Jiani Chen

TP53 alterations are common in certain pediatric cancers, making identification of putative germline variants through tumor genomic profiling crucial for patient management. We analyzed TP53 alterations in 3123 tumors from 2788 pediatric patients sequenced using tumor-only or tumor-normal paired panels. Germline confirmatory testing was performed when indicated. Somatic and germline variants were classified following published guidelines. In 248 tumors from 222 patients, 284 Tier 1/2 TP53 sequence and small copy number variants were detected. Following germline classification, 73.9% of 142 unique variants were pathogenic/likely pathogenic (P/LP). Confirmatory testing on 118 patients revealed germline TP53 variants in 28 patients (23 P/LP and 5 uncertain significance), suggesting a minimum Li-Fraumeni syndrome (LFS) incidence of 0.8% (23/2788) in this cohort, 10.4% (23/222) in patients with TP53 variant-carrying tumors, and 19.5% (23/118) with available normal samples. About 25% (7/28) of patients with germline TP53 variants did not meet LFS diagnostic/testing criteria while 20.9% (28/134) with confirmed or inferred somatic origins did. TP53 biallelic inactivation occurred in 75% of germline carrier tumors and was also prevalent in other groups, causing an elevated tumor-observed variant allelic fraction (VAF). However, somatic evidence including low VAF correctly identified only 27.8% (25/90) of patients with confirmed somatic TP53 variants. The high incidence and variable phenotype of LFS in this cohort highlights the importance of assessing germline status of TP53 variants identified in all pediatric tumors. Without clear somatic evidence, distinguishing somatic from germline origins is challenging. Classifying germline and somatic variants should follow appropriate guidelines.

Background: To compare the safety and efficacy between endoscopic sinus surgery and different biologics in treating chronic rhinosinusitis with nasal polyps in adults by reviewing the existing clinical trials.Methods: Data extraction and risk of bias assessment were conducted by 2 independent reviewers according to the PRISMA recommendations and any disagreement was resolved by a third investigator. Outcomes were measured through a random‐effects model. We searched Embase, Web of Science, MEDLINE, Cochrane, and other relevant sources from its inception to April 30, 2022. We included randomized controlled trials(RCTs) involving endoscopic sinus surgery (ESS) or biologics in treating adult patients with chronic rhinosinusitis with nasal polyps. Studies involving other miscellaneous diseases, non‐RCT design, and insufficient participants or follow‐up were excluded.Results: In this systematic review, five RCTs and 1748 patients were included. All the biologics, as well as ESS, could significantly improve key nasal outcomes in CRSwNP both at 6 months and 1 year. Dupilumab exhibited better efficacy than ESS in improving SNOT‐22 scores at one year. However, ESS showed superiority over three biologics in improving nasal congestion scores (NCS) at two various time points, except for better efficacy of Dupilumab at 1 year. For the loss of smell scores, a greater improvement was observed in the Dupilumab cohort compared with other biologics and even ESS counterparts. Safety analysis showed no significant difference between the ESS cohort and biologic treatment.Conclusions: In summary, ESS showed comparable improvement in quality of life and symptoms to Omalizumab, Mepolizumab, and Benralizumab. Dupilumab seems to be more effective than ESS in selected items, whereas head‐to‐head trials and real‐world studies are urgent to compare their efficacy. Our findings also showed that biologics could be applied as alternative or adjuvant therapy for uncontrolled severe CRSwNP.

Colorectal cancer (CRC) is becoming increasingly prevalent worldwide. Fluoropyrimidine drugs are the primary chemotherapy regimens in routine clinical practice of CRC. However, the survival rate of patients on fluoropyrimidine-based chemotherapy varies significantly among individuals. Biomarkers of fluoropyrimidine drugs’' efficacy are needed to implement personalized medicine. This review summarized fluoropyrimidine drug-related microRNA (miRNA) by affecting metabolic enzymes or showing the relevance of drug efficacy. We first outlined 42 miRNAs that may affect the metabolism of fluoropyrimidine drugs. Subsequently, we filtered another 41 miRNAs related to the efficacy of fluoropyrimidine drugs based on clinical trials. Bioinformatics analysis showed that most well-established miRNA biomarkers were significantly enriched in the cancer pathways instead of the fluoropyrimidine drug metabolism pathways. The result also suggests that the miRNAs screened from metastasis patients have a more critical role in cancer development than those from non-metastasis patients. There are five miRNAs shared between these two lists. The miR-21, miR-215, and miR-218 can suppress fluoropyrimidine drugs’' catabolism. The miR-326 and miR-328 can reduce the efflux of fluoropyrimidine drugs. These five miRNAs could jointly act by increasing intracellular levels of fluoropyrimidine drugs’' cytotoxic metabolites, leading to better chemotherapy responses. In conclusion, we demonstrated that the dynamic changes in the transcriptional regulation via miRNAs might play significant roles in the efficacy and toxicity of the fluoropyrimidine drug. The reported miRNA biomarkers would help evaluate the efficacy of fluoropyrimidine drug-based chemotherapy and improve the prognosis of colorectal cancer patients.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in cellular lineage commitment, differentiation, proliferation, and apoptosis. Deregulated FGFR signaling is observed in a subset of tumors across various histologies, making FGFRs ideal therapeutic targets. We sought to determine the genetic landscape of FGFR-family variations in a cohort of pediatric and young adult patients with solid tumors. The CHOP Comprehensive Solid Tumor Panel was performed on 1,420 patients. The panel covers 238 cancer genes and screens for single nucleotide variants (SNVs), indels, copy number alterations, and 117 fusion gene partners interrogating over 700 exons for known and novel fusions. Identified variants were categorized and reported according to the AMP/ASCO/CAP guidelines. Fifty-six patients (4.1%), including 47 children and 9 young adults, were found to carry at least one FGFR alteration in their tumors. CNS tumors accounted for most of the cases (51 total, 87.9%), with pilomyxoid astrocytoma/pilocytic astrocytoma and dysembryoplastic neuroepithelial tumor the most common (13 and 12 patients, respectively). Non-CNS solid tumors included rhabdomyosarcoma (4 patients), neuroblastoma/ganglioneuroblastoma (2), and follicular thyroid carcinoma (1). FGFR somatic alterations were found in 56 tumors including 41 SNVs and small indels, 6 internal tandem duplications (ITDs), and 15 fusions genes. The most common SNVs observed were hotspot mutations p.K656E and p.N546K of FGFR1. Sequence alterations in FGFR1 contained 35 SNVs and small indels, mostly gain of function mutations located in the kinase domain, and 6 kinase domain ITDs. One SNV was identified in FGFR2 in the immunoglobulin domain. Two SNVs were reported in FGFR3, both of which were in the fibroblast growth factor receptor family domain, and 3 SNVs were identified in FGFR4, all occurring at the p.V550 codon located on the kinase domain. Companion mutations in non-FGFR genes were detected in 27 tumors, predominantly involving RAS signaling pathway genes including NF1 (14 variants), PIK3CA (8), PTPN11 (6) and PIK3R1 (4). Among fusion variants, FGFR1-TACC1 fusions were found in 5 patients, mostly in pediatric patients. One FGFR3-TACC3 fusion was identified in one young adult patient. Seven pediatric patients tested positive for FGFR2 fusions; all with different 3’ partners. The detection of an FGFR alteration defined or changed the histologic diagnosis for 22 patients. Our results reveal that FGFR alterations account for 4.1% (56/1420) of the patients with solid tumors tested in our laboratory. The majority of the FGFR-positive tumors are low-grade CNS tumors. Further, the identification of FGFR alterations can significantly improve the tumor diagnosis and provide genomic evidence for potential targeted treatment with FGFR inhibitors. Citation Format: Jinhua Wu, Jeffrey Schubert, Feng Xu, Ariel Long, Maha Patel, Netta Golenberg, Weixuan Fu, Kajia Cao, Jiani Chen, Elizabeth H. Denenberg, Elizabeth A. Fanning, Rochelle Bagatell, Theodore W. Laetsch, Adam Resnick, Mariarita Santi, Phillip Jay B. Storm, Minjie Luo, Lea F. Surrey, Yiming Zhong, Marilyn M. Li. The spectrum of FGFR mutations in pediatric and young adult solid tumor [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 5268.

Wuzhi capsule (WZC), a preparation of Fructus Schisandra sphenanthera extract, has been widely used for the treatment of viral and drug-induced hepatitis in China. This study aimed to determine the pharmacokinetic parameters of tacrolimus (TAC) when co-administered with WZC and its dose-effect of WZC on TAC in healthy volunteers. We assessed the effect of increased dosage of WZC (1, 2, 6, and 8 capsules once daily) on the relative oral exposure of TAC to explore the dose-response relationship between WZC and TAC using bioanalysis, pharmacokinetic, genotypical analyses. We elucidate the influence of CYP3A5 and MDR1 genetic polymorphisms on the WZC dose by maintaining C_trough of TAC in Chinese healthy volunteers. When co-administered with WZC, the T_max of TAC was increased significantly while the apparent oral clearance was decreased. The plasma TAC level in volunteers with high CYP3A5 expression was greatly lower than that in those with mutant CYP3A5. However, polymorphisms of MDR1 exon26 C3435T, exon21 G2677T/A and exon12 C1236T were not associated with plasma TAC levels. Our findings provide important information on interactions between modern medications and herbal products, thus facilitating a better usage of TAC in patients receiving WZC.

Background: Chemotherapy-induced adverse effects (CIAEs) remain a challenging problem due to their high incidences and negative impacts on treatment in Chinese colorectal cancer (CRC) patients. We aimed to identify risk factors and predictive markers for CIAEs using food/nutrition data in CRC patients receiving post-operative capecitabine-based chemotherapy. Methods: Food/nutrition data from 130 Chinese CRC patients were analyzed. Univariate and multivariate analyses were used to identify CIAE-related food/nutrition factors. Prediction models were constructed based on the combination of these factors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the discrimination ability of models. Results: A total of 20 food/nutrition factors associated with CIAEs were identified in the univariate analysis after adjustments for total energy and potential confounding factors. Based on multivariate analysis, we found that, among these factors, dessert, eggs, poultry, and milk were associated with several CIAEs. Most importantly, poultry was an overall protective factor; milk and egg were risk factors for hand-foot syndrome (HFS) and bone marrow suppression (BMS), respectively. Developed multivariate models in predicting grade 1 to 3 CIAEs and grade 2/3 CIAEs both had good discrimination (AUROC values from 0.671 to 0.778, 0.750 to 0.946 respectively), which had potential clinical application value in the early prediction of CIAEs, especially for more severe CIAEs. Conclusions: Our findings suggest that patients with high milk and egg intakes should be clinically instructed to control their corresponding dietary intake to reduce the likelihood of developing HFS and BMS during capecitabine-based chemotherapy, respectively. Trial registration: ClinicalTrials.gov Identifier: NCT03030508.

Rationale: Alport syndrome (AS) is an inherited progressive renal failure, characterized by kidney disease, hearing loss, and eye abnormalities. Patient concerns: A 7-year-old male child was admitted for persistent microscopic hematuria and proteinuria. Diagnoses: Combined with clinical manifestations, laboratory testing, pathological changes of kidney and sequencing results, the patient was diagnosed as AS. Interventions: The patient was treated with ACEI and tacrolimus drugs for 2 years, but continued to have hematuria and proteinuria. Thus, a genetic analysis was performed using next-generation sequencing in four affected members from the family. Outcomes: The findings revealed triple compound heterozygous mutation of COL4A4: three novel variations, c.1045C>T (p. R349X), c.3505+1G>A (splicing), and c.2165G>A (p. G722D). Lessons: This study was novel in finding that a triple variant of the COL4A4 gene simultaneously in trans and in cis. The effects of multiple mutation sites and the type of gene mutation in AS were also underlined.