An in vitro model for postoperative cranial nerve dysfunction and a proposed method of rehabilitation with N-acetylcysteine microparticles.

PURPOSE: When operating near cranial motor nerves, transient postoperative weakness of target muscles lasting weeks to months is often observed. As nerves are typically intact at a procedure's completion, paresis is hypothesized to result from a combination of neurapraxia and axonotmesis. As both neurapraxia and axonotmesis involve Schwann cell injury and require remyelination, we developed an in vitro RSC96 Schwann cell model of injury using hydrogen peroxide (H2O2) to induce oxidative stress and investigated the efficacy of candidate therapeutic agents to promote RSC96 viability. As a first step in developing a long-term local administration strategy, the most promising of these agents was incorporated into sustained-release microparticles and investigated for bioactivity using this assay. METHODS: The concentration of H2O2 which reduced viability by 50% was determined to establish a standard for inducing oxidative stress in RSC96 cultures. Fresh cultures were then co-dosed with H2O2 and the potential therapeutics melatonin, N-acetylcysteine, resveratrol, and 4-aminopyridine. Schwann cell viability was evaluated and the most efficacious agent, N-acetylcysteine, was encapsulated into microparticles. Eluted samples of N-acetylcysteine from microparticles was evaluated for retained bioactivity. RESULTS: 100 µM N-acetylcysteine improved the viability of Schwann cells dosed with H2O2. 100 µM Microparticle-eluted N-acetylcysteine also enhanced Schwann cell viability. CONCLUSION: We developed a Schwann cell culture model of iatrogenic nerve injury and used this to identify N-acetylcysteine as an agent to promote recovery. N-acetylcysteine was packaged into microparticles and demonstrated promise as a locally administrable agent to reduce oxidative stress in Schwann cells.

Omission of Radiation in Conservative Treatment for Breast Cancer: Opportunity for De-escalation of Care.

INTRODUCTION: De-escalation of breast cancer treatment aims to reduce patient and financial toxicity without compromising outcomes. Level I evidence and National Comprehensive Cancer Network guidelines support omission of adjuvant radiation in patients aged >70 y with hormone-sensitive, pT1N0M0 invasive breast cancer treated with endocrine therapy. We evaluated radiation use in patients eligible for guideline concordant omission of radiation. METHODS: Subgroup analysis of patients eligible for radiation omission from two pooled randomized controlled trials, which included stage 0-III breast cancer patients undergoing breast conserving surgery, was performed to evaluate factors associated with radiation use. RESULTS: Of 631 patients, 47 (7.4%) met radiation omission criteria and were treated by 14 surgeons at eight institutions. The mean age was 75.3 (standard deviation + 4.4) y. Majority of patients identified as White (n = 46; 97.9%) and non-Hispanic (n = 44; 93.6%). The mean tumor size was 1.0 cm; 37 patients (88.1%) had ductal, 4 patients (9.5%) had lobular, and 17 patients (40.5%) had low-grade disease. Among patients eligible for radiation omission, 34 (72.3%) patients received adjuvant radiation. Those who received radiation were significantly younger than those who did not (74 y, interquartile range = 4 y, versus 78 y, interquartile range = 11 y, P = 0.03). There was no difference in radiation use based on size (P = 0.4), histology (P = 0.5), grade (P = 0.7), race (P = 1), ethnicity (P = 0.6), institution (P = 0.1), gender of the surgeon (P = 0.7), or surgeon (P = 0.1). CONCLUSIONS: Fewer than 10% of patients undergoing breast conservation met criteria for radiation omission. Nearly three-quarters received radiation therapy with younger age being a driver of radiation use, suggesting ample opportunity for de-escalation, particularly among younger eligible patients.

Effects of Hepatitis B Surface Antigen on Virus-Specific and Global T Cells in Patients With Chronic Hepatitis B Virus infection.

BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is characterized by the presence of defective viral envelope proteins (hepatitis B surface antigen [HBsAg]) and the duration of infection-most patients acquire the infection at birth or during the first years of life. We investigated the effects of these factors on patients' lymphocyte and HBV-specific T-cell populations. METHODS: We collected blood samples and clinical data from 243 patients with HBV infection (3-75 years old) in the United Kingdom and China. We measured levels of HBV DNA, HBsAg, hepatitis B e antigen, and alanine aminotransferase; analyzed HBV genotypes; and isolated peripheral blood mononuclear cells (PBMCs). In PBMCs from 48 patients with varying levels of serum HBsAg, we measured 40 markers on nature killer and T cells by mass cytometry. PBMCs from 189 patients with chronic infection and 38 patients with resolved infections were incubated with HBV peptide libraries, and HBV-specific T cells were identified by interferon gamma enzyme-linked immune absorbent spot (ELISpot) assays or flow cytometry. We used multivariate linear regression and performed variable selection using the Akaike information criterion to identify covariates associated with HBV-specific responses of T cells. RESULTS: Although T- and natural killer cell phenotypes and functions did not change with level of serum HBsAg, numbers of HBs-specific T cells correlated with serum levels of HBsAg (r = 0.3367; P < .00001). After we performed the variable selection, the multivariate linear regression model identified patient age as the only factor significantly associated with numbers of HBs-specific T cells (P = .000115). In patients younger than 30 years, HBs-specific T cells constituted 28.26% of the total HBV-specific T cells; this value decreased to 7.14% in patients older than 30 years. CONCLUSIONS: In an analysis of immune cells from patients with chronic HBV infection, we found that the duration of HBsAg exposure, rather than the quantity of HBsAg, was associated with the level of anti-HBV immune response. Although the presence of HBs-specific T cells might not be required for the clearance of HBV infection in all patients, strategies to restore anti-HBV immune responses should be considered in patients younger than 30 years.

CD30+OX40+ Treg is associated with improved overall survival in colorectal cancer.

Regulatory T cells (Tregs) are often enriched in tumors, where their immunosuppressive function has a key role in tumor persistence and progression. In colorectal cancer (CRC), however, Tregs are frequently associated with an improved clinical outcome. Tumor-infiltrating Tregs have been shown to exhibit a distinct signature comprising the co-stimulatory molecules (OX40, 4-1BB), cytokine receptors (IL1R2, IL21R, CCR8, CD30), and co-inhibitory molecules (PD-L1, TIGIT). Here, we showed by flow cytometry that circulating CD45RO+ Tregs from patients with CRC (n = 25) have elevated CD30 and OX40 expression compared to healthy subjects (n = 14). We identified co-expression of CD30 and OX40 on circulating CD45RO+ Tregs using single-cell images captured by the DEPArray™ system. The frequency of CD30+OX40+CD45RO+ Tregs was significantly higher in CRC patients than in healthy subjects (P < 0.001). Importantly, receiver operating characteristic analysis confirmed that this CD30+OX40+ Treg subset could strongly discriminate between CRC patients and healthy subjects with the highest accuracy of 92.3%, an AUC of 0.92, a sensitivity of 88%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 82.35%, and a trade-off value of 3.44%, compared to other Treg subsets. Consistently, multiplex-IHC/IF of tumor-infiltrating Tregs revealed a significant association between high densities of CD30+OX40+ Tregs and improved overall survival; no such association was found for other subsets. These data suggest a potential role for CD30+OX40+ Tregs as a diagnostic or prognostic biomarker in CRC.

Metabolic acidosis in a lactating woman induced by a deliberate ketogenic diet.

ABSTRACT: This article describes a rare case of lactation ketoacidosis in a patient who started a ketogenic diet while nursing an infant and toddler. The patient presented to the ED with a history of nausea, vomiting, and postural dizziness, and was found to have a significant metabolic acidosis and elevated lipase level. The metabolic changes induced in this patient could occur in anyone with high metabolic demands who also is on a strict ketogenic diet. The case highlights the importance of a dietary history in patients with unexplained metabolic derangements.

Pulmonary fluid shifts occur as a result of scuba diving at NASA's Neutral Buoyancy Lab.

Introduction: Pulmonary fluid shifts can occur while scuba diving. Such shifts, generally thought to be rare, may result in a life-threatening phenomenon known as immersion pulmonary edema (IPE). This study aims to better classify the normal physiology of diving using ultrasound (US) to determine if these fluid shifts occur routinely during commercial diving work at the NASA Neutral Buoyancy Laboratory (NBL). Methods: Chest US was performed on commercial divers prospectively pre- and post-dive to evaluate the presence of B-lines in a total of 12 intercostal points on the anterior, posterior, and lateral chest wall. The number of B-lines at each anatomic site was recorded and scored by two independent reviewers. An increase in the number of B-lines post-dive was considered a positive result. Results: There were 67 exposures; 39 (58%) had an increase of one or more B-lines post dive; 64% of the female exposures and 57% of the male exposures were positive for B-lines post-dive, suggesting no difference across gender (Fisher's exact; p = 0.763). After the dive, all divers remained asymptomatic. Conclusion: From our results, fluid shifts can be viewed as a normal, transient, and physiologic process in commercial divers. This correlation can be compared to the formation of low-grade venous gas emboli (VGE) from decompression that does not result in decompression sickness. Further study of US B-lines in symptomatic divers may define the utility of field US in the diagnosis and management of IPE, and help identify associated risk factors.

Intrahepatic CD206+ macrophages contribute to inflammation in advanced viral-related liver disease.

BACKGROUND & AIMS: Liver inflammation is key in the progression of chronic viral hepatitis to cirrhosis and hepatocellular carcinoma. The magnitude of viral replication and the specific anti-viral immune responses should govern the degree of inflammation, but a direct correlation is not consistently found in chronic viral hepatitis patients. We aim to better define the mechanisms that contribute to chronic liver inflammation. METHODS: Intrahepatic CD14+ myeloid cells from healthy donors (n=19) and patients with viral-related liver cirrhosis (HBV, HBV/HDV or HCV; n=15) were subjected to detailed phenotypic, molecular and functional characterisation. RESULTS: Unsupervised analysis of multi-parametric data showed that liver disease was associated with the intrahepatic expansion of activated myeloid cells mainly composed of pro-inflammatory CD14+HLA-DRhiCD206+ cells, which spontaneously produced TNFα and GM-CSF. These cells only showed heightened pro-inflammatory responses to bacterial TLR agonists and were more refractory to endotoxin-induced tolerance. A liver-specific enrichment of CD14+HLA-DRhiCD206+ cells was also detected in a humanised mouse model of liver inflammation. This accumulation was abrogated following oral antibiotic treatment, suggesting a direct involvement of translocated gut-derived microbial products in liver injury. CONCLUSIONS: Viral-related chronic liver inflammation is driven by the interplay between non-endotoxin-tolerant pro-inflammatory CD14+HLA-DRhiCD206+ myeloid cells and translocated bacterial products. Deciphering this mechanism paves the way for the development of therapeutic strategies specifically targeting CD206+ myeloid cells in viral-related liver disease patients. Lay summary: Viral-related chronic liver disease is driven by intrahepatic pro-inflammatory myeloid cells accumulating in a gut-derived bacterial product-dependent manner. Our findings support the use of oral antibiotics to ameliorate liver inflammation in these patients.

HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant.

BACKGROUND & AIMS: Chronic infection with hepatitis B virus (HBV) progresses through different phases. The first, called the immune-tolerant phase, has been associated with a lack of disease activity. We examined HBV-DNA integration, clonal hepatocyte expansion, HBV antigen expression, and HBV-specific immune responses in patients in the immune-tolerant phase to assess whether this designation is appropriate or if there is evidence of disease activity. METHODS: We studied HBV-DNA integration, clonal hepatocyte expansion, and expression of hepatitis B surface antigen and core antigen in liver tissues from 26 patients with chronic HBV infection (ages, 14-39 y); 9 patients were positive for hepatitis B e antigen (HBeAg) in the immune-tolerant phase and were matched for age with 10 HBeAg-positive patients with active disease and 7 HBeAg-negative patients with active disease. Peripheral blood samples were collected and HBV-specific T cells were quantified for each group. RESULTS: Detection of HBV antigens differed among groups. However, unexpectedly high numbers of HBV-DNA integrations, randomly distributed among chromosomes, were detected in all groups. Clonal hepatocyte expansion in patients considered immune tolerant also was greater than expected, potentially in response to hepatocyte turnover mediated by HBV-specific T cells, which were detected in peripheral blood cells from patients in all phases of infection. CONCLUSIONS: We measured HBV-specific T cells, HBV-DNA integration, and clonal hepatocyte expansion in different disease phases of young patients with chronic hepatitis B, with emphasis on the so-called immune-tolerant phase. A high level of HBV-DNA integration and clonal hepatocyte expansion in patients considered immune tolerant indicated that hepatocarcinogenesis could be underway-even in patients with early stage chronic HBV infection. Our findings do not support the concepts that this phase is devoid of markers of disease progression or that an immune response has not been initiated. We propose that this early phase be called a high-replication, low-inflammation stage. The timing of therapeutic interventions to minimize further genetic damage to the hepatocyte population should be reconsidered.

Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver.

The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-γ. We identified CD161(Bright) mucosal-associated invariant T (MAIT) and CD56(Bright) NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-γ, without the concomitant production of TNF-α or IL-17A. The intrahepatic IFN-γ production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-γ upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.

Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways.

RATIONALE: The liver-specific natural killer (NK) cell population is critical for local innate immune responses, but the mechanisms that lead to their selective homing and the definition of their functionally relevance remain enigmatic. OBJECTIVES: We took advantage of the availability of healthy human liver to rigorously define the mechanisms regulating the homing of NK cells to liver and the repertoire of receptors that distinguish liver-resident NK (lr-NK) cells from circulating counterparts. FINDINGS: Nearly 50% of the entire liver NK cell population is composed of functionally relevant CD56(bright) lr-NK cells that localize within hepatic sinusoids. CD56(bright) lr-NK cells express CD69, CCR5 and CXCR6 and this unique repertoire of chemokine receptors is functionally critical as it determines selective migration in response to the chemotactic stimuli exerted by CCL3, CCL5 and CXCL16. Here, we also show that hepatic sinusoids express CCL3(pos) Kupffer cells, CXCL16(pos) endothelial cells and CCL5(pos) T and NK lymphocytes. The selective presence of these chemokines in sinusoidal spaces creates a unique tissue niche for lr-CD56(bright) NK cells that constitutively express CCR5 and CXCR6. CD56(bright) lr-NK cells co-exist with CD56(dim) conventional NK (c-NK) cells that are, interestingly, transcriptionally and phenotypically similar to their peripheral circulating counterparts. Indeed, CD56(dim) c-NK cells lack expression of CD69, CCR5, and CXCR6 but express selectins, integrins and CX3CR1. CONCLUSION: Our findings disclosing the phenotypic and functional differences between lr-Nk cells and c-NK cells are critical to distinguish liver-specific innate immune responses. Hence, any therapeutic attempts at modifying the large population of CD56(bright) lr-NK cells will require modification of hepatic CCR5 and CXCR6.

N-acetylcysteine microparticles reduce cisplatin-induced RSC96 Schwann cell toxicity.

Objectives: Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug-induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin-induced Schwann cell injury and investigates the ability of the antioxidant N-acetylcysteine to promote Schwann cell viability. A local delivery system of drug-eluting microparticles was then fabricated, characterized, and investigated for bioactivity. Methods: RSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC50). In subsequent experiments, RSC96 cells were co-treated with cisplatin and both resuspended or eluted N-acetylcysteine. Cell viability was assessed with the CCK8 assay. Results: The LC50 dose of cisplatin was determined to be 3.76 µM (p = 2.2 x 10-16). When co-dosed with cisplatin and a therapeutic concentration of resuspended or eluted N-acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone. Conclusion: RSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N-acetylcysteine improved cell viability and mitigated this injury. N-acetylcysteine was packaged into microparticles and eluted N-acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin-induced ototoxicity. Level of Evidence: N/A Laryngoscope, 2023.

Saliva as a Biological Fluid in SARS-CoV-2 Detection.

BACKGROUND: The polymerase chain reaction of upper respiratory tract swab samples was established as the gold standard procedure for diagnosing SARS-CoV-2 during the COVID pandemic. However, saliva collection has attracted attention as an alternative diagnostic collection method. The goal of this study was to compare the use of saliva and nasopharyngeal swab (NPS) samples for the detection of SARS-CoV-2. METHODS: Ninety-nine paired samples were evaluated for the detection of SARS-CoV-2 by saliva and swab for a qualitative diagnosis and quantitative comparison of viral particles. Furthermore, the detection limits for each sample collection technique were determined. The cycle threshold (CT) values of the saliva samples, the vaccination status, and the financial costs associated with each collection technique were compared. RESULTS: The results showed qualitative equivalence in diagnosis (96.96%) comparing saliva and swab collection, although there was low quantitative agreement. Furthermore, the detection limit test demonstrated equivalence for both collection methods. We did not observe a statistically significant association between CT values and vaccination status, indicating that the vaccine had no influence on viral load at diagnosis. Finally, we observed that the use of saliva incurs lower financial costs and requires less use of plastic materials, making it more sustainable. CONCLUSIONS: These findings support the adoption of saliva collection as a feasible and sustainable alternative to the diagnosis of COVID-19.

N-acetylcysteine Microparticles Reduce Cisplatin-induced RSC96 Schwann Cell Toxicity.

Objectives: Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug-induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin-induced Schwann cell injury and investigates the ability of the antioxidant N-acetylcysteine to promote Schwann cell viability. A local delivery system of drug-eluting microparticles was then fabricated, characterized, and investigated for bioactivity. Methods: RSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC 50 ). In subsequent experiments, RSC96 cells were co-treated with cisplatin and both resuspended or eluted N-acetylcysteine. Cell viability was assessed with the CCK8 assay. Results: The LC 50 dose of cisplatin was determined to be 3.76 µM (p=2.2 × 10 -16 ). When co-dosed with cisplatin and therapeutic concentration of resuspended or eluted N-acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone. Conclusion: RSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N-acetylcysteine improved cell viability and mitigated this injury. N-acetylcysteine was packaged into microparticles and eluted N-acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin-induced ototoxicity. Lay Summary: Cisplatin is a chemotherapeutic agent known to cause balance and hearing problems through damage to the inner ear. This project explored cisplatin injury in a Schwann cell culture model and packaged an antioxidant into microparticles suitable for future drug delivery applications.

Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model.

HYPOTHESIS: The ototoxicity of gentamicin and cisplatin can be evaluated with a Schwann cell model to screen for otoprotective agents that can be encapsulated into poly (lactic-co-glycolic acid) (PLGA) microparticles for drug delivery to the inner ear. BACKGROUND: Aminoglycosides and cisplatin are widely prescribed but known to cause ototoxicity. There is strong evidence that compromise to Schwann cells ensheathing inner ear afferent neurons results in inner ear dysfunction mimicking drug-induced ototoxicity. There is a need for a model for ototoxic demyelination to screen medications for protective potential and to subsequently target and tune the delivery of any promising agents. METHODS: RT4-D6P2T rat schwannoma cells were used as a Schwann cell model to assess gentamicin and cisplatin toxicity and to screen for protective agents. Cell viability was evaluated with the MTT cell proliferation assay. N -acetylcysteine (NAC) was encapsulated into a PLGA microparticle, and its elution profile was determined. RESULTS: The estimated 50% lethal concentration dose for gentamicin was 805.6 µM, which was 46-fold higher than that for cisplatin (17.5 µM). In several trials, cells dosed with NAC and cisplatin demonstrated a 22.6% ( p < 0.001) increase in cell viability when compared with cisplatin alone. However, this protective effect was not consistent across all trials. NAC was encapsulated into a PLGA microparticle and elution plateaued at 5 days. CONCLUSION: When dosed at their respective therapeutic ranges, cisplatin is more likely than gentamicin to induce damage to the Schwann cell model. Although NAC demonstrates an uncertain role in protecting against cisplatin-induced Schwann cell cytotoxicity, this study establishes a method to screen for other otoprotective medications to encapsulate into a tunable microparticle for localized drug delivery.

Identification of Populations at Risk for "Choosing Un-Wisely": A SEER Population-Based Study.

BACKGROUND: Since 2016, the Choosing Wisely campaign has recommended against routine axillary surgery in elderly patients with early stage, hormone receptor positive (ER+) breast cancer. The objective was to evaluate factors associated with axillary surgery in breast cancer patients meeting criteria for sentinel lymph node biopsy (SLNB) omission and identify potential disparities. METHODS: Female patients age ≥70 years with cT1-2N0M0, ER+, HER2-negative breast cancer diagnosed after publication of the Choosing Wisely recommendations, between 2016 and 2019, were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Patient demographics and tumor characteristics associated with axillary surgery were analyzed. RESULTS: Of the 31 756 patients meeting omission criteria, 25 771 (81.2%) underwent axillary surgery. Hispanic ethnicity, median household income between $35,000 and $70,000, treatment in rural areas, poor differentiation, lobular and mixed lobular with ductal histology, T2 tumors, radiation therapy, and systemic therapy were factors associated with receiving axillary surgery on multivariable analysis. In the axillary surgery cohort, a median of 2 (IQR = 2) nodes were examined and 529 (2.1%) patients were found to have 1 or more positive lymph nodes. DISCUSSION: Among elderly patients meeting Choosing Wisely criteria for SLNB omission, particular racial, ethnic, socioeconomic, and geographic populations may be at increased risk for potential over treatment. Identification of these factors provides specific opportunities for education and implementation of de-escalation of unnecessary procedures.

Recurrence patterns among patients with sinonasal mucosal melanoma: A multi-institutional study.

OBJECTIVE: To evaluate recurrence patterns and survival after recurrence among patients with sinonasal mucosal melanoma (SNMM). METHODS: This was a multi-institutional retrospective review from seven U.S. institutions of patients with SNMM from 1991 to 2022. Recurrence was categorized as local, regional, distant, or multifocal. Kaplan-Meier tests were used to evaluate disease-free survival (DFS), overall survival (OS), and post-recurrence survival (PRS) reported with standard errors (SE) and log-rank testing used for comparison. Cox-regression was further used, with hazard ratios (HR) and 95% confidence intervals (CI) reported. RESULTS: Among 196 patients with SNMM, there were 146 patients with recurrence (74.5%). Among all patients, 60-month DFS (SE) was 15.5% (2.9%), 60-month OS (SE) was 44.7% (3.7%), mean age ± standard deviation at diagnosis was 69.7 ± 12.5 years, and 54.6% were female. In 26 patients who underwent primary treatment of the neck, 60-month DFS did not differ from no treatment (p > 0.05). Isolated distant recurrence was most common (42.8%), followed by local (28.3%), multifocal (20.7%), and regional recurrence (8.3%). Among patients with regional recurrence in the neck, there was no 60-month PRS benefit for patients undergoing salvage neck dissection or radiation (p > 0.05). Among patients with distant recurrence, only immunotherapy was associated with improved 12-month PRS (HR = 0.32, 95% CI = 0.11-0.92, p = 0.034), and no treatment group was associated with improved 24- or 60-month PRS (p > 0.05). CONCLUSION: SNMM is associated with a high recurrence rate and poor survival. Primary treatment of the neck was not associated with reduced recurrence, and immunotherapy for treatment of distant recurrence was associated with increased 12-month PRS.

Intractable Hiccups Caused by Diaphragmatic Eventration.

Intractable hiccups are a rare yet debilitating pathology with a broad differential and often indicate a more serious underlying pathology, which can range from neoplasms to structural abnormalities. In this case report, we present a 64-year-old male with seven months of intractable hiccups determined to be caused by eventration of the right hemidiaphragm. The patient was treated with baclofen to treat the hiccups pharmacologically. He was also prescribed voice therapy to establish rescue breathing techniques and reduce laryngospasm. Finally, he was referred to thoracic surgery for further evaluation and potential surgical intervention should his diaphragmatic eventration worsen or cause hypoxemia. To our knowledge, this is the first reported case of an association between diaphragmatic eventration and intractable hiccups. It is important to highlight this addition to the broad differential of intractable hiccups and to emphasize an interdisciplinary approach to workup and treatment of intractable hiccups.

A Rare Case of Laryngeal Non-IgM Lymphoplasmacytic Lymphoma.

Laryngeal lymphoplasmacytic lymphoma has been previously reported only a handful of times in the literature. It can be difficult to diagnose without significant histologic workup and proper methodology. Here, we demonstrate the first known case of laryngeal lymphoplasmacytic lymphoma with non-immunoglobulin M (IgM) features. In this case report, a 79-year-old female with seropositive rheumatoid arthritis presented with five months of dysphonia and dyspnea on exertion. Lab studies revealed high levels of serum IgA and IgG. Flexible laryngoscopy and computed tomography of the neck showed a left supraglottic submucosal mass, which was surgically excised with a carbon dioxide laser. The histology of the mass confirmed the diagnosis of lymphoplasmacytic lymphoma. The patient was treated with 30.6 Gy of radiation therapy and eight cycles of rituximab with successful remission of her lymphoma and no evidence of disease recurrence six months after treatment completion. Lymphoplasmacytic lymphoma without corresponding IgM gammopathy is unusual and has been shown to have a higher frequency of extramedullary involvement. This is the first known manifestation of non-IgM lymphoplasmacytic lymphoma in the larynx.