United States

Background: Post-transplant lymphoproliferative disorder (PTLD) is a rare but deadly complication seen in patients after solid organ transplants as well as hematopoietic stem cell transplants. Current research suggests the underlying etiology of disease progression is likely secondary to a viral reactivation in the setting of immunosuppression such as the Epstein-Barr Virus (EBV). Cutaneous findings are rare but can range from ulcerated plaques to focal alopecia, with mycosis fungoides being the most frequent manifestation of the cutaneous T-cell lymphoma category. The objective of this study was to investigate the epidemiology and various clinical features of cutaneous manifestations of PTLD. 
Methods: A systematic review of published literature regarding cutaneous post-transplant lymphoproliferative disorders was conducted with inclusion of papers that reported individual patient characteristics and clinical courses. The prevalence of cutaneous PTLD for each specific transplantation was adjusted using the respective total transplantation rates conducted in the United States of America. 
Results: 82 cutaneous PTLD patients had a mean (SD) age at diagnosis of 50.9 (20.8) years, onset from transplant to disease presentation of 7.5 (5.8) years, and males comprised 74.4% of reported patients. When adjusted for total number of transplantation types, cutaneous manifestations of PTLD were most prevalent in renal transplants (77.9%) followed by HSCT (9.1%), liver (6.6%), and cardiac (5.1%). The most common areas of skin lesions were the lower extremities (33.8%), the trunk (18.8%), and the head and neck (11.3%). 
Conclusion: Renal transplant patients comprised the highest proportion of transplantations that developed cutaneous PTLD, which was surprising given cardiac transplant patients usually undergo more intense immunosuppressive regimens. Males appear to be predominantly affected, and the onset of cutaneous PTLD can range widely from shortly after transplantation to several years afterwards, emphasizing the important role clinicians have in being diligent within this patient population. Careful examination of cutaneous findings in these high-risk patients is especially important for timely diagnosis and therapeutic interventions, and further studies are needed to characterize the specific risk factors in cutaneous PTLD patients.

AMA Research Challenge 2022

Clinical Characteristics of Post-Transplant Lymphoproliferative Disorder Involving the Skin

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Ricardo Correa, MD, EdD
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Charles Lopresto, DO

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Welcome to the largest national, multi-specialty research event featuring research from 750 medical students, residents and fellows, and international medical graduates.


Venous leg ulcers, the most common leg ulcer, occur in patients with chronic venous
insufficiency due to venous hypertension. Evidence supports the conservative treatment with lower extremity compression, ideally within the range of 30-40 mm Hg. Pressures in this range provide enough force to partially collapse lower extremity veins without restricting arterial flow in patients in patients without peripheral arterial disease. There are many options for applying such compression, and those who apply these devices have varying levels of training and backgrounds. In this quality improvement study, a single observer utilized a reusable pressure monitor to compare pressures applied using different devices by individuals in wound clinics with diverse training from specialties of dermatology, podiatry, and general surgery. Average compression was higher in the dermatology wound clinic compared to the general surgery clinic (p=.004), and wraps applied by clinic staff were nearly twice as likely as a self-applied wrap to have pressures greater than 40 mm Hg (p = .03). Pressures were also dependent upon the specific compression device used (p=.008). These results indicate that the device-provided pressure may be dependent on both the compression device and on the background and training of the applicator. We propose that standardization in the training of compression application and increased use of a point of care pressure monitor may improve the consistency of applied compression, thus improving adherence to treatment and outcomes in patients with chronic venous insufficiency.

Consistent application of compression: an under-considered variable in the prevention of venous leg ulcers

HSCAPS-2: updated prediction score to distinguish hidradenitis suppurativa (HS) 
from site-specific cutaneous abscess

Background: Bullous pemphigoid (BP) is an autoimmune blistering skin disease that may cause significant morbidity and decreased quality of life. Current therapeutic options for patients with BP include systemic and topical corticosteroids, IVIG, and systemic immunosuppressants; however, side effects of these medications are often intolerable and there are few therapeutic options for patients with exclusionary comorbidities or recalcitrant BP. Dupilumab, an IL-4 receptor-alpha antagonist, has been identified as a potential therapeutic agent for BP. We aim to evaluate long-term outcomes, including response maintenance, treatment durability, and adverse events (AEs) of BP patients on dupilumab.

Methods: This is a retrospective case series from three academic medical centers that evaluates outcomes of 17 patients with biopsy-proven BP on dupilumab followed for >6 months.

Results: Ten males and seven females with an average age of 74.2 years were included in the study. The average dupilumab treatment duration was 19.6 months. On average, the patients tried and failed four standard therapies prior to starting dupilumab. In all patients, dupilumab was used as mono-systemic therapy and controlled the disease, with no losses of efficacy recorded. Fourteen patients were clear, two were almost clear, and one was significantly improved. There were no dupilumab-related AEs reported. Three of four patients who experienced treatment interruption had resultant flares; flares fully resolved with reinitiating of treatment. 

Conclusion: This study suggests promising long-term response and safety for BP patients on dupilumab, with all patients maintaining a response. Limitations of the study are that it involved a small number of patients, there was limited time patients were on treatment, and this not a controlled trial. More studies are needed to evaluate dupilumab which is a promising treatment for BP.

Long-term treatment outcomes and safety of dupilumab as a therapy for bullous pemphigoid: A multicenter retrospective review

Background

Perineural invasion is a pathologic process of neoplastic dissemination along and invading into the nerves. It is associated with aggressive disease and a greater likelihood of poor outcomes. Melanoma-associated genes (MAGEs) are CTAs expressed in various malignancies and have been widely studied as prognostic biomarkers. 

Methods

Total RNA was extracted from FFPE tissue samples and then processed using a custom probe set via the nCounter Analysis System (NanoString Technologies) as per company’s protocol. The raw quantification that resulted from the nCounter System’s barcode analysis was normalized using the nSolver software with relation to housekeeping genes.

Results

Three out of 9 patients with cutaneous squamous cell carcinoma and perineural invasion had poor clinical outcomes. Their tumors expressed high levels of MAGE-A3, a cancer testis antigen that may contribute to key processes of tumor development. The tumors also showed poor differentiation and deep invasion and thus were classified as Brigham and Women’s Hospital tumor stage 3. Cyclin E, A and B mRNA levels were increased in these tumors compared with normal skin tissues (102.93±15.03 vs. 27.15±4.59; 36.83±19.41 vs. 11.59±5.83; 343.77±86.49 vs. 95.65±29.25, respectively; p<0.05). A431 cutaneous squamous cell carcinoma cells pretreated with MAGE-A3 antibody showed a decreased percentage S-phase cells (14.13±2.8% vs. 33.97±1.1%; p<0.05) and reduced percentage closure in scratch assays (43.88±5.49% vs. 61.17±3.97%; p=0.0058). In a syngeneic animal model of squamous cell carcinoma, immunoblot showed overexpressed MAGE-A3 and cyclin E, A, and B in tumors in 6 weeks. However, knockout of MAGE-A3 expression caused a reduction in tumor growth (mean tumor volume 155.3 mm3 vs. 3.2 mm3).

Conclusion

These results suggest that MAGE-A3 is a key mediator in cancer progression. Moreover, elevated collagen XI and matrix metalloproteases 3, 10, 11, and 13 mRNA levels were observed in poorly differentiated cutaneous squamous cell carcinoma with perineural invasion comparing with normal skin tissues (1132.56±882.7 vs. 107.62±183.62; 1118.15±1109.49 vs. 9.5±5; 2603.87±2385.26 vs. 5.29±3; 957.95±627.14 vs. 400.42±967.66; 1149.13±832.18 vs. 19.41±35.62, respectively; p<0.05). In summary, this study highlights the potential prognostic value of MAGE-A3 in clinical outcomes of patients with cutaneous squamous cell carcinoma.

MAGE-A3 and Clinical Outcome in Cutaneous Squamous Cell Carcinoma with Perineural Invasion

Background
Mohs micrographic surgery (MMS) may be an effective treatment modality for oral cavity cancers (OCC) due to possibility of more effective visualization of tumor margins, and greater preservation of benign tissue. The objective of this study is to review the existing literature on the use of MMS for the treatment of OCC, and categorize its uses and limitations. 
Methods
Systematic review was conducted in accordance with AMSTAR (Assessing the Methodological Quality of Systematic Reviews) guidelines Database search of English, Spanish, and Portuguese articles in PubMed, Scopus, and Google Scholar from inception of databases to June 2, 2022 was conducted. 
Inclusion criteria: studies that discussed the use of Mohs micrographic surgery in the management of carcinomas within boundaries of the oral cavity. 
Exclusion criteria: studies that discussed malignancies limited to the cutaneous surface of the mouth such as the cutaneous lips, vermillion lips, or perioral region.
Endpoints of interest included: type of study, category of tumors treated with MMS, number of patients or specimens analyzed, and main study outcome. 
Results
Nine studies met inclusion criteria. Seventy-seven patients were treated with MMS for OCC, 74 of which (96%) were treated for squamous cell carcinoma. The tongue was the most common site (n=57). Other cancers treated with MMS include basal cell carcinoma and melanoma. Zero patients treated with MMS had recurrence of their disease during follow-up periods, which ranged from 8-42 months. Mohs technique did not cause statistically significant increase in operating time. 
Conclusion
MMS may be an effective treatment for OCC, especially for squamous cell carcinomas, and tumors involving the tongue. Potential challenges to the use of MMS in oral tumors include: difficulty of appropriate visualization and operation in the oral cavity, the ability of Mohs surgeons to interpret histopathology from oral specimens, and the availability of labs that can process oral tissue for real-time analysis. These challenges may be overcome with stronger interdisciplinary collaboration among oral disease specialists, and the development of additional best-practice recommendations that can facilitate improved education of providers.






Systematic review of benefits and practical challenges for use of Mohs surgery in oral tumors

The authors present the case of a 29-year-old female diagnosed with acute appendicitis who underwent a laparoscopic appendectomy. Three weeks later, she returned to the emergency department with fevers, abdominal pain, chills, and nausea. Laboratory analysis revealed elevated liver enzymes and leukocytosis, and a computed tomography scan of the abdomen revealed a liver abscess. Interventional radiology placed an 8 French drainage catheter in the hepatic abscess and drained 40cc of purulent fluid. A culture of the abscess fluid revealed Streptococcus constellatus, Bacteroides fragilis, and Bacteroides ovatus. We believe appendicitis causes hematogenous spreading of bowel organisms along the portal vein, which is seeded to the liver.

Hepatic Abscess Following Acute Appendicitis

Objective: The objective of this article was to explore the efficacy of Metformin in increasing the overall survival of patients with pancreatic cancer and concurrent DM.
Methods: We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, conducted a literature search in PubMed, Science Direct, and Scopus, and eleven studies were included in the systematic review. 
Results: Metformn has been shown to have augmented survival in five studies, whereas no improvement was seen in other studies.
Conclusions: Our study found that Metformin can efficaciously improve survival in patients with pancreatic cancer with coexisting DM, but the results are still incongruent.The benefits of Metformin versus no Metformin treatment are to be considered thoughtfully in diabetic pancreatic cancer patients. 

Association between Metformin Use and Survival Outcome in Diabetic Pancreatic Cancer Patients

Background: 

Obstructive sleep apnea (OSA) is associated with increased bone mineral density loss. Hypoxia experienced in the OSA population was suspected to stimulate osteoclast activity 

and contribute to osteoporosis. Continuous positive air pressure (CPAP) therapy, the first line treatment for OSA, reduces nocturnal hypoxia. Therefore, this study evaluates the potential for CPAP therapy to slow down the process of bone loss. 

Methods: 

This is a retrospective cohort study reviewing the electronic medical records of patients between the ages of 45 to 70 years old with the diagnosis of OSA and on CPAP therapy. The OSA diagnosis was supported by a home sleep study, and the CPAP compliance was determined by 70% of usage, or an average of more than 4 hours per day with 5 days in a week. We compared the mean difference of T-score per year on Dual-energy X-ray absorptiometry scans in patients compliant with CPAP treatment and patients not compliant with CPAP, utilizing T-test analysis. 

Results: 

There are 113 patients included in the study, with 81 compliant and 32 non-compliant to CPAP therapy. The mean age of the CPAP compliant group (65.7 years) was higher than the non-compliant group (63.2 years). The mean annual change in T-score for lumbar spine, left femur neck, left femur total and left radius were -0.015 ±0.27, -0.003 ±0.19, 0.002 ±0.21, -0.019 ±0.22 respectively in CPAP compliant group, and -0.03 ±0.20, -0.050 ±0.14, -0.014 ±0.17, -0.012 ±0.26 in the non-compliant group. There was no statistical difference in annual bone density changes between the CPAP compliant and non-compliant group. 

Conclusion: 

This is the first study evaluating the effect of CPAP therapy on bone health. The mean reduction in T-score in three out of four areas each year was less in the CPAP compliant group although not reaching statistical significance, possibly limited by the small sample size. Further prospective study and larger sample size might reveal the effect of CPAP on reducing the speed of bone loss in OSA populations.

Can Continuous Positive Airway Pressure Adherence Reduce Bone Loss in Patients with Sleep Apnea?

Abstract Title:

Continuous Glucose Monitoring in Nondiabetics: A Scoping Review

Authors:

Lachlan Shiver, Jonathan Serino, Nikitha Chandran, Carlos Bellido, Francis Walson, Diana Rancourt PhD, Dominic D’Agostino PhD

Background

The use of continuous glucose monitoring (CGM) in the type 1 and 2 diabetes mellitus populations is supported by randomized clinical trials and retrospective studies that show improved A1c levels and reduced time spent in severe hyperglycemia and hypoglycemia. This research demonstrates that CGM use is feasible in populations with diabetes and also can provide data that could be useful for non-FDA-approved medical purposes, including modifying physical activity and dietary behaviors and detecting complications following an ischemic event. We are conducting a scoping review to understand the different uses of CGM populations without diabetes and the extent to which the data support these other uses.

Methods

A scoping review is underway based on the 2020 JBI and PRISMA-ScR guidelines. We searched PubMed, Embase, Web of Science, and Cochrane databases in April of 2022 to identify studies using CGMs outside of diabetes management. Case reports, review articles, and commentaries were excluded. Empirical studies investigating the reliability of CGM, studies that did not include hypotheses specific to CGM, and studies including only individuals with diabetes were excluded.

Results

Two independent raters identified 132 out of the of the initial 3,265 abstracts to be included in the review. Preliminary findings suggest that the most commonly studied uses of CGM were prevention of diabetes (n = 25), prevention and acute management of cardiovascular events (n = 20), management of congenital disorders such as cystic fibrosis and hyperinsulinism (n = 20), modifying physical activity and dietary behavior (n = 17), and management of blood glucose following bariatric surgery (n = 15). In-depth review of published findings is underway.

Conclusion

CGM use in metabolically healthy patients is a rapidly emerging field. Multiple studies support the use of CGMs in nondiabetic populations for a multitude of purposes across a broad range of ages and populations

Continuous Glucose Monitoring in Nondiabetics: A Scoping Review

Background: People with diabetes are at increased risk for complications from COVID-19 infection and are encouraged to get vaccinated. However, it has yet to be determined how mRNA vaccines affect blood glucose in people with Diabetes. The purpose of our study was to determine if people with Type I or Type II Diabetes developed a significant change in blood glucose as reported on Continuous Glucose Monitoring (CGM) devices within one week after receiving each dose of an mRNA vaccine. 

Methods: An IRB approved, retrospective review of 25 subjects data was obtained using their Dexcom® or FreeStyle Libre® CGM from 12/2020–05/2021. For seven days following each dose and seven days immediately preceding the dose (control), average, peak daily, peak postprandial, and fasting glucose was collected. Visual analog symptom scales estimated severity of symptoms following each vaccine dose. Age, BMI and concurrent medications were noted. Descriptive statistics, analyses of differences, mixed effects models and generalized estimating equations were used. Tests were two-tailed and a p value < 0.05 denoted statistical significance.

Results: Median age was 75 years, with 76% male and average BMI of 29.5kg/m2. Before and after administration of each dose, significant increases were found in average daily glucose (154 vs 159, p<0.0001), peak glucose after breakfast (183 vs 190,p= 0.0159), after lunch (185 vs 203, p = 0.0002), after dinner (194 vs 204, p = 0.003,) and fasting daily glucose (137 vs 146, p = 0.0144,). There was a significant increase in average glucose levels (156 vs 167, p = 0.0185) following vaccination in the sixteen participants with side effects. There was also a direct correlation between usage of basal insulin and rise in average glucose following vaccination (p < 0 .0001). 

Conclusion: In a small group of subjects with diabetes, we have shown that mRNA COVID-19 vaccination results in modest, temporary elevations to average, peak and fasting glucoses for up to 1 week. Additionally, we found that changes in average daily blood glucose may correlate with the presence of side effects. Our findings help raise awareness of transient hyperglycemia and the need for more vigilant glucose monitoring following vaccination.

Next from AMA Research Challenge 2022

Consistent application of compression: an under-considered variable in the prevention of venous leg ulcers

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