Katherine Xu

Importance: Laryngeal cancer has undergone a complex evolution in incidence, management, and standards of care over the past 20 years. Disease‐wide demographic and survival risk factors have yet to be elucidated.Objective: Examine incidence, management, and survival trends in laryngeal cancer from 2000 to 2019.Design, Setting, and Participants: The Surveillance, Epidemiology, and End Results database was utilized to identify age‐adjusted incidence rates (AAIRs) of laryngeal squamous cell carcinoma (LSCCa) from 2000 to 2019. Joinpoint regression was conducted to identify annual percentage changes (APCs). Chi‐squared analysis was used to find changes in demographic, clinicopathologic, and treatment changes over the study period. Finally, univariate Kaplan–Meier and COX multivariate regressions were conducted to identify survival differences.Results: There were 46 266 cases of LSCCa identified between 2000 and 2019 with AAIR of 2.7 per 100 000 person‐years with APC of −2.6% [95% CI: −2.8% to 2.4%]. These rates have largely been down‐trending among demographic substratifications. Age at initial diagnosis has been increasing (64.6 → 66.0, p < 0.001). Higher median household income was associated with lower AAIR (35 000 5.3; > $75 000 2.2) and increased annual percentage decrease (< $35 000, −1.1%*; > $75 000, −3.2%*). There were no other clinically significant differences in demographic and clinicopathologic trends although persistent demographic differences were noted. Late T‐stage at diagnosis has increased over the study period (T3, 18% → 23%, p < 0.001). Treatment with primary chemoradiotherapy has increased significantly (20.0% → 27.0%, p < 0.001). On univariate analysis, there were no significant differences in survival; however, on multivariate analysis, there has been a progressive improvement in disease‐specific and overall survival over 5‐year bins. Late‐stage disease had a progressive improvement in survival with each treatment period on both univariate and multivariate analysis.Conclusions and Relevance: There has been a progressively significant decrease in age‐adjusted incidence of LSCCa with increased utilization of primary chemoradiotherapy. When adjusted for associated characteristics, there has been a continuing improvement in survival over the study period, primarily in late‐stage disease.

Infantile hemangiomas (IH) are the most common benign tumors of childhood. Timely diagnosis and management of higher-risk IH is key in avoiding permanent disfigurement, visual impairment, and life-threatening airway compromise. Here, we identify and critically appraise existing clinical practice guidelines (CPGs) for IH diagnosis and management. A systematic search of MEDLINE, SCOPUS, and EMBASE was conducted until August 2021. Four independent reviewers assessed each CPG utilizing the Appraisal of Guidelines for Research and Evaluation, 2^nd edition (AGREE II). An scaled domain score of ≥60% demonstrated adequacy in a given domain. Intraclass correlation coefficients (ICC) assessed agreement and scoring consistency between the reviewers. Eight CPGs were eligible and included for critical appraisal. Only one CPG was classified as ‘high quality’, with the remaining seven guidelines being ‘average’ (n = 3) or ‘low’ (n = 4) quality. Six guidelines (75.0%) were conducted via nonsystematic literature searches. The ‘Applicability’ (40.4%±14.0) and ‘Rigor of development’ (46.9%±17.3) domains achieved the lowest scores, while the highest average scores were in ‘Scope and purpose’ (76.7%±11.3) and ‘Editorial independence’ (90.8%±13.0). We found high consistency between the four independent reviewers, with ‘very good’ (n = 5) or ‘good’ (n = 1) interrater reliability in all six AGREE II domains. Based on the AGREE II instrument, there is only one available high-quality consensus statement on the diagnosis and management of IH. Low scores in ‘Rigor of development’ and ‘Applicability’ suggest notable weaknesses in the development process and reporting quality of existing IH CPGs. Future guidelines should be backed by systematic literature searches and focus on guideline clinical translation.

Harris J, et al. Pediatr Gastroenterol Hepatol Nutr. 2022 Mar;25(2):109-120. https://doi.org/10.5223/pghn.2022.25.2.109

PARP7 (TIPARP) is a monoPARP which catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. Its expression is upregulated during cellular stress, including viral infection or through the activation of the aryl hydrocarbon receptor after exposure to cigarette smoke. We and others have shown that PARP7 activity suppresses the Type I interferon (IFN) response following activation by cytosolic nucleic acid sensing pathways. RBN-2397 is a first-in class PARP7 inhibitor, which induces cancer cell autonomous and immune stimulatory effects in preclinical models through enhanced Type I IFN signaling in cancer cells. Here we describe the presence of PARP7 genomic amplification with corresponding increased mRNA expression across select cancers. Elevated PARP7 expression or amplification may identify cancer patients that could derive benefit from treatment with RBN-2397. In characterizing PARP7 copy number and mRNA expression from The Cancer Genome Atlas (TCGA) database, we found the presence of PARP7 copy number amplification in a subset of tumor types, particularly those of squamous histology, as well as ovarian cancer that corresponded to higher mRNA expression levels. High PARP7 expression correlated with poor survival in squamous cancers, while it had no effect on survival in ovarian cancer. Interestingly, tumor types with high PARP7 expression also expressed higher levels of baseline interferon stimulated genes (ISGs). This parallels our findings that cancer cell lines with higher ISGs at baseline are more responsive to PARP7 inhibition. To explore PARP7 copy number variations (CNVs) in advanced cancer patients, we queried the FoundationCore® (Foundation Medicine, Inc) database. Similar to TCGA, squamous cancers as well as ovarian, breast, and pancreatic ductal adenocarcinoma (PDAC) were among the tumor types with PARP7 amplifications. Moreover, PARP7 was found to be amplified both on the background of chromosome 3q arm-level amplifications as well as focally. Congruent to our analysis of PARP7 amplifications, we evaluated PARP7 mRNA expression in both squamous and non-squamous non-small cell lung carcinoma (NSCLC), breast cancer, and PDAC primary tumor samples. Using a validated RNAscope ISH probe set, we analyzed over 1,000 patient samples and found that PARP7 was more highly expressed in tumor cells relative to corresponding normal tissues. Overall, there were varying levels of PARP7 expression across samples with higher expression levels of PARP7 in tumor cells, compared to stroma, across all cancers examined. Our analyses describing the presence of PARP7 amplifications as well as high expression levels in several tumor types including NSCLC, breast, and PDAC provides evidence for the therapeutic relevance of PARP7 inhibition and highlights potential patient selection strategies to identify those patients more likely to benefit from RBN-2397 treatment. Citation Format: Jodie Wong, Kristy Kuplast-Barr, Ryan P. Abo, Anupriya S. Kulkarni, Linda T. Nieman, Azfar Neyaz, Katherine H. Xu, Radwa Sharaf, Lee A. Albacker, David T. Ting, Heike Keilhack, Kristen A. McEachern. Elevated PARP7 expression in select cancers identifies a target population for RBN-2397 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 381.