BACKGROUND: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core outcome sets (COS) are agreed, standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition. OBJECTIVES: To identify and reach a consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) core domain set for clinical trials in PG. METHODS: Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥ 70% of participants rating a domain as 'extremely important' and < 15% of participants voting 'not important'), followed by an international meeting to reach consensus on the core domain set (consensus: < 30% disagreement). Item-generation discussions and consensus meetings were hosted via online videoconferences. The eDelphi exercise and consensus voting were performed using Qualtrics survey software. Participants were adults with PG, healthcare professionals, researchers and industry representatives. RESULTS: Collaborative discussions and systematic reviews yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed the three lowest-priority domains ('laboratory tests', 'treatment costs' and 'disease impact on family') and ranked 'pain', 'quality of life' and 'physical symptoms' as the highest-priority prospective domains. Consensus was reached on the domains of 'pain', 'quality of life' and 'clinical signs'. The domain of 'disease course/disease progression' narrowly failed to reach consensus for inclusion in the core set (32% of participants voted 'no'). Refinement of this domain definition will be required and presented for consideration at future consensus meetings. CONCLUSIONS: The UPGRADE core domain set for clinical trials in PG has been agreed by international multistakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a COS.
Pyoderma Gangrenosum , Adult , Humans , Treatment Outcome , Pyoderma Gangrenosum/diagnosis , Prospective Studies , Outcome Assessment, Health Care , Pain , Delphi Technique , Research Design
Introduction: Hidradenitis suppurativa (HS) is associated with comorbidities that are risk factors for severe COVID-19 infection. We evaluated demographics and COVID-19 outcomes in HS patients. Methods: HS patients with COVID-19 (HS+/COVID+) and a randomized age-, race-, and sex-matched control population of patients without HS with COVID-19 (HS-/COVID+) were selected through a retrospective chart review. Data were collected on demographics, medications, comorbidities, vaccination status, and COVID-19 treatment/outcomes. Fisher's exact test was used to analyze the relationship between risk factors and COVID-19 outcomes. A p value of <0.05 was considered statistically significant. Results: There were 58 HS+/COVID+ patients, primarily African American (83%, n = 48) and female (88%, n = 51). Compared to HS+/COVID+ patients, HS-/COVID+ patients were significantly more likely to have cardiovascular disease (51% vs. 24%; p = 0.0029) and be pregnant (23% vs. 4%; p = 0.0093). HS+/COVID+ and HS-/COVID+ patients did not vary significantly in vaccination rate at time of COVID-19 diagnosis (6% vs. 5%; p = 0.78). HS-/COVID+ patients were significantly more likely to have COVID-19 complications (35% vs. 7%; p = 0.001) and receive COVID-19 treatment (37% vs. 7%; p = 0.0001) when compared to HS+/COVID+ patients. Conclusion: Our findings support the growing evidence that having HS itself may not be a risk factor for severe COVID-19 outcomes.
Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle (ACTA2). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-ß as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.
Cancer-Associated Fibroblasts , Glioblastoma , Humans , Glioblastoma/genetics , Transcriptome , DNA Copy Number Variations , Endothelial Cells , Sequence Analysis, RNA
Janus kinase inhibitors (JAKis) are promising medications that the Food and Drug Administration recently approved for treatment of atopic dermatitis in January 2022. These medications offer a novel therapeutic mechanism and may be an additional treatment avenue for patients who are currently reliant on conventional immunosuppressants, such as cyclosporine A, methotrexate, or mycophenolate mofetil, or newer medications, such as dupilumab. However, redundant treatment puts patients at risk for excessive toxicity and polypharmacy, whereas abrupt tapering of a preexisting regimen may cause flares of the disease. Thus, transitioning to JAKis should be implemented strategically to retain the therapeutic benefit and minimize the risk of flares. Herein, we outline gradual transition schemas for patients needing to transition to JAKis from conventional immunosuppressants or dupilumab. There is no evidence-based guideline to instruct this transition to JAKis, and our recommendations are based on expert experience and the review of efficacy data from pivotal trials.
Introduction: Hidradenitis suppurativa (HS) can significantly impact patients' relationships. Methods: Using an anonymous electronic survey, we aimed to determine what aspects of sexual relationships are affected by HS discomfort and patients' reluctance to discuss HS with their partner. Results: Among the 873 participants, 60.9% reported that some aspect of their relationship was affected by HS discomfort, with the greatest being their sexual encounters with spouse (49.1%). Furthermore, 43.0% (320) of participants reported feeling reluctant to discuss HS with their spouse/significant other, with the more common reason being fear of partner seeing boils and scars (84.7%). Multiple aspects of relationships can be affected by HS such as sexual encounters, overall relationship, and finding a relationship. Additionally, several communication barriers are present, such as fear of partner seeing boils and scars, partner thinking they had an infection such as a sexually transmitted disease, and fear of bloody or malodorous drainage, among others. The presence of anogenital pain, Hurley stage, gender, and age significantly affect these findings. Conclusion: Addressing HS-related relationship disturbances should be included in HS management.
BACKGROUND: Childhood sun exposure is associated with development of future skin cancers. Sunscreens are an important tool to prevent harmful ultraviolet rays. OBJECTIVES: The aims of the study are to evaluate sunscreens targeted to children and to analyze cost, marketing claims, ingredients, and allergens to help consumers select products. METHODS: The top 50 pediatric sunscreens across retailers were analyzed for their cost, marketing claims, ingredients, vehicles, and containers. Ingredients were compared with the American Contact Dermatology Society 2020 Core Allergen List. RESULTS: The mean price was $6.20 per ounce (range, $0.25-$39.98). The mean sun protection factor was 48.5 (range, 30-100; SD, 48.5). There was a mean of 17.5 ingredients and a mean of 1.1 allergens in products. On average, products marketed as "sensitive skin" were not only significantly more expensive ($8.90 vs $3.50 per ounce, P = 0.01) but also were significantly more likely to not contain any allergens (36.0%, n = 18 vs 12%, n = 6; P = 0.05). Products with mineral-only UV blockers were significantly less likely to have any allergen when compared with products that had chemical UV blockers (5.6%, n = 1 vs 94.4%, n = 17; P = 0.02). CONCLUSIONS: The current market of pediatric sunscreens varies significantly in price, marketing claims, and active ingredients. Products marked as suitable for sensitive skin had significantly fewer allergens, but a majority of these products still had at least one allergen. Many sunscreens contain contact allergens, which is an important selection consideration.
Allergens , Sunscreening Agents , Humans , Child , Allergens/adverse effects , Marketing , Pharmaceutical Vehicles , Costs and Cost Analysis
Introduction: Hidradenitis suppurativa (HS) patients may be at increased risk of COVID-19 infection and complications from their medications and comorbidities. There is a lack of expert consensus on recommendations for the COVID-19 vaccine for HS patients. Herein, we aim to provide expert-driven consensus recommendations regarding COVID-19 vaccinations in HS patients. Methods: A modified Delphi consensus survey developed by a core committee of 7 dermatologist HS experts consisting of 4 demographic questions and 12 practice statements was distributed to the US HS Foundation-sponsored provider listserv. Participants were attending physician HS experts. Survey results were to be reviewed by the core group and revised and resubmitted until consensus (≥70% agreement) was achieved. Results: Among the 33 survey participants, there were 30 (87%) dermatologists, 1 general surgeon, 1 plastic surgeon, and 1 rheumatologist. Consensus for all 12 statements on vaccine counseling and HS treatment counseling was achieved after the first round. Discussion/Conclusion: For now, this consensus can serve as a resource for clinicians discussing COVID-19 vaccination with their HS patients. These recommendations will need to be updated as new evidence on COVID-19 emerges.
OBJECTIVE: To review the litigation literature related to patients with pyoderma gangrenosum (PG) to characterize the legal issues they face. DATA SOURCES: Data sources include law databases Casetext and Lexis Nexis. STUDY SELECTION: All disability and medical liability claims directly involving patients with PG were included. DATA EXTRACTION: Data extraction came directly from Casetext and Lexis Nexis. All cases extracted came from September 1965 to December 2020. This resulted in 32 cases, 18 of which were excluded because they did not mention the plaintiff having a diagnosis of PG (n = 14). DATA SYNTHESIS: The review found a total of six medical liability cases in which adverse health outcomes were reported, including prolonged suffering (2/6 cases), unnecessary treatments or procedures (2/6), exacerbation of disease (1/6 cases), and permanent scarring (1/6 cases). Despite this, two plaintiffs won their case and only one of them received any monetary award. Similarly, of the eight disability claims in the review, four were ruled in the favor of the plaintiffs and only two resulted in immediate awarding of benefits. Half of medical liability cases occurred in correctional facilities after the denial of appropriate care. CONCLUSIONS: The findings demonstrate a need for access to specialty care in incarcerated populations. Cases that occurred in a hospital setting also stress the importance of initiatives such as telemedicine to efficiently increase access to care in a cost-effective manner. Further, PG has been recognized as a severe impairment in disability claims despite patients being denied because they were deemed able to perform other work.
Disabled Persons , Malpractice , Pyoderma Gangrenosum , Humans , Databases, Factual , Liability, Legal , Pyoderma Gangrenosum/diagnosis , Pyoderma Gangrenosum/therapy
Background: Oral hypoglycemic agents are a frequent cause of hypoglycemia in nondiabetic people. Here, we report a case of recurrent hypoglycemia caused by glipizide, in which diagnosis was delayed because of a combination of delayed hypoglycemic agent screening and low sensitivity of the hypoglycemic agent screening panel used. Case Report: A 66-year-old woman repeatedly presented with symptomatic hypoglycemia. At the first presentation, the serum glucose level was 40 mg/dL (2.2 mmol/L), C-peptide level was 13.1 ng/mL (0.8-3.1 ng/mL), proinsulin level was 96.9 pmol/L (<18.8 pmol/L), and insulin level was 164 mU/L (<17 mU/L). An initial hypoglycemic agent screening, performed 24 hours after admission, yielded a negative result, leading to prolonged and recurrent hospitalizations for workup and localization of insulinoma. A hypoglycemic agent screening at a subsequent presentation, concordant with hypoglycemia, yielded a positive result for glipizide, which was at a level of 320 ng/mL (reporting limit, 40 ng/mL). An examination of the patient's home medications revealed a container, labeled as benztropine, containing glipizide tablets. After the diagnosis of glipizide-induced hypoglycemia, the patient had no further episodes of hypoglycemia. Discussion: The failure to detect glipizide using the initial hypoglycemia agent assay was likely because of a combination of a delay in the initial screening and low sensitivity of the assay for glipizide compared with that of other available assays. Here, we discuss important considerations for the interpretation of hypoglycemic agent screening in the diagnosis of hypoglycemia, including the timing of collection and reporting, pharmacokinetics of culprit agents, and sensitivity of the hypoglycemic agent panel used. Conclusion: Screening tests for hypoglycemic agents are necessary for the evaluation of hypoglycemia because their biochemical evaluation may be indistinguishable from that of insulinoma.
BACKGROUND: Novel methods in predicting survival in patients with spinal metastases may help guide clinical decision-making and stratify treatments regarding surgery vs palliative care. OBJECTIVE: To evaluate whether the frailty/sarcopenia paradigm is predictive of survival and morbidity in patients undergoing surgery for spinal metastasis. METHODS: A total of 271 patients from 4 tertiary care centers who had undergone surgery for spinal metastasis were identified. Frailty/sarcopenia was defined by psoas muscle size. Survival hazard ratios were calculated using multivariate analysis, with variables from demographic, functional, oncological, and surgical factors. Secondary outcomes included improvement of neurological function and postoperative morbidity. RESULTS: Patients in the smallest psoas tertile had shorter overall survival compared to the middle and largest tertile. Psoas size (PS) predicted overall mortality more strongly than Tokuhashi score, Tomita score, and Karnofsky Performance Status (KPS). PS predicted 90-d mortality more strongly than Tokuhashi score, Tomita score, and KPS. Patients with a larger PS were more likely to have an improvement in deficit compared to the middle tertile. PS was not predictive of 30-d morbidity. CONCLUSION: In patients undergoing surgery for spine metastases, PS as a surrogate for frailty/sarcopenia predicts 90-d and overall mortality, independent of demographic, functional, oncological, and surgical characteristics. The frailty/sarcopenia paradigm is a stronger predictor of survival at these time points than other standards. PS can be used in clinical decision-making to select which patients with metastatic spine tumors are appropriate surgical candidates.
Frailty/complications , Sarcopenia/complications , Spinal Neoplasms/mortality , Spinal Neoplasms/secondary , Spinal Neoplasms/surgery , Adult , Aged , Cohort Studies , Female , Frailty/pathology , Humans , Male , Middle Aged , Prognosis , Proportional Hazards Models , Psoas Muscles/pathology , Retrospective Studies , Sarcopenia/pathology , Treatment Outcome
Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.
Angiogenesis Inhibitors/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Neoplastic Stem Cells/drug effects , Zinc Finger E-box-Binding Homeobox 1/metabolism , Adult , Aged , Angiogenesis Inhibitors/therapeutic use , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/pharmacology , Bevacizumab/therapeutic use , Biphenyl Compounds/pharmacology , Biphenyl Compounds/therapeutic use , Brain/blood supply , Brain/pathology , Brain Neoplasms/blood supply , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Hypoxia/drug effects , Cell Line, Tumor , Chitinase-3-Like Protein 1/metabolism , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/blood supply , Glioblastoma/genetics , Glioblastoma/pathology , Human Umbilical Vein Endothelial Cells , Humans , Lignans/pharmacology , Lignans/therapeutic use , Male , Middle Aged , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/prevention & control , Neoplastic Stem Cells/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Tumor Microenvironment/drug effects , Up-Regulation , Xenograft Model Antitumor Assays , Young Adult , Zinc Finger E-box-Binding Homeobox 1/antagonists & inhibitors
Initial studies on cancer primarily focused on malignant cells themselves. The overarching narrative of cancer revolved around unchecked and rapidly proliferating cells. Special attention was given to the molecular, genetic, and metabolic profiles of isolated cancer cells in hopes of elucidating a critical factor in malignancy. However, the scope of cancer research has broadened over the past few decades to include the local environment around cancer. It has become increasingly apparent that the immune cells, vascular networks, and the extracellular matrix all have a part in cancer progression. The impact of the extracellular matrix is particularly fascinating and key stromal changes have been identified in various cancers. Pioneering work studying laminin and hyaluronate has shown that these molecules have vital roles in cancer progression. More recently, fibronectin has been included as an extracellular driver of malignancy. Fibronectin is thought to play a considerable, albeit poorly understood, role in cancer pathogenesis. In this review, we present fundamental studies that have investigated the impact of fibronectin in cancer. As an abundant component of the extracellular matrix, understanding the effect of this molecule has the potential to elucidate cancer biology.
Fibronectins/genetics , Medical Oncology/trends , Neoplasms/genetics , Disease Progression , Extracellular Matrix/genetics , Humans , Laminin/genetics , Neoplasms/metabolism , Neoplasms/pathology
OBJECTIVE: Neurosurgeons play an important role in advancing medicine through research, the funding of which is historically linked to the National Institutes of Health (NIH). The authors defined variables associated with neurosurgical NIH funding, prevalence of funded topics by neurosurgical subspecialty, and temporal trends in NIH neurosurgical funding. METHODS: The authors conducted a retrospective review of NIH-funded American Association of Neurological Surgeons members using NIH RePORTER (http://report.nih.gov/) for the years 1991-2015. RESULTS: The authors followed 6515 neurosurgeons from 1991 to 2015, including 6107 (94%) non-MD-PhD physicians and 408 (6%) MD-PhDs. NIH grants were awarded to 393 (6%) neurosurgeons, with 23.2% of all first-time grants awarded to the top 5 funded institutions. The average total funded grant-years per funded neurosurgeon was 12.5 (range 1-85 grant-years). A higher percentage of MD-PhDs were NIH funded than MDs (22% [n = 91] vs 5% [n = 297], p < 0.0001). The most common grants awarded were R01 (128, 33%), K08 (69, 18%), F32 (60, 15%), M01 (50, 13%), and R21 (39, 10%). F32 and K08 recipients were 9-fold (18% vs 2%, p < 0.001) and 19-fold (38% vs 2%, p < 0.001) more likely to procure an R01 and procured R01 funding earlier in their careers (F32: 7 vs 12 years after residency, p = 0.03; K08: 9 vs 12 years, p = 0.01). Each year, the number of neurosurgeons with active grants linearly increased by 2.2 (R2 = 0.81, p < 0.001), whereas the number of total active grants run by neurosurgeons increased at nearly twice the rate (4.0 grants/year) (R2 = 0.91, p < 0.001). Of NIH-funded neurosurgical grants, 33 (9%) transitioned to funded clinical trial(s). Funded neurosurgical subspecialties included neuro-oncology (33%), functional/epilepsy (32%), cerebrovascular (17%), trauma (10%), and spine (6%). Finally, the authors modeled trends in the number of active training grants and found a linear increase in active R01s (R2 = 0.95, p < 0.001); however, both F32 (R2 = 0.36, p = 0.01) and K08 (R2 = 0.67, p < 0.001) funding had a significant parabolic rise and fall centered around 2003. CONCLUSIONS: The authors observed an upward trend in R01s awarded to neurosurgeons during the last quarter century. However, their findings of decreased K08 and F32 training grant funding to neurosurgeons and the impact of these training grants on the ultimate success and time to success for neurosurgeons seeking R01 funding suggests that this upward trend in R01 funding for neurosurgeons will be difficult to maintain. The authors' work underscores the importance of continued selection and mentorship of neurosurgeons capable of impacting patient care through research, including the MD-PhDs, who are noted to be more represented among NIH-funded neurosurgeons.
