Multi-organ immune-related adverse events from immune checkpoint inhibitors and their downstream implications: a retrospective multicohort study.

BACKGROUND: Understanding co-occurrence patterns and prognostic implications of immune-related adverse events is crucial for immunotherapy management. However, previous studies have been limited by sample size and generalisability. In this study, we leveraged a multi-institutional cohort and a population-level database to investigate co-occurrence patterns of and survival outcomes after multi-organ immune-related adverse events among recipients of immune checkpoint inhibitors. METHODS: In this retrospective study, we identified individuals who received immune checkpoint inhibitors between May 31, 2015, and June 29, 2022, from the Massachusetts General Hospital, Brigham and Women's Hospital, and Dana-Farber Cancer Institute (Boston, MA, USA; MGBD cohort), and between April 30, 2010, and Oct 11, 2021, from the independent US population-based TriNetX network. We identified recipients from all datasets using medication codes and names of seven common immune checkpoint inhibitors, and patients were excluded from our analysis if they had incomplete information (eg, diagnosis and medication records) or if they initiated immune checkpoint inhibitor therapy after Oct 11, 2021. Eligible patients from the MGBD cohort were then propensity score matched with recipients of immune checkpoint inhibitors from the TriNetX database (1:2) based on demographic, cancer, and immune checkpoint inhibitor characteristics to facilitate cohort comparability. We applied immune-related adverse event identification rules to identify patients who did and did not have immune-related adverse events in the matched cohorts. To reduce the likelihood of false positives, patients diagnosed with suspected immune-related adverse events within 3 months after chemotherapy were excluded. We performed pairwise correlation analyses, non-negative matrix factorisation, and hierarchical clustering to identify co-occurrence patterns in the MGBD cohort. We conducted landmark overall survival analyses for patient clusters based on predominant immune-related adverse event factors and calculated accompanying hazard ratios (HRs) and 95% CIs, focusing on the 6-month landmark time for primary analyses. We validated our findings using the TriNetX cohort. FINDINGS: We identified 15 246 recipients of immune checkpoint inhibitors from MGBD and 50 503 from TriNetX, of whom 13 086 from MGBD and 26 172 from TriNetX were included in our propensity score-matched cohort. Median follow-up durations were 317 days (IQR 113-712) in patients from MGBD and 249 days (91-616) in patients from TriNetX. After applying immune-related adverse event identification rules, 8704 recipients of immune checkpoint inhibitors were retained from MGBD, of whom 3284 (37·7%) had and 5420 (62·3%) did not have immune-related adverse events, and 18 162 recipients were retained from TriNetX, of whom 5538 (30·5%) had and 12 624 (69·5%) did not have immune-related adverse events. In both cohorts, positive pairwise correlations of immune-related adverse events were commonly observed. Co-occurring immune-related adverse events were decomposed into seven factors across organs, revealing seven distinct patient clusters (endocrine, cutaneous, respiratory, gastrointestinal, hepatic, musculoskeletal, and neurological). In the MGBD cohort, the patient clusters that predominantly had endocrine (HR 0·53 [95% CI 0·40-0·70], p<0·0001) and cutaneous (0·61 [0·46-0·81], p=0·0007) immune-related adverse events had favourable overall survival outcomes at the 6-month landmark timepoint, while the other clusters either had unfavourable (respiratory: 1·60 [1·25-2·03], p=0·0001) or neutral survival outcomes (gastrointestinal: 0·86 [0·67-1·10], p=0·23; musculoskeletal: 0·97 [0·78-1·21], p=0·78; hepatic: 1·20 [0·91-1·59], p=0·19; and neurological: 1·30 [0·97-1·74], p=0·074). Similar results were found in the TriNetX cohort (endocrine: HR 0·75 [95% CI 0·60-0·93], p=0·0078; cutaneous: 0·62 [0·48-0·82], p=0·0007; respiratory: 1·21 [1·00-1·46], p=0·044), except for the neurological cluster having unfavourable (rather than neutral) survival outcomes (1·30 [1·06-1·59], p=0·013). INTERPRETATION: Reliably identifying the immune-related adverse event cluster to which a patient belongs can provide valuable clinical information for prognosticating outcomes of immunotherapy. These insights can be leveraged to counsel patients on the clinical impact of their individual constellation of immune-related adverse events and ultimately develop more personalised surveillance and mitigation strategies. FUNDING: US National Institutes of Health.

Development and validation of time-to-event models to predict metastatic recurrence of localized cutaneous melanoma.

BACKGROUND: The recent expansion of immunotherapy for stage IIB/IIC melanoma highlights a growing clinical need to identify patients at high risk of metastatic recurrence and, therefore, most likely to benefit from this therapeutic modality. OBJECTIVE: To develop time-to-event risk prediction models for melanoma metastatic recurrence. METHODS: Patients diagnosed with stage I/II primary cutaneous melanoma between 2000 and 2020 at Mass General Brigham and Dana-Farber Cancer Institute were included. Melanoma recurrence date and type were determined by chart review. Thirty clinicopathologic factors were extracted from electronic health records. Three types of time-to-event machine-learning models were evaluated internally and externally in the distant versus locoregional/nonrecurrence prediction. RESULTS: This study included 954 melanomas (155 distant, 163 locoregional, and 636 1:2 matched nonrecurrences). Distant recurrences were associated with worse survival compared to locoregional/nonrecurrences (HR: 6.21, P < .001) and to locoregional recurrences only (HR: 5.79, P < .001). The Gradient Boosting Survival model achieved the best performance (concordance index: 0.816; time-dependent AUC: 0.842; Brier score: 0.103) in the external validation. LIMITATIONS: Retrospective nature and cohort from one geography. CONCLUSIONS: These results suggest that time-to-event machine-learning models can reliably predict the metastatic recurrence from localized melanoma and help identify high-risk patients who are most likely to benefit from immunotherapy.

Retrospective analysis of onychomycosis prescribing patterns using the medicare part D prescribers database 2016-2020.

Onychomycosis, defined as a fungal nail infection, affects 5.5% of the global population. Our objectives were to analyse prescription trends of onychomycosis medications using the Medicare Part D Prescribers database from 2016 to 2020, stratified by physician specialty. There was a 4% annual increase in the total cost of onychomycosis medications, with a notable decrease of 12.8% in 2020 during the COVID-19 pandemic. Physicians demonstrated a strong consideration for price when selecting treatments, with the least expensive medications (ciclopirox and terbinafine) accounting for nearly 99% of all prescriptions. In contrast, the more costly medications (efinaconazole and tavaborole) were rarely prescribed. In addition, physicians often opted for the less costly generic versions of ciclopirox and itraconazole, prescribing them 99% and 91% of the time, respectively. Notably, physician assistants and nurse practitioners had higher overall increases in prescription rates, at 15%, compared to 1%-6% for other specialties. There are no recent United States onychomycosis guidelines, and our study emphasizes cost considerations when prescribing onychomycosis treatments.

Obesity as a Risk Factor for Adverse Outcomes After Pedestrian Trauma Accidents in the Pediatric Population.

OBJECTIVE: The aim of the study is to determine whether overweight or obese children are at an increased risk for injury and adverse outcomes following pedestrian motor vehicle accidents. METHODS: We performed a retrospective study of patients between the ages of 2 and 17 who were pedestrians injured in a collision with a motorized vehicle, presenting to a level 1 trauma center, between January 1, 2010, to December 31, 2021. Patients with admission weights falling above the 90th percentile of the Centers for Disease Control and Prevention's sex-specific growth charts were identified as overweight/obese, those below the cutoff were categorized as nonobese. Groups were compared regarding demographics, mechanism of injury, Injury Severity Score, and Abbreviated Injury Scale by body region of injury. Outcome measures included hospital admission, length of hospital stay, intensive care unit (ICU) admission, ICU length of stay, and mortality. RESULTS: Of the 306 patients included, 72 (23.5%) were overweight/obese and 234 (76.5%) were nonobese. The mean Injury Severity Score scores were higher among overweight/obese patients (5.37 vs 8.74, P = 0.008). Overweight/obese children were more likely to sustain severe abdominal injuries (Abbreviated Injury Scale ≥ 3) (12.2% vs 5.1%; odds ratio [OR], 2.64; 95% CI, 1.07-6.56; P = 0.030), be admitted to the hospital (94.5% vs 74.3%; OR, 12.07; 95% CI, 2.87-50.72; P < 0.001), require ICU admission (31.0% vs 20.0%, OR, 1.87; 95% CI, 1.03-3.36; P = 0.036), and require a longer ICU stay (0.9 vs 0.4 days, P = 0.014) compared with nonobese patients. CONCLUSIONS: Obese and overweight children are at increased risk for higher injury severity scores, severe abdominal injuries, and ICU admission after pedestrian motor vehicle accidents.

The Efficacy of Stem Cells in Wound Healing: A Systematic Review.

Wound healing is an intricate process involving coordinated interactions among inflammatory cells, skin fibroblasts, keratinocytes, and endothelial cells. Successful tissue repair hinges on controlled inflammation, angiogenesis, and remodeling facilitated by the exchange of cytokines and growth factors. Comorbid conditions can disrupt this process, leading to significant morbidity and mortality. Stem cell therapy has emerged as a promising strategy for enhancing wound healing, utilizing cells from diverse sources such as endothelial progenitor cells, bone marrow, adipose tissue, dermal, and inducible pluripotent stem cells. In this systematic review, we comprehensively investigated stem cell therapies in chronic wounds, summarizing the clinical, translational, and primary literature. A systematic search across PubMed, Embase, Web of Science, Google Scholar, and Cochrane Library yielded 22,454 articles, reduced to 44 studies after rigorous screening. Notably, adipose tissue-derived mesenchymal stem cells (AD-MSCs) emerged as an optimal choice due to their abundant supply, easy isolation, ex vivo proliferative capacities, and pro-angiogenic factor secretion. AD-MSCs have shown efficacy in various conditions, including peripheral arterial disease, diabetic wounds, hypertensive ulcers, bullous diabeticorum, venous ulcers, and post-Mohs micrographic surgery wounds. Delivery methods varied, encompassing topical application, scaffold incorporation, combination with plasma-rich proteins, and atelocollagen administration. Integration with local wound care practices resulted in reduced pain, shorter healing times, and improved cosmesis. Stem cell transplantation represents a potential therapeutic avenue, as transplanted stem cells not only differentiate into diverse skin cell types but also release essential cytokines and growth factors, fostering increased angiogenesis. This approach holds promise for intractable wounds, particularly chronic lower-leg wounds, and as a post-Mohs micrographic surgery intervention for healing defects through secondary intention. The potential reduction in healthcare costs and enhancement of patient quality of life further underscore the attractiveness of stem cell applications in wound care. This systematic review explores the clinical utilization of stem cells and stem cell products, providing valuable insights into their role as ancillary methods in treating chronic wounds.

Influence of melanoma type on incidence and downstream implications of cutaneous immune-related adverse events in the setting of immune checkpoint inhibitor therapy.

BACKGROUND: Emerging evidence suggests that cutaneous immune-related adverse events (cirAEs) are associated with a survival benefit in the setting of advanced melanoma treated with immune checkpoint inhibitor (ICI) therapy. Previous studies have not examined the role of melanoma subtypes on cirAE development and downstream therapeutic outcomes. OBJECTIVE: Examine the impact of melanoma subtypes on cirAE onset and survival among ICI recipients. METHODS: Retrospective multi-institutional cohort study. Multivariate time-series regressions were utilized to assess relationships between melanoma subtype, cirAE development, and survival. RESULTS: Among 747 ICI recipients, 236 (31.6%) patients developed a cirAE. Patients with acral melanoma were less likely to develop a cirAE (hazard ratio [HR] = 0.41, P = .016) compared to patients with nonacral cutaneous melanoma. Across all melanoma subtypes, cirAEs were associated with reduced mortality (HR = 0.76, P = .042). Patients with acral (HR = 2.04, P = .005), mucosal (HR = 2.30, P < .001), and uveal (HR = 4.09, P < .001) primaries exhibited the worst survival. LIMITATIONS: Retrospective cohort study. CONCLUSION: This is the first study to demonstrate differences in cirAE development among melanoma subtypes. The presence of cirAEs was associated with better survival. Further, the lower incidence of cirAEs may be a marker of immunotherapy response, which is reflected in the association between acral melanoma and mortality.

Impact of Ketogenic and Low-Glycemic Diets on Inflammatory Skin Conditions.

Diet plays an emerging role in dermatologic therapy. The ketogenic and low-glycemic diets have potential anti-inflammatory and metabolic effects, making them attractive for treating inflammatory skin conditions. We provide an overview of the current evidence on the effects of ketogenic and low-glycemic diets on inflammatory skin conditions including acne, psoriasis, seborrheic dermatitis (SD), atopic dermatitis (AD), and hidradenitis suppurativa (HS). We conclude that low-glycemic diets show promise for treating acne, while the evidence for ketogenic diets in treating other inflammatory skin conditions is limited. Randomized clinical trials are needed to explore the efficacy of these diets as stand-alone or adjunctive treatments for inflammatory skin conditions.

Machine learning algorithms for predicting outcomes of traumatic brain injury: A systematic review and meta-analysis.

Background: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. The use of machine learning (ML) has emerged as a key advancement in TBI management. This study aimed to identify ML models with demonstrated effectiveness in predicting TBI outcomes. Methods: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. In total, 15 articles were identified using the search strategy. Patient demographics, clinical status, ML outcome variables, and predictive characteristics were extracted. A small meta-analysis of mortality prediction was performed, and a meta-analysis of diagnostic accuracy was conducted for ML algorithms used across multiple studies. Results: ML algorithms including support vector machine (SVM), artificial neural networks (ANN), random forest, and Naïve Bayes were compared to logistic regression (LR). Thirteen studies found significant improvement in prognostic capability using ML versus LR. The accuracy of the above algorithms was consistently over 80% when predicting mortality and unfavorable outcome measured by Glasgow Outcome Scale. Receiver operating characteristic curves analyzing the sensitivity of ANN, SVM, decision tree, and LR demonstrated consistent findings across studies. Lower admission Glasgow Coma Scale (GCS), older age, elevated serum acid, and abnormal glucose were associated with increased adverse outcomes and had the most significant impact on ML algorithms. Conclusion: ML algorithms were stronger than traditional regression models in predicting adverse outcomes. Admission GCS, age, and serum metabolites all have strong predictive power when used with ML and should be considered important components of TBI risk stratification.

Comparison of the Risk Analysis Index and the modified 5-factor frailty index in predicting 30-day morbidity and mortality after spine surgery.

OBJECTIVE: Frailty's role in preoperative risk assessment in spine surgery has increased in association with the increasing size of the aging population. However, previous frailty assessment tools have significant limitations. The aim of this study was to compare the predictive ability of the Risk Analysis Index (RAI) with the 5-factor modified frailty index (mFI-5) for postoperative spine surgery morbidity and mortality. METHODS: Data were collected from the American College of Surgeons National Surgical Quality Improvement Program database for adults > 18 years who underwent spine surgery between 2015 and 2019. Multivariate modeling and receiver operating characteristic curve analysis, including area under the curve/C-statistic calculations, were performed to evaluate the comparative discriminative ability of RAI and mFI-5 on postoperative outcomes. RESULTS: In a cohort of 292,225 spine surgery patients, multivariate modeling showed that increasing RAI scores, and not increasing mFI-5 scores, were independent predictors of increased postoperative mortality for the trauma, tumor, and infection subcohorts. In the overall spine cohort, both increasing RAI and increasing mFI-5 scores were associated with increased mortality, but C-statistics indicated that the RAI (C-statistic 0.802 [95% CI 0.800-0.803], p < 0.0001, DeLong test) had superior discrimination compared with the mFI-5 (C-statistic 0.677 [95% CI 0.675-0.679], p < 0.0001, DeLong test). In subgroup analyses, the RAI had superior discriminative ability to mFI-5 for mortality in the trauma and infection groups (p < 0.001 and p = 0.039, respectively). CONCLUSIONS: The RAI demonstrates superior discrimination to the mFI-5 for predicting postoperative mortality and morbidity after spine surgery and the RAI maintains conceptual fidelity to the frailty phenotype. Patients with high RAI scores may benefit from knowing the possibility of increased surgical risk with potential spine surgery.

Impact of COVID-19 on Spinal Diagnosis and Procedural Volume in the United States.

STUDY DESIGN: Retrospective analysis of a national database. OBJECTIVES: COVID-19 resulted in the widespread shifting of hospital resources to handle surging COVID-19 cases resulting in the postponement of surgeries, including numerous spine procedures. This study aimed to quantify the impact that COVID-19 had on the number of treated spinal conditions and diagnoses during the pandemic. METHODS: Using CPT and ICD-10 codes, TriNetX, a national database, was utilized to quantify spine procedures and diagnoses in patients >18 years of age. The period of March 2020-May 2021 was compared to a reference pre-pandemic period of March 2018-May 2019. Each time period was then stratified into four seasons of the year, and the mean average number of procedures per healthcare organization was compared. RESULTS: In total, 524,394 patient encounters from 53 healthcare organizations were included in the analysis. There were significant decreases in spine procedures and diagnoses during March-May 2020 compared to pre-pandemic levels. Measurable differences were noted for spine procedures during the winter of 2020-2021, including a decrease in lumbar laminectomy and anterior cervical arthrodesis. Comparing the pandemic period to the pre-pandemic period showed significant reductions in most spine procedures and treated diagnoses; however, there was an increase in open repair of thoracic fractures during this period. CONCLUSIONS: COVID-19 resulted in a widespread decrease in spinal diagnosis and treated conditions. An inverse relationship was observed between new COVID-19 cases and spine procedural volume. Recent increases in procedural volume from pre-pandemic levels are promising signs that the spine surgery community has narrowed the gap in unmet care produced by the pandemic.

Preoperative frailty risk in deep brain stimulation patients: Risk analysis index predicts Clavien-Dindo IV complications.

OBJECTIVE: Deep brain stimulation (DBS) improves patients' quality of life in multiple movement disorders and chronic neurodegenerative diseases. There are no published studies assessing frailty's impact on DBS outcomes. We evaluated frailty's impacts on DBS outcomes, comparing discriminative thresholds of the risk analysis index (RAI) to modified frailty index-5 (mFI-5) for predicting Clavien-Dindo complications (CDIV). METHODS: Patients who underwent DBS between 2015 and 2019 in the ACS-NSQIP registry were included. We employed receiver operating characteristic (ROC) curve to examine the discriminative thresholds of RAI and mFI-5 and multivariable analyses for postoperative outcomes. Our primary outcome was CDIV, and secondary outcomes were discharge to higher-level care facility, unplanned reoperation within 30 days, in any hospital, for any procedure related to the index procedure, and extended length of stay. RESULTS: A total of 3795 patients were included. In the ROC analysis for CDIV, RAI showed superior discriminative threshold (C-statistic = 0.70, 95% CI 0.61-0.80, <0.001) than mFI-5 (C-statistic = 0.60, 95% CI 0.49-0.70, P = 0.08). On multivariable analyses, frailty stratified by RAI, had independent associations with CDIV, i.e., pre-frail 2-fold increase OR 2.04 (95% CI: 1.94-2.14) p < 0.001, and frail 39% increase OR 1.39 (95% CI: 1.27-1.53), p < 0.001. CONCLUSION: Frailty was an independent risk-factor for CDIV. The RAI had superior discriminative thresholds than mFI-5 in predicting CDIV after DBS. Our ability to identify frail patients prior to DBS presents a novel clinical opportunity for quality improvement strategies to target this specific patient population. RAI may be a useful primary frailty screening modality for potential DBS candidates.

The 5-item modified frailty index predicts spinal osteotomy outcomes better than age in adult spinal deformity patients: an ACS - NSQIP analysis.

PURPOSE: To evaluate the utility of 5-Item Modified Frailty Index (mFI-5) as compared to chronological age in predicting outcomes of spinal osteotomy in Adult Spinal Deformity (ASD) patients. METHODS: Using Current Procedural and Terminology (CPT) codes, the American College of Surgeons National Surgery Quality Improvement Program (ACS-NSQIP) database was queried for adult patients undergoing spinal osteotomy from 2015 to 2019. Multivariate regression analysis was performed to evaluate the effect of baseline frailty status, measured by mFI-5 score, and chronological age on postoperative outcomes. Receiver-operating characteristic (ROC) curve analysis was performed to analyze the discriminative performance of age versus mFI-5. RESULTS: A total of 1,789 spinal osteotomy patients (median age 62 years) were included in the analysis. Among the patients assessed, 38.5% (n = 689) were pre-frail, 14.6% frail (n = 262), and 2.2% (n = 39) severely frail using the mFI-5. Based on the multivariate analysis, increasing frailty tier was associated with worsening outcomes, and higher odds ratios (OR) for poor outcomes were found for increasing frailty tiers as compared to age. Severe frailty was associated with the worst outcomes, e.g., unplanned readmission (OR 9.618, [95% CI 4.054-22.818], p < 0.001) and major complications (OR 5.172, [95% CI 2.271-11.783], p < 0.001). In the ROC curve analysis, mFI-5 score (AUC 0.838) demonstrated superior discriminative performance than age (AUC 0.601) for mortality. CONCLUSIONS: The mFI5 frailty score was found to be a better predictor than age of worse postoperative outcomes in ASD patients. Incorporating frailty in preoperative risk stratification is recommended in ASD surgery.

Pre-Existing Inflammatory Disease Predicts Cutaneous Immunotherapy Toxicity Development: A Multi-Institutional Cohort Study.

Background: Relationships between pre-existing inflammatory diseases (pIDs) and cutaneous immune-related adverse events (cirAEs) have not been well-studied. This study is to investigate associations between pIDs and cirAEs among immune-checkpoint inhibitor (ICI) recipients at the Mass General Brigham healthcare system. Methods: Electronic health records were reviewed to ascertain cirAE status. Patients' pID status was determined using International Classification of Diseases (ICD) codes. Cox proportional hazard, logistic regression, and linear regression models were performed. Results: Among 3607 ICI recipients, 1354 had pIDs, and 672 developed cirAEs. After covariate adjustments, patients with cutaneous pIDs (HR:1.56, p<0.001) or both cutaneous and non-cutaneous pIDs (HR:1.76, p<0.001) had increased cirAE risk in contrast to patients with non-cutaneous pIDs alone (HR:1.01, p=0.9). In adjusted ordinal logistic regression modeling, cutaneous pIDs (OR:1.55, p<0.0001) and the presence of both cutaneous pIDs and non-cutaneous pIDs (OR:1.71, p=0.002) were associated with increased cirAE severity. The time to cirAE onset was different between the cutaneous pID group and the non-cutaneous pID group (Mean: 98 vs. 146 days, p=0.021; Beta: -0.11, p=0.033). Conclusions: ICI recipients with cutaneous pIDs should have increased clinical monitoring due to their increased risk of cirAE development, severity, and earlier onset.