Prophylactic Antibiotic Use in Reconstruction of Nasal Mohs Defects.

OBJECTIVE: To evaluate the effect of prophylactic antibiotics on outcomes and complications following surgical reconstructions of nasal Mohs defects in the outpatient setting. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary care center, July 2021 to June 2023. METHODS: All adult patients who underwent reconstruction of nasal Mohs defects in an outpatient office setting were examined. Patient demographics, surgical details, prophylactic postprocedural antibiotic use, and postprocedural complications (infection, flap or graft necrosis, wound dehiscence) were collected. Outcomes and complications were compared between patients who received and did not receive prophylactic antibiotics using χ2, Kruskal-Wallis, and multivariable logistic regression. RESULTS: A total of 211 patients met inclusion criteria. A majority of reconstructions utilized a local flap (70%), followed by a skin or composite graft (22%), then an interpolated flap (8%). Over half of patients (55%) were prescribed prophylactic antibiotics. Postprocedural complications were documented in 16 patients (7.6%), including infection (3.3%) and flap or graft loss or necrosis (1.4%). The rate of complications did not differ based on receipt of antibiotics. The only factors independently associated with the development of complications were history of chemoradiation and reconstruction with skin or composite grafts. CONCLUSION: Prophylactic antibiotics after nasal Mohs reconstructions performed in the office setting were not associated with any differences in the rate of postprocedural complications, including surgical site infections.

Bilateral Longus Colli Abscesses as a Complication of Advanced Bacterial Rhinosinusitis.

Known complications of acute bacterial rhinosinusitis include retropharyngeal abscess, cavernous sinus thrombosis, intracranial abscess, and associated sequelae. We describe the case of a patient with longus colli abscess formation resulting from acute pansinusitis, complicated by bilateral cavernous sinus thrombosis in the setting of concurrent viral pneumonitis, severe sepsis, and a large area cerebral infarction. The bilateral longus colli abscesses were drained via stereotactic image-guided endonasal sinus surgery, yielding Staphylococcus hominis in culture. The described disease progressed rapidly over a 2-week course amid the COVID-19 pandemic.

Utility of PET-CT in Newly Diagnosed HPV-Associated Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVE: To compare the utility of positron emission tomography-computed tomography (PET-CT) versus contrasted CT neck combined with routine chest imaging for disease staging and treatment planning in human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) with clinically evident sites of primary disease. METHODS: All adult patients with primary HPV-associated OPSCC at a single quaternary care cancer center from 2018 to 2019 were reviewed, and those with images available for re-review were included. Primary outcomes included concordance in clinical staging between the 2 imaging modalities of interest (PET-CT vs CT), as well as independent agreement of each with pathologic staging. Analysis was performed via ordinal logistic regression. A secondary outcome was treatment selection after diagnostic imaging, analyzed via chi-squared testing. RESULTS: In total, 100 patients were included for evaluation, of which 89% were male, 91% Caucasian, and mean age was 61.2 years (SD 9.6). Clinical disease staging agreed between imaging modalities in 95% of cases (54 of 57 patients). Pathologic staging agreed with clinical staging from CT neck in 93% of cases (25 of 27 patients; P = .004), and with PET-CT in 82% (14 of 17 patients; P =.003). No differences were observed between the 2 imaging modalities for subsequent treatment selection (P = .39). CONCLUSION: In uncomplicated HPV-associated OPSCC, CT offers equivalent diagnostic accuracy to that of combined whole-body PET-CT for clinical staging, and has no appreciable impact on treatment selection. A reduced reliance on routine PET-CT during initial workup of HPV-associated OPSCC may be favorable for otherwise healthy patients with clinically evident sites of primary disease.

Socioeconomic Influences on Short-term Postoperative Outcomes in Patients With Oral Cavity Cancer Undergoing Free Flap Reconstruction.

OBJECTIVE: To evaluate the associations between median household income (MHI) and area deprivation index (ADI) on postoperative outcomes in oral cavity cancer. STUDY DESIGN: Retrospective review (2000-2019). SETTING: Single-institution tertiary medical center. METHODS: MHI and ADI were matched from home zip codes. Main postoperative outcomes of interest were length of tracheostomy use, length of hospital stay, return to oral intake, discharge disposition, and 60-day readmissions. Linear and logistic regression controlled for age, sex, race, body mass index, tobacco and alcohol use history, primary tumor location, disease staging at presentation, and length of surgery. A secondary outcome was clinical disease staging (I-IV) at time of presentation. RESULTS: The cohort (N = 681) was 91.3% White and 38.0% female, and 51.7% presented with stage IV disease. The median age at the time of surgery was 62 years (interquartile range [IQR], 53-71). The median MHI was $47,659 (IQR, $39,324-$58,917), and the median ADI was 67 (IQR, 48-79). ADI and MHI were independently associated with time to return of oral intake (ß = 0.130, P = .022; ß = -0.092, P = .045, respectively). Neither was associated with length of tracheostomy, hospital stay, discharge disposition, or readmissions. MHI quartiles were associated with a lower risk of presenting with more advanced disease (Q3 vs Q1: adjusted odds ratio, 0.56 [95% CI, 0.32-0.97]). CONCLUSION: MHI is associated with oral cavity cancer staging at the time of presentation. MHI and ADI are independently associated with postoperative return to oral intake following intraoral tumor resection and free flap reconstruction.

Impact of Preoperative Risk Factors on Inpatient Stay and Facility Discharge After Free Flap Reconstruction.

OBJECTIVE: To determine the preoperative risk factors most predictive of prolonged length of stay (LOS) or admission to a skilled nursing facility (SNF) or inpatient rehabilitation center (IPR) after free flap reconstruction of the head and neck. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center. METHODS: Retrospective review of 1008 patients who underwent tumor resection and free flap reconstruction of the head and neck at a tertiary referral center from 2002 to 2019. RESULTS: Of 1008 patients (65.7% male; mean age of 61.4 years, SD 14.0 years), 161 (15.6%) were discharged to SNF/IPR, and the median LOS was 7 days. In multiple linear regression analysis, Charlson Comorbidity Index (CCI; P < .001), American Society of Anesthesiologists (ASA) classification (P = .021), female gender (P = .023), and inability to tolerate oral diet preoperatively (P = .006) were statistically significantly related to increased LOS, whereas age, body mass index (BMI), modified frailty index (MFI), a history of prior radiation or chemotherapy, and home oxygen use were not. Multiple logistic regression analysis demonstrated that CCI (odds ratio [OR] = 1.119, confidence interval [CI] 1.023-1.223), age (OR = 1.082, CI 1.056-1.108), and BMI <19.0 (OR = 2.141, CI 1.159-3.807) were the only variables statistically significantly related to posthospital placement in an SNF or IPR. CONCLUSION: Common tools for assessing frailty and need for additional care may be inadequate in a head and neck reconstructive population. CCI appears to be the best of the aggregate metrics assessed, with significant relationships to both LOS and placement in SNF/IPR.

Association of Social Determinants of Health with Time to Diagnosis and Treatment Outcomes in Idiopathic Subglottic Stenosis.

OBJECTIVES: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients. METHODS: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence. RESULTS: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression. CONCLUSIONS: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.

Child Pain Intensity and Parental Attitudes toward Complementary and Alternative Medicine Predict Post-Tonsillectomy Analgesic Use.

Parental attitudes regarding pain interventions and perceptions of their child's pain intensity likely influence the decision to administer postoperative analgesics. Our study examined the impact of daily fluctuations in child pain intensity and parental attitudes regarding complementary and alternative medicine (CAM) on analgesic administration following pediatric tonsillectomy. Parents of children undergoing tonsillectomy (n = 33) completed a survey assessing CAM attitudes and a 7-day postoperative electronic daily diary to record their child's daily pain intensity and analgesic medications (acetaminophen, ibuprofen, or oxycodone). Generalized linear mixed models with Poisson distributions evaluated the effects of within-person (child's daily pain intensity) and between-person (average postoperative pain, parental CAM attitudes) components on the number of medication doses administered. Higher daily pain intensity was associated with more oxycodone doses administered on a given day, but not acetaminophen or ibuprofen. Positive parental CAM attitudes were associated with less oxycodone use, beyond the variations accounted for by the child's daily pain intensity and average postoperative pain. Both parental CAM attitudes and their child's daily pain intensity were independently associated with parental decisions to administer opioids following tonsillectomy. Understanding factors influencing individual variability in analgesic use could help optimize children's postoperative pain management.

The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.

Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.

Passenger deletions generate therapeutic vulnerabilities in cancer.

Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.

Use of sildenafil to facilitate weaning from inhaled nitric oxide in children with pulmonary hypertension following surgery for congenital heart disease.

Pulmonary hypertension frequently complicates the postoperative management of patients after congenital cardiac surgery. Inhaled nitric oxide is an effective treatment option, but rebound pulmonary hypertension can occur upon its withdrawal. Sildenafil may facilitate its withdrawal by restoring cyclic guanosine monophosphate availability via phosphodiesterase-5 inhibition. The purpose of this study was to evaluate the use of sildenafil in facilitating weaning from inhaled nitric oxide after congenital cardiac surgery in patients who had previously failed weaning, and to compare the effects of sildenafil on pulmonary and systemic hemodynamics. Children who received sildenafil after cardiovascular surgery during a 23-month period at Riley Hospital for Children were identified. Medical records were retrospectively reviewed to determine sildenafil and nitric oxide dosing, pulmonary and systemic blood pressures, and adverse effects. Oral sildenafil was administered to 7 children who had failed attempts at inhaled nitric oxide weaning. Inhaled nitric oxide was weaned from 29.8+/-5.9 ppm prior to sildenafil initiation to 12.2+/-3.4 ppm (mean +/- SE; P= .024) in the 24 hours after sildenafil. Mean pulmonary artery and systemic arterial pressure were unchanged from baseline when measured 1 hour after sildenafil dosing (mean pulmonary artery pressure, 29+/-1 to 27+/-0.7 mm Hg, P= .066; mean systemic arterial pressure, 56+/-1.2 to 54+/-1.2 mm Hg, P= .202). Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts.

CBFA2T3-ZNF652 corepressor complex regulates transcription of the E-box gene HEB.

Transcriptional repression plays a critical role in development and homeostasis. The ETO family represents a group of highly conserved and ubiquitously expressed transcriptional regulatory proteins that are components of a diverse range of multiprotein repressor complexes. ETO proteins function as transcriptional repressors by interacting with a number of transcription factors that bind to their cognate consensus DNA binding sequences within the promoters of target genes. We previously reported that the classical C(2)H(2) zinc finger DNA-binding protein, ZNF652, specifically and functionally interacts with the ETO protein CBFA2T3 and has a role in the suppression of breast oncogenesis. Here we report the identification and validation of the ZNF652 consensus DNA binding sequence. Our results show that the E-box gene HEB is a direct target of CBFA2T3-ZNF652-mediated transcriptional repression. The CBFA2T3-ZNF652 complex regulates HEB expression by binding to a single ZNF652 response element located within the promoter sequence of HEB. This study also shows that the NHR3 and NHR4 domains of CBFA2T3 interact with a conserved proline-rich region located within the C terminus of ZNF652. Our results, together with previous reports, indicate that HEB has a complex relationship with CBFA2T3; CBFA2T3 interacts with ZNF652 to repress HEB expression, and in addition CBFA2T3 interacts with the HEB protein to inhibit its activator function. These findings suggest that CBFA2T3-ZNF652-mediated HEB regulation may play an important role in hematopoiesis and myogenesis.

ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription.

The transcriptional repressor CBFA2T3 is a putative breast tumor suppressor. To define the role of CBFA2T3, we used a segment of this protein as bait in a yeast two-hybrid screen and identified a novel uncharacterized protein, ZNF652. In general, primary tumors and cancer cell lines showed lower expression of ZNF652 than normal tissues. Together with the location of this gene on the long arm of chromosome 17q, a region of frequent loss of heterozygosity in cancer, these results suggest a possible role of ZNF652 in tumorigenesis. In silico analysis of this protein revealed that it contains multiple classic zinc finger domains that are predicted to bind DNA. Coimmunoprecipitation assays showed that ZNF652 strongly interacts with CBFA2T3 and this interaction occurs through the COOH-terminal 109 amino acids of ZNF652. In contrast, there was a weak interaction of ZNF652 with CBFA2T1 and CBFA2T2, the other two members of this ETO family. Transcriptional reporter assays further confirmed the strength and selectivity of the ZNF652-CBFA2T3 interaction. The transcriptional repression of growth factor independent-1 (GFI-1), a previously characterized ETO effector zinc finger protein, was shown to be enhanced by CBFA2T1, but to a lesser extent by CBFA2T2 and CBFA2T3. We therefore suggest that each of the various gene effector zinc finger proteins may specifically interact with one or more of the ETO proteins to generate a defined range of transcriptional repressor complexes.

FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex.

A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumor cell lines. We have shown that FBXO31, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. FBXO31 has properties consistent with a tumor suppressor, because ectopic expression of FBXO31 in two breast cancer cell lines inhibited colony growth on plastic and inhibited cell proliferation in the MCF-7 cell line. In addition, compared with the relative expression in normal breast, levels of FBXO31 were down-regulated in breast tumor cell lines and primary tumors. FBXO31 was cell cycle regulated in the breast cell lines MCF-10A and SKBR3 with maximal expression from late G(2) to early G(1) phase. Ectopic expression of FBXO31 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G(1) phase of the cell cycle. FBXO31 contains an F-box domain and is associated with the proteins Skp1, Roc-1, and Cullin-1, suggesting that FBXO31 is a component of a SCF ubiquitination complex. We propose that FBXO31 functions as a tumor suppressor by generating SCF(FBXO31) complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation.