence interval = 1.34, 2.25), and less symptom severity on the SCAT3 was associated with a shorter RTA-protocol duration (HR range = 1.31 to 1.47). The academy that the cadet attended was associated with the RTA-protocol duration (P < .05). Conclusions The initial total number of symptoms reported and varsity athlete status were strongly associated with symptom and RTA-protocol durations. These findings suggested that external (varsity status and academy) and injury (symptom burden) factors influenced the time until RTA.

Juvenile polyposis syndrome (JPS) is a childhood polyposis syndrome with up to a 50% lifetime risk of gastrointestinal cancer. Germline pathogenic variants in BMPR1A and SMAD4 are responsible for around 40% of cases of JPS, but for the majority of individuals, the underlying genetic cause is unknown. We identified a family for which polyposis spanned four generations, and the proband had a clinical diagnosis of JPS. Next-generation sequencing was conducted, followed by Sanger sequencing confirmation. We identified an internal deletion of the FOCAD gene in all family members tested that altered the reading frame and is predicted to be pathogenic. We conclude that inactivation of the FOCAD gene is likely to cause JPS in this family.

Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, MYCN-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.

High-risk solid tumors continue to pose a tremendous therapeutic challenge due to multidrug resistance. Biological mechanisms driving chemoresistance in high-risk primary and recurrent disease are distinct: in newly diagnosed patients, non-response to therapy is often associated with a higher level of tumor "stemness" paralleled by overexpression of the ABCG2 drug efflux pump, whereas in tumors relapsing after non-curative therapy, poor drug sensitivity is most commonly linked to the dysfunction of the tumor suppressor protein, p53. In this study, we used preclinical models of aggressive neuroblastoma featuring these characteristic mechanisms of primary and acquired drug resistance to experimentally evaluate a macromolecular prodrug of a structurally enhanced camptothecin analog, SN22, resisting ABCG2-mediated export, and glucuronidation. Together with extended tumor exposure to therapeutically effective drug levels via reversible conjugation to Pluronic F-108 (PF108), these features translated into rapid tumor regression and long-term survival in models of both ABCG2-overexpressing and p53-mutant high-risk neuroblastomas, in contrast to a marginal effect of the clinically used camptothecin derivative, irinotecan. Our results demonstrate that pharmacophore enhancement, increased tumor uptake, and optimally stable carrier-drug association integrated into the design of the hydrolytically activatable PF108-[SN22]

Introduction: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) comprises a collection of clinical features characterized by constitutional variants in PTEN. Several guidelines recommend thyroid screening, beginning at the pediatric age at the time of PHTS diagnosis; however, the benefits of early surveillance has not been well defined. Methods: We conducted a retrospective investigation of patients followed up at the Children’s Hospital of Philadelphia with a diagnosis of PHTS between January 2003 and June 2019. In total, 81 patients younger than 19 years were identified. Results: The most common clinical feature at presentation was macrocephaly (85.1%), followed by impaired development (42.0%), skin/oral lesions (30.9%), and autism spectrum disorder (27.2%). A total of 58 of 81 patients underwent thyroid surveillance, with 30 patients (51.7%) found to have a nodule(s). Ultimately, 16 patients underwent thyroidectomy, with 7.4% (6/81) diagnosed with thyroid cancer. All thyroid cancer patients were older than 10 years at diagnosis, and all displayed low-invasive behavior. Of the patients younger than 10 years at the time of thyroid ultrasound (US) surveillance, 71.4% (15/21) had a normal US. The remaining 6 patients had thyroid nodules, including 4 undergoing thyroid surgery with benign histology. Discussion/Conclusion: Patients with macrocephaly, impaired cognitive development and thyroid nodules, and/or early-onset gastrointestinal polyps should undergo constitutional testing for PHTS. There does not appear to be a clinical advantage to initiating thyroid US surveillance before 10 years of age. In PHTS patients with a normal physical examination, thyroid US surveillance can be delayed until 10 years of age.

Purpose Currently >50% of high-risk neuroblastoma (NB) patients, despite intensive therapy and initial partial or complete response, develop recurrent NB due to the persistence of minimal residual disease (MRD) that is resistant to conventional antitumor drugs. Indeed, their low therapeutic index prevents drug-dose escalation and protracted administration schedules, as would be required for MRD treatment. Thus, more effective and less toxic therapies are urgently needed for the management of MRD. To address this aim, we evaluated a new combination of fenretinide and lenalidomide, both endowed with antitumor activity and low-toxicity profiles. New nanomicelles were prepared as carriers for this combination to maximize bioavailability and accumulation at the tumor site because of the enhanced permeability and retention (EPR) effect. Experimental design New nanomicelles containing the fenretinide-lenalidomide combination (FLnMs) were prepared by a one-step method, providing high drug encapsulation and micelle dimensions suitable for tumor accumulation. Their administration to mice bearing human NB xenografts allowed us to evaluate their efficacy in comparison with the nanomicelles containing fenretinide alone (FnMs). Results Treatment by FLnMs significantly decreased the tumor growth of NB xenografts. FLnMs were more active than FnMs despite comparable fenretinide concentrations in tumors, and lenalidomide alone did not show cytotoxic activity in vitro against NB cells. The tumor mass at the end of treatment with FLnMs was predominantly necrotic, with a decreased Ki-67 proliferation index. Conclusion FLnMs provided superior antitumor efficacy in NB xenografts compared to FnMs. The enhanced efficacy of the combination was likely due to the antiangiogenic effect of lenalidomide added to the cytotoxic effect of fenretinide. This new nanomicellar combination is characterized by a low-toxicity profile and offers a novel therapeutic option for the treatment of high-risk tumors where the persistence of MRD requires repeated administrations of therapeutic agents over long periods of time to avoid recurrent disease.

PURPOSE The diagnosis of cancer predisposition in pediatric patients with cancer is vital for treatment decisions, surveillance, and management of at-risk family members. Somatic tumor testing can identify potential underlying constitutional variants that confer increased cancer risk. Here, we report the characteristics of constitutional variants identified through tumor testing. MATERIALS AND METHODS Data were abstracted from medical record review of 1,023 patients who received in-house somatic tumor testing over a 28-month period. Patients were identified for testing using referral criteria developed as a collaboration between genomic diagnostics, pathology, and oncology. Characteristics of patients who underwent constitutional testing, including family history and variant loss of heterozygosity, were tracked. RESULTS From 1,023 patients who underwent somatic tumor sequencing in a 28-month period, 210 variants were identified in 141 patients (13.8%) that were concerning for cancer predisposition syndromes requiring intervention. A total of 73 variants in 41 patients have undergone clinical confirmatory testing thus far. Of these, 26 variants were confirmed to be constitutionally present (35.6%). Among patients tested, 23 (56.1%) of 41 total patients were diagnosed with a cancer predisposition syndrome. CONCLUSION Our data demonstrate that more than one third of variants in tumor somatic sequencing that were concerning for underlying cancer predisposition were constitutionally confirmed. Overall, somatic tumor testing identified potential cancer predisposition syndromes in pediatric patients, and some would not have been identified on the basis of clinical history alone.

Objectives An exercise session in a hot environment may increase thermal strain during subsequent exercise sessions on the same and consecutive days. Therefore, this study was conducted to determine lasting physiological strain from moderate-high intensity, intermittent exercise in heat on subsequent exercise. Design Repeated measures laboratory study. Methods Seventeen healthy, recreationally active men (age: 22 ± 3 y, maximal oxygen consumption: 54.6 ± 5.3 mL kg−1 min−1) underwent two intermittent moderate-high intensity aerobic exercise sessions separated by 2 h of rest one day, followed by one session 24 h later in a 40 °C, 40% relative humidity environment. Heart rate, rectal temperature, heat stress perception, and environmental symptoms were assessed. Results 100%, 35%, and 71% of participants completed the full exercise protocol during the first exercise session, second exercise session, and the following day, respectively. Exercising heart rate and rectal temperature were greater during the second exercise session (189 ± 11 bpm, 38.80 ± 0.47 °C) than the first identical exercise session (180 ± 17 bpm, p = 0.004; 38.41 ± 0.52 °C, p = 0.001), respectively. Immediate post-exercise heart rate, rectal temperature, thirst, thermal sensation, fatigue, and perceived exertion were similar among exercise sessions despite a shorter exercise duration during the second exercise session (93 ± 27 min, p = 0.001) and the following day (113 ± 12 min, p = 0.032) than the first exercise session (120 ± 0 min). Conclusions Moderate-high-intensity intermittent exercise in the heat resulted in greater heat strain during a second exercise session the same day, and exercise the subsequent day.

Gastrointestinal polyps are mucosal overgrowths that, if unchecked, can undergo malignant transformation. Although relatively uncommon in the pediatric age group, they can be the harbingers of multiorgan cancer risk and require close management and follow-up. Additionally, as many polyposis syndromes are inherited, appropriate genetic testing and management of relatives is vital for the health of the entire family. In this review, we discuss both common and uncommon childhood gastrointestinal polyposis syndromes in terms of clinical presentation, management, and surveillance. We also detail any additional malignancy risk and surveillance required in the pediatric age group (

Summary: Juvenile Polyposis Syndrome is a pediatric cancer predisposition syndrome for which approximately half of patients do not have a known germline driver; we propose BMPR2 as a possible germline driver of disease in mutation-negative JPS. Background: Juvenile Polyposis Syndrome (JPS) is a cancer predisposition syndrome characterized in some cases by inactivating germline mutations in BMPR1A or SMAD4. However, in 40-60% of patients the germline driver is unknown. Methods: Through whole exome sequencing, an individual with high polyp burden and negative genetic testing for variants in SMAD4 and BMPR1A was found to have a potentially inactivating germline variant in BMPR2. Under an IRB-approved protocol, patient-derived, three-dimensional organoids were established from adjacent colon and polyp tissue of this individual, as well as an individual with a BMPR1A deletion and age- and sex-matched controls. Proliferation, metabolic activity, and protein expression of each line were measured by Western blot, Ki67 staining, EdU labelling, cell titer glo (CTG) assay. Results: Distinct phenotypic differences are evident between colonoids from an individual with a BMPR1A deletion and both the colon and polyp BMPR2 variant colonoids, such as increased crypt budding and Ki67 staining. CTG assay data indicate higher metabolic activity in BMPR2 variant colonoids in comparison to normal controls (p= 0.0104.) Through Western blot analysis, both BMPR2 colon and polyp colonoids showed decreased SMAD4 expression and phosphorylation. Conclusions: These data demonstrate that clear phenotypic differences exist between colonoid lines established from normal controls, individuals with known JPS predisposition genes, and a novel candidate driver of disease, BMPR2. Proliferation and protein expression data suggest that both known and candidate genotypes are consistent with a hyperproliferative phenotype. In vitro data support BMPR2 as a candidate germline driver of the JPS phenotype, and additional study is ongoing regarding downstream pathway regulation in colonoids with a BMPR2 variant. Citation Format: Suzanne P. MacFarland, Bridgid Greed, Michael H. Xie, Garrett M. Brodeur, Zvi Cramer, Maiah H. Dent, Melani M. Duvall, Kathryn E. Hamilton, James Howe, Tatiana Karakasheva, Petar Mamula, Christopher Lengner. Bone morphogenic protein receptor 2 (BMPR2) as a potential germline driver in Juvenile Polyposis Syndrome (JPS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5898.

[Image: see text] Conventional treatment approaches fail to provide durable control over aggressive malignancies due to intrinsic or acquired drug resistance characteristic of high-risk disease. SN-38, a potent camptothecin analog specifically targeting DNA topoisomerase I cleavage complexes, has shown promise in preclinical studies against aggressive solid tumors. However, its clinical utility is limited by inadequate solubility in pharmaceutically acceptable vehicles and by poor chemical and metabolic stability. Micelles formulated from amphiphilic invertible polymers (AIPs) can address these issues by concomitantly enabling solubilization of water-insoluble molecular cargoes and by protecting chemically labile agents from inactivation. Furthermore, the inversion of the AIP and disruption of the carrier–drug complexes triggered by contact with cell membranes makes it possible to deliver the therapeutic payload into the cell interior without compromising its biological activity. In the present study, we characterized a novel AIP-based micellar formulation of SN-38 and evaluated its growth inhibitory effect on neuroblastoma (NB) cells derived either at diagnosis or at relapse after intensive chemoradiotherapy. Colloidally stable, drug-loaded micellar assemblies with a uniform