LTßR-RelB signaling in intestinal epithelial cells protects from chemotherapy-induced mucosal damage.

The intricate immune mechanisms governing mucosal healing following intestinal damage induced by cytotoxic drugs remain poorly understood. The goal of this study was to investigate the role of lymphotoxin beta receptor (LTßR) signaling in chemotherapy-induced intestinal damage. LTßR deficient mice exhibited heightened body weight loss, exacerbated intestinal pathology, increased proinflammatory cytokine expression, reduced IL-22 expression, and proliferation of intestinal epithelial cells following methotrexate (MTX) treatment. Furthermore, LTßR-/-IL-22-/- mice succumbed to MTX treatment, suggesting that LTßR- and IL-22- dependent pathways jointly promote mucosal repair. Although both LTßR ligands LIGHT and LTß were upregulated in the intestine early after MTX treatment, LIGHT-/- mice, but not LTß-/- mice, displayed exacerbated disease. Further, we revealed the critical role of T cells in mucosal repair as T cell-deficient mice failed to upregulate intestinal LIGHT expression and exhibited increased body weight loss and intestinal pathology. Analysis of mice with conditional inactivation of LTßR revealed that LTßR signaling in intestinal epithelial cells, but not in Lgr5+ intestinal stem cells, macrophages or dendritic cells was critical for mucosal repair. Furthermore, inactivation of the non-canonical NF-kB pathway member RelB in intestinal epithelial cells promoted MTX-induced disease. Based on these results, we propose a model wherein LIGHT produced by T cells activates LTßR-RelB signaling in intestinal epithelial cells to facilitate mucosal repair following chemotherapy treatment.

Monoclonal gammopathy in the setting of Pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by ulcerative painful lesions with violaceous undermined borders. Up to 75% of PG cases develop in association with an underlying systemic disease. Monoclonal gammopathy is reportedly a concomitant condition with PG, with studies indicating immunoglobulin (Ig) A gammopathy as the most common. Whether gammopathy is associated with PG or is an incidental finding has been debated. We sought to investigate the association and characteristics of gammopathy in patients with PG. We retrospectively identified PG patients at our institution from 2010 to 2022 who were screened for plasma cell dyscrasia. Of 106 patients identified, 29 (27%) had a gammopathy; subtypes included IgA (41%), IgG (28%), and biclonal (IgA and IgG) (14%). Mean age was similar between those with and without gammopathy (60.7 vs. 55.9 years; P = .26). In addition, hematologic or solid organ cancer developed in significantly more patients with vs. without gammopathy (8/29 [28%] vs. 5/77 [6%]; P = .003). Among the subtypes of gammopathy, IgG monoclonal gammopathy had the highest proportion of patients with subsequent cancer development (4 of 8 patients, 50%). Study limitations include a retrospective, single-institution design with a limited number of patients. Overall, our data show a high prevalence of gammopathy in patients with PG; those patients additionally had an increased incidence of cancer, especially hematologic cancer.

Risk factors associated with tumor upstaging in melanomas treated with Mohs micrographic surgery with melanocytic immunohistochemistry.

Background: Mohs micrographic surgery with melanocytic immunohistochemistry (MMS-I) is increasingly utilized for special site melanoma treatment. Yet, frequency and risk factors associated with upstaging of all-stage cutaneous melanomas treated with MMS-I remain undefined. Objective: Determine upstaging frequency and factors associated with tumor upstaging for all-stage melanomas treated with MMS-I. Methods: In this retrospective, single-center case series, all cases of invasive and in situ melanoma treated with MMS-I between 2008 and 2018 were reviewed. Patient and tumor characteristics were recorded and compared between tumors that were and were not upstaged from their initial T stage. Results: Of the 962 melanoma MMS-I cases identified, 44 (4.6%) were upstaged, including 5.6% of in situ and 2.5% of invasive tumors. Risk factors for upstaging included lack of excisional intent at the time of initial biopsy (P < .01), nonlentigo maligna subtype (P = .03), female sex (P = .02), and initial in situ diagnosis (P = .03). Nonstatistically significant characteristics evaluated included patient age (P = .97), initial Breslow depth (P = .18), and biopsy type (P = .24). Limitations: Retrospective study design. Conclusions: All-stage cutaneous melanomas treated with MMS-I are associated with low upstaging rates. Tumor upstaging is associated with lack of excisional intent, female sex, and in situ tumors.

Delayed Sternal Closure vs Emergency Sternal Reopening in Adults with Congenital Heart Disease.

BACKGROUND: Limited data exist regarding outcomes of delayed sternal closure (DSC) in adults with congenital heart disease (ACHD). METHODS: We reviewed 159 ACHD patients undergoing cardiac surgery 1993-2023, who required DSC (open sternum at the end of operation, n=112) or ESR (sternum emergently reopened, n=47). Regression models were performed to determine factors associated with outcomes. RESULTS: Of 112 patients undergoing DSC, 87 patients (77.6%) underwent DSC ≤4 days, and 25 patients (22.3%) >4 days. The most common operations were valve (n=35, 31.2%), aortic (n=33, 29.4%), and right ventricular outflow tract procedures (n=23, 20.5%). Median time to chest closure was 2 days (interquartile range 1, 5). Apart from gender, baseline characteristics were similar between DSC groups. A stepwise increase in early mortality was observed from DSC≤4 days to DSC>4 days (6.8% vs 32%), as well as incidence of early complications, except sternal infection. Risk factors associated with early mortality were age (p=0.02), DSC >4 days (p<0.001), hemodynamic indication (p=0.03), and single ventricle (p=0.02). On multivariable analysis, lower ejection fraction (p=0.04), hemodynamic indication (p=0.02), single ventricle (p=0.004), and diabetes mellitus (p=0.03) were predictors of prolonged time to chest closure. Amongst hospital survivors, there was no difference in late survival between patients undergoing DSC ≤4 days vs >4 days (p=0.48). CONCLUSIONS: Brief duration of DSC in ACHD patients is associated with low morbidity and mortality. Higher early mortality and complications were observed among patients who did not achieve chest closure within 4 days.

Digital dermatopathology implementation: Experience at a multisite academic institution.

BACKGROUND: Technology has revolutionized not only direct patient care but also diagnostic care processes. This study evaluates the transition from glass-slide microscopy to digital pathology (DP) at a multisite academic institution, using mixed methods to understand user perceptions of digitization and key productivity metrics of practice change. METHODS: Participants included dermatopathologists, pathology reporting specialists, and clinicians. Electronic surveys and individual or group interviews included questions related to technology comfort, trust in DP, and rationale for DP adoption. Case volumes and turnaround times were abstracted from the electronic health record from Qtr 4 2020 to Qtr 1 2023 (inclusive). Data were analyzed descriptively, while interviews were analyzed using methods of content analysis. RESULTS: Thirty-four staff completed surveys and 22 participated in an interview. Case volumes and diagnostic turnaround time did not differ across the institution during or after implementation timelines (p = 0.084; p = 0.133, respectively). 82.5% (28/34) of staff agreed that DP improved the sign-out experience, with accessibility, ergonomics, and annotation features described as key factors. Clinicians reported positive perspectives of DP impact on patient safety and interdisciplinary collaboration. CONCLUSIONS: Our study demonstrates that DP has a high acceptance rate, does not adversely impact productivity, and may improve patient safety and care collaboration.

Simultaneous Tricuspid Valve Repair at the Time of Mitral Valve Surgery: Determinants of Postoperative Pacemaker Implantation.

OBJECTIVE: Guidelines recommend tricuspid valve (TV) repair for patients with severe tricuspid valve regurgitation (TR) undergoing surgery for degenerative mitral valve (MV) disease, but management of ≤ moderate TR is controversial. This study examines the incidence and causes of bradyarrhythmias leading to PPM implantation. METHODS: Review of patients undergoing simultaneous TV repair and MV surgery for degenerative MV disease from 2001 to 2022 (N=404). Primary endpoint was the incidence of postoperative PPM implantation. Secondary endpoints included the incidence of high-degree AV block and overall survival. RESULTS: All patients underwent TV repair at the time of MV surgery; 332 (82%) underwent MV repair and 72 (18%) MV replacement. Tricuspid valve repair techniques included flexible band (n=258, 63.8%), DeVega annuloplasty (n=78, 19.3%), complete flexible ring (n=49, 12.1%), and incomplete rigid ring (n=19, 4.7%). The 30-day mortality was 0.5% (n=2). A total of 35 (8.7%) patients had a PPM implanted postoperatively, 26 (6.4%) for high-degree AV block. On multivariable analysis, only older age was associated with PPM implantation. Patients who received a PPM due to high-degree AV block had reduced overall survival (Figure, p=0.01). CONCLUSIONS: Need for permanent pacing following TV repair at the time of MV surgery is not uncommon, but there are few modifiable factors that might reduce this risk. Careful selection of patients with less-than-severe TR and surgical techniques may reduce PPM-related risks and complications.

Single-Center Prospective Study of Cross-Clamp vs Balloon Occlusion in Robotic Mitral Surgery.

BACKGROUND: Transthoracic aortic cross-clamp and endoaortic balloon occlusion have both been shown to have comparable safety profiles for aortic occlusion. Because most surgeons use only one technique, we sought to compare the outcomes when a homogeneous group of surgeons changed their occlusion technique from aortic cross-clamp to balloon occlusion. METHODS: We changed our technique from aortic cross-clamp to balloon occlusion in November 2022. This allowed us to conduct a prospective treatment comparison study in the same group of surgeons. Propensity score matching was used to match cases (balloon occlusion) 1:3 to controls (aortic cross-clamp) based on age, sex, body mass index, concomitant maze procedure, and tricuspid valve repair. RESULTS: Total of 411 patients underwent robotic mitral surgery from 2020 through 2023. Propensity score matching was used to match 56 balloon occlusion patients to 168 aortic cross-clamp patients. The 224 patients were a median age of 65 years (interquartile range, 55.6-70.0 years), and 119 (53%) were men. All valves were successfully repaired. Balloon occlusion had a shorter median cardiopulmonary bypass (CPB) time compared with aortic cross-clamp (84.0 vs 94.5 minutes, P = .006). Median cross-clamp time (64.0 vs 64.0 minutes, P = .483) and total surgery time (5.9 vs 6.1 hours, P = .495) did not differ between groups. There were no in-hospital deaths. There were 5 surgeons who performed various combinations of console and bedside roles. CPB, cross-clamp, and surgery durations were not significantly affected by the different surgeon combinations. CONCLUSIONS: Compared with aortic cross-clamp, balloon occlusion has similar perioperative and early postoperative outcomes. Additionally, it likely introduces a 10-minute reduction in total CPB time.

Outcomes of aortic surgery in patients with Takayasu arteritis.

OBJECTIVE: To investigate the presentation, aortic involvement, and surgical outcomes in patients with Takayasu arteritis undergoing aortic surgery. METHODS: We queried our surgical database for patients with Takayasu arteritis who underwent aortic surgery from 1994 to 2022. RESULTS: There were a total of 31 patients with Takayasu arteritis who underwent aortic surgery. Patients' median age at the time of diagnosis was 35.0 years (interquartile range, 25.0-42.0). The majority were female (n = 27, 87.0%). Most patients (n = 28, 90.3%) were diagnosed before surgery, and 3 patients (9.6%) were diagnosed perioperatively. The median time interval from diagnosis to surgery was 2.8 years (interquartile range, 0.5-13.9). The most common presentation was ascending aorta aneurysm (n = 22, 70.9%), and severe aortic regurgitation was the most common valve insufficiency (n = 17, 54.8%). The most common operation was ascending aorta replacement (n = 20, 64.5%), and aortic valve replacement was the most common valve intervention (n = 17, 54.8%). Active vasculitis was identified in 2 (11.7%) aortic valve specimens. Early mortality was 6.5% (n = 2). A total of 6 deaths occurred over a median follow-up of 13.1 years (interquartile range, 6.1-25.2). Survival at 10 years was 86.7% (95% CI, 75.4-99.7). A total of 5 patients (16.1%) required a subsequent operation in a median of 1.9 years (interquartile range, 0.2-7.4). Freedom from reoperation was 96.9% (95% CI, 90.1-100) at 1 year, 89.4% (95% CI, 78.7-100.0) at 5 years, and 77.5% (95% CI, 61.2-98.1) at 10 and 15 years. CONCLUSIONS: Ascending aorta aneurysm and aortic valve regurgitation are the most frequent presentations in patients with Takayasu arteritis requiring aortic surgery. Surgery in these individuals is safe, with acceptable short- and long-term results.

Neuropathological Applications of Microscopy with Ultraviolet Surface Excitation (MUSE): A Concordance Study of Human Primary and Metastatic Brain Tumors.

Whereas traditional histology and light microscopy require multiple steps of formalin fixation, paraffin embedding, and sectioning to generate images for pathologic diagnosis, Microscopy using Ultraviolet Surface Excitation (MUSE) operates through UV excitation on the cut surface of tissue, generating images of high resolution without the need to fix or section tissue and allowing for potential use for downstream molecular tests. Here, we present the first study of the use and suitability of MUSE microscopy for neuropathological samples. MUSE images were generated from surgical biopsy samples of primary and metastatic brain tumor biopsy samples (n = 27), and blinded assessments of diagnoses, tumor grades, and cellular features were compared to corresponding hematoxylin and eosin (H&E) images. A set of MUSE-treated samples subsequently underwent exome and targeted sequencing, and quality metrics were compared to those from fresh frozen specimens. Diagnostic accuracy was relatively high, and DNA and RNA integrity appeared to be preserved for this cohort. This suggests that MUSE may be a reliable method of generating high-quality diagnostic-grade histologic images for neuropathology on a rapid and sample-sparing basis and for subsequent molecular analysis of DNA and RNA.

Adult-onset linear IgA bullous dermatosis: a retrospective single-center cohort study of 81 patients and literature review.

BACKGROUND: Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder that may be drug-induced or paraneoplastic. We aim to characterize features of LABD and determine differentiating factors among idiopathic, drug-induced, or malignancy-associated diseases. METHODS: We conducted a single-center retrospective chart review of adult patients with linear IgA bullous dermatosis at a large tertiary referral center and a literature review of adult linear IgA bullous dermatosis. RESULTS: Eighty-one patients were included in the study. Ten patients (12.3%) had comorbid malignancy and nine (11.1%) had inflammatory bowel disease. Median disease duration was significantly shorter in both drug-induced (1.2 vs. 48.8 months; P < 0.001) and malignancy-associated (1.7 vs. 48.8 months; P < 0.001) LABD compared with idiopathic LABD. Recurrent episodes occurred significantly more often in idiopathic LABD compared to those with drug-induced (76.1 vs. 11.5%; P < 0.001) or malignancy-associated disease (76.1 vs. 33.3%; P = 0.019). Time to diagnosis was significantly shorter in the drug-induced (0.2 vs. 5.4 months; P < 0.001) and malignancy-associated groups (0.7 vs. 5.4 months; P = 0.049) compared with idiopathic; similarly, time to improvement was significantly shorter in both drug-induced (0.4 vs. 3.0 months; P < 0.001) and malignancy-associated disease (1.1 vs. 3.0 months; P = 0.016). Clinical morphology was indistinguishable between groups. Limitations included retrospective data collection, data from tertiary referral centers, and limited racial and ethnic diversity. CONCLUSION: Screening for underlying malignancy, as well as for a predisposing medication or possibly inflammatory bowel disease, may be advisable in patients with LABD, particularly when it is newly diagnosed.

National In-Hospital Outcomes of Mechanical Mitral Valve Replacement in the Pediatric Population.

Background: National data about the outcomes of children undergoing mechanical mitral valve replacement (m-MVR) are scarce. Methods: A retrospective review of hospitalizations from the Kids' Inpatient Database was performed for patients ≤18 years of age in the United States. A total of 500 patients underwent m-MVR in 2009, 2012, 2016, and 2019. Patients with single ventricle physiology were excluded (n = 13). These patients were categorized into three groups according to age: neonates (<1 month, n = 20), infants (1-12 months, n = 76 patients), and children (1-18 years, n = 404). Outcomes were compared between the three groups. Results: The proportion of m-MVR involving children undergoing MV procedures (repair and replacement) has increased from 17.3% in 2009 to 30.8% in 2019 (Ptrend < .01). History of cardiac surgery was present in 256 patients (51.2%). Concomitant procedures were performed in 119 patients (23.8%). Intra- or postoperative extracorporeal membrane oxygenation was required in 19 patients (3.8%). The overall in-hospital mortality was 4.8% and was significantly higher in neonates and infants compared with older children (10% vs 11.8% vs 3.2%, P = .003). The length of hospital stay was longer in the neonatal group (median, 57 days, interquartile range, [24.8-90] vs 29.5 days [15.5-61] vs 10 days [7-18], P < .01). Nonhome discharges were more common in neonates and infants (40% vs 36.8% vs 13.1%, P < .01). Conclusion: Mechanical mitral valve replacement is increasingly performed over time with acceptable in-hospital morbidity and mortality, especially in older children and adolescents. Neonates and infants are associated with worse hospital survival, prolonged hospitalization, and significant rates of nonhome discharges.

Outcomes of Surgical Repair of Aberrant Subclavian Arteries in Adults.

BACKGROUND: Symptoms, imaging characteristics, and early and midterm surgical outcomes for aberrant subclavian arteries (ASCA) are not well defined in the adult population. METHODS: A single-institution retrospective review was conducted of adults undergoing surgical repair of ASCA and descending aorta origin/Kommerell diverticulum (KD) from January 1, 2002, to December 31, 2021. Symptom improvement and differences in imaging characteristics between anatomic groups and the number of symptoms were assessed. RESULTS: Mean age was 46 ± 17 years. There were 23 of 37 left aortic arches with right ASCA (62%) and 14 of 37 right aortic arches with left ASCA (38%). Of these, 31 of 37 (84%) were symptomatic, and 19 of 37 (51%) had KD size/growth meeting criteria for surgical repair. KD aortic origin diameter was larger in more symptomatic patients: 20.60 mm (interquartile range [IQR], 16.42-30.68 mm) in patients with ≥3 symptoms vs 22.05 mm (IQR, 17.52-24.21 mm) for 2 symptoms vs 13.72 mm (IQR, 12.70-15.95 mm) for 1 symptom (P = .018). Aortic replacement was required in 22 of 37 (59%). There were no early deaths. Complications occurred in 11 of 37 (30%): vocal cord dysfunction (4 of 37 [11%]), chylothorax (3 of 37 [8%]), Horner syndrome (2 of 37 [5%]), spinal deficit (2 of 37 [5%]), stroke (1 of 37 [3%]), and temporary dialysis requirement (1 of 37 [3%]). Over a median follow-up of 2.3 years (IQR, 0.8-3.9 years), there was 1 endovascular reintervention and no reoperations. Dysphagia and shortness of breath resolved in 92% and 89%, respectively, whereas gastroesophageal reflux persisted in 47%. CONCLUSIONS: The KD aortic origin diameter correlates with the number of symptoms, and surgical repair of ASCA and descending aorta origin/KD effectively relieves symptoms, with low rates of reintervention. Given the operative complexity, surgical repair should be performed in patients meeting size criteria or with significant dysphagia or shortness of breath symptoms.

Prevalence and spectrum of infectious and inflammatory dermatologic conditions occurring in pediatric heart transplant patients on a predominantly mTOR-based immune suppressive regimen: A retrospective chart review.

INTRODUCTION: Pediatric heart transplant patients are routinely followed in dermatology clinics due to elevated risk of cutaneous malignancy. However, transplant patients may experience other, non-cancer-related dermatologic conditions including skin infections, inflammatory diseases, and drug eruptions that can cause significant medical and psychosocial comorbidity. METHODS: A retrospective chart review of all pediatric heart transplant patients at Mayo Clinic Children's Center in Rochester, MN, was performed to determine the prevalence and spectrum of non-cancer dermatologic conditions. Statistical analysis was conducted to look for associations between episodes of rejection and skin condition development. RESULTS: Of the 65 patients who received heart transplants under the age of 18 and were followed at Mayo Clinic, 69% (N = 45) were diagnosed with at least one skin condition between transplant and the time of most recent follow-up. Sixty-two percent (N = 40) of patients were diagnosed with an inflammatory skin condition (most commonly acne and atopic dermatitis), 45% (N = 29) with an infectious skin condition (most commonly warts and dermatophyte infection), and 32% (N = 21) with a drug eruption (most commonly unspecified rash and urticaria). No association was found between presence of skin disease and number of rejection episodes. CONCLUSIONS: Non-cancer dermatologic conditions are prevalent within pediatric heart transplant recipients and may directly impact their medical needs and quality of life. Dermatologist involvement in the care of post-transplant pediatric patients is important, not only for cancer screening but also for diagnosis and treatment of common infectious and inflammatory skin conditions.

Association of Lower Extremity Lymphedema and Nonmelanoma Skin Cancers.

OBJECTIVE: To determine whether patients with lymphedema of a lower extremity (LE) had a greater risk of skin cancer than those without lymphedema. PATIENTS AND METHODS: This retrospective cohort study included patients with LE lymphedema examined at Mayo Clinic in Rochester, MN, USA, from January 1, 2000, through December 31, 2020. All patients with the phrase "lower extremity lymphedema" and a diagnostic code for lymphedema present in their electronic health record, as well as their age-, race-, and sex-matched controls without lymphedema, were included in the study. A Kaplan-Meier curve was constructed to examine the time to development of the first skin cancer for the lymphedema cohort and the controls. A Cox proportional hazards regression model was used to calculate hazard ratios. RESULTS: In total, 4437 patients had lymphedema within the study period. Compared with the matched control group, the lymphedema group had a significantly increased risk of skin cancer. For the subset of patients with unilateral lymphedema, the lymphedematous extremity was 2.65 times as likely as the nonlymphedematous LE to have skin cancer, particularly basal cell carcinoma. CONCLUSION: Lower extremity lymphedema appears to be a risk factor for squamous cell carcinoma, basal call carcinoma, and as expected, angiosarcoma. Clinicians caring for patients with LE lymphedema should be aware of this increased risk and monitor at-risk patients accordingly.

Systemic Atrioventricular Valve Surgery in Patients With Congenitally Corrected Transposition of the Great Vessels.

BACKGROUND: Limited data exist regarding the long-term outcomes of systemic atrioventricular valve (SAVV) intervention (morphologic tricuspid valve) in congenitally corrected transposition (ccTGA). OBJECTIVES: The goal of this study was to evaluate the mid- and long-term outcomes of SAVV surgery in ccTGA. METHODS: We performed a retrospective review of 108 ccTGA patients undergoing SAVV surgery from 1979 to 2022. The primary outcome was a composite endpoint of mortality, cardiac transplantation, or ventricular assist device implantation. The secondary outcome was long-term systemic right ventricular ejection fraction (SVEF). Cox proportional hazard and linear regression models were used to analyze survival and late SVEF data. RESULTS: The median age at surgery was 39.5 years (Q1-Q3: 28.8-51.0 years), and the median preoperative SVEF was 39% (Q1-Q3: 33.2%-45.0%). Intrinsic valve abnormality was the most common mechanism of SAVV regurgitation (76.9%). There was 1 early postoperative mortality (0.9%). Postoperative complete heart block occurred in 20 patients (18.5%). The actuarial 5-, 10-, and 20-year freedom from death or transplantation was 92.4%, 79.1%, and 62.9%. The 10- and 20-year freedom from valve reoperation was 100% and 93% for mechanical prosthesis compared with 56.6% and 15.7% for bioprosthesis (P < 0.0001). Predictors of postoperative mortality were age at operation (P = 0.01) and preoperative SVEF (P = 0.04). Preoperative SVEF (P < 0.001), complex ccTGA (P = 0.02), severe SAVV regurgitation (P = 0.04), and preoperative creatinine (P = 0.003) were predictors of late postoperative SVEF. CONCLUSIONS: SAVV surgery remains a valuable option for the treatment of patients with ccTGA, with low early mortality and satisfactory long-term outcomes, particularly in those with SVEF ≥40%. Timely referral and accurate patient selection are the keys to better long-term outcomes.