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Background: Pediatric interventional oncology (PIO) is a growing field intended to provide additional or alternative treatment options for pediatric patients with benign or malignant tumors. Large series of patients treated uniformly and subjected to rigorous endpoints for efficacy are not available., Methods: We designed a collaborative initiative to capture data from pediatric patients with benign and malignant tumors who underwent a therapeutic interventional radiology procedure. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was utilized as a measure of radiologic response and data were collected regarding improvement in pain and functional endpoints. Cumulative incidence of progressive disease was calculated using both the treated site and the patient as the analytic unit., Findings: Forty patients, 16 with malignant tumors and 24 with benign tumors, underwent a total of 88 procedures. Cryo- and radiofrequency ablation were the most frequently utilized techniques for both cohorts of patients. A complete or partial response, or prolonged disease stability, were achieved in approximately 40% of patients with malignant tumors and 60% of patients with benign tumors. No patients had progressive disease as their best response. Resolution of pain and improved mobility with return-to-baseline activity were demonstrated across patients from both cohorts. Only minor complications were experienced., Interpretation: Interventional radiology-guided interventions can serve as an alternative or complementary approach to the treatment of benign and malignant tumors in pediatric patients. Prospective, multi-institutional trials are required to adequately study utility, treatment endpoints, and durability of response., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The survival of childhood Wilms tumor is currently around 90%, with many survivors reaching reproductive age. Chemotherapy and radiotherapy are established risk factors for gonadal damage and are used in both COG and SIOP Wilms tumor treatment protocols. The risk of infertility in Wilms tumor patients is low but increases with intensification of treatment including the use of alkylating agents, whole abdominal radiation or radiotherapy to the pelvis. Both COG and SIOP protocols aim to limit the use of gonadotoxic treatment, but unfortunately this cannot be avoided in all patients. Infertility is considered one of the most important late effects of childhood cancer treatment by patients and their families. Thus, timely discussion of gonadal damage risk and fertility preservation options is important. Additionally, irrespective of the choice for preservation, consultation with a fertility preservation (FP) team is associated with decreased patient and family regret and better quality of life. Current guidelines recommend early discussion of the impact of therapy on potential fertility. Since most patients with Wilms tumors are prepubertal, potential FP methods for this group are still considered experimental. There are no proven methods for FP for prepubertal males (testicular biopsy for cryopreservation is experimental), and there is just a single option for prepubertal females (ovarian tissue cryopreservation), posing both technical and ethical challenges. Identification of genetic markers of susceptibility to gonadotoxic therapy may help to stratify patient risk of gonadal damage and identify patients most likely to benefit from FP methods., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer., Methods: Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype-directed therapy were determined., Results: Among 11,947 patients across > 50 malignancies, 17% (n = 2,037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; < 1% level 4). BRCA1/2 variants accounted for 42% of therapeutically actionable findings, followed by CHEK2 (13%), ATM (12%), mismatch repair genes (11%), and PALB2 (5%). When limited to the 9,079 patients with metastatic or recurrent cancer, 8% (n = 710) harbored level 1 or 3B genetic findings and 3.2% (n = 289) received germline genotype-directed therapy. Germline genotype-directed therapy was received by 61% and 18% of metastatic cancer patients with level 1 and level 3B findings, respectively, and by 54% of BRCA1/2 , 75% of mismatch repair, 43% of PALB2 , 35% of RAD51C/D , 24% of BRIP1 , and 19% of ATM carriers. Of BRCA1/2 patients receiving a poly(ADP-ribose) polymerase inhibitor, 45% (84 of 188) had tumors other than breast or ovarian cancer, wherein the drug, at time of delivery, was delivered in an investigational setting., Conclusion: In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype-directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer., Competing Interests: Zsofia K. StadlerConsulting or Advisory Role: Allergan (I), Genentech/Roche (I), Regeneron (I), Optos (I), Adverum (I), Novartis (I), Regenxbio (I), Gyroscope (I), Neurogene (I) Debyani ChakravartyConsulting or Advisory Role: Medendi Medical Travel Christopher J. FongStock and Other Ownership Interests: Various biotech ETFsPatents, Royalties, Other Intellectual Property: Ultra-Wideband Radar System for Animals Patent September 11, 2018, Patent issuer and number US20150181840A1, Monitoring Treatment of Peripheral Artery Disease (PAD) using Diffuse Optical Imaging, Imaging interfaces for full finger and full hand optical tomography, Systems and methods for dynamic imaging of tissue using digital optical tomography. Karen CadooHonoraria: OncLiveConsulting or Advisory Role: GlaxoSmithKline/Tesaro, AstraZeneca, MSD, GlaxoSmithKline, MJH Life SciencesResearch Funding: AstraZeneca, Syndax, MSD Ying LiuResearch Funding: AstraZeneca, Tesaro/GSK Maria I. CarloConsulting or Advisory Role: PfizerOther Relationship: Prostate Cancer Foundation, Robert Wood Johnson Foundation Alicia LathamOther Relationship: Conquer Cancer Foundation Ritika KundraStock and Other Ownership Interests: Pfizer Carol AghajanianConsulting or Advisory Role: Mersana, Eisai, Roche, AbbVie, AstraZeneca/Merck, Roche/Genentech, Repare TherapeuticsResearch Funding: Genentech/Roche, AbbVie, Clovis Oncology, AstraZeneca Nadeem Abu-RustumHonoraria: Prime OncologyResearch Funding: Stryker/Novadaq, GrailTravel, Accommodations, Expenses: Prime Oncology Anna VargheseConsulting or Advisory Role: RocheResearch Funding: Lilly, Verastem, BioMed Valley Discoveries, Bristol Myers Squibb, Silenseed, IlluminaTravel, Accommodations, Expenses: Roche Eileen M. O'ReillyConsulting or Advisory Role: Merck, Agios, AstraZeneca, Bayer, BeiGene, Berry Genomics, Celgene, CytomX Therapeutics, Debiopharm Group, Eisai, Exelixis/Ipsen, Flatiron Health, Incyte, Janssen, LAM Therapeutics, Lilly, Loxo, Genentech/Roche, Minapharma, QED Therapeutics, RedHill Biopharma, Sillajen, SOBI, Yiviva, Autem Medical, Gilead Sciences, Ipsen, Silenseed, TheraBionic, twoXAR, Vector HealthResearch Funding: AstraZeneca/MedImmune, Acta Biologica, Bristol Myers Squibb, Celgene, Genentech, Halozyme, MabVax, Roche, Silenseed Michael MorrisConsulting or Advisory Role: Bayer, Endocyte, Advanced Accelerator Applications, ORIC Pharmaceuticals, Johnson & Johnson, Curium Pharma, AthenexResearch Funding: Bayer, Sanofi, Endocyte, Progenics, Corcept Therapeutics, Roche/Genentech, JanssenTravel, Accommodations, Expenses: Endocyte, Fujifilm Wassim AbidaHonoraria: CARET, Roche, Medscape, Aptitude HealthConsulting or Advisory Role: Clovis Oncology, Janssen, MORE Health, ORIC Pharmaceuticals, Daiichi SankyoResearch Funding: AstraZeneca, Zenith Epigenetics, Clovis Oncology, GlaxoSmithKline, ORIC Pharmaceuticals, EpizymeTravel, Accommodations, Expenses: GlaxoSmithKline, Clovis Oncology, ORIC Pharmaceuticals Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicans' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerviewConsulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, Verastem, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare TherapeuticsResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology Ahmet ZehirStock and Other Ownership Interests: Arcus Biosciences, Mirati TherapeuticsHonoraria: Illumina Marc LadanyiConsulting or Advisory Role: Bristol Myers Squibb, BayerResearch Funding: Loxo, Helsinn Therapeutics, Merus NV, Elevation Oncology David SolitStock and Other Ownership Interests: Loxo, Scorpion Therapeutics, Vividion Therapeutics, Fore TherapeuticsConsulting or Advisory Role: Pfizer, Illumina, Lilly, QED Therapeutics, BridgeBio Pharma, Scorpion Therapeutics, Vividion Therapeutics, Syros Pharmaceuticals Michael F. BergerResearch Funding: GrailPatents, Royalties, Other Intellectual Property: Provisional patent pending for “Systems and Methods for Detecting Cancer via cfDNA Screening” Luis A. DiazLeadership: Personal Genome Diagnostics, Jounce TherapeuticsStock and Other Ownership Interests: PapGene Inc, Personal Genome Diagnostics, Jounce Therapeutics, Zydecom, Thrive Earlier Detection Corp, Neophore, Amgen, Four Paws, Seer, Kinnate BiopharmaConsulting or Advisory Role: Merck, Personal Genome Diagnostics, Zydecom, Neophore, Innovatus Capital Partners, Four Paws, Seer, Kinnate BiopharmaResearch Funding: MerckPatents, Royalties, Other Intellectual Property: US-2010041048-A1—Circulating Mutant DNA to Assess Tumor Dynamics, US-2015344970-A1—Personalized Tumor Biomarkers, WO-2010118016-A2—Digital quantification of DNA methylation, US-2005202465-A1—Thymidylate synthase gene and metastasis, US-2014227271-A1—Somatic mutations in atrx in brain cancer, WO-2012094401-A2—Genes frequently altered in pancreatic neuroendocrine tumors, US-2013323167-A1—Detecting and treating solid tumors through selective disruption of tumor vasculature, EP-2912468-B1—Papanicolaou test for ovarian and endometrial cancers, US-9976184-B2—Mutations in pancreatic neoplasms, US-2017267760-A1—Checkpoint Blockade and Microsatellite Instability, US-2018171413-A1—Head and neck squamous cell carcinoma assays, US-2018086832-A1—HLA-restricted epitopes encoded by somatically mutated genes, US-2018258490-A1—Assaying ovarian cyst fluid, US-2016208340-A1—TERT Promoter Mutations in Urothelial Neoplasia, US-2015252415-A1—Arid1b and neuroblastoma, WO-2018071796-A2—Compositions and methods for identifying functional anti-tumor T cell responses, EP-3322824-A1—Detection of tumor-derived DNA in CSF, US-2016273049-A1—Systems and methods for analyzing nucleic acid, US-2018135044-A1—Non-unique barcodes in a genotyping assay, US-2017016075-A1—Neoantigen analysisTravel, Accommodations, Expenses: Merck Mark RobsonConsulting or Advisory Role: Change HealthCareResearch Funding: AstraZeneca, Pfizer, MerckOther Relationship: Research to Practice, Clinical Care Options, Physicans' Education Resource, Invitae, PfizerUncompensated Relationships: Merck, Pfizer, Daiichi Sankyo, Epic SciencesOpen Payments Link: https://openpaymentsdata.cms.gov/physician/612669/summaryNo other potential conflicts of interest were reported.

Purpose: Several aggressive pediatric cancers harbor alterations in SMARCB1 , including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between SMARCB1 genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors., Experimental Design: We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or SMARCB1 genomic alterations on prior somatic sequencing., Results: SMARCB1 two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of SMARCB1 was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a SMARCB1 alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors., Conclusions: A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers., (©2020 American Association for Cancer Research.)

Prior small reports have postulated a link between gastrointestinal polyposis and childhood and young adulthood cancer (CYAC) treatment (therapy-associated polyposis; TAP), but this remains a poorly understood phenomenon. The aim of this study was to describe the phenotypic spectrum of TAP in a multi-institutional cohort. TAP cases were identified from eight high-risk cancer centers. Cases were defined as patients with ≥10 gastrointestinal polyps without known causative germline alteration or hereditary colorectal cancer predisposition syndrome who had a history of prior treatment with chemotherapy and/or radiotherapy for CYAC. A total of 34 TAP cases were included (original CYAC: 27 Hodgkin lymphoma, three neuroblastoma, one acute myeloid leukemia, one medulloblastoma, one nephroblastoma, and one non-Hodgkin lymphoma). Gastrointestinal polyposis was first detected at a median of 27 years (interquartile range, 20-33) after CYAC treatment. A total of 12 of 34 (35%) TAP cases had ≥50 colorectal polyps. A total of 32 of 34 (94%) had >1 histologic polyp type. A total of 25 of 34 (74%) had clinical features suggestive of ≥1 colorectal cancer predisposition syndrome [e.g., attenuated familial adenomatous polyposis (FAP), serrated polyposis syndrome, extracolonic manifestations of FAP, mismatch repair-deficient colorectal cancer, or hamartomatous polyposis] including 8 of 34 (24%) with features of multiple such syndromes. TAP is an apparently acquired phenomenon that should be considered in patients who develop significant polyposis without known causative germline alteration but who have had prior treatment for a CYAC. Patients with TAP have features that may mimic various hereditary colorectal cancer syndromes, suggesting multiple concurrent biologic mechanisms, and recognition of this diagnosis may have implications for cancer risk and screening., (©2020 American Association for Cancer Research.)

Importance: Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention., Objective: To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines., Design, Setting, and Participants: From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017., Exposure: Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines., Main Outcomes and Measures: Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing., Results: Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing., Conclusions and Relevance: In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study., Trial Registration: clinicaltrials.gov Identifier: NCT01775072.

We performed a pilot clinical trial with safingol (L-threo-dihydrosphingosine), a protein kinase C-specific inhibitor that potentiates the effect of doxorubicin (DOX) in tumor-bearing animals. Safingol was initially administered as a 1-h infusion at escalating doses. Fourteen days later, patients received the same dose of safingol in combination with a fixed dose of DOX. The combination was repeated at 3-week intervals. Safingol dose levels ranged from 15 to 120 mg/m2. The plasma levels achieved at the final dose level were comparable to those associated with potentiation of DOX in animals. The mean Cmax and area under the curve for safingol at the 120 mg/m2 dose level were 1040 +/- 196 ng/ml and 1251 +/- 317 mg x h/ml, respectively. The mean plasma half-life for safingol was 3.97 +/- 2.51 h, the mean estimated clearance was 3140 +/- 765 ml/min, and the mean volume of distribution was of 995 +/- 421 liters. Coadministration of a fixed dose of DOX did not significantly change the pharmacokinetics of safingol, nor did increasing doses of safingol significantly affect the pharmacokinetics of DOX. Minor responses were observed in three patients with pancreatic cancer and one patient with angiosarcoma of the scalp. This pilot Phase I study indicates that the protein kinase C inhibitor safingol can be given safely with 45 mg/m2 of DOX at a dose that is potentially pharmacologically active without dose-limiting toxicity.