Search

Glycyrrhizin, a bioactive component of the licorice plant, has recently been revealed to be particularly efficient in suppressing SARS-associated viral replication and reducing the development and cytopathology of herpes simplex virus type I in human aneuploid HEp2 cells. According to the researchers, glycyrrhizin suppressed antigen expression and lowered hepatitis

Purpose To report the poor visual outcome of ruptured globe caused by camel bites. Observations A 48-year-old camel caregiver presented to the emergency department after being bitten by a camel in the left side of his face. Ophthalmic examination revealed a superior scleral wound from 9 to 2 o'clock, about 6 mm from the limbus extending to the equator with prolapse of uveal and vitreous tissues, an opaque cornea, total hyphema, diffuse subconjunctival hemorrhage, and a lower lid laceration involving the lid margin and the nasolacrimal duct. The patient has undergone surgical repairs of ruptured globe and lid laceration, followed by retinal detachment surgery. Following these surgical interventions, the patient preserved a light perception vision with flat retina. Conclusion Camel-related injuries might primarily involve the ophthalmic structures, especially in camel bites. Camel-related eye trauma might lead to poor visual and anatomical outcomes which might not improve following surgical interventions.

To provide a brief overview of the options available for reconstruction of the skull base and to discuss their technical considerations. To review the contemporary literature surrounding adjunctive measures such as acetazolamide and perioperative cerebrospinal fluid (CSF) diversion. A recent randomized, control trial examining perioperative lumbar drainage following endoscopic skull base surgery has demonstrated that perioperative lumbar drainage is significantly associated with decreased incidence of postoperative CSF leak in specific anatomical subsites. Many factors must be weighed when considering proper skull base reconstruction. For large defects, multilayered repair with vascularized tissue is the gold standard. Perioperative lumbar drainage is recommended for large anterior or posterior fossa defects. The effect of acetazolamide on postoperative CSF leak remains unclear. Indocyanine green angiography (ICG) is a promising innovation that can aid in assessment of vascularized flaps.

Objectives: To examine the frequency in which angled endoscopes are necessary to visualize the true maxillary ostium (TMO) following uncinectomy and prior to maxillary antrostomy. Additionally, to identify preoperative computed tomography (CT) measures that predict need for an angled endoscope to visualize the TMO. Study Design: Retrospective study. Setting: Tertiary academic hospital. Patients and Methods: Patients who underwent endoscopic sinus surgery (ESS) between December of 2017 and August of 2018 were retrospectively identified. Cases were reviewed if they were primary ESS cases for chronic rhinosinusitis without polyposis and if they were at least 18 years of age. Results: Sixty-three maxillary antrostomies were reviewed (82.5% were from bilateral cases). Thirty-five cases (55.6%) required an angled endoscope in order to visualize the TMO. Of the preoperative CT measures examined, a smaller sphenoid keel-caudal septum-nasolacrimal duct (SK-CS-NL) angle was significantly associated with need for an angled endoscope intraoperatively to visualize the TMO (17.1° SD ± 3.2 vs 15.0° SD ± 2.9; P = .010). Conclusion: Angled endoscopes are likely required in the majority of maxillary antrostomies to visualize the TMO. This is important to recognize in order to prevent iatrogenic recirculation. The SK-CS-NL angle may help to identify cases preoperatively which require an angled endoscope to identify the TMO during surgery.

BACKGROUNDSevere COVID-19 pneumonia results from a hyperinflammatory immune response (cytokine storm, CS), characterized by GM-CSF mediated activation and trafficking of myeloid cells, leading to elevation of downstream inflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-6, IL-1), and other markers of systemic inflammation (CRP, D-dimer, ferritin). CS leads to fever, hypotension, coagulopathy, respiratory failure, ARDS, and death. Lenzilumab is a novel Humaneered® anti-human GM-CSF monoclonal antibody that directly binds GM-CSF and prevents signaling through its receptor. The LIVE-AIR Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to assess the potential for lenzilumab to improve the likelihood of ventilator-free survival (referred to herein as survival without ventilation, SWOV), beyond standard supportive care, in hospitalized subjects with severe COVID-19.METHODSSubjects with COVID-19 (n=520), ≥18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Subjects were followed through Day 28 following treatment.RESULTSBaseline demographics were comparable between the two treatment groups: male, 64.7%; mean age, 60.5 years; mean BMI, 32.5 kg/m2; mean CRP, 98.36 mg/L; CRP was CONCLUSIONLenzilumab significantly improved SWOV in hospitalized, hypoxic subjects with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Subjects with CRPNCT04351152

OBJECTIVE/HYPOTHESIS Frailty has emerged as a powerful risk stratification tool across surgical specialties; however, an analysis of the impact of frailty on outcomes following skull base surgery has not been published. The aim of this study was to assess the validity of the 5-factor modified frailty index (mFI-5) as a predictor of perioperative morbidity and mortality in patients undergoing skull base surgery. METHODS A mFI-5 score was calculated for patients undergoing skull base surgeries using the National Surgical Quality Improvement Program (NSQIP) database from 2005 to 2018. Multivariate logistic regression analysis was used to evaluate the association of increasing frailty with complications in the 30-day postoperative period, with a subanalysis by operative location. RESULTS A total of 17,912 patients who underwent skull base procedures were identified, with 45.5% of patients having a frailty score of one or greater; 44.9% were male and the mean age was 52.0 (±16.1 SD) years. Multivariable regression analysis revealed frailty to be an independent predictor of overall complications (odds ratio [OR]: 1.325, P

Sleep-disordered breathing (SBD) is an under recognized comorbidity in the cystic fibrosis (CF) population across the lifespan. Nocturnal hypoxemia, obstructive sleep apnea, and nocturnal hypoventilation are respiratory abnormalities that occur commonly during sleep in patients with lung disease, and have deleterious consequences to the quality of life in people with CF. Effective screening for these abnormalities is needed to allow for timely initiation of treatment, which has been reported to be efficacious. Lack of treatment leads to worsened pulmonary, cardiovascular, and metabolic outcomes in patients. In this review, we give an overview of SBD for the CF clinician, including prevalence, treatment, and suggestions for future research. We strongly encourage the CF community to incorporate evaluation for SBD in CF clinical care so that outcomes for the subset of the CF patients with comorbid SBD improve.

Objectives: To compare the diagnostic performance of the Hum Test against the Weber Test using pure tone audiometry (PTA) as the “gold standard” comparator. Methods: 29 participants with normal hearing of ages 18 to 35 without any history of hearing abnormalities or otologic conditions were enrolled. Subjects underwent three tests (Hum Test, Weber Test, and PTA) across two conditions: with an ear plug in one ear (side randomized) and without ear plugs. Results: When examining the ability of the Hum Test to detect simulated conductive hearing loss (CHL), the test had a sensitivity of 89.7% and specificity of 100% with high pitched humming and 93.1% and 100%, respectively, with low pitched humming. The Weber Test had a sensitivity and specificity of 96.6% and 100%, respectively. McNemar’s test demonstrated agreement between the Hum Test, performed with either high pitched ( P = .32) or low pitched ( P = .56) humming, and the Weber Test. Receiver operating characteristic (ROC) curves for the Hum Test (both high and low pitched) and Weber test were compared and demonstrated no statistically significant difference. Conclusion: The Hum Test is comparable to the Weber Test with regards to its sensitivity, specificity, and diagnostic accuracy in assessing new onset unilateral CHL in previously normal hearing subjects.

Objectives/Hypothesis To describe the distribution of recurrent respiratory papillomatosis (RRP) lesions across 21 laryngeal anatomic regions in previously untreated patients at initial presentation to provide insight regarding the natural history of RRP. Study Design Multi-institutional, retrospective case series. Methods Initial laryngoscopic examination videos of 83 previously untreated patients with adult-onset RRP were reviewed. Papilloma locations were recorded using a 21-region laryngeal schematic. Multivariate analyses by anatomic subsite were conducted for the entire population and for subgroups stratified by sex, age, and proton pump inhibitor (PPI) usage. Heat maps were generated, hierarchically color coding the anatomic distribution of disease. Results In this cohort, RRP was most likely to occur on the true vocal folds (TVFs) and anterior commissure (P

Rhinoscopy became a formal field of study in the mid-nineteenth century as improvements in nasal specula were made and the potent vasoconstrictive effects of cocaine on the intranasal tissues were discovered. Since then, a multitude of advances in visualization and illumination have been made. The advent of the Storz-Hopkins endoscope in the mid-twentieth century represents a culmination of efforts spanning nearly 2 centuries, and illumination has evolved concomitantly. The future of endoscopic sinus surgery may integrate developing technologies, such as 3-dimensional endoscopy, augmented reality navigation systems, and robotic endoscope holders.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for pts with R/R LBCL with ≥ 2 prior systemic therapies. With a median follow-up of 27.1 months in ZUMA-1, the objective response rate (ORR) with axi-cel was 83% (58% complete response rate) in pts with refractory LBCL. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 11% and 32% of pts, respectively (Locke FL, et al. LancetOncol. 2019). Although CRS can be ameliorated with use of the anti-IL-6 receptor antibody tocilizumab, NEs may be unaffected or worsened by tocilizumab (Gust J, et al. Cancer Discov. 2017; Lee DW, et al. Blood. 2014; Santomasso BD, et al. Cancer Discov. 2018; Locke FL, et al. ASH 2017. #1547). Identification of mitigation strategies for NEs is complicated by a significant association between CAR T cell expansion and both ORR and Grade ≥ 3 NEs, suggesting a correlation between efficacy and adverse events (AEs; Neelapu SS, et al. N EnglJ Med. 2017). ZUMA-1 Cohort 4 suggested that earlier utilization of systemic corticosteroids for broad immune system suppression in pts with mild NEs and low-grade CRS may reduce the incidence of Grade ≥ 2 NEs without significant impact on efficacy (Topp MS, et al. ASH 2019. #243). However, this reactive approach has not fully abrogated NEs; as such, proactive strategies to further improve safety management with CAR T cell therapy without negatively impacting efficacy are needed. Upon tumor challenge, CAR T cells produce granulocyte-macrophage colony-stimulating factor (GM-CSF; Giavridis T, et al. Nat Med. 2018), which acts to promote myeloid activation, expansion, and cytokine production (Spath S, et al. Immunity. 2017). GM-CSF was among the cytokines significantly associated with Grade ≥ 3 NEs in ZUMA-1 (Neelapu SS, et al. N Engl J Med. 2017). Notably, peak GM-CSF levels occurred before those of most other cytokines, and no direct association was observed between GMCSF levels and ORR (Rossi JM, et al. EMA Workshop, 2016). These findings suggest that GM-CSF may initiate inflammatory events that cause NEs and that GM-CSF inhibition has the potential to improve the safety of CAR T cells, without impacting efficacy. GM-CSF depletion with lenzilumab, a humanized monoclonal antibody that neutralizes GM-CSF, prevented CRS and NEs in preclinical models of CAR T cell toxicity (Sterner RM, et al. Blood2019). The Phase 1/2 ZUMA19 study is evaluating sequenced therapy with lenzilumab and axi-cel to prevent axi-cel-related CRS and NEs in pts with R/R LBCL. Methods: Eligible pts are adults (≥ 18 y) with LBCL who relapsed after ≥ 2 systemic lines of therapy or are chemorefractory - defined as i) a best response of progressive disease (PD) or stable disease (SD) to ≥ 4 cycles of first-line systemic therapy (SD duration ≤ 6 months); or ii) a best response of PD or SD after ≥ 2 cycles of the most recent second-or-later line of systemic therapy. Prior therapy must have included an anti-CD20 monoclonal antibody and an anthracycline-containing regimen. Pts will undergo leukapheresis and may receive optional corticosteroid bridging therapy. Pts will then receive lymphodepleting chemotherapy on Days ‒3 to ‒5 followed by Day 0 administration of lenzilumab and, 6 hours later, a single infusion of axi-cel (target dose, 2 × 106 CAR T cells/kg). Phase 1 will initially enroll pts in 2 dose-escalation cohorts; each will receive a single infusion of lenzilumab. Safety data will be reviewed after 3 and 6 (if needed) pts in each cohort have been followed for 28 days. The recommended Phase 2 dose (RP2D) of lenzilumab will be based on the dose-limiting toxicity rate (phase 1 primary endpoint), and, if necessary, translational assessment of GM-CSF axis suppression. Phase 2 will assume a Simon 2-stage design. The primary endpoint for phase 2 is the incidence of Grade ≥ 2 NEs within 28 days of axi-cel administration. Efficacy, safety (including CRS and NEs), and blood levels of CAR T cells and cytokines (including GM-CSF) will be evaluated as secondary endpoints. An interim analysis will be performed when 14 subjects have received the RP2D in Phase 1 or 2 and are followed for ≥ 28 days after axi-cel infusion. If futility criteria are not met, enrollment will continue. Primary analysis will be performed after 30 pts are treated with RP2D of lenzilumab and have ≥ 6 months of follow up. ZUMA-19 is open and actively recruiting pts. Disclosures Kenderian: Mettaforge: Patents & Royalties; Humanigen: Consultancy, Patents & Royalties, Research Funding; Lentigen: Research Funding; MorphoSys: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; BMS: Research Funding; Juno: Research Funding; Gilead: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy. Oluwole:Bayer: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy. McCarthy:Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Reshef:Celgene: Consultancy; Pharmacyclics: Research Funding; Shire: Research Funding; Bluebird: Research Funding; Kiadis: Research Funding; Monsanto: Consultancy; Takeda: Research Funding; Atara: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Research Funding; Immatics: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria; Magenta: Consultancy. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Ahmed:Humanigen, Inc.: Current Employment, Current equity holder in publicly-traded company. Le Gall:Kite, a Gilead Company: Ended employment in the past 24 months; Gilead Sciences: Current equity holder in publicly-traded company. Nahas:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Tang:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Neelapu:Takeda Pharmaceuticals: Patents & Royalties; Cellectis: Research Funding; Calibr: Other; Precision Biosciences: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Acerta: Research Funding; Karus Therapeutics: Research Funding; Poseida: Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding; N/A: Other; Adicet Bio: Other; Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees.

Introduction Despite the remarkable activity of CD19 directed chimeric antigen receptor T cell (CART19) therapy in the treatment of B cell malignancies, limitations include neurotoxicity (NT) and cytokine release syndrome (CRS). Emerging literature suggests that inhibitory myeloid cells and their cytokines induce CAR-T cell toxicities and inhibit effector functions. GM-CSF was specifically identified as a critical cytokine in the development of NT and CRS. Neutralization of GM-CSF in preclinical models has been shown to prevent CRS, enhance CART anti-tumor activity, and reduce the presence of tumor associated macrophages. In addition, there appears to be a direct effect on CART19 cells. Objectives In this study, we aimed to evaluate the direct effect of GM-CSF on CART cells. Methods We used a guide RNA (gRNA) targeting exon 3 of GM-CSF in a CRISPR-Cas9 lentiviral vector to knock out GM-CSF during CART cell manufacturing. Edited and wildtype T cells and CART cells were sent for whole exome sequencing (WES) and RNA sequencing. We also used flow cytometry to assess the expression of GM-CSF receptors on CART cells, activated using CD3/CD28 beads or irradiated NALM6 cells. Results WES analysis revealed no significant difference in the single nucleotide variants or indel counts between GM-CSFk/o and GM-CSFwt CART19 (Fig 1A). WES was significant for only two alterations in the gene targeted by the gRNA (Fig 1B). This high efficiency and accuracy indicated that the improvement in CART function is unlikely related to an off-target effect of the gRNA and suggests a direct interaction between GM-CSF and CART cells as a potential mechanism behind the improved anti-tumor activity. Further investigation robustly indicates that while resting CART cells do not express any GM-CSF receptors, activated CART cells significantly upregulate both α and β subunits of the GM-CSF receptor. This finding was significant both when CART cells were activated through their T cell receptor (Fig 1C) or CAR (Fig 1D). This was also seen in GM-CSFk/o CART19 cells, indicating this is specifically induced by T cell stimulation. These data suggest a direct interaction between GM-CSF and upregulated GM-CSFR on activated CART cells. Finally, we sought to uncover the downstream changes resulting from this effect. Transcriptome interrogation of GM-CSFk/o CART19 revealed a distinct signature, including significant inhibition of the Fas death pathway (Fig 1E). This suggests a potential mechanism for enhanced CART19 activity following GM-CSF depletion. Conclusion Our results strongly indicate that CART cells increase expression of GM-CSF receptor subunits when activated, resulting in modulation of CART cell functions. Furthermore, GM-CSFk/o CART19 revealed a distinct transcriptome signature compared to GM-CSFwt CART19. These results illuminate a novel mechanism for a direct modulatory effect of GM-CSF on activated CART cells.

Data on health care disparities by socioeconomic status for chronic rhinosinusitis (CRS) are lacking, and the available literature shows mixed results. The aim of this study was to evaluate several indicators of disease complexity in patients with CRS undergoing endoscopic sinus surgery between a private and a public hospital to determine if there are any disparities in the severity of disease presentation or in access to care.Two hundred patients with CRS who underwent endoscopic sinus surgery from 2015 to 2017 were retrospectively reviewed. Demographics, disease-specific data, and pre- and postoperative management were collected.Public hospital patients (n = 100) were significantly more likely to be non-Caucasian (73.0% vs 25.0%, P.0001) and to have Medicaid or no insurance (86.0% vs 4.0%, P.0001). Patients from the public hospital were more likely to have CRS with nasal polyposis (85.0% vs 60.0%, P.0001) and to have longer wait times for surgery (68 vs 45 days, P.0001) and were more likely to be lost to follow-up (26.0% vs 16.0%, P = .031). Patients at the public hospital had CRS symptoms 21% longer ( P = .0206), and if a patient carried a diagnosis of asthma, he or she had on average more severe asthma ( P = .0021).This study suggests that patients of lower socioeconomic status had a longer duration of disease prior to surgery, more often had nasal polyposis, and had decreased access to care, as indicated by increased surgical wait times and being lost to follow-up. Acting as a foundation for further investigation, the ultimate intent of this study is to improve care for all patients.

Objectives: Standards of care for total laryngectomy (TL) patients in the postoperative period have not been established. Perioperative care remains highly variable and perhaps primarily anecdotally based. The aim of this study was to survey members of the American Head and Neck Society to capture management practices in the perioperative care of TL patients. Methods: In this survey study, an electronic survey was distributed to the international attending physician body of the American Head and Neck Society. Forty-five-question electronic surveys were distributed. A total of 777 members were invited to respond, of whom 177 (22.8%) fully completed the survey. The survey elicited information on management preferences in the perioperative care of TL patients. Differences in management on the basis of irradiation status and pharyngeal repair (primary closure vs regional or free flap reconstruction) were ascertained. Main outcomes and measures were time to initiate oral feeding, perioperative antibiotic selection and duration, and estimated pharyngocutaneous fistula rates. These measures were stratified by patient type. Results: Most respondents completed head and neck fellowships (77.0%) and practice at academic tertiary centers (72.3%). Ampicillin/sulbactam was the most preferred perioperative antibiotic (43.2%-49.1% depending on patient type), followed by cefazolin and metronidazole in combination (32.0%-33.7%) and then clindamycin (10.8%-12.6%). Compared with nonirradiated patients, irradiated patients were significantly more likely to have longer durations of antibiotics ( P < .05), longer postoperative times to initiate oral feeding ( P < .05), and higher estimated fistula rates ( P < .05). Additionally, in nonirradiated patients, flap-repaired patients (vs primary repair) were significantly more likely to have longer durations of antibiotics (odds ratio, 1.29; 95% confidence interval, 1.13-1.48) and postoperative times to initiate oral feeding (odds ratio, 2.24; 95% confidence interval, 1.76-2.84). Conclusions: Perioperative management of TL patients is highly variable. Management of antibiotics and oral feeding are significantly affected by irradiation status and scope of pharyngeal repair. Further studies are needed to standardize perioperative care for this unique patient population.

Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell–associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF–deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.

Objective Perioperative lumbar drain (LD) use in the setting of endoscopic cerebrospinal fluid (CSF) leak repair is a well-established practice. However, recent data suggest that LDs may not provide significant benefit and may thus confer unnecessary risk. To examine this, we conducted a meta-analysis to investigate the effect of LDs on postoperative CSF leak recurrence following endoscopic repair of CSF rhinorrhea. Data Sources A comprehensive search was performed with the following databases: Ovid MEDLINE (1947 to November 2015), EMBASE (1974 to November 2015), Cochrane Review, and PubMed (1990 to November 2015). Review Method A meta-analysis was performed according to PRISMA guidelines. Results A total of 1314 nonduplicate studies were identified in our search. Twelve articles comprising 508 cases met inclusion criteria. Overall, use of LDs was not associated with significantly lower postoperative CSF leak recurrence rates following endoscopic repair of CSF rhinorrhea (odds ratio: 0.89, 95% confidence interval: 0.40-1.95) as compared with cases performed without LDs. Subgroup analysis of only CSF leaks associated with anterior skull base resections (6 studies, 153 cases) also demonstrated that lumbar drainage did not significantly affect rates of successful repair (odds ratio: 2.67, 95% confidence interval: 0.64-11.10). Conclusions There is insufficient evidence to support that adjunctive lumbar drainage significantly reduces postoperative CSF leak recurrence in patients undergoing endoscopic CSF leak repair. Subgroup analysis examining only those patients whose CSF leaks were associated with anterior skull base resections demonstrated similar results. More level 1 and 2 studies are needed to further investigate the efficacy of LDs, particularly in the setting of patients at high risk for CSF leak recurrence.

OBJECTIVES/HYPOTHESIS To develop a clinically relevant model of oropharyngeal concurrent chemoradiation therapy (CCRT) in order to quantify the effects of CCRT on tongue function and structure. CCRT for advanced oropharyngeal cancer commonly leads to tongue base dysfunction and dysphagia. However, no preclinical models currently exist to study the pathophysiology of CCRT-related morbidity, thereby inhibiting the development of targeted therapeutics. STUDY DESIGN Animal model. METHODS Twenty-one male Sprague-Dawley rats were randomized into three groups: 2 week (2W), 5 month (5M), and control (C). The 2W and 5M animals received cisplatin, 5-fluorouracil, and five fractions of 7 Gy to the tongue base; the C animals received no intervention. In vivo tongue strength and displacement, as well as hyoglossus muscle collagen content, were assessed. Analyses were conducted 2 weeks or 5 months following completion of CCRT in the 2W and 5M groups, respectively. RESULTS Peak tetanic and twitch tongue forces were significantly reduced in both 2W and 5M animals compared to controls (tetanic: P = .0041, P = .0089, respectively; twitch: P = .0201, P = .0020, respectively). Twitch half-decay time was prolonged in 2W animals compared to controls (P = .0247). Tongue displacement was significantly reduced across all testing parameters in 5M animals compared to both the C and 2W groups. No differences in collagen content were observed between experimental groups. CONCLUSIONS The current study is the first to describe a preclinical model of CCRT to the head and neck with an emphasis on clinical relevance. Tongue strength decreased at 2 weeks and 5 months post-CCRT. Tongue displacement increased only at 5 months post-CCRT. Fibrosis was not detected, implicating alternative causative factors for these findings. LEVEL OF EVIDENCE NA Laryngoscope, 1783-1790, 2018.

Rhinoscopy became a formal field of study in the mid-nineteenth century as improvements in nasal specula were made and the potent vasoconstrictive effects of cocaine on the intranasal tissues were discovered. Since then, a multitude of advances in visualization and illumination have been made. The advent of the Storz-Hopkins endoscope in the mid-twentieth century represents a culmination of efforts spanning nearly 2 centuries, and illumination has evolved concomitantly. The future of endoscopic sinus surgery may integrate developing technologies, such as 3-dimensional endoscopy, augmented reality navigation systems, and robotic endoscope holders.

To describe the distribution of recurrent respiratory papillomatosis (RRP) lesions across 21 laryngeal anatomic regions in previously untreated patients at initial presentation to provide insight regarding the natural history of RRP.Multi-institutional, retrospective case series.Initial laryngoscopic examination videos of 83 previously untreated patients with adult-onset RRP were reviewed. Papilloma locations were recorded using a 21-region laryngeal schematic. Multivariate analyses by anatomic subsite were conducted for the entire population and for subgroups stratified by sex, age, and proton pump inhibitor (PPI) usage. Heat maps were generated, hierarchically color coding the anatomic distribution of disease.In this cohort, RRP was most likely to occur on the true vocal folds (TVFs) and anterior commissure (P .0001, odds ratio [OR]: 7.02); within the TVFs, the membranous vocal folds (MVFs) were most likely to be affected (P .0001, OR: 3.56). The cohort was predominantly male (80.7%); males had a higher average number of affected sites (P = .005) and were more likely to have lesions in any laryngeal subsite (P .0001, OR: 2.88,) compared to females. PPI users were more likely than nonusers to have disease in any laryngeal subsite (P = .0037, OR: 1.62), particularly in the posterior and subglottic regions (P = .0061, OR: 2.53). Age was not correlated with lesion prevalence or distribution.In untreated patients presenting to three laryngology clinics, the MVFs were most likely to be affected by RRP. Males had more anatomic sites affected by papilloma than females. The influence of PPI use on RRP distribution warrants further investigation.4. Laryngoscope, 128:138-143, 2018.

There is no universally accepted quantitative metric that defines the ideal nasal tip rotation and projection.To identify the ideal nasal tip projection (NTP) and rotation by using 3 classic NTP methods (Crumley 1, Crumley 2, and Goode).Lateral facial portraits of normal-appearing white women aged 18 to 25 years were selected from a previously validated and attractiveness-scored database of images. Each image was digitally modified to fit the NTP ideals outlined by the Crumley 1, Crumley 2, and Goode methods with columellar facial angles (rotation metric) of 96°, 101°, 106°, 111°, and 116° (15 modified images per portrait). These variants were incorporated into electronic surveys that were distributed to traditional focus-group and online social-network participants. Analysis was performed using paired comparison analysis, a consumer preference research analytic. The traditional focus-group participants were undergraduate students at the University of California, Irvine, whose online social-network contacts were also used.Mean ranks.There were no significant differences in preference between the traditional focus-group (n = 106) and online participants (n = 3872) (P .05). The most preferred rotation variant for all 3 NTP methods was 106° (Crumley 1: mean rank, 2.11 [95% CI, 2.07-2.16]; Crumley 2: mean rank, 2.07 [95% CI, 2.02-2.12]; and Goode: mean rank, 2.05 [95% CI, 1.99-2.11]; P .001). Crumley 1 was considered to be the most attractive NTP method (mean rank, 1.84 [95% CI, 1.82-1.85]; P .001) overall and was the most preferred NTP method for faces of above-average attractiveness (mean rank, 1.78 [95% CI, 1.76-1.80]; P .001). No significantly preferred NTP method was found for faces of average attractiveness (P .05). The most aesthetic combination of tip rotation and projection was a columellar facial angle of 106° with the Crumley 1 tip projection.To our knowledge, this is the first population-based study to attempt to simultaneously determine the ideal NTP and rotation. Each classic NTP method uses measurements dependent on both projection and rotation; thus, ideal rotation for each NTP method must be determined before comparison of the ideals. A rotation of 106° (columellar facial angle) was found to be the most aesthetic. The Crumley 1 method was determined to be the most attractive nasal tip variant overall.NA.

Despite the remarkable activity of CD19 directed chimeric antigen receptor T cell (CART19) therapy in the treatment of B cell malignancies, the therapy is limited by the development of severe life-threatening complications such as neurotoxicity (NT) and cytokine release syndrome (CRS). Additionally, durable efficacy following CART19 therapy is not optimal. Emerging literature suggests that inhibitory myeloid cells and their cytokines play an important role in inducing CAR-T cell toxicities and also contribute to the inhibition of their effector functions. Specifically, GM-CSF was identified as a critical cytokine in the development of NT and CRS after CART19 therapy. Neutralization of GM-CSF in preclinical models has been shown to prevent CRS and enhance CART anti-tumor activity through modulation of myeloid cell behavior, resulting in reduction of tumor associated macrophages. In addition to the predominant effect of GM-CSF on myeloid cells, there appears to be a direct effect on CART19 cells. In this study, we aimed to evaluate the direct effect of GM-CSF on CART cells. Our initial finding of enhanced anti-tumor activity of CART19 cells after GM-CSF inhibition suggested a direct effect of GM-CSF on CART cells (Sterner et al. 2019, Blood). In these experiments, a guide RNA (gRNA) targeting exon 3 of GM-CSF in a CRISPR-Cas9 lentiviral vector was used to knock out GM-CSF during CART cell manufacturing. This resulted in a disruption efficiency of approximately 70% of the GM-CSF gene. Using a high tumor burden xenograft model for relapsed acute lymphoblastic leukemia established through the engraftment of the CD19+ luciferase+ NALM6 cell line (1x106 cells intravenously) in immunocompromised NOD-SCID-γ-/- mice, treatment with low doses of GM-CSFk/o CART19 resulted in improved anti-tumor activity and overall survival compared to GM-CSFwt CART19. The lack of myeloid cells in this model pointed to an intrinsic effect of GM-CSF on CAR-T cells. To ensure that this was not related to an off-target effect of the gRNA, whole exome sequencing (WES) of the modified cells was performed. There was no difference in the single nucleotide variants or indel counts between GM-CSFk/o CART19 and GM-CSFwt CART19 (Figure 1A). WES was significant for only two alterations in the exon 3 targeted by the gRNA (Figure 1B). The high efficiency and accuracy of targeting exon 3 of GM-CSF indicated that the improvement in CART function is unlikely related to an off-target effect of the gRNA and suggested the possibility of a direct interaction between GM-CSF and CART cells as a potential mechanism behind the improved anti-tumor activity. To investigate this interaction, we first assessed the expression of GM-CSF receptors on CART cells. While resting CART cells do not express any GM-CSF receptors, our analysis robustly indicates that activated CART cells significantly upregulate both α and β subunits of the GM-CSF receptor. This finding was significant both when CART cells are activated through their T cell receptor with CD3/CD28 beads (Figure 1C) or through the CAR with irradiated NALM6 cells (Figure 1D). Additionally, activated GM-CSFk/o CART19 cells also upregulated GM-CSF receptors, indicating this upregulation is induced by T cell stimulation. These results suggest a direct interaction between GM-CSF and upregulated GM-CSFR on activated CART cells. Having demonstrated that 1) GM-CSF depletion enhances CART19 efficacy in xenograft models in the absence of monocytes and 2) T cell activation increases GM-CSF receptor expression, we sought to uncover the downstream changes resulting from this effect. Transcriptome interrogation of GM-CSFk/o CART19 revealed a distinct signature including a significant inhibition of the Fas death pathway, a known critical pathway in inducing CART cell apoptosis. This suggests a potential mechanism for enhanced CART19 activity following GM-CSF depletion (Figure 1E). In summary, our results strongly indicate that CART cells increase expression of GM-CSF receptor subunits when activated, resulting in modulation of CART cell functions. Furthermore, GM-CSFk/o CART19 revealed a distinct transcriptome signature compared to GM-CSFwt CART19. These results illuminate a novel mechanism for a direct modulatory effect of GM-CSF on activated CART cells. Disclosures Cox: Humanigen: Patents & Royalties. Sterner:Humanigen: Patents & Royalties. Sakemura:Humanigen: Patents & Royalties. Ahmed:Humanigen: Employment. Chappell:Humanigen: Employment. Durrant:Humanigen: Employment. Parikh:Acerta Pharma: Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Lentigen: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Kite/Gilead: Research Funding; Morphosys: Research Funding.

Chimeric antigen receptor T-cell therapy (CART) is limited by the development of cytokine release syndrome (CRS) and neurotoxicity (NT). CRS is related to extreme elevation of cytokines and massive T cell expansion. Preliminary studies suggest that NT might be mediated by myeloid cells that cross the blood brain barrier. This is supported by correlative analysis from CART19 pivotal trials where CD14+ cell numbers were increased in the cerebrospinal fluid of patients that developed severe NT (Locke et al, ASH 2017). Thus, we aimed to investigate the role of GM-CSF neutralization in preventing CRS and NT after CART cell therapy via monocyte control. The human GM-CSF neutralizing antibody lenzilumab (Humanigen, Burlingame, California), which has been shown to be safe in phase II clinical trials, does not impair CART cell function in vitro (10 ug/mL) when CART19 cells are stimulated with the CD19+ Luciferase+ acute lymphoblastic leukemia (ALL) cell line NALM6. Lenzilumab results in enhanced CART cell antigen specific proliferation in the presence of monocytes. In vivo, NOD-SCID-g−/− mice were engrafted with high disease burdens of NALM6 and treated with low doses of CART19 or control T cells, in combination with lenzilumab or isotype control antibody. The combination of CART19 and lenzilumab does not impair CART cell activity in vivo (Fig 1A). The impact of GM-CSF neutralization on CART toxicities in a novel patient derived xenograft model was explored. NOD-SCID-g−/− mice were engrafted with primary ALL blasts (1-3 × 106 cells). Mice were treated with high doses of CART19 cells (2-5 × 106 iv) and developed CART cell related toxicities. The combination of CART19, lenzilumab (to neutralize human GM-CSF), and murine GM-CSF blocking antibody (to neutralize mouse GM-CSF) resulted in prevention of weight loss (Fig 1B), decrease in critical myeloid cytokines (Fig 1C-D), reduction of cerebral edema (Fig 1E), enhanced leukemic disease control in the brain (Fig 1F), and reduction in brain macrophages (Fig 1G). As CRISPR/Cas9 gene editing of the GM-CSF gene during the process of CART cell manufacturing would result in CART cells with innately reduced secretion of GM-CSF, we designed guide RNA targeting exon 3 of the GM-CSF gene to generate GM-CSFk/o CART19 cells. These CARTs produce significantly less GM-CSF upon activation but other T cell cytokine production is not inhibited (Fig 1H). Using the NALM6 high tumor burden relapse xenograft model as described above, GM-CSFk/o CART19 cells resulted in slightly enhanced disease control compared to CART19 cells (Fig 1I). These studies illuminate a novel approach to abrogate NT and CRS through GM-CSF blockade that also potentially enhances CART cell functions. Based on these results, we have designed a phase II clinical trial using lenzilumab as a modality to prevent CART related toxicities in patients with diffuse large B cell lymphoma.

Introduction Congenital maxillomandibular syngnathia, or fusion of the jaws, is a rare condition that has a broad spectrum of presentations. The restricted mouth opening can lead to issues with feeding, swallowing, and respiration resulting in failure to thrive and temporomandibular joint ankylosis. Early recognition and treatment is necessary for proper growth and development. Case report We report a 1-day-old male with isolated bilateral soft tissue alveolar fibrous bands. He presented with difficulty feeding secondary to trismus. No bony or muscular involvement in the synechiae was noted and the remainder of the physical exam was unremarkable. The bilateral alveolar synechiae were divided under local anesthesia using surgical scissors. The patient immediately showed improvement in mouth opening and had resolution of his feeding problems. He is now gaining weight and developing appropriately. Discussion The accompanying review of the literature demonstrates only 11 cases worldwide of isolated maxillomandibular fusion. Depending upon the composition of the synechiae, simple surgical division under local anesthesia can be curative.

Objective Perioperative lumbar drain (LD) use in the setting of endoscopic cerebrospinal fluid (CSF) leak repair is a well-established practice. However, recent data suggest that LDs may not provide significant benefit and may thus confer unnecessary risk. To examine this, we conducted a meta-analysis to investigate the effect of LDs on postoperative CSF leak recurrence following endoscopic repair of CSF rhinorrhea. Data Sources A comprehensive search was performed with the following databases: Ovid MEDLINE (1947 to November 2015), EMBASE (1974 to November 2015), Cochrane Review, and PubMed (1990 to November 2015). Review Method A meta-analysis was performed according to PRISMA guidelines. Results A total of 1314 nonduplicate studies were identified in our search. Twelve articles comprising 508 cases met inclusion criteria. Overall, use of LDs was not associated with significantly lower postoperative CSF leak recurrence rates following endoscopic repair of CSF rhinorrhea (odds ratio: 0.89, 95% confidence interval: 0.40-1.95) as compared with cases performed without LDs. Subgroup analysis of only CSF leaks associated with anterior skull base resections (6 studies, 153 cases) also demonstrated that lumbar drainage did not significantly affect rates of successful repair (odds ratio: 2.67, 95% confidence interval: 0.64-11.10). Conclusions There is insufficient evidence to support that adjunctive lumbar drainage significantly reduces postoperative CSF leak recurrence in patients undergoing endoscopic CSF leak repair. Subgroup analysis examining only those patients whose CSF leaks were associated with anterior skull base resections demonstrated similar results. More level 1 and 2 studies are needed to further investigate the efficacy of LDs, particularly in the setting of patients at high risk for CSF leak recurrence.

Despite its efficacy, chimeric antigen receptor T-cell therapy (CART) is limited by the development of cytokine release syndrome (CRS) and neurotoxicity (NT). While CRS is related to extreme elevation of cytokines and massive T cell expansion, the exact mechanisms for NT have not yet been elucidated. Preliminary studies suggest that NT might be mediated by myeloid cells that cross the blood brain barrier. This is supported by correlative analysis from CART19 pivotal trials where CD14+ cell numbers were increased in the cerebrospinal fluid of patients that developed severe NT (Locke et al, ASH 2017). Therefore, we aimed to investigate the role of GM-CSF neutralization in preventing CRS and NT after CART cell therapy via monocyte control. First, we investigated the effect of GM-CSF blockade on CART cell effector functions. Here, we used the human GM-CSF neutralizing antibody (lenzilumab, Humanigen, Burlingame, California) that has been shown to be safe in phase II clinical trials. Lenzilumab (10 ug/kg) neutralizes GM-CSF when CART19 cells are stimulated with the CD19+ Luciferase+ acute lymphoblastic leukemia (ALL) cell line NALM6, but does not impair CART cell function in vitro. We have found that malignancy associated macrophages reduce CART proliferation. GM-CSF neutralization with lenzilumab results in enhanced CART cell antigen specific proliferation in the presence of monocytes. To confirm this in vivo, NOD-SCID-g-/- mice were engrafted with high disease burdens of NALM6 and treated with low doses of CART19 or control T cells (to induce tumor relapse), in combination with lenzilumab or isotype control antibody. The combination of CART19 and lenzilumab resulted in significant anti-tumor activity and overall survival benefit compared to control T cells (Fig 1A), similar to mice treated with CART19 combined with isotype control antibody, indicating that GM-CSF neutralization does not impair CART cell activity in vivo. This anti-tumor activity was validated in an ALL patient derived xenograft model. Next, we explored the impact of GM-CSF neutralization on CART cell related toxicities in a novel patient derived xenograft model. Here, NOD-SCID-g-/- mice were engrafted with leukemic blasts (1-3x106 cells) derived from patients with high risk ALL. Mice were then treated with high doses of CART19 cells (2-5x106 intravenously). Five days after CART19 treatment, mice began to develop progressive motor weakness, hunched bodies, and weight loss that correlated with massive elevation of circulating human cytokine levels. Magnetic Resonance Imaging (MRI) of the brain during this syndrome showed diffuse enhancement and edema, associated with central nervous system (CNS) infiltration of CART cells and murine activated myeloid cells. This is similar to what has been reported in CART19 clinical trials in patients with severe NT. The combination of CART19, lenzilumab (to neutralize human GM-CSF) and murine GM-CSF blocking antibody (to neutralize mouse GM-CSF) resulted in prevention of weight loss (Fig 1B), decrease in critical myeloid cytokines (Fig 1C-D), reduction of cerebral edema (Fig 1E), enhanced leukemic disease control in the brain (Fig 1F), and reduction in brain macrophages (Fig 1G). Finally, we hypothesized that disrupting GM-CSF through CRISPR/Cas9 gene editing during the process of CART cell manufacturing would result in functional CART cells with reduced secretion of GM-CSF. We designed guide RNA targeting exon 3 of the GM-CSF gene and generated GM-CSFk/o CART19 cells. Our preliminary data suggest that these CARTs produce significantly less GM-CSF upon activation but continue to exhibit similar production of other cytokines and exhibit normal effector functions in vitro (Fig 1H). Using the NALM6 high tumor burden relapse xenograft model as described above, GM-CSFk/o CART19 cells resulted in slightly enhanced disease control compared to CART19 cells (Fig 1I). Thus, modulating myeloid cell behavior through GM-CSF blockade can help control CART mediated toxicities and may reduce their immunosuppressive features to improve leukemic control. These studies illuminate a novel approach to abrogate NT and CRS through GM-CSF neutralization that also potentially enhances CART cell functions. Based on these results, we have designed a phase II clinical trial using lenzilumab as a modality to prevent CART related toxicities in patients with diffuse large B cell lymphoma. Disclosures Ahmed: Humanigen: Employment. Sahmoud:Humanigen: Employment. Durrant:Humanigen: Employment. Russell:Vyriad: Equity Ownership. Kay:Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding. Kenderian:Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding.

Although there are various available treatment options for unilateral severe-to-profound hearing loss, these options do not provide the benefits of binaural hearing since sound is directed from the poorer ear to the better ear. The purpose of this investigation was to review our center's experience with cochlear implantation in such patients in providing improved auditory benefits and useful binaural hearing.Retrospective chart review.Twelve adult patients and four pediatric patients with unilateral severe-to-profound hearing loss received an implant in the poorer ear. Outcome measures performed preoperatively on each ear and binaurally included consonant-nucleus-consonant (CNC) monosyllabic words and sentences in noise. The mean pure-tune average in the better ear was within normal range.Test scores revealed a significant improvement in CNC and sentence in noise test scores from the preoperative to most recent postoperative evaluation in the isolated implant ear. All adult subjects use the device full-time.The data reveal significant improvement in speech perception performance in quiet and in noise in patients with single-sided deafness after implantation. Performance might depend on factors including length of hearing loss, age at implantation, and device usage.

Objectives:1) Examine postoperative complications of patients who underwent vestibular schwannoma excision. 2) Determine significant clinical predictors of postoperative complications.Methods:Case data for vestibular schwannoma excisions performed in California from 1996-2010 were examined using the California Hospital Inpatient Discharge Database (CHIDD). Cases were identified if they contained the principle procedure ICD-9-CM code 04.01. Postoperative complications were identified if cases contained ICD-9-CM codes for specific diagnoses and procedures.Results:Overall, 7,002 cases were examined. Most patients (76.2%) were 35-64 years old, 40.5% had ≥ 1 comorbidity, and 86.5% were at high volume centers (≥ 100 excisions performed during 1996-2010). Additionally, 24.4% had ≥ 1 of 34 pre-defined postoperative complications and 0.2% died. Cerebrospinal fluid (CSF) leakage occurred in 2.8%, intracranial hemorrhage occurred in 0.4%, and ventriculostomy was required in 0.7%. Differences in complications between...

Objective: 1) To examine surgical outcomes, charges, and demographics information for patients who have undergone an acoustic neuroma excision. 2) To determine if outcome measures and charges are significantly different between high-volume and low-volume centers.Method: Case data for acoustic neuroma excisions performed in California from 2008 to 2010 were examined using California Hospital Discharge Data (CHDD). Cases were identified if they contained the principal procedure ICD-9-CM code 04.01. Postoperative complications were identified if cases contained ICD-9-CM codes for specific diagnoses and procedures (ie, meningitis, ventriculostomy, etc).Results: There were 1158 cases. Most patients were between the ages of 35 and 64 years (72.8%), women (54%), and white (76.0%). The median total charge was $103,485, the average hospital stay was 5.1 days, 90.3% of patients were discharged routinely (ie, home), and 7.3% of patients endured postoperative complications. High-volume centers (10 ≤ surgeries per yea...