The prevalence of fibrotic diseases and the lack of pharmacologic modalities to effectively treat them impart particular importance to the discovery of novel antifibrotic therapies. The repurposing ...of drugs with existing mechanisms of action and/or clinical data is a promising approach for the treatment of fibrotic diseases. One paradigm that pervades all fibrotic diseases is the pathological myofibroblast, a collagen-secreting, contractile mesenchymal cell that is responsible for the deposition of fibrotic tissue. In this study, we use a gene expression paradigm characteristic of activated myofibroblasts in combination with the Connectivity Map to select compounds that are predicted to reverse the pathological gene expression signature associated with the myofibroblast and thus contain the potential for use as antifibrotic compounds. We tested a small list of these compounds in a first-pass screen, applying them to fibroblasts, and identified the retinoic acid receptor agonist Ch55 as a potential hit. Further investigation exhibited and elucidated the antifibrotic effects of Ch55 in vitro as well as showing antiscarring activity upon intradermal application in a preclinical rabbit ear hypertrophic scar model. We hope that similar predictions to uncover antiscarring compounds may yield further preclinical and ultimately clinical success.
Pituitary tumors (PTs) continue to present unique challenges given their proximity to the cavernous sinus, whereby invasive behavior can limit the extent of resection and surgical outcome, especially ...in functional tumors. The aim of this study was to elucidate patterns of cavernoinvasive behavior by PT subtype.
A total of 169 consecutive first-time surgeries for PTs were analyzed; 45% of the tumors were functional. There were 64 pituitary transcription factor-1 (PIT-1)-expressing, 62 steroidogenic factor-1 (SF-1)-expressing, 38 T-box transcription factor (TPIT)-expressing, and 5 nonstaining PTs. The gold standard for cavernous sinus invasion (CSI) was based on histopathological examination of the cavernous sinus medial wall and intraoperative exploration.
Cavernous sinus disease was present in 33% of patients. Of the Knosp grade 3 and 4 tumors, 12 (19%) expressed PIT-1, 7 (11%) expressed SF-1, 8 (21%) expressed TPIT, and 2 (40%), were nonstaining (p = 0.36). PIT-1 tumors had a significantly higher predilection for CSI: 53% versus 24% and 18% for TPIT and SF-1 tumors, respectively (OR 6.08, 95% CI 2.86-13.55; p < 0.001). Microscopic CSI-defined as Knosp grade 0-2 tumors with confirmed invasion-was present in 44% of PIT-1 tumors compared with 7% and 13% of TPIT and SF-1 tumors, respectively (OR 11.72, 95% CI 4.35-35.50; p < 0.001). Using the transcavernous approach to excise cavernous sinus disease, surgical biochemical remission rates for patients with acromegaly, prolactinoma, and Cushing disease were 88%, 87%, and 100%, respectively. The granule density of PIT-1 tumors and corticotroph functional status did not influence CSI.
The likelihood of CSI differed by transcription factor expression; PIT-1-expressing tumors had a higher predilection for invading the cavernous sinus, particularly microscopically, compared with the other tumor subtypes. This elucidates a unique cavernoinvasive behavior absent in cells from other lineages. Innovative surgical techniques, however, can mitigate tumor behavior and achieve robust, reproducible biochemical remission and gross-total resection rates. These findings can have considerable implications on the surgical management and study of PT biology and behavior.
STUDY DESIGNRetrospective cohort. OBJECTIVEDue to anterior cervical discectomy and fusion (ACDF) popularity, it is important to predict postoperative complications, unfavorable 90-day readmissions, ...and two-year reoperations to improve surgical decision-making, prognostication, and planning. SUMMARY OF BACKGROUND DATAMachine learning has been applied to predict postoperative complications for ACDF; however, studies were limited by sample size and model type. These studies achieved ≤0.70 area under the curve (AUC). Further approaches, not limited to ACDF, focused on specific complication types and resulted in AUC between 0.70 and 0.76. MATERIALS AND METHODSThe IBM MarketScan Commercial Claims and Encounters Database and Medicare Supplement were queried from 2007 to 2016 to identify adult patients who underwent an ACDF procedure (N=176,816). Traditional machine learning algorithms, logistic regression, and support vector machines, were compared with deep neural networks to predict: 90-day postoperative complications, 90-day readmission, and two-year reoperation. We further generated random deep learning model architectures and trained them on the 90-day complication task to approximate an upper bound. Last, using deep learning, we investigated the importance of each input variable for the prediction of 90-day postoperative complications in ACDF. RESULTSFor the prediction of 90-day complication, 90-day readmission, and two-year reoperation, the deep neural network-based models achieved AUC of 0.832, 0.713, and 0.671. Logistic regression achieved AUCs of 0.820, 0.712, and 0.671. Support vector machine approaches were significantly lower. The upper bound of deep learning performance was approximated as 0.832. Myelopathy, age, human immunodeficiency virus, previous myocardial infarctions, obesity, and documentary weakness were found to be the strongest variable to predict 90-day postoperative complications. CONCLUSIONSThe deep neural network may be used to predict complications for clinical applications after multicenter validation. The results suggest limited added knowledge exists in interactions between the input variables used for this task. Future work should identify novel variables to increase predictive power.
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Fibrosis is a pathological repair process common among organs, that responds to tissue damage by replacement with non-functional connective tissue. Despite the widespread prevalence ...of tissue fibrosis, manifesting in numerous disease states across myriad organs, therapeutic modalities to prevent or alleviate fibrosis are severely lacking in quantity and efficacy. Alongside development of new drugs, repurposing of existing drugs may be a complementary strategy to elect anti-fibrotic compounds for pharmacologic treatment of tissue fibrosis. Drug repurposing can provide key advantages to de novo drug discovery, harnessing the benefits of previously elucidated mechanisms of action and already existing pharmacokinetic profiles. One class of drugs with a wealth of clinical data and extensively studied safety profiles is the statins, a class of antilipidemic drugs widely prescribed for hypercholesterolemia. In addition to these widely utilized lipid-lowering effects, increasing data from cellular, pre-clinical mammalian, and clinical human studies have also demonstrated that statins are able to alleviate tissue fibrosis originating from a variety of pathological insults via lesser-studied, pleiotropic effects of these drugs. Here we review literature demonstrating evidence for direct effects of statins antagonistic to fibrosis, as well as much of the available mechanistic data underlying these effects. A more complete understanding of the anti-fibrotic effects of statins may paint a clearer picture of their anti-fibrotic potential for various clinical indications. Additionally, more lucid comprehension of the mechanisms by which statins exert anti-fibrotic effects may aid in development of novel therapeutic agents that target similar pathways but with greater specificity or efficacy.
Candidates for anterior cervical discectomy and fusion (ACDF) have a higher rate of opioid use than does the public, but studies on preoperative opioid use have not been conducted. We aimed to ...understand how preoperative opioid use affects post-ACDF outcomes.
The MarketScan Database was queried from 2007 to 2015 to identify adult patients who underwent an ACDF. Patients were classified into separate cohorts based on the number of separate opioid prescriptions in the year before their ACDF. Ninety-day postoperative complications, postoperative readmission, reoperation, and total inpatient costs were compared between opioid strata. Propensity score-matched patient cohorts were calculated to balance comorbidities across groups.
Of 81,671 ACDF patients, 31,312 (38.3%) were nonusers, 30,302 (37.1%) were mild users, and 20,057 (24.6%) were chronic users. Chronic opioid users had a higher comorbidity burden, on average, than patients with less frequent opioid use (P < 0.001). Chronic opioid users had higher rates of postoperative complications (9.1%) than mild opioid users (6.0%) and nonusers (5.3%) (P < 0.001) and higher rates of readmission and reoperation. After balancing opioid nonusers versus chronic opioid users along with demographic characteristics, preoperative comorbidity, and operative characteristics, postoperative complications remained elevated for chronic opioid users relative to opioid nonusers (8.6% vs. 5.7%; P < 0.001), as did rates of readmission and reoperation.
Chronic opioid users had more comorbidities than opioid nonusers and mild opioid users, longer hospitalizations, and higher rates of postoperative complication, readmission, and reoperation. After balancing patients across covariates, the outcome differences persisted, suggesting a durable association between preoperative opioid use and negative postoperative outcomes.
Background
Though meningioma is the most common primary brain tumor, there is a paucity of epidemiologic studies investigating disparities in treatment and patient outcomes. Therefore, we sought to ...explore how sociodemographic factors are associated with rates of gross total resection (GTR) and radiotherapy as well as survival.
Methods
The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was queried to identify adult patients with meningioma diagnosed between 2005 and 2015. Socioeconomic status (SES) was determined using a validated composite index in which patients were stratified into tertiles and quintiles. Multivariable logistic regression and Cox proportional hazards analyses were used to identify predictors of treatment and survival, respectively.
Results
71,098 patients met our inclusion criteria. Low SES quintile was associated with reduced odds of receiving GTR (OR 0.76, 95% CI 0.69–0.83, p < 0.0001) and radiotherapy (OR 0.83, 95% CI 0.76–0.91, p < 0.0001) as well as worse survival (HR 1.48, 95% CI 1.41–1.56) as compared to the highest SES quintile. Black patients had reduced odds of GTR (OR 0.74, 95% CI 0.67–0.71, p < 0.0001) and worse survival (HR 1.23, 95% CI 1.18–1.29, p < 0.0001) as compared to white patients.
Conclusions
This national study of patients with meningioma found socioeconomic status and race to be independent inverse correlates of likelihood of GTR, radiotherapy, and survival. Limited access to care may underlie these disparities in part, and future studies are warranted to identify specific causes for these findings.
Fibrotic skin conditions, such as hypertrophic and keloid scars, frequently result from injury to the skin and as sequelae to surgical procedures. The development of skin fibrosis may lead to patient ...discomfort, limitation in range of motion, and cosmetic disfigurement. Despite the frequency of skin fibrosis, treatments that seek to address the root causes of fibrosis are lacking. Much research into fibrotic pathophysiology has focused on dermal pathology, but less research has been performed to understand aberrations in fibrotic epidermis, leading to an incomplete understanding of dermal fibrosis. Herein, literature on occlusion, a treatment modality known to reduce dermal fibrosis, in part through accelerating wound healing and regulating aberrant epidermal inflammation that otherwise drives fibrosis in the dermis, is reviewed. The review focuses on epidermal-dermal crosstalk, which contributes to the development and maintenance of dermal fibrosis, an underemphasized interplay that may yield novel strategies for treatment if understood in more detail.
We assessed whether the insurance type reflects a patient's quality of care after an anterior discectomy and fusion (ACDF) procedure by comparing differences in the postoperative complications, ...readmission rates, reoperation rates, lengths of hospital stay, and cost of treatment between patients with Medicare versus private insurance.
Propensity score matching was used to match patient cohorts insured by Medicare and private insurance in the MarketScan Commercial Claims and Encounters Database (2007–2016). Age, sex, year of operation, geographic region, comorbidities, and operative factors were used to match cohorts of patients who had undergone an ACDF procedure.
A total of 110,911 patients met the inclusion criteria. Of these patients, 97,543 patients (87.9%) were privately insured and 13,368 patients (12.1%) were insured by Medicare. The propensity score matching algorithm matched 7026 privately insured patients to 7026 Medicare patients. After matching, no significant differences were found in the 90-day postoperative complication rates, lengths of stay, or reoperation rates between the Medicare and privately insured cohorts. The Medicare group had had lower postoperative readmission rates for all time points: 30 days (1.8% vs. 4.6%; P < 0.001), 60 days (2.5% vs. 6.3%; P < 0.001), and 90 days (4.2% vs. 7.7%; P < 0.001). The median payment to physicians was significantly lower for the Medicare group ($3885 vs. $5601; P < 0.001).
In the present study, propensity score matched patients covered by Medicare and private insurance who had undergone an ACDF procedure had had similar treatment outcomes.
Deep brain stimulation (DBS) surgery is an established treatment for many patients with neurologic disease, and a common complication of DBS is surgical site infection (SSI). In 2016, neurosurgeons ...at our institution began enclosing implantable pulse generators (IPGs) within fully absorbable, antibacterial envelopes in patients who underwent initial DBS implantation. We sought to determine whether the use of antibacterial envelopes reduced IPG-related SSIs.
We performed a retrospective chart review of all adult patients who underwent initial DBS implantation at Stanford Hospital between November 14, 2012, and November 9, 2020. Operative details, perioperative antibiotics, comorbidities, and postoperative complications were extracted for all patients. Univariate and multivariate logistic regression were used to identify factors associated with SSIs within three months of surgery, and interrupted time-series analysis was performed to assess whether the departmental adoption of the antibacterial envelope led to a reduction in IPG SSIs.
Of 344 patients who underwent initial IPG implantation with the antibacterial envelope, one developed an SSI within three months of surgery (0.3%), compared with six of 204 patients (2.9%) who underwent the same procedure without the antibacterial envelope (odds ratio: 0.10, 95% CI: 0.01-0.80, p = 0.031). Univariate logistic regression revealed that the antibacterial envelope and 2000-mg intravenous cefazolin perioperatively were associated with reduced SSI risk, whereas no other factors reached statistical significance. After adjusting for comorbidities, no association remained statistically significant. Interrupted time-series analysis showed a reduction in SSIs after 2016, but the effect was not significant.
The adoption of antibacterial envelopes was found to reduce IPG SSIs at the univariate level, but this association did not remain significant after controlling for confounding variables including perioperative antibiotic administration. Although encouraging, this study does not conclusively establish that the use of antibacterial pouches in patients who underwent initial DBS implantation reduces the incidence of IPG SSIs. Future prospective studies that control for confounding variables are necessary to determine the efficacy of antibacterial envelopes in reducing post-DBS infections at the IPG site before clear recommendations can be made.
Retrospective cohort study.
Anterior cervical discectomy and fusion (ACDF) is a common surgical intervention for patients diagnosed with cervical degenerative diseases with or without myelopathy. A ...thorough understanding of outcomes in patients with and without myelopathy undergoing ACDF is required because of the widespread utilization of ACDF for these indications.
Non-ACDF approaches achieved inferior outcomes in certain myelopathic cases. Studies have compared patient outcomes across procedures, but few have compared outcomes concerning myelopathic versus nonmyelopathic cohorts.
The MarketScan database was queried from 2007 to 2016 to identify adult patients who were ≤65 years old, and underwent ACDF using the international classification of diseases 9th version and current procedural terminology codes. Nearest neighbor propensity-score matching was employed to balance patient demographics and operative characteristics between myelopathic and nonmyelopathic cohorts.
Of 107,480 patients who met the inclusion criteria, 29,152 (27.1%) were diagnosed with myelopathy. At baseline, the median age of patients with myelopathy was higher (52 years vs. 50 years, p <0.001), and they had a higher comorbidity burden (mean Charlson comorbidity index, 1.92 vs. 1.58; p <0.001) than patients without myelopathy. Patients with myelopathy were more likely to undergo surgical revision at 2 years (odds ratio OR, 1.63; 95% confidence interval CI, 1.54-1.73) or are readmitted within 90 days (OR, 1.27; 95% CI, 1.20-1.34). After patient cohorts were matched, patients with myelopathy remained at elevated risk for reoperation at 2 years (OR, 1.55; 95% CI, 1.44-1.67) and postoperative dysphagia (2.78% vs. 1.68%, p <0.001) compared to patients without myelopathy.
We found inferior postoperative outcomes at baseline for patients with myelopathy undergoing ACDF compared to patients without myelopathy. Patients with myelopathy remained at significantly greater risk for reoperation and readmission after balancing potential confounding variables across cohorts, and these differences in outcomes were largely driven by patients with myelopathy undergoing 1-2 level fusions.
