Robotic and endoscopic trans-oral total laryngectomy, a systematic review and meta-analysis.

Trans-oral total laryngectomy (TOTL) is a novel minimally invasive approach to narrow-field laryngectomy. The objective of this study was to review published data on robotic and endoscopic-assisted TOTL to examine oncologic, functional, and adverse outcomes. MEDLINE, Web of Science, and Cochrane databases were searched between January 2009 and December 2023. PRISMA guidelines were used for data abstraction independently by two reviewers. Proportional meta-analysis (random effects model) was used for analysis. Main outcomes included oncologic outcomes (margin status, recurrence rate) and surgical complications (fistula, hemorrhage, need for second operation). Eight studies were included (total of 37 patients). Cases included 31 robotic-assisted, 3 endoscopic-assisted, and 3 robotic cases which required conversion to open approach. Most cases were performed for laryngeal SCC (22 patients, 59.5%). Primary closure was achieved in all patients. Negative margins were achieved in 20 of 21 patients with LSCC. Recurrence data was reported in 20 LSCC patients with disease recurrence in 4 patients (20%). Follow-up was described for 15 patients (mean of 3.5 years, range 1.6-5.8 years). Eleven complications occurred including fistula, bleed, and stomal stenosis with a pooled rate of 33.7% (95% CI: 16.4-53.0%, I2 = 0). Six fistulas occurred with a pooled rate of 23.2% (95% CI: 5.8-45.4%, I2 = 0). TOTL is an emerging treatment modality appropriate for select patients requiring TL and offers a minimally invasive approach with less tissue disruption. This is the first systematic review and meta-analysis to examine its oncologic outcomes and complications. Larger case series with adequate follow-up are needed to better characterize TOTL outcomes.

The influence of perioperative enoxaparin on bleeding after TORS oropharyngectomy.

Perioperative enoxaparin is often avoided in patients undergoing transoral robotic (TORS) oropharyngectomy. Our goal was to quantify the risk of postoperative hemorrhage (POH) in patients receiving enoxaparin after TORS oropharyngectomy. This was a retrospective database cohort study set up in 89 separate healthcare organizations. The TriNetX electronic database was queried for patients with OPSCC who underwent TORS oropharyngectomy. Propensity-score matching was used to create two cohorts, one receiving and one not receiving perioperative enoxaparin. Outcome measures were the POH rate within 1 day of surgery ("primary") and POH rate within 2-30 days of surgery ("secondary"). 1109 patients undergoing TORS for OPSCC were identified, 400 of which received perioperative enoxaparin. One-to-one propensity score matching resulted in 310 patients per cohort. After matching, the primary POH rates between patients receiving and not receiving enoxaparin were 3.23% for both cohorts (OR 1.000, 95% CI 0.410 to 2.438). The secondary POH rates between those receiving and not receiving enoxaparin were 5.47% vs. 3.54% (OR 1.577, 95% CI 0.726 to 3.424). The number needed to harm (NNH) with perioperative enoxaparin use for secondary POH after TORS was 53; no difference was found in primary POH rates. While not statistically significant, the use of perioperative enoxaparin after TORS is associated with increased odds of secondary POH with a NNH of 53; no difference was found in rates of primary POH. For patients undergoing TORS, enoxaparin use requires careful weighing of the risks and benefits.

Sex-specific sequels of early life stress on serine/threonine kinase activity in visceral adipose tissue from obese mice.

Adverse childhood experiences (ACEs) are an established independent risk factor for chronic disease including obesity and hypertension; however, only women exposed to multiple ACEs show a positive relationship with BMI. Our lab has reported that maternal separation and early weaning (MSEW), a mouse model of early life stress, induces sex-specific mechanisms underlying greater blood pressure response to a chronic high fat diet (HF). Specifically, female MSEW mice fed a HF display exacerbated perigonadal white adipose tissue (pgWAT) expansion and a metabolic syndrome-like phenotype compared to control counterparts, whereas hypertension is caused by sympathoactivation in male MSEW mice. Thus, this study aimed to determine whether there is a sex-specific serine/threonine kinase (STKA) activity in pgWAT adipose tissue associated with early life stress. Frozen pgWAT was collected from MSEW and control, male and female mice fed a HF to assess STKA activity using the Pamstation12 instrument. Overall, MSEW induces significant reduction of 7 phosphokinases (|Z| >=1.5) in females (QIK, MLK, PKCH, MST, STE7, PEK, FRAY) and 5 in males (AKT, SGK, P38, MARK, CDK), while 15 were downregulated in both sexes (DMPK, PKA, PKG, RSK, PLK, DYRK, NMO, CAMK1, JNK, PAKA, RAD53, ERK, PAKB, PKD, PIM, AMPK). This data provides new insights into the sex-specific dysregulation of the molecular network controlling cellular phosphorylation signals in visceral adipose tissue and identifies possible target phosphokinases implicated in adipocyte hypertrophy as a result of exposure to early life stress. Identifying functional metabolic signatures is critical to elucidate the underlying molecular mechanisms behind the sex-specific obesity risk associated with early life stress.

Human papillomavirus circulating tumor DNA: a diagnostic tool in squamous cell carcinoma of unknown primary-a pilot study.

Introduction: Neck mass is the most common presentation of human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinoma (OPSCC). Recently, circulating tumor HPV-DNA (ctHPVDNA) assays have been developed to detect active OPSCC. This pilot study investigates the diagnostic accuracy of ctHPVDNA in establishing HPV status for known vs. unknown OPSCC presenting as a neck mass. Methods: A single-institution pilot study was conducted on all patients with OPSCC presenting as a neck mass between 2021 and 2022. The diagnostic accuracy of ctHPVDNA was compared to that of standard diagnostic procedures used to obtain HPV status according to the American Society of Clinical Oncology (ASCO) guideline for squamous cell carcinoma of unknown primary (SCCUP). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ctHPVDNA were calculated. Results: A total of 27 patients were included; 70.4% were current or former smokers, 48.1% (N = 13) had identifiable primaries, and 51.9% (N = 14) had SCCUP. Four patients with known primaries required operative direct laryngoscopy with biopsy (DLB) to establish HPV status. Two patients with SCCUP underwent diagnostic transoral robotic surgery (TORS) to establish HPV status and localize the primary. Twelve patients underwent therapeutic TORS and neck dissection. The gold standard for HPV status was based on final histopathologic p16 or HPV in situ hybridization (ISH) staining during workup/treatment. ctHPVDNA had 95.8% sensitivity, 100% specificity, 100% PPV, and 75% NPV in predicting HPV-positive OPSCC in the whole sample. Binary logistic regression model using ctHPVDNA results to predict HPV-positive OPSCC was significant (-2 log likelihood = 5.55, χ2 = 8.70, p <.01, Nagelkerke's R squared = .67). Among patients with identifiable primaries, all patients had HPV-positive tumors on final pathology, and ctHPVDNA was positive in 100%. In the unknown primary patients, ctHPVDNA had 90.9% sensitivity, 100% specificity, 100% PPV, and 75% NPV. Discussion: ctHPVDNA demonstrated good diagnostic accuracy for both known and unknown primaries. Incorporation of ctHPVDNA into the diagnostic algorithm for SCCUP may reduce the need for multiple procedures to establish HPV status.

Complications following salvage transoral robotic surgery with and without reconstruction: A systematic review of the literature.

BACKGROUND: Transoral robotic surgery (TORS) has been used in the salvage setting for head and neck cancers both with and without reconstruction. The complications of salvage TORS and the effect of reconstruction on complications has not been studied. OBJECTIVE: To study the complications of salvage TORS and examine the effect of reconstruction on complication rates. METHOD: An electronic search of the English- language literature using PubMed, Medline, and the Cochrane database was conducted and a systematic review performed in accordance with PRISMA guidelines (CRD42020181057). RESULTS: A total of 23 studies including 533 patients have been published on salvage TORS.The average patient age was 61.2 years.Prior treatment was described for 420 patients.205 (48.8%) underwent prior definitive radiotherapy (RT).160 (38.1%) underwent definitive chemoradiotherapy (CRT).Only 55 (13.1%) had prior surgery.Overall, there were 158 complications with a pooled rate of 33.6% (95%CI: 25.4-42.3%).77 were major complications requiring surgical intervention with a pooled rate of 18.9% (95% CI: 14.8-23.3%).The number of patients undergoing reconstruction among salvage cases in the literature is 59 (9.19%), with 24 local flaps and 25 microvascular free flaps.Reconstruction was associated with lower overall hemorrhage rates but had no impact on major hemorrhage rates. CONCLUSIONS: The pooled incidence rates of major complications, major POH and emergency tracheostomy following salvage TORS are 18.9%, 10.5%, and 4.4%.The rate of death following salvage TORS is 3.6%. Reconstruction was associated with lower overall hemorrhage rate after salvage TORS but had no impact on major postoperative hemorrhage rates.

Minimal synthetic enhancers reveal control of the probability of transcriptional engagement and its timing by a morphogen gradient.

How enhancers interpret morphogen gradients to generate gene expression patterns is a central question in developmental biology. Recent studies have proposed that enhancers can dictate whether, when, and at what rate promoters engage in transcription, but the complexity of endogenous enhancers calls for theoretical models with too many free parameters to quantitatively dissect these regulatory strategies. To overcome this limitation, we established a minimal promoter-proximal synthetic enhancer in embryos of Drosophila melanogaster. Here, a gradient of the Dorsal activator is read by a single Dorsal DNA binding site. Using live imaging to quantify transcriptional activity, we found that a single binding site can regulate whether promoters engage in transcription in a concentration-dependent manner. By modulating the binding-site affinity, we determined that a gene's decision to transcribe and its transcriptional onset time can be explained by a simple model where the promoter traverses multiple kinetic barriers before transcription can ensue.

Complications and Outcomes of Endovascular Embolization for Intractable Epistaxis: A Systematic Review and Meta-analysis.

OBJECTIVES: Endovascular embolization has emerged as an effective treatment for intractable epistaxis. This systematic review and meta-analysis aimed to calculate the rates of success, rebleeds, and complications and to identify the etiologies and complications of patients who undergo endovascular embolization. METHODS: This systematic review and meta-analysis was conducted per the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Articles were extracted from Scopus, PubMed, Web of Science, and Cochrane Central and were filtered by a systematic review process using Rayyan software. A random-effects model was used to quantify the rates success, rebleeds, and complications. RESULTS: Forty-two studies were included, totaling 1660 patients. The pooled success rate was 89% (95% confidence interval [CI] 86%-92%) and the pooled rebleed rate was 19% (95% CI 16%-22%). The pooled minor complication rate was 18% (95% CI 11%-27%). The most common major complication was soft tissue necrosis followed by stroke. The most common minor complication was facial pain. No minor complications were reported to be permanent. Of the patients who failed initial embolization, 42% underwent repeat embolization and 34% underwent surgical arterial ligation. CONCLUSIONS: Endovascular embolization is an effective treatment for intractable epistaxis. The decision to perform embolization should be carefully weighed given the rare but significant major complications.

Endoscopic Endonasal Orbital Apex Decompression for Carotid Cavernous Fistula.

SIGNIFICANCE STATEMENT: This case report demonstrates a novel approach to treating a rare indirect carotid cavernous fistula (CCF) and associated abducens palsy. Although endovascular treatment is the standard of care in the management of CCFs, it was contraindicated in this patient. Instead, she underwent an endoscopic endonasal approach (EEA) with decompression of the medial orbital apex, including the cavernous sinus and optic nerve, with complete resolution of headache, lateral gaze palsy, and diplopia within 2 months.

Contralateral Transmaxillary Approach for Resection of Chondrosarcoma of the Petrous Apex: A Case Report.

BACKGROUND: Deep location and neurovascular structures make access to lesions of the petrous apex a significant challenge. A novel approach for these tumors is the contralateral transmaxillary approach. CLINICAL PRESENTATION: A 31-year-old male was evaluated for left abducens nerve palsy. Magnetic resonance imaging (MRI) and computed tomography revealed an enhancing, lytic lesion of the petrous apex with extension to the cavernous sinus and petroclival junction. The patient underwent a combined endoscopic contralateral transmaxillary and endoscopic endonasal transclival approach for resection of the lesion. No new or worsening neurologic deficits were noted following the procedure. Pathology revealed low-grade chondrosarcoma (grade I). Postoperative MRI revealed gross total resection of the lesion. Patient underwent adjuvant radiation therapy at the discretion of radiation oncology. CONCLUSION: The contralateral transmaxillary approach to the petrous apex allows for resection of lesions of the petrous apex with the ability to extend the dissection laterally. Excellent results achieved by institutions with advanced extended endoscopic endonasal experience can be reproduced in institutions with less experience. Further characterization of the risks and benefits of this approach is needed.

Predictive modeling reveals that higher-order cooperativity drives transcriptional repression in a synthetic developmental enhancer.

A challenge in quantitative biology is to predict output patterns of gene expression from knowledge of input transcription factor patterns and from the arrangement of binding sites for these transcription factors on regulatory DNA. We tested whether widespread thermodynamic models could be used to infer parameters describing simple regulatory architectures that inform parameter-free predictions of more complex enhancers in the context of transcriptional repression by Runt in the early fruit fly embryo. By modulating the number and placement of Runt binding sites within an enhancer, and quantifying the resulting transcriptional activity using live imaging, we discovered that thermodynamic models call for higher-order cooperativity between multiple molecular players. This higher-order cooperativity captures the combinatorial complexity underlying eukaryotic transcriptional regulation and cannot be determined from simpler regulatory architectures, highlighting the challenges in reaching a predictive understanding of transcriptional regulation in eukaryotes and calling for approaches that quantitatively dissect their molecular nature.

Botulinum toxin A for the treatment of first bite syndrome-a systematic review.

Background: First bite syndrome (FBS) is a rare post-surgical complication resulting in peri-parotid pain after the first bite of meals. Intra-parotid Botulinum toxin A may offer relief for these symptoms. There is no consensus on the optimal dosage, timing to symptom improvement, need for repeat injections, and safety of this treatment. The objective of this systematic review was to assess the efficacy and safety of intra-parotid Botulinum toxin A injection in treating FBS. Methods: The MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar were searched from the inception until July 2020. Case reports, case series, prospective and retrospective trials in which patients with post-surgical FBS were treated with intra-parotid botulinum toxin A injection were included. The primary outcome was improvement of FBS symptoms. Secondary outcomes were time to symptom improvement and complications. Risk of bias was assessed with National Institute of Health (NIH) Quality Assessment Tools. Results: Search results yielded 41 studies. Thirty-three articles were excluded after screening titles, abstracts, and full texts, yielding eight studies, from which 22 patients were included. No studies included a control. All studies were of lower quality and had at least moderate risk of bias. The initial botulinum toxin A injection dose ranged from 10-75 U. Time from surgical treatment to injection ranged from 1 month to 3 years. Seven studies, containing 17 patients, reported individual patient outcomes. Clinical improvement was reported in 16 patients lasting between 1-30 months post injection. Eight of 8 (100%) patients receiving at least 40 U botulinum toxin A had symptom improvement. Ten of 22 (45.5%) patients received a second botulinum toxin A injection due to return of pain at a mean of 3.8 months after the first injection. Seven of 22 (38.1%) patients had complete symptom resolution at a mean of 12.1 months. There were no reported injection complications, including: facial paralysis, infection, injection site reaction, and allergic reaction. Discussion: There are no controlled studies comparing intra-parotid botulinum toxin A to observation for FBS. However, botulinum toxin A appears to be a potentially safe, effective treatment.

Intraoperative Indocyanine Green Angiography for Assessing Flap Perfusion in Skull Base Reconstruction: A Systematic Review.

Objective This study was aimed to study the current use of intraoperative indocyanine green (ICG) angiography during skull base reconstruction and understand its efficacy in predicting postoperative magnetic resonance imaging (MRI) enhancement and flap. Study Design The Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Google Scholar databases were searched from the date of inception until August 2020 for studies of ICG flap perfusion assessment during skull base reconstruction. The primary outcome of interest was the development of cerebrospinal fluid (CSF) leak after skull base reconstruction. Secondary outcomes of interest included postoperative meningitis, flap MRI enhancement, flap necrosis, flap perfusion measurements, and total complications. Results Search results yielded 189 studies, from which seven studies with a total of 104 patients were included in the final analysis. There were 44 nasoseptal flaps (NSF), two lateral nasal wall flaps (LNWF), 14 pericranial flaps (PCF), and 44 microvascular free flaps. The rates of CSF leak and postoperative MRI enhancement were 11 and 94%, respectively. There was one case of postoperative meningitis. Pooled analysis of the available data showed that intraoperative ICG flap perfusion was associated with flap enhancement on postoperative MRI ( p = 0.008) and CSF leak ( p = 0.315) by Fisher's exact test. Conclusion The available literature suggests intraoperative ICG enhancement is associated with postoperative MRI enhancement. Given the small sample sizes in the literature and the rarity of complications associated with skull base reconstruction, intraoperative ICG enhancement has not been predictive of flap necrosis or postoperative complications such as CSF leak or meningitis. Level of Evidence This study presents level 3 evidence as a systematic review of case studies, case reports, and retrospective and prospective trials with no blinding, controls, and inconsistently applied reference standards.

Factors Associated With a Prolonged Diagnosis-to-Treatment Interval in Laryngeal Squamous Cell Carcinoma.

OBJECTIVE: Evaluate factors associated with treatment delays and their effect on survival in laryngeal squamous cell carcinoma. STUDY DESIGN: Retrospective cohort study. SETTING: National Cancer Database. METHODS: Patients receiving primary radiation or surgery for laryngeal squamous cell carcinoma were included from 2004 to 2017. The primary outcomes were the diagnosis-to-treatment interval (DTI) and 5-year survival. Variables of prolonged DTI (>30 days) were assessed via logistic regression models. Survival was then assessed through Cox proportional hazards models. Candidate variables for both outcomes included age, sex, race, ethnicity, distance to treatment facility, insurance coverage, treatment facility type, TNM T stage, nodal status, and DTI (in models estimating survival). RESULTS: An overall 136,203 patients with laryngeal cancer were identified, from which 51,747 remained after exclusions were applied: 18,499 received primary surgery and 33,248 received primary radiation. Being a member of a racial or ethnic minority, advanced age, female sex, ≥30 miles from treatment facility, lack of insurance, treatment at an academic cancer center, and primary radiation were associated with a prolonged DTI. However, in spite of a faster DTI, treatment at a community cancer center was independently associated with higher mortality (hazard ratio, 1.2; P < .0001). CONCLUSIONS: Despite being associated with prolonged DTI, receiving treatment at a high-volume academic facility was associated with significantly improved survival. Our results indicate that improved referral pathways or outreach may help improve survival in laryngeal cancer, especially in high-risk populations.

The Nasoseptal Flap for Reconstruction of Lateral Oropharyngectomy Defects: A Clinical Series.

OBJECTIVES/HYPOTHESIS: To study use of the nasoseptal flap (NSF) to reconstruct lateral transoral robotic surgery (TORS) oropharyngectomy defects. STUDY DESIGN: Retrospective case series. METHODS: A clinical series of six patients undergoing NSF reconstruction of lateral TORS oropharyngectomy defects was retrospectively studied. All patients underwent TORS for the treatment of intermediate-risk human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma of the lateral pharyngeal wall between January and June 2017. All patients underwent NSF reconstruction of lateral TORS defects with retrospective analysis of outcomes and complications. RESULTS: Six patients underwent NSF reconstruction of lateral TORS defects. Operative times decreased from 180 minutes to 90 minutes over the study period. There were two cases of partial flap dehiscence and partial necrosis. There were no major donor site complications. All patients had temporary nasal obstruction and crusting. Two experienced temporary aural fullness. In all patients, the lateral wall was mucosalized in 1-3 weeks. Cephalometric analysis of preoperative imaging revealed that patients with high-arched palates (>3 cm) and defect lengths that are longer than NSF flap lengths are poor candidates for this technique. CONCLUSIONS: This NSF is a vascularized, locoregional rotational flap that can reconstruct lateral TORS defects in salvages cases or those where the parapharyngeal carotid or mandibular bone are exposed. Postoperative morbidity is limited to temporary nasal dyspnea, aural fullness, and crusting. Preoperative imaging can determine which patient will have successful defect coverage. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:53-60, 2022.

Minimally invasive treatment of laryngoceles: a systematic review and pooled analysis.

Laryngoceles are best treated with surgery. The goal of this study is to compare patient outcomes and complications in patients undergoing removal of laryngoceles with either transoral endoscopic/microlaryngoscopic or robotic approaches. A systematic review of the published literature was conducted using Pubmed, Web of Science, and the Cochrane Clinical Trials databases. A pooled analysis of individual data was used to compare outcomes between robotic and endoscopic approaches. A total of 30 studies were included. Nine studies with 95 patients were included in the final analysis. Eighty-one (85.26%) were treated with microlaryngoscopic surgery and 14 (14.74%) were treated with robotic-assisted surgery. The rates of tracheostomy (RR = 1.44, 95% CI = 0.389-5.332), complications (RR = 0.329, 95% CI = 0.047-2.294) and recurrence (RR = 0.354, 95% CI = 0.021-5.897) were not statistically different between groups. Within the endoscopic subgroup, 66 laryngoceles (78.57%) were completely excised, while 18 (21.43%) laryngoceles were treated with marsupialization. Marsupialization was associated with an increased risk of recurrence (RR = 4.889, 95% CI = 1.202-19.891). In the robotic subgroup, there was an increased risk of nasogastric tube use (RR = 103.867, 95% CI = 6.379-1619.214) and a longer mean length of hospital stay (p = 0.0001). Transoral treatment of laryngoceles has complication and recurrence rates of 18.95% and 7.37%, respectively. Robotic approaches are associated with higher rates of NGT use and increased hospital stay, however much of this is due to one robotic surgeon's preference for routine NGT placement and higher rates of combined laryngocele removal via robotic approach. Complete excision of combined laryngoceles is possible with transoral approaches. Marsupialization, reported in traditional endoscopic approaches, is associated with a significantly higher rate of recurrence (22.22% vs. 4.76%).

Real-time single-cell characterization of the eukaryotic transcription cycle reveals correlations between RNA initiation, elongation, and cleavage.

The eukaryotic transcription cycle consists of three main steps: initiation, elongation, and cleavage of the nascent RNA transcript. Although each of these steps can be regulated as well as coupled with each other, their in vivo dissection has remained challenging because available experimental readouts lack sufficient spatiotemporal resolution to separate the contributions from each of these steps. Here, we describe a novel application of Bayesian inference techniques to simultaneously infer the effective parameters of the transcription cycle in real time and at the single-cell level using a two-color MS2/PP7 reporter gene and the developing fruit fly embryo as a case study. Our method enables detailed investigations into cell-to-cell variability in transcription-cycle parameters as well as single-cell correlations between these parameters. These measurements, combined with theoretical modeling, suggest a substantial variability in the elongation rate of individual RNA polymerase molecules. We further illustrate the power of this technique by uncovering a novel mechanistic connection between RNA polymerase density and nascent RNA cleavage efficiency. Thus, our approach makes it possible to shed light on the regulatory mechanisms in play during each step of the transcription cycle in individual, living cells at high spatiotemporal resolution.