A comparison of endoscopic endonasal versus open approaches for skull base chordoma: a comprehensive National Cancer Database analysis.

OBJECTIVE: The authors of this study aimed to investigate independent prognostic factors of survival with a particular focus on comparing the safety and efficacy of endoscopic endonasal versus open approaches in the surgical management of skull base chordoma. METHODS: A retrospective National Cancer Database review of skull base chordoma patients was performed to capture resection cases from 2010 to 2020, evaluating overall survival (OS), early postoperative mortality, readmission rates, and hospital length of stay (LOS) between surgical approaches and the independent prognostication of death utilizing Cox multivariate regression analysis. RESULTS: Among the 736 patients included in the cohort, 456 patients (62.0%) and 280 patients (38.0%) underwent endoscopic endonasal and open resection, respectively. These values represent a rate of change over the study period of +4.1 versus -0.14 cases per year, respectively. Gross-total resection was achieved in 32.5% of cases. A positive margin status was found in 51.8% of cases. There was no association between extent of resection and surgical approach (p = 0.257). There was no difference in OS (p = 0.562), 30- and 90-day mortality (p = 0.209 and 0.126, respectively), and 30-day readmission (p = 0.438) between the two surgical groups. The mean LOS was reduced by 2.1 days in the endoscopic cohort (p = 0.013) compared with the open approach cohort. Finally, multivariate analysis revealed a tumor size ≥ 4 cm (HR 4.03, p = 0.005) and public insurance (HR 2.76, p = 0.004) as negative predictors of survival and treatment at an academic center (HR 0.36, p = 0.043) as a positive prognosticator of survival. CONCLUSIONS: The endoscopic endonasal approach has been increasingly utilized over time and touts noninferiority with respect to safety and efficacy with a marked improvement in LOS, which carries substantial implications for both healthcare costs and enhanced patient recovery. Future prospective studies are necessary to further delineate trends and surgical outcomes for skull base chordoma.

Special Considerations in Pediatric Endoscopic Skull Base Surgery.

Originally pioneered in adults, endoscopic endonasal approaches for skull base pathology are being increasingly applied as a minimally invasive alternative for young children. Intrinsic anatomic differences between these patient populations have sparked discussions on the feasibility, safety, and efficacy of these techniques in pediatric patients. This work aims to serve as a primer for clinicians engaged in the rapidly evolving field of pediatric endoscopic skull base surgery. A succinct overview of relevant embryology, sinonasal anatomy, and diagnostic workup is presented to emphasize key differences and unique technical considerations. Additional discussions regarding select skull base lesions, reconstructive paradigms, potential surgical complications, and postoperative care are also highlighted in the setting of multidisciplinary teams.

A bacterial toxin co-opts caspase-3 to disable active gasdermin D and limit macrophage pyroptosis.

During infections, host cells are exposed to pathogen-associated molecular patterns (PAMPs) and virulence factors that stimulate multiple signaling pathways that interact additively, synergistically, or antagonistically. The net effect of such higher-order interactions is a vital determinant of the outcome of host-pathogen interactions. Here, we demonstrate one such complex interplay between bacterial exotoxin- and PAMP-induced innate immune pathways. We show that two caspases activated during enterohemorrhagic Escherichia coli (EHEC) infection by lipopolysaccharide (LPS) and Shiga toxin (Stx) interact in a functionally antagonistic manner; cytosolic LPS-activated caspase-11 cleaves full-length gasdermin D (GSDMD), generating an active pore-forming N-terminal fragment (NT-GSDMD); subsequently, caspase-3 activated by EHEC Stx cleaves the caspase-11-generated NT-GSDMD to render it nonfunctional, thereby inhibiting pyroptosis and interleukin-1ß maturation. Bacteria typically subvert inflammasomes by targeting upstream components such as NLR sensors or full-length GSDMD but not active NT-GSDMD. Thus, our findings uncover a distinct immune evasion strategy where a bacterial toxin disables active NT-GSDMD by co-opting caspase-3.

Biologic Therapy in Pediatric Chronic Rhinosinusitis: A Systematic Review.

OBJECTIVE: Provide clinicians with current evidence for biologic therapy in children with chronic rhinosinusitis with nasal polyposis (CRSwNP). DATA SOURCES: PubMed, MEDLINE, Cochrane, and clinical trial registries. REVIEW METHODS: Key search terms related to biologic therapy in pediatric CRSwNP were identified via a structured query of current medical literature and clinical trial databases. CONCLUSIONS: There is a dearth of active clinical trials and research studies for biologics targeting pediatric CRSwNP. There is an ongoing compassionate-use clinical trial involving Dupilumab for children with nasal polyps as well as only 1 published work specifically focused on Dupilumab for pediatric CRSwNP in the setting of aspirin-exacerbated respiratory disease. IMPLICATIONS FOR PRACTICE: For children with atopic dermatitis, asthma, and chronic idiopathic urticaria, biologic therapies such as Omalizumab, Dupilumab, and Mepolizumab have gained Food and Drug Administration approval. The role of biologic therapy in pediatric CRSwNP demonstrates significant promise in the comprehensive management of the unified airway. Additional Phase III trials are necessary to broaden clinical indications for children with comorbid conditions and complex sinonasal disease.

The impact of menarche on hippocampal mechanisms of severity of psychotic-like experiences in the ABCD study.

Accumulating evidence suggests that estrogens play an important modulatory role in the pathogenesis of psychosis. Estrogens come online within a dynamic developmental context of emerging psychopathology and neurodevelopment. As a result, estradiol (the primary form of estrogen) may influence psychosis lability directly or indirectly through its neurodevelopmental influence on estrogens-sensitive areas like the hippocampus. Understanding this influence may provide novel insight into mechanisms of psychosis lability. This study included baseline and year 2 timepoints from 4422 female participants from the Adolescent Brain Cognitive Development (ABCD) study (age 8-13), who varied in estradiol availability (pre-menarche, post-menarche, pre- and post-menarche timepoints). Estradiol availability was related to psychotic-like experiences (PLE) severity both directly and as an interactive effect with hippocampal connectivity using menarche status (pre/post) in a multilevel model. PLE severity was highest in individuals with early menarche emphasizing the importance of the developmental timing. Although PLE severity decreased over time in the sample, it stayed clinically-relevant over 2 years. Lower hippocampal connectivity was related to elevated PLE severity. This effect was moderated by estradiol; before the availability of estradiol (pre-menarche), lower hippocampal connectivity significantly contributed to the PLE severity, but when estradiol was available (post-menarche) hippocampal dysconnectivity did not account for PLE severity. This moderation suggests that the estrodiol's influence on hippocampal plasticity also reduced the mechanistic role of the hippocampus on PLE severity. Further, the lack of a significant direct reduction of PLE severity post-menarche, may suggest an increased role for other interacting psychosis lability factors during this critical developmental period.

Surgical Complexity and Physician Workload in Craniofacial Surgery: Do RVUs Need to be Adjusted?

RVU valuations need to be revisited regularly as procedure complexity and patient care pathways continue to evolve. The NSQIP-P database was queried for craniofacial procedures performed in North America between 2012 and 2019. Multivariate regression was performed to determine correlation coefficients of perioperative variables deemed to reflect procedure severity, including procedure duration, blood transfusion, length of stay, serious adverse events, related readmission, and related reoperation. CPT 21159 Le Fort III with forehead advancement remains the craniofacial procedure with the highest RVUs using our model at 33.93 units. The most underestimated procedure is CPT 42235 Repair of anterior palate, including vomer flap, with a suggested change of +8.27 units, which is a 194% increase from current compensation. Adjusted RVUs based on quantitative and nationally representative perioperative variables that reflect procedure severity might be a better alternative for procedure valuation over current survey methods to determine appropriate insurance compensation.

To study the expression of estrogen, progesterone receptor and p53 immunohistochemistry markers in subtyping endometrial carcinoma.

Background: Endometrial cancer is one of the most commonly diagnosed cancers in women worldwide. Aim and Objectives: To study the expression of estrogen receptor (ER), progesterone receptor (PR) and p53 immunohistochemistry (IHC) markers in subtyping endometrial carcinoma. Materials and Methods: A total of 100 cases of carcinoma endometrium submitted during January 2016 to October 2018 were included in our study. The ER, PR and p53 expressions were scored as per the adopted scoring system. Agreement between ER, PR and p53 IHC expression and the consensus HE diagnosis, FIGO grading and tumour staging were assessed using Chi square tests. Results: There was a statistical association between ER, PR and p53 status and tumour histologic type with a P value < 0.01. There was no statistical significance observed between ER and PR expressions and different FIGO grades. Statistical significance (P = 0.036) between p53 and different FIGO grades seen. No statistical significance was observed between ER, PR and p53 expressions and different tumour stages and tumour invasiveness. There was a statistical association between ER and PR status and lymph node metastasis. p53 did not show a statistical significance. Conclusion: Combination of ER, PR and p53 IHC markers can be used to distinguish type 1 and type 2 endometrial cancers. PR expression is more specific than ER in endometrioid carcinomas. p53 expression is more specific in serous carcinoma, however, p53 IHC alone cannot be used to distinguish different grades of endometrioid carcinomas as there is variability of staining in endometrioid carcinomas.

Chordoma: A Comprehensive Systematic Review of Clinical Trials.

This systematic review aims to characterize ongoing clinical trials and therapeutic treatment options for chordoma, a rare notochordal remnant tumor that primarily affects the cranial base, mobile spine, and sacrum. While radical surgical resection remains the cornerstone for chordoma management, unique technical challenges posed by its proximity to critical neurovascular structures confer a tendency towards disease recurrence which often requires additional treatment modalities. In an attempt to better understand the current treatment landscape, a systematic review was designed to identify clinical trials directed at chordoma. A total of 108 chordoma trials were identified from four clinical trial databases; fifty-one trials were included in the final analysis, of which only 14 were designated as completed (27.5%). Aggregate data suggests most chordoma interventions are repurposed from other neoplasms that share common molecular pathways, with a recent emphasis on combination therapeutics within and across drug classes. Naturally, the publication and dissemination of clinical trial results remain a concern (n = 4, 28.6%), highlighting the need for enhanced reporting and transparency measures. Active clinical trial efforts are quite promising, with a renewed focus on novel biotherapeutic targets and deciphering the natural history, as well as survivorship of this complex disease.

Trigeminal Schwannoma: A Retrospective Analysis of Endoscopic Endonasal Management, Treatment Outcomes, and Neuropathic Sequelae.

Introduction Trigeminal schwannomas (TS) are rare skull base tumors that have been associated with significant neuropathic sequalae for patients. The authors aim to evaluate the clinical features, treatment outcomes, and neuropathic sequelae following endoscopic endonasal approach (EEA) for TS. Methods The study involves a retrospective review of patients who underwent EEA for resection of TS at a single academic institution between 2004 and 2020. Radiographic and clinical data were recorded and analyzed. Results A total of 16 patients were abstracted, with a mean age at the time of surgery of 44 years with a slight female (1.83:1) predominance. Primary preoperative symptomatology included facial pain/neuralgia ( n = 5, 31.3%), facial hypoesthesia ( n = 4, 25.0%), and headache ( n = 4, 25.0%). Following TS resection, patients were found to have facial hypoesthesia ( n = 11, 68.8%), neuropathic keratopathy ( n = 4, 25.0%), and mastication musculature atrophy ( n = 3, 18.8%). Patients with preoperative facial pain/neuralgia ( n = 5, 31.3%) were significantly more likely to try adjunctive pain therapies ( p = 0.018) as well as seek pain consultation ( p = 0.018). Patients with preoperative migraines ( n = 2, 12.5%) were significantly more likely to trial adjunctive pain therapies ( p = 0.025) and undergo evaluation with pain specialists ( p = 0.025). Finally, patients with preoperative pharmacologic agent utilization were significantly more likely to trial adjunctive pain therapies ( p = 0.036) and pursue pain consultation ( p = 0.036). Conclusion Some degree of trigeminal dysfunction may be more common than previously reported following EEA for TS resection. Factors that appear to play a role in the development of trigeminal dysfunction include pre-existing pain syndromes such as facial pain/neuralgia or headache and preoperative medication utilization.

Pediatric Spontaneous Cerebrospinal Fluid Leak Repair: An Endoscopic Endonasal Approach.

Background: Spontaneous cerebrospinal fluid (CSF) rhinorrhea in the pediatric population is an exceedingly rare condition that occurs when the dura mater is breached, resulting in CSF drainage from the subarachnoid space into surrounding sinonasal tissue. Objective: This work delineates a step-by-step surgical approach to visually demonstrate the feasibility of an uninarial endoscopic endonasal approach for pediatric spontaneous CSF leak repair. Postoperative Outcome: A 2-year-old male with a 6-month history of clear rhinorrhea, intermittent headaches, and a previous episode of bacterial meningitis was evaluated as an inpatient consultation. Computed tomography cisternography revealed active CSF extravasation at the right sphenoid sinus roof. An endoscopic endonasal approach was performed including a complete sphenoethmoidectomy plus middle turbinectomy to provide access to the skull base defect. Once identified, a middle turbinate free mucosal graft was placed for cranial base reconstruction given the child's young agre. Sinonasal debridement 3 weeks following surgery under anesthesia revealed an intact viable graft with no evidence of CSF leak. There was no evidence of CSF leak recurrence or complications 1 year following surgery. Conclusion: The uninarial endoscopic endonasal approach is a safe and effective option for the surgical management of spontaneous CSF leak rhinorrhea in the pediatric population.

Pyroptosis-induced inflammation and tissue damage.

Pyroptosis is a programmed necrotic cell death executed by gasdermins, a family of pore-forming proteins. The cleavage of gasdermins by specific proteases enables their pore-forming activity. The activation of the prototype member of the gasdermin family, gasdermin D (GSDMD), is linked to innate immune monitoring by inflammasomes. Additional gasdermins such as GSDMA, GSDMB, GSDMC, and GSDME are activated by inflammasome-independent mechanisms. Pyroptosis is emerging as a key host defense strategy against pathogens. However, excessive pyroptosis causes cytokine storm and detrimental inflammation leading to tissue damage and organ dysfunction. Consequently, dysregulated pyroptotic responses contribute to the pathogenesis of various diseases, including sepsis, atherosclerosis, acute respiratory distress syndrome, and neurodegenerative disorders. This review will discuss the inflammatory consequences of pyroptosis and the mechanisms of pyroptosis-induced tissue damage and disease pathogenesis.

Otologic use of porcine small intestinal submucosal graft (biodesign): A MAUDE database review.

OBJECTIVE: To review and summarize reported adverse events related to the use of porcine small intestine submucosal grafts (Biodesign™) in otologic procedures. STUDY DESIGN: Retrospective cross-sectional analysis. SETTING: Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database. MATERIAL AND METHODS: The MAUDE database was queried for all medical device reports (MDR) related to otologic use of Biodesign™ (Cook Medical, Bloomington, IN) from January 2016 to November 2022. Adverse events (AEs) were identified by reviewing all reports with the basic search term "Biodesign" and "Biodesign, Otologic". Reports were individually reviewed and categorized with special attention to AEs. RESULTS: A total of 500 reports were reviewed. Since FDA approval of Biodesign™ in 2016, there have been 5 adverse events reported for use of Biodesign™ during otologic surgery (tympanoplasty, n = 3; stapes surgery, n = 2). All reported events described patient injury, and all cases required at least one revision surgery. Four cases described significant foreign body inflammatory reactions. Complications included hearing loss (n = 3), severe otalgia (n = 2), persistent perforation (n = 2), vertigo (n = 2), and facial paralysis (n = 1). CONCLUSION: The use of porcine small intestinal submucosal graft has been thought to be a safe and effective option for otologic surgery, with the advantage of availability without graft harvest in minimally invasive endoscopic surgery. However, foreign body or granulomatous reactions have been documented and should be considered prior to its use in otologic surgery.

Dual Option Microtia Clinic: A Comparison of Outcomes in Microtia Reconstruction Using Autologous Rib or Porous Polyethylene Implant.

Introduction: Auricular reconstruction techniques most frequently utilize either autologous costal cartilage or alloplastic porous polyethylene (PPE) implant. Objectives: To compare the aesthetic outcomes, number of surgeries, and complications in children who underwent microtia reconstruction with either rib or PPE implant by blinded photograph review. Methods: This retrospective cohort study included consecutive pediatric patients who underwent auricular reconstruction with either autologous cartilage or PPE between November 2017 and February 2022. Blinded observers rated each postoperative ear through a web-based survey. Data on patient characteristics, operative time, length of admission, and complications were collected, bivariate analyses were performed using chi-square or Fisher's exact tests for categorical variables and Wilcoxon rank-sum test for continuous variables. Results: Forty-four ears were included, 28 of which (63.6%) were reconstructed with cartilage. Median patient age was 8 years (range 4-18 years) and 29 (65.9%) were male. The cartilage group had more surgeries (median 2.5 vs. 1.0, p < 0.001), and total operating time across all surgeries did not differ significantly. Conclusion: The two groups in our study had similar rates of complications and aesthetic scores, and aesthetic scores were worse for ears with wound complications requiring unplanned revisions.

Fat-free mass accounts for most of the variance in alcohol elimination rate in women.

BACKGROUND: Understanding how blood alcohol concentrations (BAC) achieved after drinking are determined is critical to predicting alcohol exposure to the brain and other organs and alcohol's effects. However, predicting end-organ exposures is challenging, as there is wide variation in BAC achieved after drinking a specified volume of alcohol. This variation is partly due to differences in body composition and alcohol elimination rates (AER), but there are limited data on how obesity affects AER. Here, we assess associations between obesity, fat-free mass (FFM), and AER in women and examine whether bariatric surgeries, which are linked to an increased risk of alcohol misuse, affect these associations. METHODS: We analyzed data from three studies that used similar intravenous alcohol clamping procedures to estimate AER in 143 women (21 to 64 years old) with a wide range of body mass index (BMI; 18.5 to 48.4 kg/m2 ). Body composition was measured in a subgroup using dual-energy X-ray absorptiometry (n = 42) or Bioimpedance (n = 60), and 19 of the women underwent bariatric surgery 2.1 ± 0.3 years before participation. We analyzed data using multiple linear regression analyses. RESULTS: Obesity and older age were associated with a faster AER (BMI: rs  = 0.70 and age: rs  = 0.61, both p < 0.001). Compared to women with normal weight, AER was 52% faster (95% Confidence Interval: 42% to 61%) in women with obesity. However, BMI lost predictive value when adding fat-free mass (FFM) to the regression model. Age, FFM, and its interaction explained 72% of individual variance in AER (F (4, 97) = 64.3, p < 0.001). AER was faster in women with higher FFM, particularly women in the top tertile of age. After controlling for FFM and age, bariatric surgery was not associated with differences in AER (p = 0.74). CONCLUSIONS: Obesity is associated with a faster AER, but this association is mediated by an obesity-related increase in FFM, particularly in older women. Previous findings of a reduced alcohol clearance following bariatric surgery compared with prior to surgery are likely explained by a reduction in FFM post-surgery.

CD169+ macrophage intrinsic IL-10 production regulates immune homeostasis during sepsis.

Macrophages facilitate critical functions in regulating pathogen clearance and immune homeostasis in tissues. The remarkable functional diversity exhibited by macrophage subsets is dependent on tissue environment and the nature of the pathological insult. Our current knowledge of the mechanisms that regulate the multifaceted counter-inflammatory responses mediated by macrophages remains incomplete. Here, we report that CD169+ macrophage subsets are necessary for protection under excessive inflammatory conditions. We show that in the absence of these macrophages, even under mild septic conditions, mice fail to survive and exhibit increased production of inflammatory cytokines. Mechanistically, CD169+ macrophages control inflammatory responses via interleukin-10 (IL-10), as CD169+ macrophage-specific deletion of IL-10 was lethal during septic conditions, and recombinant IL-10 treatment reduced lipopolysaccharide (LPS)-induced lethality in mice lacking CD169+ macrophages. Collectively, our findings show a pivotal homeostatic role for CD169+ macrophages and suggest they may serve as an important target for therapy under damaging inflammatory conditions.

Structural basis for GSDMB pore formation and its targeting by IpaH7.8.

Gasdermins (GSDMs) are pore-forming proteins that play critical roles in host defence through pyroptosis1,2. Among GSDMs, GSDMB is unique owing to its distinct lipid-binding profile and a lack of consensus on its pyroptotic potential3-7. Recently, GSDMB was shown to exhibit direct bactericidal activity through its pore-forming activity4. Shigella, an intracellular, human-adapted enteropathogen, evades this GSDMB-mediated host defence by secreting IpaH7.8, a virulence effector that triggers ubiquitination-dependent proteasomal degradation of GSDMB4. Here, we report the cryogenic electron microscopy structures of human GSDMB in complex with Shigella IpaH7.8 and the GSDMB pore. The structure of the GSDMB-IpaH7.8 complex identifies a motif of three negatively charged residues in GSDMB as the structural determinant recognized by IpaH7.8. Human, but not mouse, GSDMD contains this conserved motif, explaining the species specificity of IpaH7.8. The GSDMB pore structure shows the alternative splicing-regulated interdomain linker in GSDMB as a regulator of GSDMB pore formation. GSDMB isoforms with a canonical interdomain linker exhibit normal pyroptotic activity whereas other isoforms exhibit attenuated or no pyroptotic activity. Overall, this work sheds light on the molecular mechanisms of Shigella IpaH7.8 recognition and targeting of GSDMs and shows a structural determinant in GSDMB critical for its pyroptotic activity.

The Transcaruncular Corridor of the Medial Transorbital Approach to the Frontal Lobe: Technical Nuances and Applications.

BACKGROUND AND IMPORTANCE: Medial orbital access through a transcaruncular corridor has yet to be fully characterized as a potential approach to intradural lesions within the skull base. Transorbital approaches present unique potential in the management of complex neurological pathologies and require subspecialty collaboration across multiple disciplines. CLINICAL PRESENTATION: A 62-year-old man presented with progressive confusion and mild left-sided weakness. He was found to have a right frontal lobe mass with significant vasogenic edema. A comprehensive systemic workup was otherwise unremarkable. A multidisciplinary skull base tumor board conference recommended a medial transorbital approach through transcaruncular corridor, which was performed by neurosurgery and oculoplastics services. Postoperative imaging demonstrated gross total resection of the right frontal lobe mass. Histopathologic evaluation was consistent with amelanotic melanoma with BRAF (V600E) mutation. At his last follow-up visit, 3 months after surgery, the patient did not experience any visual symptoms and had an excellent cosmetic outcome after surgery. CONCLUSION: The transcaruncular corridor through a medial transorbital approach provides a safe and reliable access to the anterior cranial fossa.

Postoperative Outcomes in Pediatric Septoplasty.

OBJECTIVE: Identify risk factors and perioperative morbidity for pediatric patients undergoing septoplasty. METHODS: The American College of Surgeons National Surgical Quality Improvement Program Pediatric (NSQIP-P) database was retrospectively queried to identify patients who underwent septoplasty (CPT 30520) for a diagnosis of deviated nasal septum (ICD J34.2) from 2018 to 2019. Outcomes analyzed include patient demographics, medical comorbidities, surgical setting, operative characteristics, length of stay, and postoperative outcomes. RESULTS: A total of 729 children were identified. Median age at time of surgery was 15.8 years, with most patients (82.8%) >12 years of age; no significant association was identified between age at time of surgery and adverse surgical outcomes. Overall, postoperative complications were uncommon (0.6%), including readmission (0.4%), septic shock (0.1%), and surgical site infection (0.1%). A history of asthma was found to be a significant risk factor for postoperative complications (P = .035) as well as BMI (P = .028). CONCLUSION: The 30-day postoperative complications following pediatric septoplasty in children reported in the NSQIP-P database are infrequent. Special considerations regarding young age, complex sinonasal anatomy, and surgical technique remain important features in considering corrective surgery for the pediatric nose and certainly warrant further investigation in subsequent studies.