Eastern Regional Meeting 2021

2021 Journal of Investigative Medicine  
Purpose of study Doxorubicin (DOX), an anthracycline used in anti-cancer therapy, has significant cardiotoxic effects that cause cardiomyopathies. Activation of stress signaling molecules, including p38 MAPK isoforms p38a, p38b, p38g and p38d, has been implicated in the development of cardiotoxic effects. We previously demonstrated that p38d deletion provides cardioprotection during DOX treatment in female but not in male mice. We hypothesized that DOX cardiotoxicity can similarly be attenuated
more » ... by p38 inhibition in an isoform-and sex-specific manner in human organotypic cardiac slices. Methods used Slices (400mm) were prepared from the left ventricle of human donor hearts that were not used in transplantation. Slices were cultured for 24 hours in the presence of DOX (0, 0.5, 1, 5, 10 and 50 mM) and 1) SB203580 (p38a/b inhibitor, 10mM), 2) Compound62 (pan p38 inhibitor, 1mM) or 3) p38 isoform-specific siRNA. Slices were optically mapped and conduction velocity (CV) was determined. Slices were fixed and RNAseq was performed. Summary of Results CV was reduced with increasing DOX dose, with 62% male slices and 29% female slices viable at the highest DOX dose of 50 mM. However, at 5 mM DOX, CV was reduced by 22% in males (21.7 to 16.7 cm/s) and 5% in females (21.0 to 20.0 cm/s). RNAseq revealed 1652 differentially expressed genes (DEGs) in male versus female DOX-treated slices while only 71 DEGs were observed between male versus female control slices. SB203580 failed to prevent DOX-induced CV slowing in mice of both sexes (19% and 18% CV reduction in males and females, respectively). On the other hand, Compound62 + 5 mM DOX, preserved CV, preferentially in females (10% vs 3% CV reduction in males and females, respectively). Finally, preliminary data from p38 isoform-specific siRNA treated slices revealed preservation of CV in the presence of DOX only in slices with p38m knockdown. Conclusions These findings reveal sexual dimorphism in DOXinduced cardiotoxicity in human organotypic cardiac slices via a mechanism that involves differential sex-specific gene expression changes. Furthermore, DOX cardiotoxicity is mitigated by inhibition of specific p38 MAPK isoforms in a sex-specific manner. Purpose of study Stereotactic ablative radiosurgery (SABR) is an emerging modality of treatment for patients with lung neoplasms. The evaluation of response after treatment with ablative therapies is challenging due to a residual scar and posttreatment inflammation. Recently, the value and ideal timing of PET-CT imaging for grading response to ablative therapy have been debated. The objective of this study is to validate our previously described modified response evaluation in solid tumors (RECIST) criteria, which incorporate PET scans to evaluate response after ablative therapy. Methods used We retrospectively reviewed outcomes of 35 patients with lung neoplasm treated with SABR which included only patients receiving pre-treatment and post-treatment (2-6 months following SABR) PET/CT scans. Responses were graded using our modified RECIST criteria: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Patients were followed in the clinic and monitored for progression. We stratified the overall survival (OS) and progression free survival (PFS) based on response to treatment for patients with primary neoplasm and recurrent neoplasm. We performed landmark Kaplan Meier analysis for survival and recurrence, and times were offset by six months to correct for immortal time bias. Summary of results Thirty-five patients (primary lung tumors n=14; recurrent lesions n=21; median age 71 years) were treated with a median dose of 48 Gy. Responses were graded as: 3 CR, 17 PR, 7 SD, and 8 PD. Modified PET/CT responses were dichotomized as CR/PR vs SD/PD. Among 14 patients treated for primary lung cancer, patients with CR/PR had equivalent OS (p = 0.90), but improved PFS by a median of 7 months (p = 0.02) (figure 1). Among 21 treated for recurrence, those with CR/PR had significantly improved OS vs. SD/PD, with a median improvement of 9 months(p = 0.02). Similarly, PFS was significantly better for CR/PR vs. SD/PD (p = 0.006), with a median improvement of 8 months. Conclusions In this study, we demonstrate the potential validity of our modified RECIST criteria incorporating PET scans 2-6 months after SABR, as an early surrogate for response to treatment and progression and survival. Further studies examining other factors predictive of response to SABR may improve patient selection and treatment efficacy. Abstract 2 Figure 1 Progression-free survival following treatment of primary disease Abstracts J Investig Med 2021;69:901-943 901
doi:10.1136/jim-2021-erm fatcat:xdufm735hvadxnmnqeutlhigce