Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.

Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFß-stimulated pulmonary myofibroblast differentiation in vitro and decreases bleomycin-induced pulmonary fibrosis in vivo. Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist.

MYC overrides HIF-1α to regulate proliferating primary cell metabolism in hypoxia.

Hypoxia requires metabolic adaptations to sustain energetically demanding cellular activities. While the metabolic consequences of hypoxia have been studied extensively in cancer cell models, comparatively little is known about how primary cell metabolism responds to hypoxia. Thus, we developed metabolic flux models for human lung fibroblast and pulmonary artery smooth muscle cells proliferating in hypoxia. Unexpectedly, we found that hypoxia decreased glycolysis despite activation of hypoxia-inducible factor 1α (HIF-1α) and increased glycolytic enzyme expression. While HIF-1α activation in normoxia by prolyl hydroxylase (PHD) inhibition did increase glycolysis, hypoxia blocked this effect. Multi-omic profiling revealed distinct molecular responses to hypoxia and PHD inhibition, and suggested a critical role for MYC in modulating HIF-1α responses to hypoxia. Consistent with this hypothesis, MYC knockdown in hypoxia increased glycolysis and MYC over-expression in normoxia decreased glycolysis stimulated by PHD inhibition. These data suggest that MYC signaling in hypoxia uncouples an increase in HIF-dependent glycolytic gene transcription from glycolytic flux.

Concussion Guidelines in National and International Professional and Elite Sports.

The Berlin statement on sport-related concussion was published in 2017 using evidence-based recommendations. We aimed to examine (1) the implementation of, distribution and education based on the Berlin recommendations, and the development of sport-specific protocols/guidelines among professional and elite sports, (2) the implementation of guidelines at the community level, (3) translation of guidelines into different languages, and (4) research activities. Senior medical advisers and chief medical officers from Australian Football League, All Japan Judo Federation, British Horseracing Authority, Cricket Australia, Fédération Equestre Internationale, Football Association, Gaelic Athletic Association, International Boxing Association, Irish Horseracing Regulatory Board, Major League Baseball, National Football League, National Hockey League, National Rugby League, and World Rugby completed a questionnaire. The results demonstrated that all 14 sporting organizations have published concussion protocols/guidelines based on the Berlin recommendations, including Recognize, Removal from play, Re-evaluation, Rest, Recovery, and Return to play. There is variable inclusion of Prolonged symptoms. Prevention and Risk reduction and Long-term effects are addressed in the guidelines, rules and regulations, and/or sport-specific research. There is variability in education programs, monitoring compliance with guidelines, and publication in other languages. All sporting bodies are actively involved in concussion research. We conclude that the Berlin recommendations have been included in concussion protocols/guidelines by all the sporting bodies, with consistency in the essential components of the recommendations, whilst also allowing for sport- and regional-specific variations. Education at the elite, community, and junior levels remains an ongoing challenge, and future iterations of guidelines may consider multiple language versions, and community- and junior-level guidelines.

Invasive pseudomembranous upper airway and tracheal Aspergillosis refractory to systemic antifungal therapy and serial surgical debridement in an Immunocompetent patient.

BACKGROUND: The development of respiratory infections secondary to Aspergillus spp. spores found ubiquitously in the ambient environment is uncommon in immunocompetent patients. Previous reports of invasive upper airway aspergillosis in immunocompetent patients have generally demonstrated the efficacy of treatment regimens utilizing antifungal agents in combination with periodic endoscopic debridement, with symptoms typically resolving within months of initiating therapy. CASE PRESENTATION: A 43-year-old previously healthy female presented with worsening respiratory symptoms after failing to respond to long-term antibiotic treatment of bacterial sinusitis. Biopsy of her nasopharynx and trachea revealed extensive fungal infiltration and Aspergillus fumigatus was isolated on tissue culture. Several months of oral voriconazole monotherapy failed to resolve her symptoms and she underwent mechanical debridement for symptom control. Following transient improvement, her symptoms subsequently returned and failed to fully resolve in spite of increased voriconazole dosing and multiple additional tissue debridements over the course of many years. CONCLUSIONS: Invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients. In the rare instances that such infections do occur, combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach. However, some patients may continue to experience refractory symptoms. In such cases, continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved.

Diagnostic utility of flexible fiberoptic nasopharyngolaryngoscopy recorded onto a smartphone: A pilot study.

OBJECTIVES: To evaluate the diagnostic accuracy of flexible fiberoptic examinations of the larynx recorded onto smartphones. METHODS: Prospective, blinded study of inpatients requiring laryngoscopy. A live exam was performed, then a smartphone was attached to the endoscope using a novel coupling device and the same examination was recorded. The live and recorded exams were evaluated by two laryngologists, each blinded to the findings of the other. RESULTS: Eighteen subjects were evaluated. Evaluation of airway patency was identical (Kappa = 1.0 [1, 1]). Evaluation of vocal cord motion was identical for 14 subjects: 9 normal, 3 paretic, 2 paralytic (Kappa = 0.69 [0.38, 1]). CONCLUSION: There is high correlation between laryngeal diagnoses using live flexible fiberoptic laryngoscopy and recordings using a coupling device to transfer the recordings on to smartphones. Critical findings such as airway patency and vocal fold motion showed the highest correlation.

Cost effectiveness of a gene expression score and myocardial perfusion imaging for diagnosis of coronary artery disease.

BACKGROUND: Over 3 million patients annually present with symptoms suggestive of obstructive coronary artery disease (oCAD) in the United States (US), but a cardiac etiology is found in as few as 10% of cases. Usual care may include advanced cardiac testing with myocardial perfusion imaging (MPI), with attendant radiation risks and increased costs of care. We estimated the cost effectiveness of CAD diagnostic strategies including "no test," a gene expression score (GES) test, MPI, and sequential strategies combining GES and MPI. METHODS: We developed a Markov-based decision analysis model to simulate outcomes and costs in patients presenting to clinicians with symptoms suggestive of oCAD in the US. We estimated quality-adjusted life years (QALYs), total costs, and incremental cost-effectiveness ratios (ICERs) for each strategy. RESULTS: In our base case, the 2-threshold GES strategy is the most cost-effective strategy at a threshold of $100,000 per QALY gained, with an ICER of approximately $72,000 per QALY gained relative to no testing. Myocardial perfusion imaging alone and the 1-threshold strategy are weakly dominated. In sensitivity analysis, ICERs fall as the probability of oCAD increases from the base case value of 15%. The ranking of ICERs among strategies is sensitive to test costs, including the time cost for testing. The analysis reveals ways to improve on prespecified GES thresholds. CONCLUSIONS: Diagnostic testing for oCAD with a novel GES strategy in a 2-threshold model is cost effective by conventional standards. This diagnostic approach is more efficient than usual care of MPI alone or a 1-threshold GES strategy in most scenarios.

Inflammatory protein expression in human subglottic stenosis tissue mirrors that in a murine model.

OBJECTIVES: We undertook to describe the genetic and protein composition of subglottic stenosis (SGS) by measuring an array of protein expression and messenger RNA levels within human SGS tissue. We also sought to compare this human array to cytokine expression from a murine model of SGS in order to confirm the effective translational nature of our animal model. METHODS: Human granulation tissue from 10 patients with early symptomatic SGS was compared to control bronchus. The expression levels of 24 different cytokines were measured by a Luminex protein assay and real-time polymerase chain reaction. RESULTS: The protein expression in human SGS mirrors that seen in murine SGS. Transforming growth factor ß1, interleukin 1ß, and matrix metalloproteinase 9 were markedly elevated in both human and mouse SGS tissues. The protein array showed a statistically significant elevation in the proinflammatory cytokines tumor necrosis factor α, interleukin 1, granulocyte macrophage colony-stimulating factor, and interferon γ. CONCLUSIONS: This is the first study, to our knowledge, to measure an array of protein expression within human SGS tissue. The expression profile suggests that symptomatic tracheal granulation tissue is mostly within the early inflammatory phase of wound healing and has only begun fibrotic and angiogenic remodeling. This study validates our murine model of SGS, and also helps to define the exact pathways of tissue injury, in the hope of leading to new treatments for this difficult condition.

Economic analysis of bevacizumab, cetuximab, and panitumumab with fluoropyrimidine-based chemotherapy in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC).

OBJECTIVE: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Canada (excluding non-melanoma skin cancers). Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to human vascular endothelial growth factor. A sub-study confirmed its effectiveness in KRAS wild-type patients. Recent evidence has shown clinical benefit from anti-epidermal growth factor treatments cetuximab and panitumumab in these patients. The cost-effectiveness, to the Canadian healthcare system, of fluoropyrimidine-based chemotherapy (FBC) in combination with bevacizumab, cetuximab, or panitumumab was assessed for first-line treatment of KRAS wild-type mCRC patients. METHODS: A Markov model was developed and calibrated to progression-free/overall survival, using separately reported trial survival and adverse event results for each comparator. Health-state resource utilization was derived from published data and oncologist input. Utilities and unit prices were obtained from published literature and standard Canadian sources. RESULTS: Results per patient are over a lifetime horizon, to a maximum of 10 years, with 5% annual discounting. Comparators are ordered by total cost and the incremental cost-effectiveness ratio (ICER) of each is determined against the previous non-dominated therapy. Compared to FBC alone, bevacizumab + FBC has an ICER of $131,600 per QALY gained. Compared to bevacizumab + FBC, panitumumab + FBC is dominated and cetuximab + FBC has an ICER of $3.8 million per QALY. In probabilistic sensitivity analysis, bevacizumab + FBC had ∼100%, ∼100%, and 98.9% probabilities of being more cost-effective than both of the other combination treatments at thresholds of $50,000/QALY, $100,000/QALY, and $200,000/QALY, respectively. CONCLUSION: For first-line treatment of KRAS-WT mCRC, bevacizumab + FBC is associated with substantially lower costs as compared to panitumumab + FBC or cetuximab + FBC. Key limitations were that survival curves and adverse event rates were taken from separate clinical trials and that an indirect comparison was not included. Given these findings, bevacizumab is likely to offer the best value for money for this patient population.

Cost effectiveness of targeted high-dose atorvastatin therapy following genotype testing in patients with acute coronary syndrome.

BACKGROUND: Results from the PROVE IT trial suggest that patients with acute coronary syndrome (ACS) treated with atorvastatin 80 mg/day (A80) have significantly lower rates of cardiovascular events compared with patients treated with pravastatin 40 mg/day (P40). In a genetic post hoc substudy of the PROVE IT trial, the rate of event reduction was greater in carriers of the Trp719Arg variant in kinesin family member 6 protein (KIF6) than in noncarriers. We assessed the cost effectiveness of testing for the KIF6 variant followed by targeted statin therapy (KIF6 Testing) versus not testing patients (No Test) and treating them with P40 or A80 in the USA from a payer perspective. METHODS: A Markov model was developed in which 2-year event rates from PROVE IT were extrapolated over a lifetime horizon. Costs and utilities were derived from published literature. All costs were in 2010 US dollars except the cost of A80, which was in 2012 US dollars because the generic formulation was available in 2012. Expected costs and quality-adjusted life-years (QALYs) were estimated for each strategy over a lifetime horizon. RESULTS: Lifetime costs were US$31,700; US$37,100 and US$41,300 for No Test P40, KIF6 Testing and No Test A80 strategies, respectively. The No Test A80 strategy was associated with more QALYs (9.71) than the KIF6 Testing (9.69) and No Test P40 (9.57) strategies. No Test A80 had an incremental cost-effectiveness ratio (ICER) of US$232,100 per QALY gained compared with KIF6 Testing. KIF6 Testing had an ICER of US$45,300 per QALY compared with No Test P40. CONCLUSIONS: Testing ACS patients for KIF6 carrier status may be a cost-effective strategy at commonly accepted thresholds. Treating all patients with A80 is more expensive than treating patients on the basis of KIF6 results, but the modest gain in QALYs is achieved at a cost/QALY that is generally considered unacceptable compared with the KIF6 Testing strategy. Compared with treating all patients with P40, the KIF6 Testing strategy had an ICER below US$50,000 per QALY. The conclusions from this study are sensitive to the price of generic A80 and the effect on adherence of knowing KIF6 carrier status. The results were based on a post hoc substudy of the PROVE IT trial, which was not designed to test the effectiveness of KIF6 testing.

Pulse steroid therapy inhibits murine subglottic granulation.

OBJECTIVE: Using a functional model of airway granulation tissue in subglottic stenosis, we investigated changes in inflammatory markers within granulation tissue in response to intraperitoneal dexamethasone injections. Changes in inflammatory markers will allow us to identify potential targets for immunological therapy. STUDY DESIGN: Institutional Animal Care and Use Committee-approved animal study. SETTING: Philadelphia Veterans Administration Medical Center animal research facility. SUBJECTS AND METHODS: Laryngotracheal complexes of donor mice underwent direct airway injury and were transplanted into subcutaneous tissue of 19 recipient mice in 2 groups: steroid treated and untreated, with sample sizes of 10 and 9, respectively. The steroid-treated arm received intraperitoneal injection of dexamethasone for 3 weeks. Laryngotracheal complexes were then harvested, and granulation formation was measured. The messenger RNA (mRNA) expression of transforming growth factor (TGF)-ß(1) and interleukin (IL)-1 was quantified. RESULTS: At 3 weeks posttransplantation, there were statistically significant differences in observable granulation formation as well as mRNA expression of TGF-ß(1) and IL-1ß in all groups within the steroid treated arm as compared with the untreated arm. CONCLUSIONS: Systemic steroids have been used to prevent formation of granulation tissue and subglottic stenosis. However, the study of the immunologic markers and the corresponding changes with steroid treatment has not been well studied in animal models. Using a previously described novel murine model, we begin to delineate inflammatory markers that can be applied for potential therapeutic targets.

Methicillin-resistant Staphylococcus aureus laryngitis: a report of two cases with different clinical presentations.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infection has been described in multiple areas of the head and neck. Recently, otolaryngologists have recognized MRSA infection in the glottis. We describe 2 cases of MRSA laryngitis with divergent clinical presentations: acute airway obstruction and recalcitrant hoarseness. METHODS: Report of 2 cases and review of the literature. RESULTS: In the first case, a 44-year-old woman presented with near aphonia despite maximal medical therapy. Examination showed diffuse erythema and edema of the endolarynx with yellowish plaques lining the glottis and supraglottis. Complete resolution was achieved with long-term trimethoprim-sulfamethoxazole. In the second case, a 54-year-old woman presented with recent-onset hoarseness with rapid progression to respiratory distress and biphasic stridor. Endoscopy revealed exuberant granulation tissue in the glottis with a narrowed airway. Treatment required prolonged courses of antibiotics and steroids. Diagnosis in both cases was confirmed with biopsies taken during direct laryngoscopy. CONCLUSIONS: MRSA treatment is a growing part of otolaryngologic practice and should be included in the differential diagnosis of hoarseness and stridor.

Cellular adaptive inflammation mediates airway granulation in a murine model of subglottic stenosis.

OBJECTIVE: To determine the contribution of B- and T-cell-mediated inflammation in a murine airway granulation model. STUDY DESIGN: Pilot study in a modified murine model. SETTING: Philadelphia VA Medical Center Research Building. SUBJECTS AND METHODS: Laryngotracheal complexes (LTCs) from 54 donor C57BL/6 mice were harvested and divided into 3 groups: (1) uninjured, (2) mechanically injured using a wire brush, and (3) chemically injured using hydrochloric acid. One donor LTC from each group was placed in deep dorsal subcutaneous pockets of either severe combined immunodeficiency (SCID)- or C57BL-recipient mice, for a total of 3 transplanted tracheas per recipient mouse. After 3 weeks, the transplanted LTCs were harvested from both C57BL- and SCID-recipient mice. Tissues were fixed, sectioned, and stained with hematoxylin and eosin. Representative slides were reviewed by a blinded pathologist to determine the formation of granulation tissue and graded as to the degree of formation of granulation tissue. RESULTS: Despite significant granulation formation in C57BL-recipient mice, direct airway injury did not induce the formation of granulation tissue under the disrupted epithelium of airway mucosa in SCID mice 3 weeks after injury. CONCLUSION: The data indicate that the immune response that results in the formation of granulation tissue is mediated by circulating B- and/or T-cell processes rather than resident airway immune cells. Further studies focusing on cellular adaptive immune processes in response to airway injury may provide a novel treatment modality for subglottic stenosis.

Inhaled triamcinolone with proton pump inhibitor for treatment of vocal process granulomas: a series of 67 granulomas.

OBJECTIVES: We sought to analyze the outcomes of vocal process granulomas treated with proton pump inhibitors and inhaled triamcinolone acetonide. METHODS: We reviewed the medical records of patients with a diagnosis of contact granuloma or vocal process granuloma between 1995 and 2008. Data included age, gender, intubation history, reflux history, lesion location, previous treatment methods, treatment course, and recurrence. All patients were treated with daily or twice-daily protein pump inhibitors and inhaled triamcinolone acetonide (300 microg 3 times a day). RESULTS: Sixty-seven granulomas were diagnosed in 54 patients: 13 bilateral and 41 unilateral. Twenty patients, including all 11 women, had a recent history of intubation. Sixty-two granulomas in 50 patients were treated with triamcinolone and a proton pump inhibitor. Of the 57 granulomas that completed treatment, 5 (9%) did not respond (mean follow-up, 50 weeks; range, 30.3 to 78.3 weeks), 13 (22%) partially responded (mean follow-up, 11 weeks; range, 3 to 30 weeks), and 40 (69%) completely responded (mean follow-up, 21 weeks; range, 5.9 to 84.6 weeks). Three cases had recurrence: 2 nonresponders and 1 complete responder. One patient developed oral thrush. CONCLUSIONS: In this study, vocal process granulomas occurred more frequently in men, whereas women developed granulomas only after intubation. The anti-inflammatory action of inhaled triamcinolone combined with antireflux proton pump inhibitors successfully treats most vocal process granulomas with low rates of side effects and recurrence.

Primary tracheoesophageal puncture in stapler-assisted total laryngectomy.

BACKGROUND/AIMS: The purpose of this article was to present a novel technique for primary tracheoesophageal puncture (TEP) in patients undergoing stapler-assisted laryngectomy. METHODS: A case series of 10 consecutive patients treated with stapler-assisted laryngectomy that underwent primary TEP at the time of the initial surgery was conducted. The technique involves the use of a flexible esophagoscope and a modified Seldinger technique to safely create the TEP under direct visualization without disrupting the stapler closure. This series was performed at a single academic institution. The primary outcome measured was ability of alaryngeal speech. RESULTS: A total of 10 consecutive patients had the procedure done. All patients achieved alaryngeal speech and there were no complications. CONCLUSION: This method allows for a safe and efficient TEP creation at the time of stapler-assisted laryngectomy, obviating the need for secondary procedures, either in the office or operating room.

An atypical case of fatal zygomycosis: simultaneous cutaneous and laryngeal infection in a patient with a non-neutropenic solid prostatic tumor.

We describe what we believe is the first reported case of simultaneous highly invasive cutaneous and laryngopharyngeal zygomycosis in a non-neutropenic, nondiabetic but immunosuppressed patient with prostate cancer. An invasive fungal process was not suspected until late in the patient's hospital course; when it was, a tracheotomy and direct laryngoscopic biopsies were performed. Unresectable invasive zygomycosis with Rhizopus rhizopodiformis was diagnosed. The patient was managed with liposomal amphotericin B initially and later with palliative medical therapy until he died. This case emphasizes the need for a rapid and specific diagnosis with timely introduction of appropriate antifungal management, particularly now that voriconazole is frequently used as empiric prophylaxis against aspergillosis in high-risk patients.