Recent Research Publications- June 2023
Sia TY, Tew WP, Purdy C, Chi DS, Menzin AW, Lovecchio JL, Bookman MA, Cohn DE, Teoh DG, Friedlander M,, Mutch DG, Gershenson DM, Tewari KS, Wenham RM, Wahner Hendrickson AE, Lee RB, Gray HJ, Secord AA, Van Le L, Lichtman SM
Gynecol Oncol. 2023 May 4;173:130-137. doi: 10.1016/j.ygyno.2023.03.018. Epub ahead of print. PMID: 37148580.
- To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction.
- Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages <70 and ≥ 70 years. Baseline characteristics, treatment compliance, toxicities, and clinical outcomes were compared.
- We included a total of 3686 patients, with 620 patients (16.8%) ≥ 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09-1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04-1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00-3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00-1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade ≥ 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups.
Conclusions: In women with advanced EOC receiving chemotherapy, age ≥ 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade ≥ 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities. Clintrials.gov: NCT00011986.
Pierce J, Harte SE, Afari N, Griffith JW, Kim J,, Naliboff BD, Rodriguez LV, Taple BJ, Williams D, Harris RE, Schrepf A; MAPP Research Network.
Pain. 2023 May 5. doi: 10.1097/j.pain.0000000000002895. Epub ahead of print. PMID: 37144687.
Urologic chronic pelvic pain syndrome (UCPPS) is a complex, debilitating condition in which patients often report nonpelvic pain in addition to localized pelvic pain. Understanding differential predictors of pelvic pain only vs widespread pain may provide novel pathways for intervention. This study leveraged baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network's Symptom Pattern Study to investigate the impact of childhood sexual and nonsexual violent trauma on pelvic and nonpelvic pain sensitivity among adult patients with UCPPS, as well as potential mediators of this association. Study participants who met inclusion criteria for UCPPS completed questionnaires assessing childhood and recent trauma, affective distress, cognitive dysfunction, and generalized sensory sensitivity. Experimental pain sensitivity was also evaluated using standardized pressure pain applied to the pubic region and the arm. Bivariate analyses showed that childhood violent trauma was associated with more nonviolent childhood trauma, more recent trauma, poorer adult functioning, and greater pain sensitivity at the pubic region, but not pain sensitivity at the arm. Path analysis suggested that childhood violent trauma was indirectly associated with pain sensitivity at both sites and that this indirect association was primarily mediated by generalized sensory sensitivity. More experiences of recent trauma also contributed to these indirect effects. The findings suggest that, among participants with UCPPS, childhood violent trauma may be associated with heightened pain sensitivity to the extent that trauma history is associated with a subsequent increase in generalized sensory sensitivity.
Dixit G, Skurski J, Dickerson EB, Nothnick WB, Issuree PD, Leslie KK, Maretzky T
Clin Transl Med. 2023 May;13(5):e1223. doi: 10.1002/ctm2.1223. PMID: 37165578; PMCID: PMC10172618.
Background: Mutations in the receptor tyrosine kinase gene fibroblast growth factor receptor 2 (FGFR2) occur at a high frequency in endometrial cancer (EC) and have been linked to advanced and recurrent disease. However, little is known about how these mutations drive carcinogenesis.
Methods: Differential transcriptomic analysis and two-step quantitative real-time PCR (qRT-PCR) assays were applied to identify genes differentially expressed in two cohorts of EC patients carrying mutations in the FGFR2 gene as well as in EC cells harbouring mutations in the FGFR2. Candidate genes and target signalling pathways were investigated by qRT-PCR assays, immunohistochemistry and bioinformatics analysis. The functional roles of differently regulated genes were analysed using in vitro and in vivo experiments, including 3D-orthotypic co-culture systems, cell proliferation and migration protocols, as well as colony and focus formation assays together with murine xenograft tumour models. The molecular mechanisms were examined using CRISPR/Cas9-based loss-of-function and pharmacological approaches as well as luciferase reporter techniques, cell-based ectodomain shedding assays and bioinformatics analysis.
Results: We show that common FGFR2 mutations significantly enhance the sensitivity to FGF7-mediated activation of a disintegrin and metalloprotease (ADAM)17 and subsequent transactivation of the epidermal growth factor receptor (EGFR). We further show that FGFR2 mutants trigger the activation of ADAM10-mediated Notch signalling in an ADAM17-dependent manner, highlighting for the first time an intimate cooperation between EGFR and Notch pathways in EC. Differential transcriptomic analysis in EC cells in a cohort of patients carrying mutations in the FGFR2 gene identified a strong association between FGFR2 mutations and increased expression of members of the Notch pathway and ErbB receptor family. Notably, FGFR2 mutants are not constitutively active but require FGF7 stimulation to reprogram Notch and EGFR pathway components, resulting in ADAM17-dependent oncogenic growth.
Conclusions: These findings highlight a pivotal role of ADAM17 in the pathogenesis of EC and provide a compelling rationale for targeting ADAM17 protease activity in FGFR2-driven cancers.
Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.
Praiss AM, Miller A, Smith J, Lichtman SM, Bookman M, Aghajanian C, Sabbatini P, Backes F, Cohn DE, Argenta P, Friedlander M, Mutch DG, Gershenson DM, Tewari KS, Wenham RM, Wahner Hendrickson AE, Lee RB, Gray H, Secord AA, Van Le L, O'Cearbhaill RE
Gynecol Oncol. 2023 May 23;174:213-223. doi: 10.1016/j.ygyno.2023.05.013. Epub ahead of print. PMID: 37229879.
Objective: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl).
Methods: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event.
- AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively.
- The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.
Maternal and Fetal Mitochondrial Gene Dysregulation in Hypertensive Disorders of Pregnancy.
Ricci CA, Reid DM, Sun J, Phillips NR, Goulopoulou S.
Physiol Genomics. 2023 May 15. doi: 10.1152/physiolgenomics.00005.2023. Epub ahead of print.
Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive. Here, we investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH; further, we measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) were conducted in publicly available high throughput sequencing transcriptomic datasets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia. Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, while 9 were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, while fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load. Our findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy.
Systematic Review of Interventions to Reduce Suicide Risk in Transgender and Gender Diverse Youth.
Christensen JA, Oh J, , Imhof RL, Croarkin PE, Bostwick JM, McKean AJS.
Child Psychiatry Hum Dev. 2023 May 10. doi: 10.1007/s10578-023-01541-w. Epub ahead of print. PMID: 37162659.
Transgender youth experience high rates of suicidal ideation and suicide attempts. This systematic review sought to examine interventions for suicide prevention in transgender children and adolescents. Literature related to suicide in the transgender population was systematically collected in accordance with PRISMA criteria. Searches identified studies with at least one suicide prevention method for participants ages 24 years or younger with gender identity and sex clearly defined. Primary outcomes include suicide-related thoughts and behaviors. A total of 1558 citations were identified with 17 articles meeting inclusion criteria. Interventions with potential effectiveness included a gender-affirming crisis hotline, medical care via interdisciplinary gender clinics, online media-based outreach, safety and connectedness in schools, and family system-based interventions. In the included studies, the overall quality of evidence was low and the risk of bias high. Further high-quality studies are needed.
Vieira-Baptista P, , Sobel J (eds). Lisbon: Admedic, 2023. doi: 10.59153/adm.rdtv.001. (booklet)