Standardizing Retrospective Observational Research in Cutaneous Squamous Cell Carcinoma: Expert Panel Guidelines from ITSCC.

Importance: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant disease in the US. Although it typically carries a good prognosis, a subset of CSCCs are highly aggressive, carrying regional and distant metastatic potential. Due to its high incidence, this aggressive subset is responsible for considerable mortality, with an overall annual mortality estimated to equal or even surpass melanoma. Despite this morbidity, CSCC is excluded from national cancer registries, making it difficult to study its epidemiology and outcomes. Therefore, the bulk of the CSCC literature is composed of single-center and multi-institutional retrospective cohort analyses. Given variations in reporting measures and analyses in these studies, interpretability between studies and the ability to pool results are limited. Objective: To define standardized reporting measures for retrospective CSCC studies. Findings: An expert panel was convened to determine standardized guidelines for recording and analyzing retrospective CSCC data. A total of 13 dermatologists and dermatologic surgeons with more than 5 years of posttraining experience and considerable experience with performing CSCC outcomes research were recruited to the panel. Consensus recommendations were achieved for CSCC retrospective study reporting measures, definitions, and analyses. Conclusions and Relevance: The recommendations in this report present the potential to standardize future CSCC retrospective studies. With such standardization, future work may have greater interstudy interpretability and allow for pooled analyses.

QUIN 2.0 - new release of the QUaternary fault strain INdicators database from the Southern Apennines of Italy.

QUIN database integrates and organizes structural-geological information from published and unpublished sources to constrain deformation in seismotectonic studies. The initial release, QUIN1.0, comprised 3,339 Fault Striation Pairs, mapped on 445 sites exposed along the Quaternary faults of central Italy. The present Data Descriptor introduces the QUIN 2.0 release, which includes 4,297 Fault Striation Pairs on 738 Structural Sites from southern Italy. The newly investigated faults span ~500 km along the Apennines chain, with strikes transitioning from ~SE to ~SW and comprehensively details Fault Striation Pairs' location, attitude, kinematics, and deformation axes. Additionally, it offers a shapefile of the fault traces hosting the data. The QUIN 2.0 release offers a significant geographic extension to the QUIN 1.0, with comprehensive description of local geometric-kinematic complexities of the regional pattern. The QUIN data may be especially relevant for constraining intra-Apennine potential seismogenic deformation patterns, where earthquake data only offer scattered or incomplete information. QUIN's data will support studies aimed at enhancing geological understanding, hazard assessment and comprehension of fault rupture propagation and barriers.

An Institutional Experience of a Tertiary Referral Center in Surgically Managing Patients With Gorlin Syndrome.

BACKGROUND: The lifetime risk for basal carcinoma (BCC) is 90% in patients with Gorlin syndrome, also known as basal cell nevus syndrome. Compared with non-Gorlin patients, Gorlin patients often develop BCCs at a younger age and in greater numbers up to 500 BCCs in a lifetime. OBJECTIVE: To review the options available for Gorlin patients and highlight existing knowledge gaps where future studies are indicated to optimize the care of this unique population. METHODS: We review the current literature on managing patients with Gorlin syndrome from the lens of a dermatologic surgeon. RESULTS: Although Mohs surgery is still the gold standard for large and aggressive BCCs, other less-invasive approaches may be considered for smaller, more numerous lesions. As dermatologic surgeons, we must be open to the full spectrum of surgical and nonsurgical options to individualize treatment and optimize patients' quality of life. Without maintaining a balance between optimal cure rate and volume management, Gorlin patients become at risk for surgical burn out and loss to follow-up. CONCLUSION: Gorlin patients undergo numerous surgeries especially on the central face which can lead to disfigurement and reduce the quality of life. Identifying gaps in the current literature, continuing ongoing research, and eventually establishing appropriate guidelines that help to guide the formation of an individualized treatment plan is crucial in developing a balance between conservative and complex treatments for this population.

Anticipated Versus Unanticipated Incomplete Mohs Micrographic Surgery for Keratinocyte Carcinomas: Impact on Treatment Delays and Final Margin Status.

BACKGROUND: Mohs micrographic surgery may be discontinued with positive margins as an anticipated strategy for multidisciplinary care or as an unanticipated occurrence. Management of primary tumors has not been compared after anticipated versus unanticipated incomplete Mohs micrographic surgery (iMMS). OBJECTIVE: To compare rates and timing of adjuvant surgery after iMMS and final margin status when iMMS is anticipated versus unanticipated. Secondary outcomes were preoperative and intraoperative clinicopathologic factors associated with iMMS. METHODS: Cases of iMMS of keratinocyte carcinomas at a tertiary academic center between 2005 and 2022 were classified as anticipated (preoperative assembly of multidisciplinary teams) or unanticipated (ad hoc management of positive margins). Rate, timing, and final margin status of adjuvant surgery was compared between anticipated and unanticipated iMMS cohorts using χ2/Fisher exact test for categorical variables and t-test for continuous variables. RESULTS: Of 127 iMMS cases, 51.2% (65/127) were anticipated. Anticipated iMMS cases were more likely to undergo additional resection (98.5% vs 72.6%, p < .001), with fewer delays (3.9 vs 13.2 days, p < .001) and higher rates of final margin clearance (84.6% vs 59.7%, p < .001). CONCLUSION: When iMMS is anticipated as part of multidisciplinary care, patients are more likely to undergo additional resection, with fewer delays to next surgery and higher final margin clearance rates.

Oral Nicotinamide for Actinic Keratosis Prevention in Kidney Transplant Recipients: A Pilot Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: Oral nicotinamide (NAM) has shown promise in preventing actinic keratoses (AKs) in trials based outside of the United States. We assessed the efficacy of oral NAM supplementation in kidney transplant recipients with a history of keratinocyte carcinoma. MATERIAL AND METHODS: Patients enrolled in a 2-week run-in phase, during which NAM 1000 mg was taken twice daily. After a washout period, patients who tolerated the run-in phase were randomized to NAM 500 mg twice daily or placebo. At baseline, 4, 8, and 12 months, dermatologists conducted full-body skin exams to document area-specific AKs. Routine lab work was collected to ensure the stability of renal allograft function. RESULTS: The dosage was reduced from 1000 to 500 mg due to gastrointestinal symptoms in the run-in phase. Patients were randomized to NAM (n = 10) or placebo (n = 11). At 12 months, mean AK count was 30.8 (95% CI -11.7-73.4) for NAM and 26.6 (95% CI 10.8-42.5) for placebo. The difference in percent AK count change at 12 months compared with baseline was 259.8% (95% CI -385.9 to 905.5) for NAM and 72.4% (95% CI -118.6 to 263.5) for placebo. The between-group difference in percent AK change was not significant (P = .38). There was no attrition in the placebo group and 40% attrition in the NAM arm. DISCUSSION: Nicotinamide did not decrease AK development among kidney transplant recipients. Limitations include drug tolerability, small sample size, and single-center trial nature.

Patient Preferences for Pain Control After Mohs Micrographic Surgery: A Single-Center Discrete Choice Experiment.

Importance: Patient preferences for pain medications after Mohs micrographic surgery are important to understand and have not been fully studied. Objective: To evaluate patient preferences for pain management with only over-the-counter medications (OTCs) or OTCs plus opioids after Mohs micrographic surgery given varying levels of theoretical pain and opioid addiction risk. Design, Setting, and Participants: This prospective discrete choice experiment was conducted in a single academic medical center from August 2021 to April 2022 among patients undergoing Mohs surgery and their accompanying support persons (≥18 years). A prospective survey was administered to all participants using the Conjointly platform. Data were analyzed from May 2022 to February 2023. Main outcome and measure: The primary outcome was the pain level at which half of the respondents chose OTCs plus opioids equally to only OTCs for pain management. This pain threshold was determined for varying opioid addiction risk profiles (low, 0%; low-moderate, 2%; moderate-high, 6%; high, 12%) and measured via a discrete choice experiment and linear interpolation of associated parameters (pain levels and risk of addiction). Results: Of the 295 respondents (mean [SD] age, 64.6 [13.1] years; 174 [59%] were female; race and ethnicity were not considered) who completed the discrete choice experiment, 101 (34%) stated that they would never consider opioids for pain management regardless of the pain level experienced, and 147 (50%) expressed concern regarding possible opioid addiction. Across all scenarios, 224 respondents (76%) preferred only OTCs vs OTCs plus opioids after Mohs surgery for pain control. When the theoretical risk of addiction was low (0%), half of the respondents expressed a preference for OTCs plus opioids given pain levels of 6.5 on a 10-point scale (90% CI, 5.7-7.5). At higher opioid addiction risk profiles (2%, 6%, 12%), an equal preference for OTCs plus opioids and only OTCs was not achieved. In these scenarios, patients favored only OTCs despite experiencing high levels of pain. Conclusion and relevance: The findings of this prospective discrete choice experiment indicate that the perceived risk of opioid addiction affects the patient's choice of pain medications after Mohs surgery. It is important to engage patients undergoing Mohs surgery in shared decision-making discussions to determine the optimal pain control plan for each individual. These findings may encourage future research on the risks associated with long-term opioid use after Mohs surgery.

A retrospective case series of Mohs micrographic surgery and interdisciplinary management of female genital skin cancers: Local recurrence rates and patient-reported outcomes.

BACKGROUND: Conventional excision of female genital skin cancers has high rates of local recurrence and morbidity. Few publications describe local recurrence rates (LRRs) and patient-reported outcomes (PROs) after Mohs micrographic surgery (MMS) for female genital skin cancers. OBJECTIVE: To evaluate LRRs, PROs, and interdisciplinary care after MMS for female genital skin cancers. METHODS: A retrospective case series was conducted of female genital skin cancers treated with MMS between 2006 and 2021 at an academic center. The primary outcome was local recurrence. Secondary outcomes were PROs and details of interdisciplinary care. RESULTS: Sixty skin cancers in 57 patients were treated with MMS. Common diagnoses included squamous cell cancer (n = 26), basal cell cancer (n = 12), and extramammary Paget disease (n = 11). Three local recurrences were detected with a mean follow-up of 61.1 months (median: 48.8 months). Thirty-one patients completed the PROs survey. Most patients were satisfied with MMS (71.0%, 22/31) and reported no urinary incontinence (93.5%, 29/31). Eight patients were sexually active at follow-up and 75.0% (6/8) experienced no sexual dysfunction. Most cases involved interdisciplinary collaboration 71.7% (43/60). LIMITATIONS: Limitations include the retrospective single-center design, heterogeneous cohort, and lack of preoperative function data. CONCLUSIONS: Incorporating MMS into interdisciplinary teams may help achieve low LRRs and satisfactory function after genital skin cancer surgery.

Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma that typically presents as a rapidly enlarging violaceous papulonodule on sun-damaged skin in elderly patients. MCC has high rates of local recurrence, metastasis, and poor survival. Treatment of the primary tumor involves surgical excision with possible adjuvant radiation therapy, whereas regional nodal disease is treated with some combination of lymph node dissection and radiation therapy. Immune checkpoint inhibitors, such as avelumab and pembrolizumab, are first-line agents for metastatic MCC. Monitoring for recurrence can be aided by Merkel cell polyomavirus oncoprotein antibody titers.

Cutaneous Oncology in the Immunosuppressed.

Patients with immunosuppressive conditions experience an increased frequency and severity of cutaneous malignancies. This article highlights management of keratinocyte carcinoma, melanoma, Merkel cell carcinoma, and Kaposi sarcoma in the setting of lymphoproliferative disorders, acquired immunodeficiencies, and organ transplantation. Advances in the safety of organ transplant recipient immunosuppression, early identification of risk factors, and new targeted therapies are improving skin cancer outcomes in immunocompromised populations.

The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism.

Thyroglobulin (TG), the predominant glycoprotein of the thyroid gland, functions as matrix protein in thyroid hormonegenesis. TG deficiency results in thyroid dyshormonogenesis. These variants produce a heterogeneous spectrum of congenital goitre, with an autosomal recessive mode of inheritance. The purpose of this study was to identify and functionally characterize new variants in the TG gene in order to increase the understanding of the molecular mechanisms responsible for thyroid dyshormonogenesis. A total of four patients from two non-consanguineous families with marked alteration of TG synthesis were studied. The two families were previously analysed in our laboratory, only one deleterious allele, in each one, was detected after sequencing the TG gene (c.2359 C > T [p.Arg787*], c.5560 G > T [p.Glu1854*]). These findings were confirmed in the present studies by Next-Generation Sequencing. The single nucleotide coding variants of the TG gene were then analyzed to predict the possible variant causing the disease. The p.Pro2232Leu (c.6695 C > T), identified in both families, showing a low frequency population in gnomAD v2.1.1 database and protein homology, amino acid prediction, and 3D modeling analysis predict a potential pathogenic effect of this variant. We also transiently express p.Pro2232Leu in a full-length rat TG cDNA clone and confirmed that this point variant was sufficient to cause intracellular retention of mutant TG in HEK293T cells. Consequently, each family carried a compound heterozygous for p.Arg787*/p.Pro2232Leu or p.Glu1854*/p.Pro2232Leu variants. In conclusion, our results confirm the pathophysiological importance of altered TG folding as a consequence of missense variants located in the ChEL domain of TG.

Surface faulting earthquake clustering controlled by fault and shear-zone interactions.

Surface faulting earthquakes are known to cluster in time from historical and palaeoseismic studies, but the mechanism(s) responsible for clustering, such as fault interaction, strain-storage, and evolving dynamic topography, are poorly quantified, and hence not well understood. We present a quantified replication of observed earthquake clustering in central Italy. Six active normal faults are studied using 36Cl cosmogenic dating, revealing out-of-phase periods of high or low surface slip-rate on neighboring structures that we interpret as earthquake clusters and anticlusters. Our calculations link stress transfer caused by slip averaged over clusters and anti-clusters on coupled fault/shear-zone structures to viscous flow laws. We show that (1) differential stress fluctuates during fault/shear-zone interactions, and (2) these fluctuations are of sufficient magnitude to produce changes in strain-rate on viscous shear zones that explain slip-rate changes on their overlying brittle faults. These results suggest that fault/shear-zone interactions are a plausible explanation for clustering, opening the path towards process-led seismic hazard assessments.

Phthalate exposure among U.S. college-aged women: Biomonitoring in an undergraduate student cohort (2016-2017) and trends from the National Health and Examination Survey (NHANES, 2005-2016).

IMPORTANCE: Phthalates are ubiquitous and many are known or suspected human reproductive and endocrine-disrupting toxicants. A data gap exists in reporting on biomonitoring of phthalate biomarkers in college-aged adults. OBJECTIVE: To analyze phthalate exposure in a cross-sectional sample of female college students using urinary phthalate metabolite concentrations and compare to reference populations including college-aged women sampled in the National Health and Nutrition Examination Survey (NHANES). METHODS: Nine monoester phthalate metabolites were analyzed in spot urine collected from 215 female undergraduates (age 18-22, 2016-2017) at a public university in Charleston, SC USA and a subset of participants completed a questionnaire detailing demographics and behaviors including personal care and cosmetic product use (e.g. in the past 6 or 24 hrs). Urine specific gravity was used to assess effect of urine dilution. Phthalate metabolite concentrations were compared to reference populations and the temporal trends of the same age-group in the National Health and Nutrition Examination Survey (NHANES) were analyzed. RESULTS: Total urinary phthalate metabolite concentrations in individuals ranged three orders of magnitude (geometric mean 56.6 ng/mL, IQR 26.6-114 ng/mL). A third of urine samples had relatively high urine specific gravity levels indicating potential dehydration status. All geometric mean concentrations were similar to the U.S. female population in the most recent NHANES cycle (2015-2016) except for MEP and mono-isobutyl phthalate (MiBP). Relatively low MEP and MiBP may be explained by a time trend of declining MEP in the general U.S. population, the sociocultural character of this cohort, and the time of day of spot sampling in evening. NHANES data indicate a significant effect of sample timing on phthalate metabolite concentrations and decline in most, but not all, phthalate metabolites sampled in women aged 18-22 years over the decade (2005-2016). SIGNIFICANCE: This study reports phthalate metabolites in college-aged women, an understudied group, emphasizes the benefit of survey information for interpreting biomonitoring data, and is a useful case study for communicating phthalate chemical exposure risks to college students.

Presence of optrA-mediated linezolid resistance in multiple lineages and plasmids of Enterococcus faecalis revealed by long read sequencing.

Transferable linezolid resistance due to optrA, poxtA, cfr and cfr-like genes is increasingly detected in enterococci associated with animals and humans globally. We aimed to characterize the genetic environment of optrA in linezolid-resistant Enterococcus faecalis isolates from Scotland. Six linezolid-resistant E. faecalis isolated from urogenital samples were confirmed to carry the optrA gene by PCR. Short read (Illumina) sequencing showed the isolates were genetically distinct (>13900 core SNPs) and belonged to different MLST sequence types. Plasmid contents were examined using hybrid assembly of short and long read (Oxford Nanopore MinION) sequencing technologies. The optrA gene was located on distinct plasmids in each isolate, suggesting that transfer of a single plasmid did not contribute to optrA dissemination in this collection. pTM6294-2, BX5936-1 and pWE0438-1 were similar to optrA-positive plasmids from China and Japan, while the remaining three plasmids had limited similarity to other published examples. We identified the novel Tn6993 transposon in pWE0254-1 carrying linezolid (optrA), macrolide (ermB) and spectinomycin [ANT(9)-Ia] resistance genes. OptrA amino acid sequences differed by 0-20 residues. We report multiple variants of optrA on distinct plasmids in diverse strains of E. faecalis. It is important to identify the selection pressures driving the emergence and maintenance of resistance against linezolid to retain the clinical utility of this antibiotic.