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The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patients tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice-an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.

Objective: This study sought to analyze the efficacy and safety of postoperative prednisone to reduce reliance on opioids in adult benign oropharyngeal surgery., Study Design: Prospective cohort study., Setting: Single tertiary-care facility., Methods: Patients undergoing tonsillectomy (T), tonsillectomy and adenoidectomy (T&A), and/or modified uvulopalatopharyngoplasty (UPPP) from December 2020 to January 2023 received the standard of care postoperative management. A prednisone taper was dependent on surgeon preference. Cohorts were based on the prescription of postoperative steroids. Patients completed a survey to assess opioid usage, pain scores, and steroid compliance., Results: Seventy-two patients were included. The nonsteroid cohort (N = 29) received an average of 467 ± 94.1 morphine milligram equivalents (MME), and the steroid cohort (N = 43) received an average of 285 ± 128 MME (P < 0.001). The nonsteroid cohort consumed 1.62 times more opioids than the steroid cohort (P < 0.002). There were no significant differences in complication or refill rates between treatment groups. There were no significant differences in pain scores on the day of surgery or postoperative days 1, 5, or 10 (P = 0.34, P = 0.66, P = 0.62, and P = 0.22, respectively). Patients undergoing T&A (p = 0.019) or who had current psychiatric medication use (P < 0.006) consumed significantly more opioids. Patients who received a total opioid prescription of >300 MME (40 5-mL doses of 5 mg/5 mL liquid oxycodone) consumed 2.27 times more postoperative opioids than patients with opioid prescriptions ≤300 MME (P < 0.001)., Conclusion: Patients who did not receive steroids consumed 1.62 times more postoperative opioids compared to those who completed a steroid taper. Corticosteroid use was not associated with changes in pain scores, refill rates, or complication rates and may be considered in a multimodal approach to pain management in adults undergoing benign oropharyngeal surgery, although further study is warranted., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Background: Anti-3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) antibodies are associated with a subtype of immune-mediated necrotising myopathy (IMNM)., Aims: To determine clinical associations of anti-HMGCR antibodies for anti-HMGCR-associated IMNM (HMGCR-IMNM) among a cohort of patients in Western Australia and to determine whether serial HMGCR antibody levels parallel disease activity., Methods: Adult patients with positive anti-HMGCR antibodies detected by enzyme-linked immunosorbent assay between January 2015 and November 2019 were included. Symptoms, examination findings, imaging findings and blood test results were reviewed retrospectively using patient records and laboratory database results., Results: Among 26 patients with positive anti-HMGCR antibodies, 23 were diagnosed with HMGCR-IMNM representing a positive predictive value (PPV) of 88%. Myopathy was frequently severe at diagnosis with limb weakness graded as Medical Research Council score 3 or below in 78% of patients, bulbar muscle weakness in 39% and an average creatine kinase (CK) at diagnosis of 7986 U/L. The majority (83%) required at least two therapies to maintain remission, 48% had at least one flare of disease and 57% did not achieve CK normalisation. Correlation between CK and anti-HMGCR antibody level at diagnosis was low (r = 0.04). Anti-HMGCR antibodies fell with treatment in 10 of 12 patients, but remained persistently positive in 83% of patients., Conclusions: The PPV of anti-HMGCR antibodies for HMGCR-IMNM in this Western Australian cohort is 88%. Patients typically present with proximal limb weakness, dysphagia and markedly elevated CK, and, despite multiagent immunosuppression, a significant number of patients have evidence of persistent biochemical myositis. Anti-HMGCR antibodies did not correlate with CK levels at diagnosis., (© 2023 Royal Australasian College of Physicians.)

A crucial component of nonalcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation in vivo. We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages. This hypothesis was tested by using RNA-sequencing methods to characterize and analyze sort-purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol. The addition of cholesterol to a high-fat diet triggered hepatic pathology reminiscent of advanced nonalcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized low-density lipoprotein, increased recruitment of hepatic macrophages, and significant fibrosis. RNA-sequencing analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells (KCs) and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased KCs and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized low-density lipoprotein recapitulated some of the transcriptional changes observed in the RNA-sequencing study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that KCs are purely proinflammatory in NASH. Conclusion: This comprehensive view of macrophage populations in NASH indicates mechanisms by which cholesterol contributes to NASH progression and identifies potential therapeutic targets for this common disease., (© 2018 by the American Association for the Study of Liver Diseases.)

Purpose: To determine the rate of persistent tympanic membrane perforation after intratympanic steroid injection. To determine which comorbid conditions and risk factors are associated with prolonged time to perforation closure following intratympanic steroid injection., Materials and Methods: Clinical data were gathered for patients who had undergone intratympanic steroid injection to treat sudden sensorineural hearing loss or Ménière's disease. Primary outcomes analysis included rate of persistent tympanic membrane perforation, defined as perforation at least 90days following last injection, and time to perforation healing. Age, sex, number of injections, smoking status, diabetes mellitus, previous head and neck irradiation, and concurrent oral steroids, were analyzed as potential predictors of persistent perforation., Results: One hundred ninety two patients were included in this study. Three patients (1.6%) had persistent tympanic membrane perforations. All three patients received multiple injections. One patient underwent tympanoplasty for repair of persistent perforation. The median time to perforation healing was 18days. There was no statistically significant variable associated with time to perforation healing. However, patients with prior history of head and neck radiation averaged 36.5days for perforation healing compared to 17.5days with no prior history of radiation and this approached statistical significance (p=0.078)., Conclusions: The rate of persistent tympanic membrane perforation following intratympanic steroid injection is low. Patients with a history of radiation to the head and neck may be at increased risk for prolonged time for closure of perforation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Since first described in the mid 1990s, there has been burgeoning literature on IgG4-related sclerosing disease. The number of sites that may be involved is ever increasing, with the pancreas, salivary glands, and lymph nodes being the most commonly affected organs. There are no well-documented cases arising in the gastrointestinal tract. In this report, we present the first case to our knowledge of IgG4-related sclerosing disease involving the small bowel with a distinctly unusual clinicopathologic presentation. A previously well 46-year-old woman presented with a 2-year history of intermittent abdominal pain with recent worsening due to small bowel obstruction. Following imaging, which showed jejunitis with surrounding mesenteric inflammatory changes, she proceeded to a segmental small bowel resection. The resected jejunum revealed an isolated, stenosing chronic ulcer associated with a necrotizing mesenteric arteritis. A transmural inflammatory infiltrate rich in IgG4 plasma cells was seen in the wall of the bowel and mesenteric artery. Abundant IgG4 interfollicular plasma cells were also identified in a mesenteric lymph node. The serum IgG4 level was elevated at >800 mg/dL (reference range 8 to 140 mg/dL). Although phlebitis is an almost constant feature of this disease, arteritis is not described other than in the lung and aorta. In this report, we also discuss the diagnostic pitfalls and the differential diagnoses that should be considered when this condition arises in the gastrointestinal tract.

Rupture of the extracranial carotid arteries or their major branches is known as carotid blowout syndrome (CBS). CBS is a well-recognized complication of cancer of the head and neck and subsequent radiation therapy. A few treatment modalities are available, including open ligation and different endovascular techniques, but questions regarding both the immediate and delayed complications of these procedures persist. In this case report, we describe the management of acute CBS in a 54-year-old man who had previously been treated for follicular thyroid carcinoma. The patient was hemorrhaging from a pseudoaneurysm of the left common carotid artery. A self-expanding polytetrafluoroethylene (Teflon) -covered stent was successfully deployed endovascularly, and this resulted in cessation of the bleeding and restoration of flow through the vessel. We examine the covered-stent approach to treating acute CBS, and we discuss other treatment approaches that have been described in the literature.

Object: The expanded endoscopic approach to craniopharyngiomas has recently been described in several small case series. The authors present their experience with this technique and review the available literature., Methods: Between September 2006 and September 2009, 14 patients underwent a purely endoscopic, endonasal approach for resection of newly diagnosed craniopharyngiomas. These procedures represent index surgeries; no patient had undergone previous tumor resection. A retrospective review of endocrinological and ophthalmological outcomes, extent of resection, and complication prevalence was completed. Additionally, a review of the English literature was performed to evaluate outcomes of similar endoscopic techniques for resection of craniopharyngiomas., Results: Four patients (28.6%) underwent gross-total resection; near total resection or better was achieved in 9 patients (64.3%). All patients presented with some form of visual field or acuity deficit. Postoperatively, 12 patients (85.7%) experienced visual improvement, with 6 patients (42.9%) having complete visual recovery. One patient experienced worsening of her visual deficit. Visual acuity improved in 8 patients ((57.1%), while visual field defects improved in 11 (78.6%). The pituitary stalk was preserved in all cases. Eight (57.1%) of 14 patients experienced some form of anterior pituitary dysfunction postoperatively. Although 9 patients (64.3%) were documented to have either transient or permanent new diabetes insipidus immediately after surgery, at 1-month follow-up only 1 patient met clinical criteria. Five patients (35.7%) developed CSF leaks that were successfully treated by subsequent endoscopic revision. All CSF leaks occurred early in the series. Two patients (14.2%) were treated for presumed meningitis postoperatively., Conclusions: The endoscopic endonasal approach is a minimally invasive alternative to open transcranial approaches for select craniopharyngiomas. Similar to previous transcranial series, rates of endocrinopathy and gross-total resection were dependent upon the adherence of the tumor capsule to the hypothalamus, pituitary stalk, and associated vasculature. A review of the literature suggests that the results of the current series are similar to other published series on this topic.