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Therapy with radiation plus cisplatin kills human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) by increasing reactive oxygen species beyond cellular antioxidant capacity. To explore why some patients fail these standard treatments, we evaluated whether the variation in HPV oncoprotein levels among HPV+ OPSCCs impacts mitochondrial metabolism, a source of antioxidant capacity. In cell line and patient-derived xenograft models, levels of HPV full-length E6 (fl-E6) inversely correlated with oxidative phosphorylation, antioxidant capacity, and therapy resistance, and fl-E6 was the only HPV oncoprotein to display such correlation. Ectopically expressing fl-E6 in models with low levels reduced mitochondrial mass, depleted antioxidant capacity, and sensitized to therapy. In this setting, fl-E6 repressed the PGC-1α/ERRα pathway for mitochondrial biogenesis by reducing p53-dependent PGC-1α transcription. Concordant observations were made in three clinical cohorts, where expression of mitochondrial components was higher in tumors of patients with reduced survival. These tumors contained the lowest fl-E6 levels, highest p53 target gene expression, and an activated PGC-1α/ERRα pathway. Our findings demonstrate that E6 can potentiate treatment responses by depleting mitochondrial antioxidant capacity and provide evidence for low E6 negatively impacting patient survival. E6’s interaction with the PGC-1α/ERRα axis has implications for predicting and targeting treatment resistance in OPSCC.

Introduction: The diagnostic utility of molecular profiling for the evaluation of indeterminate pediatric thyroid nodules is unclear. We aimed to assess pediatric cases with indeterminate thyroid fine-needle aspiration (FNA) alongside clinicopathologic features and mutational analysis. Methods: A retrospective review of 126 patients with indeterminate cytology who underwent FNA between January 2010 and December 2021 at the Children’s Hospital of Philadelphia was performed. Indeterminate cases defined by The Bethesda System for Reporting Thyroid Cytopathology (AUS/FLUS or TBSRTC III; FN/SFN or TBSRTC IV; SM or TBSRTC V) were correlated to clinicopathologic and genetic characteristics. Results: Of the 114 surgical cases, 48% were malignant, with the majority of malignant cases diagnosed as follicular variant of papillary thyroid carcinoma (28/55). Risk of malignancy increased with TBSRTC category: 23% for AUS/FLUS, 51% for FN/SFN, and 100% for SM nodules. There were significant differences in surgical approach (p < 0.01), performance of lymph node dissection (p < 0.01), histological diagnosis (p < 0.01), primary tumor focality/laterality (p = 0.04), and lymphatic invasion (p = 0.02) based on TBSRTC classification, with resultant differences in post-surgical risk stratification per American Thyroid Association (ATA) Pediatric Guidelines (p = 0.01). Approximately 89% (49/55) of cases were classified as ATA low risk, and 5 of 6 patients with ATA intermediate- or high-risk disease had SM cytology. Somatic molecular testing was performed in 40% (51/126) of tumors; 77% (27/35) of malignant cases and 38% (6/16) of benign cases harbored driver alteration(s). Of the driver-positive malignant cases, 52% (14/27) were associated with low risk (DICER1, PTEN, RAS, and TSHR mutations), 33% (9/27) were associated with high risk (BRAF mutations and ALK, NTRK, and RET fusions), and 15% (4/27) had unreported risk for invasive disease (APC, BLM, and PPM1D mutations and TG-FGFR1 fusion). Incidence of high-risk drivers increased with TBSRTC category. Approximately 23% (8/35) of patients harboring thyroid malignancy did not have an identifiable driver alteration. Conclusions: Molecular analysis is useful to discriminate benign and malignant thyroid nodules with indeterminate cytology. Patients with driver genetic alteration(s) and indeterminate cytology should consider surgical management secondary to the high incidence (82%; 27/33) of thyroid malignancy in these patients.

To determine whether androgen, estrogen, and/or progesterone signaling play a role in the pathophysiology of adherent perinephric fat (APF). We prospectively recruited patients undergoing robotic assisted partial nephrectomy during 2015-2017. The operating surgeon documented the presence or absence of APF. For those with clear cell renal cell carcinoma (ccRCC), representative sections of tumor and perinephric fat were immunohistochemically stained with monoclonal antibody to estrogen α, progesterone, and androgen receptors. Patient characteristics, operative data, and hormone receptor presence were compared between those with and without APF. Of 51 patients total, 18 (35.3%) and 33 (64.7%) patients did and did not have APF, respectively. APF was associated with history of diabetes mellitus (61.1% vs 24.2%, p = 0.009) and larger tumors (4.0 cm vs 3.0 cm, p = 0.017) but not with age, gender, BMI, Charleston comorbidity index, smoking, or preoperative estimated glomerular filtration rate. APF was not significantly associated with length of operation, positive margins, or 30-day postoperative complications but incurred higher estimated blood loss (236.5 mL vs 209.2 mL, p = 0.049). Thirty-two had ccRCC and completed hormone receptor staining. The majority of tumors and perinephric fat were negative for estrogen and progesterone while positive for androgen receptor expression. There was no difference in hormone receptor expression in either tumor or perinephric fat when classified by presence or absence of APF (p 0.05). APF is more commonly present in patients with diabetes or larger tumors but was not associated with differential sex hormone receptor expression in ccRCC.

The ethylene vinyl alcohol copolymer, Onyx® (ev3, Inc., MN, USA), is an embolic agent used in the management of arteriovenous malformations (AVMs) and was approved by the US FDA in 2005. Use of Onyx has resulted in higher curative rates compared with previous embolic agents such as N-butyl-2-cyanoacrylate. Onyx has several advantages over previous embolic agents. For instance, Onyx is a copolymer and does not adhere to catheters but solidifies slowly owing to the diffusion of its solvent dimethyl sulfoxide. This review focuses on different results obtained from the experience of different neurointerventionalists with an emphasis on the aim to cure. The studies presented are compared in terms of curative rates, morbidity and mortality. Ideas are presented for future treatment options for AVM rupture using nanotargeted therapy with the guide of specific markers highly expressed on the surface of cells or tissues of interest. Such nanotargeted therapy might transform AVM treatment with new embolic agents.