Current status of artificial intelligence methods for skin cancer survival analysis: a scoping review.

Skin cancer mortality rates continue to rise, and survival analysis is increasingly needed to understand who is at risk and what interventions improve outcomes. However, current statistical methods are limited by inability to synthesize multiple data types, such as patient genetics, clinical history, demographics, and pathology and reveal significant multimodal relationships through predictive algorithms. Advances in computing power and data science enabled the rise of artificial intelligence (AI), which synthesizes vast amounts of data and applies algorithms that enable personalized diagnostic approaches. Here, we analyze AI methods used in skin cancer survival analysis, focusing on supervised learning, unsupervised learning, deep learning, and natural language processing. We illustrate strengths and weaknesses of these approaches with examples. Our PubMed search yielded 14 publications meeting inclusion criteria for this scoping review. Most publications focused on melanoma, particularly histopathologic interpretation with deep learning. Such concentration on a single type of skin cancer amid increasing focus on deep learning highlight growing areas for innovation; however, it also demonstrates opportunity for additional analysis that addresses other types of cutaneous malignancies and expands the scope of prognostication to combine both genetic, histopathologic, and clinical data. Moreover, researchers may leverage multiple AI methods for enhanced benefit in analyses. Expanding AI to this arena may enable improved survival analysis, targeted treatments, and outcomes.

Gammopathic dermopathy: characterization of cutaneous MGUS.

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a clonal plasma cell disorder that is considered preneoplastic, asymptomatic, and only requiring observation. However, MGUS may result in cutaneous complications, which are poorly understood, causing treatment delays and patient suffering. We present 30 patients with cutaneous findings associated with MGUS, characterizing clinical presentations, isoforms, treatments, and outcomes. These included: MGUS-associated 'rashes' (pruritic eczematous rashes), reactive and mucin-depositional conditions (pyoderma gangrenosum, scleromyxedema), M-protein-related deposition disorders (POEMS syndrome, Waldenstrom macroglobulinemia), and cutaneous lymphomas. Twelve of 30 (40%) patients received multiple myeloma drugs (MMDs). Eleven (92%) patients improved, and those not receiving MMDs rarely improved, suggesting that MMDs have efficacy for cutaneous manifestations of MGUS. Therefore, trialing MMDs may be warranted for patients with MGUS not responding to other therapies. Moreover, evaluation for monoclonal gammopathy in elderly patients with intractable pruritus or other chronic skin conditions that are non-responsive to skin-directed therapies should be considered.

Febrile Ulceronecrotic Mucha-Habermann Disease Associated With Hemophagocytic Lymphohistiocytosis: A Case Report and Review of the Literature.

ABSTRACT: Mucha-Habermann disease (MHD) is an inflammatory skin disease characterized by polymorphous eruptions of erythematous, necrotic macules that have been reported for similarities to cutaneous T-cell lymphoma. Febrile ulceronecrotic MHD (FUMHD) represents a severe variant of MHD, marked by ulcers, hemorrhagic bullae, and systemic symptoms. Herein, we report a case of a severely atypical lymphomatoid expression of FUMHD associated with hemophagocytic lymphohistiocytosis (HLH). A previously healthy 21-year-old woman was admitted to the hospital with a rapidly progressive necrotic papular rash. Physical examination revealed right orbital swelling, bilateral hemorrhagic auricular bullae, and multiple ulcerative purpuric papulonodules on the trunk, face, and extremities. Biopsy indicated a dermal and subcutaneous infiltrate of atypical CD8 + lymphocytes with loss of CD5 and reduction in CD7 expression, along with features of lymphomatoid vasculitis. A diagnosis of a severely atypical lymphomatoid expression of FUMHD was made. The patient also met 7 of 9 HLH-2004 criteria, leading to a diagnosis of HLH. Positron emission tomography/computed tomography, flow cytometry, and rheumatologic workup were unremarkable. Treatment with an eight-week course of etoposide and dexamethasone for HLH led to rapid clinical improvement. Over time, her skin lesions regressed and eventually scabbed over to leave hyperpigmented scars, confirming the diagnosis of MHD. She has remained stable, off therapy for 4 years. Although potentially fatal, FUMHD often exhibits favorable outcomes and may resolve without recurrence, as in our patient. FUMHD should be considered in the differential diagnosis for patients presenting with cutaneous CD8 + necrotizing angiocentric lymphoproliferative disease complicated by HLH.

Characterizing Gender and Leadership Trends Among Mohs Micrographic Surgery Fellowship Directors.

BACKGROUND: Fellowship directors (FDs) play a key role in shaping Mohs micrographic surgery (MMS). Studies characterizing director trends are lacking and may provide a framework for improving gender diversity. OBJECTIVE: To explore characteristics of FDs and trends in gender of both fellows and FDs over time. MATERIALS AND METHODS: The authors compiled a comprehensive list of FDs and fellows for all Accreditation Council for Graduate Medical Education-accredited Micrographic Surgery & Dermatologic Oncology programs from 1996 to 2023. Publicly available data from various internet sources from February 1, 2023 to May 30, 2023 were used to assess characteristics of MMS FDs. RESULTS: The percentage of female FDs increased from 6% to 25% from 1996 to 2023. Female directors were more likely to select female fellows than male directors ( p = .0002) and had fewer years between fellowship completion and FD appointment (9.1 ± 4.7 years) compared with male directors (13.6 ± 8.8 years; p = .036). H-index, program type, and academic rank were similar between male and female directors. CONCLUSION: Although gender parity among MMS trainees has been achieved, discrepancies remain in the gender composition of FDs. Further studies are required to determine why women are underrepresented as FDs.

Clusters, crop dusters, and myth busters: a scoping review of environmental exposures and cutaneous T-cell lymphoma.

INTRODUCTION: Cutaneous T-cell lymphoma (CTCL) is a heterogenous group of non-Hodgkin lymphomas. Similar presentation to benign conditions, significant genetic variation, and lack of definitive biomarkers contributes to diagnostic delay. The etiology of CTCL is unknown, and environmental exposures, such as geographic, occupational, chemicals, sunlight, and insects have been investigated. EVIDENCE ACQUISITION: Review of the literature for CTCL and exposures was performed in PubMed and Google Scholar in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension for Scoping Reviews. This search yielded 193 total results, which were initially screened with defined inclusion and exclusion criteria. The 45 remaining articles were reviewed and classified by exposure type. EVIDENCE SYNTHESIS: The most frequently investigated CTCL exposure type was geographic (13/45 articles, 29%). Chemical exposures were commonly discussed (10/45 articles, 22%), along with occupational (10/45 articles, 22%). Insect exposures (6/45, 13%) and sun exposure (3/45, 7%) were also reviewed, along with articles describing multiple exposure types (3/45, 7%). Article types ranged from cases to systematic reviews and case-control studies. Evidence linking CTCL and these exposures was mixed. Limitations of this investigation include reliance on patient reporting and frequent speculation on disease association versus causality. CONCLUSIONS: This investigation synthesizes the current literature on exposures potentially implicated in the pathogenesis of CTCL, while offering guidance on patient history-taking to ensure potential exposures are captured. Awareness of these possible associations may improve understanding of disease pathogenesis and diagnosis. Moreover, these insights may help with public health decision-making and disease mitigation.

Trends in Orthopaedic Foot and Ankle Publications.

Background: Scientific publication and original articles remain the primary method of sharing scientific findings and advancing the knowledge base of that subject. Despite the value of these publications, little research has surveyed what topics are being published. This study aims to identify and characterize the most common topics in current foot and ankle literature. Methods: We reviewed all 1514 published articles in a 5.5-year period (January 2014-June 2019) in 2 foot and ankle-specific journals: Foot & Ankle International (FAI) and Foot and Ankle Surgery (FAS). The articles were sorted into different topic domains to identify the 3 most common categories of publication. The top 3 domains were further characterized by level of evidence (LOE) as well as citations. Results: The 3 most published topics in foot and ankle literature were hallux valgus (8.3%), total ankle arthroplasty (TAA) (8.3%), and ankle fracture (6.6%). These 3 subjects accounted for 351 articles (23.2%). Other common topics were patient-reported outcomes (5.0%), osteochondritis dissecans (3.9%), syndesmotic injury (3.8%), ankle instability (3.7%), hallux rigidus (3.0%), and anatomy (2.8%). The average LOE for articles on hallux valgus, TAA, and ankle fracture was 3.27 from FAI, and the average number of annual citations for a given article in both journals was 3.05. Based on our study, there is no correlation between LOE and number of overall citations, but there is a significant, negative linear correlation in ankle fracture data. We also found that articles on TAA had the highest impact factor and that articles from FAI were cited more often than articles from FAS. Conclusion: The 3 most published topics in foot and ankle literature comprise only 23.2% of all articles. This finding is indicative of the wide variety of cases performed by orthopaedic foot and ankle surgeons. High-quality data are still needed in all topics. Level of Evidence: Level III, retrospective cohort study.

A clinically applicable integrative molecular classification of meningiomas.

Meningiomas are the most common primary intracranial tumour in adults1. Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; however, they do not accurately reflect the clinical behaviour of all meningiomas2. Molecular classifications of meningioma that reliably reflect tumour behaviour and inform on therapies are required. Here we introduce four consensus molecular groups of meningioma by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance in a unified analysis. These molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of the newly defined molecular groups and uncovered highly abundant and group-specific protein targets that we validated using immunohistochemistry. Single-cell RNA sequencing revealed inter-individual variations in meningioma as well as variations in intrinsic expression programs in neoplastic cells that mirrored the biology of the molecular groups identified.

Scaffold-mediated CRISPR-Cas9 delivery system for acute myeloid leukemia therapy.

Leukemia stem cells (LSCs) sustain the disease and contribute to relapse in acute myeloid leukemia (AML). Therapies that ablate LSCs may increase the chance of eliminating this cancer in patients. To this end, we used a bioreducible lipidoid-encapsulated Cas9/single guide RNA (sgRNA) ribonucleoprotein [lipidoid nanoparticle (LNP)-Cas9 RNP] to target the critical gene interleukin-1 receptor accessory protein (IL1RAP) in human LSCs. To enhance LSC targeting, we loaded LNP-Cas9 RNP and the chemokine CXCL12α onto mesenchymal stem cell membrane-coated nanofibril (MSCM-NF) scaffolds mimicking the bone marrow microenvironment. In vitro, CXCL12α release induced migration of LSCs to the scaffolds, and LNP-Cas9 RNP induced efficient gene editing. IL1RAP knockout reduced LSC colony-forming capacity and leukemic burden. Scaffold-based delivery increased the retention time of LNP-Cas9 in the bone marrow cavity. Overall, sustained local delivery of Cas9/IL1RAP sgRNA via CXCL12α-loaded LNP/MSCM-NF scaffolds provides an effective strategy for attenuating LSC growth to improve AML therapy.

Osimertinib as neoadjuvant therapy in a patient with stage IIIA non-small cell lung cancer: a case report.

INTRODUCTION: Tyrosine kinase inhibitors (TKI) targeting epidermal growth factor receptor (EGFR) are approved for use in metastatic non-small cell lung cancer (NSCLC). CASE PRESENTATION: Here we present a case of a African American patient with stage IIIA NSCLC treated with osimertinib in the neoadjuvant setting with concurrent radiation, followed by resection. The patient remains disease-free 4 months after surgery. CONCLUSION: This case report suggests that osimertinib may be effective as neoadjuvant therapy in resectable stage III disease. Additionally, we provide a summary of previous case reports and ongoing clinical trials for neoadjuvant EGFR inhibition in stage III NSCLC patients.

Evaluation of the Asian Smokers' Quitline: A Centralized Service for a Dispersed Population.

INTRODUCTION: Asian immigrants to the U.S. smoke at higher rates than U.S.-born Asians. However, few programs exist to help these immigrants quit and little is known about their real-world effectiveness. The Centers for Disease Control and Prevention funded the Asian Smokers' Quitline to serve Chinese, Korean, and Vietnamese immigrants nationwide. This study examines service utilization and outcomes from the first 7 years of the program. METHODS: From August 2012 to July 2019, the Asian Smokers' Quitline enrolled 14,073 Chinese-, Korean-, and Vietnamese-speaking smokers. Service utilization rates and cessation outcomes were compared with those of an earlier trial (conducted 2004-2008) that demonstrated the efficacy of an Asian-language telephone counseling protocol. Data were analyzed in 2019. RESULTS: Asian Smokers' Quitline participants came from all 50 states and the District of Columbia. The main referral sources were Asian-language newspapers (37.2%), family and friends (16.4%), healthcare providers (11.9%), and radio (11.9%). Overall, 37.6% were uninsured, 38.8% had chronic health conditions, and 15.4% had mental health conditions. Compared with participants in the earlier trial, Quitline participants received 1 fewer counseling session (3.8 vs 4.9, p<0.001) but were more likely to use pharmacotherapy (73.6% vs 20.9%, p<0.001). More than 90% were satisfied with the services they received. Six-month prolonged abstinence rates were higher in the Quitline than in the trial (complete case analysis: 28.6% vs 20.0%, p<0.001; intention-to-treat analysis: 20.5% vs 16.4%, p=0.005). CONCLUSIONS: The Asian Smokers' Quitline was utilized by >14,000 Asian-language-speaking smokers across the U.S. in its first 7 years. This quitline could serve as a model for delivering other behavioral services to geographically dispersed linguistic minority populations.

A departmental policy can reduce opioid prescribing after orthopedic surgery.

OBJECTIVE: The authors hypothesized that implementation of a department-wide opioid prescribing program would reduce opioid tablets and morphine milligram equivalents (MMEs) prescribed as well as prescription refills. DESIGN: A retrospective study was conducted to determine the effects of a department wide opioid prescribing policy. SETTING: A university teaching hospital Orthopaedic Surgery Department. PATIENTS, PARTICIPANTS: All prescriptions written by members of our department were reviewed for 3 months before and 3 months after program implementation. There were 1,445 patients in the pre-intervention and 1,209 patients in the post-intervention cohort. Two thousand two hundred forty-six total prescriptions written during the pre-intervention period and 1,530 written during the post-intervention period of the study. INTERVENTIONS: A departmental opioid prescribing policy was introduced through several department teaching sessions. The policy included recommendations on numbers of tablets per procedures and patient education about the dangers of narcotic medications. MAIN OUTCOME MEASURE(S): The primary study outcome measures were the number of opioid tablets prescribed, the number of MMEs prescribed, and the number of prescription refills. RESULTS: The mean number of tablets per prescription decreased from 47.2 (95% confidence interval (CI): 46.4-47.9) tab-lets in the pre-intervention cohort to 39.2 (95% CI: 38.1-40.4) tablets in the post-intervention cohort (p < 0.0001). Likewise, the mean MME per prescription decreased from 354 (95% CI: 344-364) in the pre-intervention cohort to 265 (95% CI: 249-281) in the post-intervention cohort (p < 0.0001). A refill prescription was provided 949 times in the pre-intervention group and 404 times in the post-intervention group. Prior to the introduction of prescription guidelines, the average number of prescriptions was 1.76 per patient (95% CI: 1.71-1.81). This fell to 1.34 prescriptions per patient (95% CI: 1.31-1.38) after policy institution. Noncompliance with policy was not related to provider, service, or procedure size. CONCLUSIONS: Implementation of a departmental policy can successfully reduce the number of opioid tablets and MMEs prescribed per procedure. Policies also decrease the number of refill prescriptions per procedure. Standardization of prescription practices is effective in improving opioid prescription stewardship. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

E-Cigarette Design Preference and Smoking Cessation: A U.S. Population Study.

INTRODUCTION: Electronic cigarette (e-cigarette) designs may be described as "closed" or "open." Closed systems are disposable or reloadable with prefilled cartridges (cigalikes). Open systems feature a prominent chamber (tank), refillable with e-liquid. This study examined user design preference and its association with smoking cessation. METHODS: A probability sample of current e-cigarette users (n=923) among adult ever smokers (n=6,560) in the U.S. was surveyed online between February 28 and March 31, 2014, and analyzed in September 2014. Photos of e-cigarette devices were presented alongside survey questions to facilitate respondents' understanding of the questions. RESULTS: Most e-cigarette users were exclusive users of one design: 51.4% used only closed systems and 41.1% used only open systems, with 7.4% using both. Former smokers were more likely to use open systems than current smokers (53.8% vs 35.2%, p=0.002). Current smokers who attempted to quit in the last 12 months were more likely to use open systems than those who did not (41.4% vs 27.7%, p=0.029). Open system users were more likely than closed system users to use e-cigarettes daily (50.2% vs 22.9%, p<0.0001). Open system users were less likely to report their devices resembled (3.1% vs 73.0%, p<0.0001) or tasted like (29.1% vs 53.3%, p<0.0001) a cigarette but were more likely to report that their devices satisfied cravings than closed system users (82.8% vs 67.2%, p=0.001). CONCLUSIONS: Preference of e-cigarette design is associated with smoking cessation. A device's ability to deliver more nicotine and its flexibility in use might contribute to users' success in quitting smoking.

A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma.

Survivin is a microtubule-associated protein believed to be involved in preserving cell viability and regulating tumor cell mitosis, and it is overexpressed in many primary tumor types, including melanoma. YM155 is a first-in-class survivin suppressant. The purpose of this Phase 2 study was to evaluate the 6-month progression-free survival (PFS) rate in patients with unresectable Stage III or IV melanoma receiving a combination of YM155 plus docetaxel. The study had two parts: Part 1 established the dose of docetaxel that was tolerable in combination with YM155, and Part 2 evaluated the tolerable docetaxel dose (75 mg/m(2) ) in combination with YM155 (5 mg/m(2) per day continuous infusion over 168 h every 3 weeks). The primary endpoint was 6-month PFS rate. Secondary endpoints were objective response rate (ORR), 1-year overall survival (OS) rate, time from first response to progression, clinical benefit rate (CBR), and safety. Sixty-four patients with metastatic melanoma were treated with docetaxel and YM155. Eight patients received an initial docetaxel dose of 100 mg/m(2) and 56 patients received 75 mg/m(2) of docetaxel. Six-month PFS rate per Independent Review Committee (IRC) was 34.8% (n = 64; 95% CI, 21.3-48.6%), and per Investigator was 31.3% (n = 64; 95% CI, 19.5-43.9%). The best ORR (complete response [CR] + partial response [PR]) per IRC was 12.5% (8/64). The stable disease (SD) rate was 51.6% (33/64), leading to a CBR (CR + PR + SD) of 64.1% (41/64). Estimated probability of 1-year survival was 56.3%. YM155 is a novel agent showing modest activity when combined with docetaxel for treating patients with melanoma. YM155 was generally well tolerated, but the predetermined primary efficacy endpoint (i.e., 6-month PFS rate ≥20%) was not achieved.

Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists.

A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.

Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor.

Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K(i) value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.

Discovery of 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-4-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia.

A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.