ABSTRACT
TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50-60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. Here, we investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models. Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.
Subject(s)
Everolimus , Head and Neck Neoplasms , Mice , Animals , Humans , Everolimus/pharmacology , Everolimus/therapeutic use , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/genetics , Lymphangiogenesis , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Mice, Nude , Tumor Suppressor Protein p53/genetics , TOR Serine-Threonine Kinases/metabolism , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Cell Line, Tumor , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , STAT3 Transcription Factor/metabolismABSTRACT
BACKGROUND: A wide variety of techniques for the surgical repair of nasal septal perforations (NSPs) have been described. Surgical management of NSPs can be broadly divided into open versus endonasal approaches, with additional variables involving unilateral or bilateral flaps, use of grafts, and placement of splints. The objective of this study was to compare surgical approaches and their outcomes. METHODS: PubMed, EMBASE, and CINAHL Plus databases were examined for patients undergoing NSP repair. English-language studies reporting surgical management of patients with the primary diagnosis of NSP were included. Outcome measures of interest included perforation size, surgical approach characteristics, and success rate defined as complete closure assessed by surgeon postoperatively. The quality of articles was assessed with the methodological index for nonrandomized studies (MINORS) criteria. A random-effects model was used to calculate pooled proportions for the different outcomes. RESULTS: The electronic database search yielded 1076 abstracts for review. A total of 64 articles met the inclusion criteria, with 1591 patients: 1127 (71%) underwent an endonasal approach and 464 (29%) an open approach. The median (range) MINORS score was 10 (5-12) out of 16 points. Overall, 91% of patients had total closure (95% confidence interval [CI], 0.89-0.93, p < 0.01), with moderate heterogeneity between studies (I2 = 42.03%). There was no difference in closure success between open and endonasal approaches. Use of bilateral versus unilateral flaps, interposition grafts, and intranasal splints and packing were not associated with differences in outcomes. CONCLUSION: Nasal septal perforation surgical repair success rates are comparable regardless of technique.
Subject(s)
Nasal Septal Perforation , Humans , Nasal Septum , Surgical Flaps , Treatment OutcomeABSTRACT
OBJECTIVE: The purpose of this study was to investigate whether somatic nonsynonymous variants in tumor tissue can potentially be identified in circulating cell-free DNA (cfDNA) of head and neck oropharyngeal squamous cell carcinoma (OPSCC) patients using next-generation sequencing and can predict recurrence or persistence disease. METHODS: A total of 22 OPSCC patients with tumor tissue and respective plasma samples were included in this study. Matching cfDNA and tumor tissues were processed, and DNA sequencing was conducted using the MiSeq platform. Variants were identified using Biomedical Genomic Workbench and Genialis's online data analysis platform for Swift Biosciences' Accel-amplicon panels. RESULTS: Among 11 nonresponders, 6 matched mutations were detected in 5 patients suggesting a predictive factor for patients with likelihood of recurrence. The matched variants and their allele frequencies identified in the nonresponder group were (tumor DNA/cfDNA in %): TP53 G325fs (27/0.62), TP53 R282W (48/1.74), TP53 R273C (39/2.17), FBXW7 R505G (30/0.6), FBXW7 R505L (31/0.65), and TP53 Q331H (56.5/0.52). Interestingly, the matched somatic mutations were only detected in patients who did not respond to therapy or had persistent disease. CONCLUSIONS: Somatic nonsynonymous variants in tumor tissue can potentially be identified in cfDNA of OPSCC patients using NGS. The likelihood of variant detection in cfDNA is greater in nonresponders, especially in human papillomavirus-negative nonresponders, rendering it beneficial as a less invasive detection method for disease persistence/recurrence and prognosis. LEVEL OF EVIDENCE: Cohort study.