A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.

Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly "drug-tolerant" cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.

Postoperative Pain and Opioid Use after Facial Feminization Surgery.

The objective of this study is to characterize surgical pain after facial feminization surgery (FFS) and delineate postoperative opioid usage. It is a retrospective cohort study. It was performed in a multicenter integrated health care system. Electronic medical records were reviewed for patient demographic characteristics, medical history, pain medication prescriptions, and responses to a postoperative pain survey. Student's t-test and the Mann-Whitney U-test were used for bivariate analysis. Fisher's exact tests were used for categorical data. Seventy-four patients who underwent FFS were included. The mean (standard deviation) reported "average" postoperative pain score was 4.3 (2.3) out of 10. A total of 58% of patients reported pain lasting 5 or fewer days after surgery. The severity and duration of postoperative pain was similar between patients who underwent partial-FFS or full-FFS. A total of 68% of patients required fewer than 15 opioid tablets. There were no significant differences in the quantity of opioids prescribed or used between patients who underwent partial-FFS or full-FFS. Older age and premorbid mood disorder did not correlate with greater severity/duration of pain or number of opioids used after surgery. Most patients required fewer than 15 opioid tablets after surgery and experienced less than a week of postoperative pain. Patients undergoing full-FFS did not appear to experience significantly greater pain than those undergoing fewer procedures. Older age and premorbid mood disorder were not predictors of worse pain outcomes or greater opioid utilization.

Is There an Increasing Interest in Facial Feminization Surgery? A Search Trends Analysis.

Facial feminization surgery (FFS) has increased in prevalence and recent studies show that transgender women are just as likely to want facial feminization surgery compared to genital affirmation surgery. While previous research has demonstrated an increase in individuals seeking gender affirmation surgery, little is known on the prevalence of facial feminization surgery. Categorizing the number of facial feminization surgeries performed is difficult given lack of reimbursement rates and paucity of centers of excellence which publish data on their case numbers. Research has also shown a general increase in the information that patients seek on the internet with respect to gender affirmation surgery as procedures have become more prevalent. However, to date, there have been no studies looking at the overall interest in individuals seeking information on facial feminization surgery on the internet. Therefore, this study looks for the first time at an analysis of Google Trends data with respect to global interest in facial feminization surgery.

Solid Implants in Facial Plastic Surgery: Potential Complications and How to Prevent Them.

Allogenic implants are an effective alternative to autologous grafts in the reconstruction of facial defects. These implants are used to reconstruct a variety of bony and soft-tissue defects, including the frontal and temporal regions; internal orbit; infraorbital rim; malar, paranasal, and nasal regions; mandible; and chin. In comparison to their autologous counterparts, alloplastic materials are more readily available, lack donor-site morbidity, decrease surgical time and cost, and still have relatively good postoperative tissue tolerance. However, these implants are not without their own spectrum of complications. Common solid implant materials include silicone, GoreTex (expanded polytetrafluorethylene; W. L. Gore & Associates Inc., Flagstaff, AZ), MedPor (high-density porous polyethylene; Porex Industries, Fairburn, GA), and Mersilene mesh (nonresorbable polyester fiber; Ethicon, Somerville, NJ). Each of these materials poses certain complication risks based on their surface contour (smooth vs. porous), pliability, and reactivity with surrounding tissue. In addition, certain implant locations within the head and neck are at risk for different postoperative complications. Although there are no evidence-based guidelines for implant reconstruction to help avoid common complications, there are several principles and techniques that are commonly employed by surgeons to help reduce complication rates. These include careful patient selection, proper choice of operative procedure, infection control practices (including pre/intraoperative systemic antibiotics, meticulous aseptic technique, impregnation/soaking of implant in antibiotic, irrigation of implant pocket with antibiotic, careful closure of tissue layers, and postoperative oral antibiotics), preoperative implant shaping, choice of surgical approach, and intraoperative surgical techniques. Larger, controlled trials are needed to confirm the efficacy of the aforementioned techniques in the reduction of postoperative complications.

Gender and Ethnic Diversity in Academic Facial Plastic Surgery.

OBJECTIVE: Characterize academic facial plastic surgeons by demographics, time in practice, academic productivity, and faculty position. STUDY TYPE: Cross-sectional study. METHODS: Facial plastic surgery faculty in US otolaryngology residencies with a title of assistant professor, associate professor, or professor were identified. Demographics and academic data were obtained from public profiles and Scopus. RESULTS: One hundred sixty-eight surgeons were identified. Females comprised 25.6%. Most surgeons were White (69.6%), followed by Asian (25%), Hispanic (3.6%), and Black (1.8%). Mean h-index was similar between sexes when controlling for years in practice (1.13 vs. 1.14, p = 0.575). Female representation was greater among early-career surgeons (41%) than among mid- or late-career surgeons (24% and 13%, respectively) (p = 0.006). The correlation of years in practice with academic title was similar between sexes. There was no difference in h-index (p = 0.384) or distribution of academic positions (p = 0.658) between White and non-White surgeons. There was no statistical difference in full professorship (p = 1.0) or research productivity (p = 0.974) between late-career White and non-White academic facial plastic surgeons. There was no statistical difference in promotion from assistant professorship (p = 0.506) or research productivity (p = 0.857) between White and non-White surgeons in practice for over 5 years. CONCLUSION: Female representation in academic facial plastic surgery is low, though greater gender parity among younger surgeons suggests an improving trend. Hispanic and Black surgeons remain significantly underrepresented in the field. Although increased diversity is needed in academic facial plastic surgery, established minority surgeons have experienced similar research productivity and advancement through academic ranks as their majority counterparts. LEVEL OF EVIDENCE: N/A Laryngoscope, 133:1869-1874, 2023.

HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy.

Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2(YVMA)) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2(YVMA) is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2(YVMA) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.

Quality of Life Outcomes After Facial Feminization Surgery.

Objective: Report a large single-institution cohort of quality of life (QOL) data before and after facial feminization surgery (FFS). Study Design: Case series. Methods: Patients who underwent FFS at our institution between 2017 and 2019 and completed a pre- and postoperative QOL survey were included in this study. Responses were scored on a 5-point scale with 1 corresponding to least agreement and 5 corresponding to most agreement. Paired t-test was used to compare pre- and postoperative mean scores for each response. Two-tailed t-test was used to compare the mean postoperative delta for each response by demographics. Results: One hundred seven of 341 patients completed a pre- and postoperative survey. The average age was 36 years (range 18-67). The mean time to postoperative survey completion was 96 days (interquartile range 43). Significant improvements in all aspects of QOL assessed on the survey were noted after surgery, including self-perceived facial femininity (2.1-3.8, p < 0.001) and publicly perceived facial femininity (2.0-3.6, p < 0.001). Patients also felt less limited in social activities (3.2-2.0, p < 0.001) and professional activities (2.7-1.7, p < 0.001). Conclusion: FFS improves self-perceived and externally perceived facial femininity and reduces limitations in social and professional activities.

Psychological Effect of the COVID-19 Pandemic Among Facial Feminization Surgery Patients.

BACKGROUND: The COVID-19 pandemic has disproportionately impacted mental health among the lesbian, gay, bisexual, transgender, queer community, with the delay of medical services as a factor. The pandemic's psychological effect on the transfeminine community pursuing facial feminization surgery remains unstudied. METHODS: Patients at our institution whose facial feminization surgeries were delayed due to the COVID-19 pandemic were included. A chart review collected validated, self-reported depression and psychological distress measures, as well as perceived facial femininity and desire for feminizing facial surgery prior to the pandemic. The data were compared to repeat measures during the pandemic (March-April 2020). RESULTS: Thirty patients were included in the study, 11 of whom had repeat data. Respondents during the pandemic (compared to prepandemic) felt their face was more feminine (p = 0.026) and more likely to be perceived as feminine by others (p = 0.026). They indicated a lower desire to alter their appearance with surgery (p = 0.041). Depression and distress indices were greater during the pandemic (p = 0.0018 and p = 0.026, respectively). CONCLUSION: This study is consistent with increasing depression and psychological distress among transfeminine individuals pursuing facial feminization surgery during the pandemic. The study revealed greater perceived facial femininity and a lower desire for surgery during the pandemic.

Craniofacial Microsomia.

Craniofacial microsomia (CFM) encompasses a broad spectrum of phenotypes. It is thought to result from defective development of the first and second pharyngeal arch structures, and generally presents with anomalies of the mandible and other facial bones, ears, and overlying soft tissues. The cause of CFM is thought to involve both extrinsic and genetic risk factors. Several classification systems have been developed to help stratify patients based on the severity of their defects. Treatment of patients includes repair of bony asymmetry as well as soft tissue defects and auricular anomalies. Surgical intervention is individualized based on each patient's deficits.

Antibodies directed against integration host factor mediate biofilm clearance from Nasopore.

OBJECTIVES/HYPOTHESIS: Intranasal resorbable packing, such as Nasopore, is commonly used during sinus surgery despite a paucity of evidence that demonstrates clinical benefit. We theorized that Nasopore supports bacterial growth and biofilm formation. The DNABII family of bacterial nucleic acid binding proteins stabilizes the extracellular polymeric substance of the biofilm, thus protecting bacteria from host defenses and traditional antibiotics. We tested the hypothesis that use of anti-IHF antibodies in conjunction with antibiotics would enhance biofilm eradication from Nasopore. STUDY DESIGN: In vitro experiments. METHODS: Nontypeable Haemophilus influenzae (NTHI) biofilms were grown on Nasopore. Following 24-hour incubation, biofilms were incubated for an additional 16 hours with either medium alone, naïve rabbit serum, rabbit anti-IHF serum, amoxicillin/clavulanate, or anti-IHF serum + amoxicillin/clavulanate. Computer statistics (COMSTAT) analysis was performed on images of biofilms obtained via confocal microscopy. RESULTS: NTHI readily formed a biofilm on Nasopore. Treatment with amoxicillin/clavulanate alone mediated an increase in biomass by 92% to 6.63 µ(2) /µ(3) compared to incubation in sterile medium alone (3.46 µ(2) /µ(3)). Treatment with anti-IHF alone reduced the biomass by 77% to 1.29 µ(2) /µ(3) compared to incubation with naïve rabbit serum (5.53 µ(2) /µ(3)). Anti-IHF + amoxicillin/clavulanate reduced biomass by 88% to 0.66 µ(2) /µ(3) (P <0.02) compared to incubation with naïve rabbit serum. CONCLUSION: Antibiotics alone were ineffective in eradicating NTHI biofilms that had formed on Nasopore in vitro. Anti-IHF antibodies plus amoxicillin/clavulanate therapy synergistically reduced biofilm biomass by 88%. These data support clinical studies for the use of anti-IHF combined with antibiotics to reduce biofilm formation on intranasal packing.

Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors.

In mice, Lkb1 deletion and activation of Kras(G12D) results in lung tumors with a high penetrance of lymph node and distant metastases. We analyzed these primary and metastatic de novo lung cancers with integrated genomic and proteomic profiles, and have identified gene and phosphoprotein signatures associated with Lkb1 loss and progression to invasive and metastatic lung tumors. These studies revealed that SRC is activated in Lkb1-deficient primary and metastatic lung tumors, and that the combined inhibition of SRC, PI3K, and MEK1/2 resulted in synergistic tumor regression. These studies demonstrate that integrated genomic and proteomic analyses can be used to identify signaling pathways that may be targeted for treatment.

Sunitinib prolongs survival in genetically engineered mouse models of multistep lung carcinogenesis.

Non-small cell lung cancer (NSCLC) has a poor prognosis, with substantial mortality rates even among patients diagnosed with early-stage disease. There are few effective measures to block the development or progression of NSCLC. Antiangiogenic drugs represent a new class of agents targeting multiple aspects of tumor progression, including cell proliferation, invasion, migration, and outgrowth of metastatic deposits. We tested the multitargeted angiogenesis inhibitor sunitinib in a novel endogenous mouse model of NSCLC, which expresses a conditional activating mutation in Kras with or without conditional deletion of Lkb1; both alterations are frequent in human NSCLC. We showed that daily treatment with sunitinib reduced tumor size, caused tumor necrosis, blocked tumor progression, and prolonged median survival in both the metastatic (Lkb1/Kras) and nonmetastatic (Kras) mouse models; median survival was not reached in the nonmetastatic model after 1 year. However, the incidence of local and distant metastases was similar in sunitinib-treated and untreated Lkb1/Kras mice, suggesting that prolonged survival with sunitinib in these mice was due to direct effects on primary tumor growth rather than to inhibition of metastatic progression. These collective results suggest that the use of angiogenesis inhibitors in early-stage disease for prevention of tumor development and growth may have major survival benefits in the setting of NSCLC.

HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice.

Members of the hypoxia-inducible factor (HIF) family of transcription factors regulate the cellular response to hypoxia. In non-small cell lung cancer (NSCLC), high HIF2alpha levels correlate with decreased overall survival, and inhibition of either the protein encoded by the canonical HIF target gene VEGF or VEGFR2 improves clinical outcomes. However, whether HIF2alpha is causal in imparting this poor prognosis is unknown. Here, we generated mice that conditionally express both a nondegradable variant of HIF2alpha and a mutant form of Kras (KrasG12D) that induces lung tumors. Mice expressing both Hif2a and KrasG12D in the lungs developed larger tumors and had an increased tumor burden and decreased survival compared with mice expressing only KrasG12D. Additionally, tumors expressing both KrasG12D and Hif2a were more invasive, demonstrated features of epithelial- mesenchymal transition (EMT), and exhibited increased angiogenesis associated with mobilization of circulating endothelial progenitor cells. These results implicate HIF2alpha causally in the pathogenesis of lung cancer in mice, demonstrate in vivo that HIF2alpha can promote expression of markers of EMT, and define HIF2alpha as a promoter of tumor growth and progression in a solid tumor other than renal cell carcinoma. They further suggest a possible causal relationship between HIF2alpha and prognosis in patients with NSCLC.