Sebaceous carcinoma in Western Australia: A registry-based study of site-related outcomes.

Sebaceous carcinoma is a rare cutaneous malignancy which is typically regarded as relatively aggressive and has traditionally been subdivided into periorbital or extraorbital tumours. We conducted a retrospective review of all cases of sebaceous carcinoma reported to the Western Australian Cancer Registry between 1987 and May 2019. The incidence of sebaceous carcinoma in Western Australia has increased over the last three decades, with extraorbital tumours being much more common than periorbital tumours. Very few sebaceous carcinomas have led directly to the death of patients; however, adverse outcomes were more likely with periorbital tumours, in particular local recurrence and the need for major surgical intervention.

Mitotically Active Nevus and Nevoid Melanoma: A Clinicopathological and Molecular Study.

ABSTRACT: The distinction between nevoid melanoma and a mitotically active nevus can be challenging at the microscopic level. In this study, we performed cytogenetic testing on a cohort of 25 mitotically active melanocytic proliferations resembling common melanocytic nevus from 25 patients. Based on cytogenetic findings, the lesions were classified as "nevoid melanoma" (n = 13) or "mitotically active nevus" (n = 12). Subsequently, we compared the clinicopathological features between these 2 groups. Nevoid melanomas occurred in older patients (P = 0.007); however, there were no significant differences in gender, size, or anatomical distribution between the 2 groups. Histologically, deep/marginal mitoses (P = 0.006), lack of maturation with depth (P = 0.036), and pseudo-maturation (P = 0.006) were significantly more common in nevoid melanomas. Immunohistochemically, complete loss of p16 was an important divisive feature (P = 0.0004), seen in 70% of nevoid melanomas, and highly correlated with loss of CDKN2A gene (chromosome 9p21). Our findings suggest that such reproducible immunomorphological differences can be of value in distinguishing nevoid melanoma from mitotically active nevus. Nevoid melanomas demonstrated a spectrum of chromosomal aberrations similar to those seen in common subtypes of melanoma, which can serve as a powerful adjunct diagnostic tool in morphologically challenging lesions.

Eczematous graft-vs-host disease: A report of three cases and review of the literature.

Graft-vs-host disease (GVHD) is the most common complication following hematopoietic cell transplantation, which affects skin frequently. Acute and chronic forms of GVHD manifest commonly as maculopapular to morbilliform eruptions and sclerotic or lichen-planus-like lesions, respectively; however, atypical presentations such as eczema-like GVHD may occur at times. We describe three cases of GVHD with diverse and polymorphous cutaneous eruptions including pompholyx-like and vasculitis-like rash as well as erythematous plaques and papulosquamous eruptions, with skin biopsy showing unifying histopathological findings with concurrent changes of spongiotic dermatitis and vacuolar interface reaction with apoptotic keratinocytes. In addition, the clinical and pathological features of previously reported cases of eczema-like GVHD are reviewed. It is emphasized that the course of the disease can be variable and successful management often involves a combination of multiple therapeutic modalities including immunosuppression with or without ultraviolet therapy. These cases highlight the importance of meticulous clinicopathological correlation with careful exclusion of mimicking conditions to arrive at the correct diagnosis.

Histologically Diverse BAP1-Deficient Melanocytic Tumors in a Patient With BAP1 Tumor Predisposition Syndrome.

BRCA1-associated protein-1 (BAP1)-deficient cutaneous tumors are common in patients with BAP1 tumor predisposition syndrome, frequently presenting before other associated neoplasms, and can serve as an early marker to identify individuals with this disease. The typical lesions are dermal based and composed of a combination of larger epithelioid melanocytes with abundant glassy cytoplasm and smaller cells resembling those of a conventional nevus. There is often a component of interspersed lymphocytes. However, BAP1-deficient melanocytic tumors can show a spectrum of histologic appearances, ranging from lesions with pure epithelioid, pure conventional nevus, or rhabdoid cells and tumors with an intraepidermal component. To demonstrate such morphologic variation, we present a case of a 50-year-old woman with multiple histologically diverse BAP1-deficient melanocytic tumors and germline BAP1 mutation, identified after a diagnosis of pleural mesothelioma. We also discuss the pathogenesis and potential histopathological and clinical indications of germline versus sporadic etiology in the assessment of BAP1-deficient melanocytic tumors.

Validating the Electronic Cardiac Arrest Risk Triage (eCART) Score for Risk Stratification of Surgical Inpatients in the Postoperative Setting: Retrospective Cohort Study.

OBJECTIVE: Assess the accuracy of 3 early warning scores for predicting severe adverse events in postoperative inpatients. SUMMARY OF BACKGROUND DATA: Postoperative clinical deterioration on inpatient hospital services is associated with increased morbidity, mortality, and cost. Early warning scores have been developed to detect inpatient clinical deterioration and trigger rapid response activation, but knowledge regarding the application of early warning scores to postoperative inpatients is limited. METHODS: This was a retrospective cohort study of adult patients hospitalized on the wards after surgical procedures at an urban academic medical center from November, 2008 to January, 2016. The accuracies of the Modified Early Warning Score (MEWS), National Early Warning Score (NEWS), and the electronic cardiac arrest risk triage (eCART) score were compared in predicting severe adverse events (ICU transfer, ward cardiac arrest, or ward death) in the postoperative period using the area under the receiver operating characteristic curve (AUC). RESULTS: Of the 32,537 patient admissions included in the study, 3.8% (n = 1243) experienced a severe adverse outcome after the procedure. The accuracy for predicting the composite outcome was highest for eCART [AUC 0.79 (95% CI: 0.78-0.81)], followed by NEWS [AUC 0.76 (95% CI: 0.75-0.78)], and MEWS [AUC 0.75 (95% CI: 0.73-0.76)]. Of the individual vital signs and labs, maximum respiratory rate was the most predictive (AUC 0.67) and maximum temperature was an inverse predictor (AUC 0.46). CONCLUSION: Early warning scores are predictive of severe adverse events in postoperative patients. eCART is significantly more accurate in this patient population than both NEWS and MEWS.

Polypoid Compound Melanocytic Proliferations: A Clinicopathological Study.

Nevi can show a polypoid appearance both clinically and histologically. Anecdotally, polypoid compound melanocytic nevus may exhibit a spectrum of junctional architectural and cytologic atypia, at times creating a diagnostic challenge by mimicking the radial growth phase of melanoma. To investigate this issue, we prospectively reviewed 40 polypoid compound melanocytic proliferations without overt malignant features. The lesions frequently occurred in young female patients and were predominantly from the trunk and intertriginous areas. Commonly observed atypical features included asymmetry (30%), shouldering (47.5%), poor circumscription (37.5%), and deep extension of melanocytes along the adnexal structures (67.5%). Severe cytologic junctional atypia (22.5%), dermal mitoses (10%), and pagetoid spread of melanocytes (5%) were less commonly seen. All lesions showed a reassuring dermal component with negligible cytologic atypia and maturation with depth. Overall, 7 lesions could not be readily classified as benign nevus; 5 of these in which a benign diagnosis was strongly favored were classified as atypical polypoid compound melanocytic nevi, whereas 2 lesions with diffuse severe junctional cytologic atypia and dermal mitoses were classified as ambiguous melanocytic proliferations. Atypical/ambiguous lesions were significantly larger and predominantly located in the axilla and groin. On molecular studies, none of the lesions tested showed the molecular profile of melanoma. We confirmed that polypoid compound melanocytic nevus can exhibit a variable degree of junctional atypia, likely related to frequent episodes of trauma and regeneration resulting in melanocytic proliferation. Pathologists should be aware of this phenomenon to avoid overdiagnosis.

Pathological Sampling of Basal Cell Carcinoma Re-excision Specimens: How Much is Enough?

Basal cell carcinoma (BCC) is the most common cutaneous malignancy, comprising approximately 75%-80% of all skin cancers. Surgical excision is the most common first line treatment modality, with the intent of obtaining clear margins. If the initial excision is incomplete or inadequate, a re-excision will often be performed in an attempt to achieve histological clearance. The pathological examination of these specimens requires a balance between the need for adequate assessment and efficient use of laboratory resources. In this study, we sought to systematically compare different approaches to the pathological sampling of these specimens in the hope of providing an evidential basis for a rational approach. Seventy-four BCC re-excision specimens were entirely sampled and retrospectively examined to determine the rate of detection of residual BCC which would have been achieved using different sampling methodologies. Residual BCC was identified in 37 specimens (50%). Limited transverse sections through the centre of the ellipse resulted in a sensitivity for detection of residual BCC of 78% (or 85% if only "significant" residual tumor is considered). By including the entire scar or the remainder of the specimen except the polar pieces, the sensitivity improved to 95% and 97%, respectively. Only one case showed residual tumor in the apical sections alone, with tumor extending to the new surgical margin in that case. We hope that this data may help laboratories develop sampling protocols appropriate to their own cost-benefit analyses and patient populations.

Skin biopsy in the diagnosis of inflammatory skin disease.

BACKGROUND: Most non-neoplastic skin conditions are readily diagnosed by a combination of clinical history and examination, but in a small number of cases, biopsy for histopathology and other laboratory investigations can be invaluable tools. Close attention to communication of appropriate clinical details, selection of biopsy site and biopsy technique have a marked impact on the diagnostic yield of this procedure. OBJECTIVE: The objectives of this article are to provide general principles related to the biopsy of non-neoplastic skin conditions and offer practical advice on the approach to some common skin conditions. DISCUSSION: In this article, we discuss a number of general principles that will ensure maximum benefits can be achieved when a biopsy is per-formed for the diagnosis of non-neoplastic skin disease.

Skin biopsy in the diagnosis of neoplastic skin disease.

BACKGROUND: Biopsy for diagnostic and therapeutic purposes is a central component in the management of neoplastic skin conditions. While the technical aspects of performing biopsies are familiar to most clinicians, a number of other aspects of the skin biopsy pathway are equally important. OBJECTIVE: The objectives of this article are to provide general principles related to the biopsy of neoplastic skin conditions and offer practical advice on the approach to some common skin neoplasms. DISCUSSION: Careful attention to the selection of biopsy site and type, and communication of appropriate clinical details will ensure optimal patient care, minimising the chance of diagnostic errors with potentially serious medical and medico-legal consequences.

Importance of Adequate Lymphadenectomy in Gastrointestinal Cancer.

One of the most important factors influencing cancer-specific survival in the field GI oncology is the presence of positive lymph nodes. Although it remains controversial, adequate lymph node examination is required for accurate staging such that patients can receive correct adjuvant treatments and for stratification in clinical trials. Nevertheless, wide variation in the quality of lymph node examination exists in the US and many centers are not meeting guideline treatment recommendations.

Cutaneous Metastatic Melanoma Resembling a Halo Nevus, in the Setting of PD-1 Inhibition.

Malignant melanoma is a common source of cutaneous metastases and can occasionally adopt a histological appearance which mimics a primary melanocytic lesion, either benign or malignant. The authors describe a case of new cutaneous deposits of metastatic melanoma in a 70-year-old woman with a prominent admixed lymphocytic infiltrate, imparting a striking resemblance to a halo nevus. The authors believe this appearance was a direct reflection of treatment with pembrolizumab, a humanized antibody against the immune checkpoint inhibitor programmed death-1. With increasing use of immune-modulating drugs, this potential histological mimic may be seen more frequently in the future.

A large-scale complex haploinsufficiency-based genetic interaction screen in Candida albicans: analysis of the RAM network during morphogenesis.

The morphogenetic transition between yeast and filamentous forms of the human fungal pathogen Candida albicans is regulated by a variety of signaling pathways. How these pathways interact to orchestrate morphogenesis, however, has not been as well characterized. To address this question and to identify genes that interact with the Regulation of Ace2 and Morphogenesis (RAM) pathway during filamentation, we report the first large-scale genetic interaction screen in C. albicans.Our strategy for this screen was based on the concept of complex haploinsufficiency (CHI). A heterozygous mutant of CBK1(cbk1Δ/CBK1), a key RAM pathway protein kinase, was subjected to transposon-mediated, insertional mutagenesis. The resulting double heterozygous mutants (6,528 independent strains) were screened for decreased filamentation on SpiderMedium (SM). From the 441 mutants showing altered filamentation, 139 transposon insertion sites were sequenced,yielding 41 unique CBK1-interacting genes. This gene set was enriched in transcriptional targets of Ace2 and, strikingly, the cAMP-dependent protein kinase A (PKA) pathway, suggesting an interaction between these two pathways. Further analysis indicates that the RAM and PKA pathways co-regulate a common set of genes during morphogenesis and that hyperactivation of the PKA pathway may compensate for loss of RAM pathway function. Our data also indicate that the PKA­regulated transcription factor Efg1 primarily localizes to yeast phase cells while the RAM­pathway regulated transcription factor Ace2 localizes to daughter nuclei of filamentous cells, suggesting that Efg1 and Ace2 regulate a common set of genes at separate stages of morphogenesis. Taken together, our observations indicate that CHI­based screening is a useful approach to genetic interaction analysis in C. albicans and support a model in which these two pathways regulate a common set of genes at different stages of filamentation.

Social determinants of health, the microbiome, and surgical injury.

ABSTRACT: Postinjury infection continues to plague trauma and emergency surgery patients fortunate enough to survive the initial injury. Rapid response systems, massive transfusion protocols, and the development of level 1 trauma centers, among others, have improved the outcome for millions of patients worldwide. Nonetheless, despite this excellent initial care, patients still remain vulnerable to postinjury infections that can result in organ failure, prolonged critical illness, and even death. While risk factors have been identified (degree of injury, blood loss, time to definitive care, immunocompromise, etc.), they remain probabilistic, not deterministic, and do not explain outcome variability at the individual case level. Here, we assert that analysis of the social determinants of health, as reflected in the patient's microbiome composition (i.e., community structure, membership) and function (metabolomic output), may offer a "window" with which to define individual variability following traumatic injury. Given emerging knowledge in the field, a more comprehensive evaluation of biomarkers within the patient's microbiome, from stool-based microbial metabolites to those in plasma and those present in exhaled breath, when coupled with clinical metadata and machine learning, could lead to a more deterministic assessment of an individual's risk for a poor outcome and those factors that are modifiable. The aim of this piece is to examine how measurable elements of the social determinants of health and the life history of the patient may be buried within the ecologic memory of the gut microbiome. Here we posit that interrogation of the gut microbiome in this manner may be used to inform novel approaches to drive recovery following a surgical injury.

TXA does not affect levels of TBI-related biomarkers in blunt TBI with ICH: A secondary analysis of the prehospital TXA for TBI trial.

BACKGROUND: Brain specific biomarkers such as glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein-2 (MAP-2) have been identified as tools for diagnosis in traumatic brain injury (TBI). Tranexamic acid (TXA) has been shown to decrease mortality in patients with intracranial hemorrhage (ICH). The effect of TXA on these biomarkers is unknown. We investigated whether TXA affects levels of GFAP, UCH-L1, and MAP-2, and whether biomarker levels are associated with mortality in patients receiving TXA. METHODS: Patients enrolled in the prehospital TXA for TBI trial had GFAP, UCHL-1 and MAP-2 levels drawn at 0 hour and 24 hours postinjury (n = 422). Patients with ICH from blunt trauma with a GCS <13 and SBP >90 were randomized to placebo, 2 g TXA bolus, or 1 g bolus +1 g/8 hours TXA infusion. Associations of TXA and 24-hour biomarker change were assessed with multivariate linear regression. Association of biomarkers with 28-day mortality was assessed with multivariate logistic regression. All models were controlled for age, GCS, ISS, and AIS head. RESULTS: Administration of TXA was not associated with a change in biomarkers over 24 hours postinjury. Changes in biomarker levels were associated with AIS head and age. On admission, higher GFAP (odds ratio [OR], 1.75; confidence interval [CI], 1.31-2.38; p < 0.001) was associated with increased 28-day mortality. At 24 hours postinjury, higher levels of GFAP (OR, 2.09; CI, 1.37-3.30; p < 0.001 and UCHL-1 (OR, 2.98; CI, 1.77-5.25; p < 0.001) were associated with mortality. A change in UCH levels from 0 hour to 24 hours postinjury was also associated with increased mortality (OR, 1.68; CI, 1.15-2.49; p < 0.01). CONCLUSION: Administration of TXA does not impact change in GFAP, UCHL-1, or MAP-2 during the first 24 hours after blunt TBI with ICH. Higher levels of GFAP and UCH early after injury may help identify patients at high risk for 28-day mortality. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Trauma surgical skill sustainment at the University of Chicago AMEDD Military-Civilian Trauma Team Training Site: an observation report.

Background: The Army Medical Department (AMEDD) Military-Civilian Trauma Team Training (AMCT3) Program was developed to enhance the trauma competency and capability of the medical force by embedding providers at busy civilian trauma centers. Few reports have been published on the outcomes of this program since its implementation. Methods: The medical and billing records for the two AMCT3 embedded trauma surgeons at the single medical center were retrospectively reviewed for care provided during August 2021 through July 2022. Abstracted data included tasks met under the Army's Individual Critical Task List (ICTL) for general surgeons. The Knowledge, Skills, and Abilities (KSA) score was estimated based on previously reported point values for procedures. To assess for successful integration of the embedded surgeons, data were also abstracted for two newly hired civilian trauma surgeons. Results: The annual clinical activity for the first AMCT3 surgeon included 444 trauma evaluations and 185 operative cases. The operative cases included 80 laparotomies, 15 thoracotomies, and 15 vascular exposures. The operative volume resulted in a KSA score of 21 998 points. The annual clinical activity for the second AMCT3 surgeon included 424 trauma evaluations and 194 operative cases. The operative cases included 92 laparotomies, 8 thoracotomies, and 25 vascular exposures. The operative volume resulted in a KSA score of 22 799 points. The first civilian surgeon's annual clinical activity included 453 trauma evaluations and 151 operative cases, resulting in a KSA score of 16 738 points. The second civilian surgeon's annual clinical activity included 206 trauma evaluations and 96 operative cases, resulting in a KSA score of 11 156 points. Conclusion: The AMCT3 partnership at this single center greatly exceeds the minimum deployment readiness metrics established in the ICTLs and KSAs for deploying general surgeons. The AMEDD experience provided a deployment-relevant case mix with an emphasis on complex vascular injury repairs.

State-Level Analysis of Intimate Partner Violence, Abortion Access, and Peripartum Homicide: Call for Screening and Violence Interventions for Pregnant Patients.

BACKGROUND: Despite representing 4% of the global population, the US has the fifth highest number of intentional homicides in the world. Peripartum people represent a unique and vulnerable subset of homicide victims. This study aimed to understand the risk factors for peripartum homicide. STUDY DESIGN: We used data from the 2018 to 2020 National Violent Death Reporting System to compare homicide rates of peripartum and nonperipartum people capable of becoming pregnant (12 to 50 years of age). Peripartum was defined as currently pregnant or within 1-year postpartum. We additionally compared state-level peripartum homicide rates between states categorized as restrictive, neutral, or protective of abortion. Pearson's chi-square and Wilcoxon rank-sum tests were used. RESULTS: There were 496 peripartum compared with 8,644 nonperipartum homicide victims. The peripartum group was younger (27.4 ± 71 vs 33.0 ± 9.6, p < 0.001). Intimate partner violence causing the homicide was more common in the peripartum group (39.9% vs 26.4%, p < 0.001). Firearms were used in 63.4% of homicides among the peripartum group compared with 49.5% in the comparison (p < 0.001). A significant difference was observed in peripartum homicide between states based on policies regarding abortion access (protective 0.37, neutral 0.45, restrictive 0.64; p < 0.01); the same trend was not seen with male homicides. CONCLUSIONS: Compared with nonperipartum peers, peripartum people are at increased risk for homicide due to intimate partner violence, specifically due to firearm violence. Increasing rates of peripartum homicide occur in states with policies that are restrictive to abortion access. There is a dire need for universal screening and interventions for peripartum patients. Research and policies to reduce violence against pregnant people must also consider the important role that abortion access plays in protecting safety.

Digital twin mathematical models suggest individualized hemorrhagic shock resuscitation strategies.

BACKGROUND: Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting. METHODS: We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation. RESULTS: The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well as the outcome and time of death in the PROMMTT cohort. Model simulation suggests that resuscitation with plasma and red blood cells outperformed resuscitation with crystalloid or plasma alone, and that earlier plasma resuscitation reduced injury severity and increased survival time. CONCLUSIONS: This workflow may serve as a translational bridge from pre-clinical to clinical studies in trauma-associated hemorrhagic shock and other complex disease settings.

Research to improve survival in patients with severe bleeding after major trauma presents many challenges. Here, we created a computer model to simulate the effects of severe bleeding. We refined this model using data from existing animal studies to ensure our simulations were accurate. We also used patient data to further refine the simulations to accurately predict which patients would live and which would not. We studied the effects of different treatment protocols on these simulated patients and show that treatment with plasma (the fluid portion of blood that helps form blood clots) and red blood cells jointly, gave better results than treatment with intravenous fluid or plasma alone. Early treatment with plasma reduced injury severity and increased survival time. This modelling approach may improve our ability to evaluate new treatments for trauma-associated bleeding and other acute conditions.

Social Vulnerability and Firearm Violence: Geospatial Analysis of 5 US Cities.

BACKGROUND: Firearm violence is now endemic to certain US neighborhoods. Understanding factors that impact a neighborhood's susceptibility to firearm violence is crucial for prevention. Using a nationally standardized measure to characterize community-level firearm violence risk has not been broadly studied but could enhance prevention efforts. Thus, we sought to examine the association between firearm violence and the social, structural, and geospatial determinants of health, as defined by the Social Vulnerability Index (SVI). STUDY DESIGN: In this cross-sectional study, we merged 2018 SVI data on census tract with shooting incidents between 2015 and 2021 from Baltimore, Chicago, Los Angeles, New York City, and Philadelphia. We used negative binomial regression to associate the SVI with shooting incidents per 1,000 people in a census tract. Moran's I statistics and spatial lag models were used for geospatial analysis. RESULTS: We evaluated 71,296 shooting incidents across 4,415 census tracts. Fifty-five percent of shootings occurred in 9.4% of census tracts. In all cities combined, a decile rise in SVI resulted in a 37% increase in shooting incidents (p < 0.001). A similar relationship existed in each city: 30% increase in Baltimore (p < 0.001), 50% in Chicago (p < 0.001), 28% in Los Angeles (p < 0.001), 34% in New York City (p < 0.001), and 41% in Philadelphia (p < 0.001). Shootings were highly clustered within the most vulnerable neighborhoods. CONCLUSIONS: In 5 major US cities, firearm violence was concentrated in neighborhoods with high social vulnerability. A tool such as the SVI could be used to inform prevention efforts by directing resources to communities most in need and identifying factors on which to focus these programs and policies.