Postinflammatory Hyperpigmentation Following Mohs Micrographic Surgery: An Observational Study.

IMPORTANCE: Functional and cosmetic outcomes following Mohs micrographic surgery (MMS) are poorly studied in individuals with skin of color (SOC). Postinflammatory hyperpigmentation (PIH) may be long-lasting and highly distressing. SOC individuals are particularly susceptible to PIH following procedures.  Objective: To characterize factors that contribute to the development of PIH following MMS in SOC. DESIGN: This retrospective study included 72 SOC individuals with 83 cases of keratinocyte carcinoma treated with MMS between August 2020 and August 2021 at a single medical center in the Bronx, New York. RESULTS: Postinflammatory hyperpigmentation following Mohs micrographic surgery was more common in Fitzpatrick skin types (FST) IV to V (48.0%) compared to FST I to III (18.2%; P=0.006). Grafts and granulation resulted in higher rates of PIH compared to linear repairs and flaps (87.5% vs 30.7%; P=0.003). Cases with postoperative complications resulted in higher rates of PIH compared to cases without (81.8% vs 29.2%; P=0.001). In a subset analysis of linear repairs, polyglactin 910 as a subcutaneous suture produced a higher rate of PIH compared to poliglecaprone 25 (46.2% vs 7.1%; P=0.015).  Conclusions and Relevance: Individuals with SOC (FST IV to V) are more likely to develop PIH following MMS. Grafts and granulation lead to PIH more often than linear repairs and flaps. Postoperative complications significantly increase the risk of PIH. Surgeons should consider these risk factors during surgical planning in an effort to mitigate PIH in SOC individuals. Studies with larger sample sizes are indicated.  J Drugs Dermatol. 2024;23(5):316-321. doi:10.36849/JDD.8146.

Bacterial Decolonization for Prevention of Radiation Dermatitis: A Randomized Clinical Trial.

Importance: Evidence-based approaches for the prevention of acute radiation dermatitis (ARD) are limited, and additional strategies are necessary to optimize care. Objective: To determine the efficacy of bacterial decolonization (BD) to reduce ARD severity compared with standard of care. Design, Setting, and Participants: This phase 2/3 randomized clinical trial was conducted from June 2019 to August 2021 with investigator blinding at an urban academic cancer center and enrolled patients with breast cancer or head and neck cancer receiving radiation therapy (RT) with curative intent. Analysis was performed on January 7, 2022. Interventions: Intranasal mupirocin ointment twice daily and chlorhexidine body cleanser once daily for 5 days prior to RT and repeated for 5 days every 2 weeks through RT. Main Outcomes and Measures: The primary outcome as planned prior to data collection was the development of grade 2 or higher ARD. Based on wide clinical variability of grade 2 ARD, this was refined to grade 2 ARD with moist desquamation (grade 2-MD). Results: Of 123 patients assessed for eligibility via convenience sampling, 3 were excluded, and 40 refused to participate, with 80 patients in our final volunteer sample. Of 77 patients with cancer (75 patients with breast cancer [97.4%] and 2 patients with head and neck cancer [2.6%]) who completed RT, 39 were randomly assigned BC, and 38 were randomly assigned standard of care; the mean (SD) age of the patients was 59.9 (11.9) years, and 75 (97.4%) were female. Most patients were Black (33.7% [n = 26]) or Hispanic (32.5% [n = 25]). Among patients with breast cancer and patients with head and neck cancer (N = 77), none of the 39 patients treated with BD and 9 of the 38 patients (23.7%) treated with standard of care developed ARD grade 2-MD or higher (P = .001). Similar results were observed among the 75 patients with breast cancer (ie, none treated with BD and 8 [21.6%] receiving standard of care developed ARD grade ≥2-MD; P = .002). The mean (SD) ARD grade was significantly lower for patients treated with BD (1.2 [0.7]) compared with patients receiving standard of care (1.6 [0.8]) (P = .02). Of the 39 patients randomly assigned to BD, 27 (69.2%) reported regimen adherence, and only 1 patient (2.5%) experienced an adverse event related to BD (ie, itch). Conclusions and Relevance: The results of this randomized clinical trial suggest that BD is effective for ARD prophylaxis, specifically for patients with breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03883828.

Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system.

Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.

Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response.

Selective small-molecule inhibitors represent powerful tools for the dissection of complex biological processes. ES(I) (eeyarestatin I) is a novel modulator of ER (endoplasmic reticulum) function. In the present study, we show that in addition to acutely inhibiting ERAD (ER-associated degradation), ES(I) causes production of mislocalized polypeptides that are ubiquitinated and degraded. Unexpectedly, our results suggest that these non-translocated polypeptides promote activation of the UPR (unfolded protein response), and indeed we can recapitulate UPR activation with an alternative and quite distinct inhibitor of ER translocation. These results suggest that the accumulation of non-translocated proteins in the cytosol may represent a novel mechanism that contributes to UPR activation.

The phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 is effective in inhibiting regrowth of tumour cells after cytotoxic therapy.

PURPOSE: Regrowth of tumour cells between cycles of chemotherapy is a significant clinical problem. Treatment strategies where antiproliferative agents are used to inhibit tumour regrowth between chemotherapy cycles are attractive, but such strategies are difficult to test using conventional monolayer culture systems. METHODS: We used the in vitro tumour spheroid model to study regrowth of 3-D colon carcinoma tissue after cytotoxic therapy. Colon carcinoma cells with wild-type or mutant phosphatidyl inositol 3-kinase catalytic subunit (PI3KCA) or KRAS alleles were allowed to form multicellular spheroids and the effects of different pharmacological compounds were studied after sectioning and staining for relevant markers of cell proliferation and apoptosis. RESULTS: Studies using colon cancer cells with gene disruptions suggested that the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway was essential for proliferation in 3-D culture. The dual PI3K-mTOR inhibitor NVP-BEZ235, currently in clinical trials, was found to inhibit phosphorylation of the mTOR target 4EBP1 in 3-D cultured cells. The ability of NVP-BEZ235 to inhibit tumour cell proliferation and to induce apoptosis was markedly more pronounced in 3-D cultures compared to monolayer cultures. It was subsequently found that NVP-BEZ235 was effective in inhibiting regrowth of 3-D cultured cells after treatment with two cytotoxic inhibitors of the ubiquitin-proteasome system (UPS), methyl-13-hydroxy-15-oxokaurenoate (MHOK) and bortezomib (Velcade®). CONCLUSIONS: The dual PI3K-mTOR inhibitor NVP-BEZ235 was found to reduce cell proliferation and to induce apoptosis in 3-D cultured colon carcinoma cells, NVP-BEZ235 is a promising candidate for use in sequential treatment modalities together with cytotoxic drugs to reduce the cell mass of solid tumours.