United States

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&lt;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&lt;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&lt;0.05). In summary, this study highlights the potential prognostic value of MAGE-A3 in clinical outcomes of patients with cutaneous squamous cell carcinoma.

2022 AMA Research Challenge

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

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Ricardo Correa, MD, EdD
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Jessica Li, MD/PhD Candidate
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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.


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.

poster

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.

Effect of mRNA Covid-19 Vaccines on Blood Glucose Levels in People with Type I or Type II Diabetes

Turner's syndrome is the most common chromosomal abnormality and is associated with either complete or partial loss of one X chromosome. The average age at the time of the diagnosis is around 15 years. It is well-established that patients suffer from multiple endocrinal disorders later in life with multisystem involvement. Our case series suggest a need to optimize the transition from pediatric to adult endocrine care in TS patients. It is essential to have a continuous and integrated approach to treating TS patients with a timely referral to the adult endocrine service to improve the quality of life and prevent complications.

Retrospective analysis of seven TS patients in an outpatient Adult Endocrine Clinic

Objective: To compare standardized quality measures between telemedicine and office in a largeintegrated health system.
Materials and Methods: This retrospective cohort study compared graded exposure to telemedicine (office-only, blended, and telemedicine-only) across 16 National Quality Forum HEDIS measures from 03/1/2020 - 11/30/2021. A historical 1.5-year (pre-pandemic) quality performance baseline was established across 200+ sites in Pennsylvania. Chi-squared tests determined statistically significant (P
<0.01) differences between exposure groups. Multivariable logistic regression controlled for sociodemographic factors and comorbidities.
Results: There were 523,874 patients meeting inclusion criteria (409,732 office, 112,199 blended, 4,943 telemedicine). Statistically significant performance differences favored blended-telemedicine in 11 of 16 (cardiovascular: blood pressure 7.84%; lipid panel 7.63%; diabetes: HbA1c, 6.06%; nephropathy testing 9.98%; prevention & wellness: cervical cancer 12.98%, breast cancer 17.90%, colon cancer 8.80%, tobacco intervention 13.29%, influenza vaccination 10.39%, pneumococcal vaccination 5.77%; behavioral health: depression screening 5.07%) and favored office-only in 3 of 16 (cardiovascular care: antiplatelet 6.55%, statin 1.75%; pulmonary: antibiotics in bronchitis, 2.08%). There were insignificant differences between office and blended groups for 2 of 16 measures (cardiovascular care: beta blocker 1.08%, P = 0.1741; diabetes: statin 0.93%, P = 0.0406).
Discussion: Telemedicine had a favorable impact on quality performance, especially in quality measures involving testing and preventive care. A blended telemedicine-office approach might promote higher value care. Further study could determine superiority and graded effect of telemedicine in specific clinical scenarios.
Conclusion: This study demonstrates telemedicine’s ability to enhance primary care capacity while sustaining or improving quality performance.

Comparable Quality Between Telemedicine and In-Office Primary Care 

Introduction: Gallbladder cancer is the most common biliary tract cancer and is a fatal malignancy with a 5-year survival rate of only 18%. The Incidence of gallbladder cancer is 0.26% for women and 0.25% for men globally. It is unclear how the burden of this disease differs between nations. Using the Global Burden of Disease (GBD) Study database, we studied the trends in mortality, Incidence, and disability-adjusted life years (DALYs) from gallbladder cancer between 1990-2019 in European Union (EU) 15+ nations, which constitutes a comparable group of countries for observation analyses.

Methods: We extracted data from the GBD Study database between 1990 - 2019 based on the International Classification of Disease, including Age-Standardized Incidence Rates (ASIR), Mortality (ASMR), Mortality-to-Incidence (MIR) ratios, as well as DALYs for gallbladder cancer. Joinpoint regression analysis was carried out for the evaluation of trends. EU15+ countries is a readily comparable group of 19 countries with similar healthcare infrastructure. We also computed the male-to-female ratio to evaluate the difference in burden between the two genders.
Results: ASIR decreased globally (-2.54% males, -20.93% females) as well as for EU15+ countries except for males in Norway +6.1%, Greece+18.1% and Denmark +27.4%. At the same time, Incidence decreased by approximately 8 times in females than in males. ASMRs also decreased globally (-5.42% males, -22.47% females) by approximately 4 times higher in females. Similarly, ASMR decreased for all EU15+ countries except Greece (+14.5%) for males. Along with Incidence and mortality, MIR also decreased globally (-2.96% males, -1.95% females) and for EU15+ countries except for Sweden (+9.7% males, +28.9% females). We also observed a decreasing trend in DALYs globally for both genders (males -9.3%, females -24.2%). Amongst EU15+ countries, DALYS decreased for all countries except for males in Greece (+13.3%). 
Conclusion: Overall, Incidence, mortality, and DALYs due to gallbladder cancer have decreased globally and in most EU15+ countries. However, countries like Greece have shown discordant trends. Interestingly, the burden of gallbladder cancer has significantly decreased for females with a disproportionate decrease for males. Further studies will help evaluate these discordant trends in detail.

A comparison of the burden of gallbladder cancer between the European Union 15+ countries, 1990-2019: estimates from the Global Burden of Disease Study

Background: Liver failure (LF) is associated with a high mortality rate, requiring a liver transplant as the definitive treatment. The Molecular Adsorbent Recirculating System (MARS) is a non-biologic system that removes toxic metabolites from the bloodstream by providing extracorporeal support while waiting for a liver transplant. Conflicting pieces of evidence from multiple studies are present regarding the outcome of MARS therapy. We evaluated the effect of MARS therapy on patients with liver failure by measuring the changes in their laboratory parameters. 

Methods: In this retrospective cohort analysis, we evaluated 44 patients, by comparing relevant laboratory variables measured before and after MARS therapy. Paired t-test was used for statistical analysis. The primary outcome was an improvement in laboratory parameters following MARS therapy. 

Results: Most of our study cohort were females (63.64%) and white (72.72%). The predominant causes of liver failure were NASH (non-alcoholic steatohepatitis) (22.73%) and alcoholism (22.73%). At admission, the mean Child-Pugh score was 11.45 (SD: 1.97), and the mean SOFA (sequential organ failure assessment) score was 10.95 (SD: 3.65). The mean number of MARS sessions was 4.32 (SD: 2.28) and the mean duration for patients on MARS therapy was 4.64 days (SD: 2.44).
Our analysis demonstrates a statistically significant improvement in mean serum bilirubin, ammonia, urea, creatinine, ALT, and AST levels following MARS therapy. The mean model for end-stage liver disease (MELD-Na) scores also significantly improved. 59.09% of our total patient population survived the hospital stay and 40.91% died in hospital, with 73.07% of the survivors eventually receiving a liver transplant. 94.74% of the patients with whom we were able to bridge MARS therapy until liver transplant, had survived through the follow-up period.

Conclusion: Our study findings suggest that MARS improves the liver-failure-associated laboratory parameters and may be effective therapy as a bridge to liver transplant.


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

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