Local recurrence rates after resection of large colorectal serrated lesions with or without margin thermal ablation.

INTRODUCTION: Serrated lesions (SLs) including traditional serrated adenomas (TSA), large hyperplastic polyps (HP) and sessile serrated lesions (SSLs) are associated with high incomplete resection rates. Margin ablation combined with EMR (EMR-T) has become routine to reduce local recurrence while cold snare polypectomy (CSP) is becoming recognized as equally effective for large SLs. Our aim was to evaluate local recurrence rates (LRR) and the use of margin ablation in preventing recurrence in a retrospective cohort study. METHODS: Patients undergoing resection of ≥15 mm colorectal SLs from 2010-2022 were identified through a pathology database and electronic medical records search. Hereditary CRC syndromes, first follow-up > 18 months or no follow-up, surgical resection were excluded. Primary outcome was LRRs (either histologic or visual) during the first 18-month follow-up. Secondary outcomes were LRRs according to size, and resection technique. RESULTS: 191 polyps in 170 patients were resected (59.8% women; mean age, 65 years). The mean size of polyps was 22.4 mm, with 107 (56.0%) ≥20 mm. 99 polyps were resected with EMR, 39 with EMR-T, and 26 with CSP. Mean first surveillance was 8.2 mo. Overall LRR was 18.8% (36/191) (16.8% for ≥20 mm, 17.9% for ≥30 mm). LRR was significantly lower after EMR-T when compared with EMR (5.1% vs. 23.2%; p = 0.013) or CSP (5.1% vs. 23.1%; p = 0.031). There was no difference in LRR between EMR without margin ablation and CSP (p = 0.987). CONCLUSION: The local recurrence rate for SLs ≥15 mm is high with 18.8% overall recurrence. EMR with thermal ablation of the margins is superior to both no ablation and CSP in reducing LRRs.

Ectopically Expressed Meiosis-Specific Cancer Testis Antigen HORMAD1 Promotes Genomic Instability in Squamous Cell Carcinomas.

Genomic instability is a prominent hallmark of cancer, however the mechanisms that drive and sustain this process remain elusive. Research demonstrates that numerous cancers with increased levels of genomic instability ectopically express meiosis-specific genes and undergo meiomitosis, the clash of mitotic and meiotic processes. These meiotic genes may represent novel therapeutic targets for the treatment of cancer. We studied the relationship between the expression of the meiosis protein HORMAD1 and genomic instability in squamous cell carcinomas (SCCs). First, we assessed markers of DNA damage and genomic instability following knockdown and overexpression of HORMAD1 in different cell lines representing SCCs and epithelial cancers. shRNA-mediated depletion of HORMAD1 expression resulted in increased genomic instability, DNA damage, increased sensitivity to etoposide, and decreased expression of DNA damage response/repair genes. Conversely, overexpression of HORMAD1 exhibited protective effects leading to decreased DNA damage, enhanced survival and decreased sensitivity to etoposide. Furthermore, we identified a meiotic molecular pathway that regulates HORMAD1 expression by targeting the upstream meiosis transcription factor STRA8. Our results highlight a specific relationship between HORMAD1 and genomic instability in SCCs, suggesting that selectively inhibiting HORMAD1, possibly, through STRA8 signaling, may provide a new paradigm of treatment options for HORMAD1-expressing SCCs.

Longitudinal Plasma Proteomics Analysis Reveals Novel Candidate Biomarkers in Acute COVID-19.

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose-bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.

Tools used to assay genomic instability in cancers and cancer meiomitosis.

Genomic instability is a defining characteristic of cancer and the analysis of DNA damage at the chromosome level is a crucial part of the study of carcinogenesis and genotoxicity. Chromosomal instability (CIN), the most common level of genomic instability in cancers, is defined as the rate of loss or gain of chromosomes through successive divisions. As such, DNA in cancer cells is highly unstable. However, the underlying mechanisms remain elusive. There is a debate as to whether instability succeeds transformation, or if it is a by-product of cancer, and therefore, studying potential molecular and cellular contributors of genomic instability is of high importance. Recent work has suggested an important role for ectopic expression of meiosis genes in driving genomic instability via a process called meiomitosis. Improving understanding of these mechanisms can contribute to the development of targeted therapies that exploit DNA damage and repair mechanisms. Here, we discuss a workflow of novel and established techniques used to assess chromosomal instability as well as the nature of genomic instability such as double strand breaks, micronuclei, and chromatin bridges. For each technique, we discuss their advantages and limitations in a lab setting. Lastly, we provide detailed protocols for the discussed techniques.

Use of Apremilast in Patients Who Are Dissatisfied With Stable Maintenance Topical Therapy

Objective: To explore the impact of adding apremilast to a regimen of topical corticosteroids in patients with moderate plaque-type psoriasis. Research Design and Methods: This was an open label, 16-week study of apremilast in combination with topical steroids with a 4-week follow up off-treatment. Twenty qualified subjects were enrolled. Assessments included investigators assessments: sPGA, PASI, BSA; and subject assessments: DLQI, pruritis, and TSQM-2 (treatment satisfaction questionnaire). The primary efficacy measure was mean change and mean percent change in product of BSA (%) x sPGA at week 16 compared to baseline. Assessments were made at baseline (week 0), week 4, week 8, week 16, and week 20. Results: There was a statistically significant improvement in the mean change and mean percent change from baseline in product of sPGA x BSA at week 16, compared to baseline. Mean and median reductions in BSA achieved statistical significance by week 8. By week 16, there was a 36% improvement in median BSA from baseline (P=.006). The proportion of patients achieving PASI-50 at weeks 8 and 16 was 15% and 40%, respectively. Thirty percent of subjects achieved PASI-75 at week 16. Subject quality of life was statistically significantly improved from baseline at weeks 8 and 16, as evidenced by deceases in DLQI scores. Reductions in pruritus were evident at week 4 and achieved statistical significance at week 8. Two of the four domains of the TSQM domains achieved statistical significance by week 4 and through week 20. A total of 34 adverse events were reported in 17 subjects, the majority of the events were related to the gastrointestinal system and determined to be related to the study medication. Conclusion: The addition of apremilast for subjects with moderate plaque-type psoriasis, who are not satisfied by topical treatment alone, produced a statistically significant improvement in the improvement of their disease despite experienced adverse events. J Drugs Dermatol. 2019;18(4):336-340.

Cohort Using a Ceramides Containing Cleanser and Cream With Salicylic Acid for Dry, Flaking, and Scaling Skin Conditions

Introduction: The skin of subjects with dry, flaking, and/or scaling conditions is characterized by decreased water and skin lipids content among other findings. It is well understood that daily use of gentle cleansers and moisturizers may help to restore and maintain an optimal skin barrier function. A cohort study of patients with dry skin was developed to evaluate efficacy of daily use of a ceramide containing cleanser and cream that also has salicylic acid. Methods: Thirty-five adults with mild-to-moderate dry skin conditions were recruited from four dermatology centers in Canada. With consent, the subjects received twice daily treatment with the ceramides containing cleanser and cream that also has salicylic acid. Physician and subject assessed skin condition comparing baseline versus (day 0) versus day 28 (end) was scored using the Dry skin classification scale and the Global Aesthetic Improvement Scale (GAIS). Subjects also rated satisfaction, product features, quality of life aspects, safety, and tolerability. Results: Thirty-four subjects completed the treatment and study period; one was lost to follow up. Daily use of the evaluated cleanser and moisturizer significantly improved skin condition when comparing day 0 versus day 28 (+/- 5 days (end)) results. Both the physicians and subjects using the dry skin classification scale and GAIS scored a significant improvement of the dry skin condition. After treatment subjects reported a significant improvement in the quality of their professional life, self-image, and social life. The products were shown to be safe, comfortable, and well tolerated. Conclusion: The results indicated the cleanser and moisturizer to offer an effective, easy and comfortable option for dry skin conditions. J Drugs Dermatol. 2019;18(1):80-85.

Treatment of Moderate Acne Vulgaris in Fitzpatrick Skin Type V or VI: Efficacy and Tolerability of Fixed Combination Clindamycin Phosphate 1.2%/Benzoyl Peroxide 3.75% Gel.

BACKGROUND: Acne vulgaris (acne) is the most common skin disease in patients who have darker skin with most frequent sequelae of post inflammatory hyperpigmentation (PIH). METHODS: Open label study in 20 patients (mean age 32 years) with Fitzpatrick Skin Type V or VI and with moderate facial acne treated with clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel (CL-BP 3.75%) once-daily for 16 weeks. Assessments included improvement in Investigator Global Assessment (IGA) of acne severity, PIH severity and distribution, and lesion count reduction. Adverse events (AEs) were assessed throughout. RESULTS: Significant reductions in inflammatory, noninflammatory and total lesions occurred within the first 4 weeks compared to baseline. At week 16, percent changes from baseline were 76%, 62%, and 71%, respectively (all P less than equal to .0002). There was also a significant reduction in IGA to week 16 (P equals.0001); 70% (N=14) of patients were 'clear' or 'almost clear' and all patients experienced at least a 1-grade improvement in IGA. Additionally, PIH severity and distribution were also significantly reduced by week 16. In 40% of patients PIH severity was rated as 'none' or 'slight'; 19 (95%) and 15 (75%) of patients experienced at least a 1-grade improvement in PIH severity or distribution. Ten patients experienced a total of 21 AEs. There were no serious AEs. Only one AE was possibly related to study drug (facial tattoo tightening) and resolved with no residual effects at the end of the study. CONCLUSIONS: Patients with Fitzpatrick Skin Type V and VI treated with clindamycin phosphate 1.2%/ benzoyl peroxide 3.75% gel experienced significant reductions in facial acne severity, lesion counts and PIH severity/distribution. Tolerability was excellent. J Drugs Dermatol. 2018;17(10):1107-1112.