Epidermal growth factor receptor inhibitors in advanced cutaneous squamous cell carcinoma: A systematic review and meta-analysis.

Patients with advanced cutaneous squamous cell carcinoma (cSCC) who are not eligible for or who fail to respond to anti-PD1 immunotherapy have few treatment options. Epidermal growth factor receptor (EGFR) inhibitors have been investigated as a therapeutic option for advanced cSCC; however, data are limited to small single-arm trials or retrospective studies. A systematic review and meta-analysis was conducted to PRISMA guidelines (CRD42023394300). Studies reporting on outcomes of EGFR inhibition in advanced cSCC were identified. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and adverse event (AE) rate were pooled using a random effects model and the inverse variance method. Twelve studies (six prospective, six retrospective) were identified, representing 324 patients. Pooled ORR was 26% (95% confidence interval [CI] 18-36), median PFS was 4.8 months (95% CI 3.9-6.6) and median OS was 11.7 months (95% CI 9.2-14.1). Any grade AEs occurred in 93% of patients (95% CI 85-97) while grade 3 and higher AEs occurred in 30% (95% CI 14-54). These results were similar between anti-EGFR monoclonal antibodies (MAbs) and tyrosine kinase inhibitors (TKIs). EGFR inhibitors can be considered in patients with advanced cSCC who are contraindicated for or progress on first-line anti-PD1 immunotherapy. Future studies should evaluate their activity and safety following anti-PD1, identify predictive biomarkers for their efficacy and explore combination approaches.

Response to adalimumab in Caucasian and Asian patients with hidradenitis suppurativa: A retrospective cohort study of an Australian cohort stratified by patient-reported ethnicity.

BACKGROUND/OBJECTIVES: Caucasian and Asian patients with hidradenitis suppurativa demonstrate significant differences with regard to age, gender and body mass index. Demographic characteristics are known to influence the efficacy and drug survival of hidradenitis suppurativa therapeutics including biologic therapies. What remains unknown is the impact of ethnicity upon the efficacy of therapeutics once demographic and disease characteristics have been taken into account. This is an important question given the expansion of biologic therapies for HS into the global patient community. METHODS: We assessed 170 patients from a single HS specialist centre in Australia stratified by patient-identified ethnicity including those identifying as either Caucasian or Asian. RESULTS: Asian patients demonstrated lower BMI, higher rates of smoking and greater odds of Hurley stage 3 disease with tunnels than Caucasian patients in line with the reported literature. There was no significant difference between percentage of individuals achieving HiSCR50 or IHS4-55 at Week 16. Significant differences were seen in median time to secondary loss of response, and Kaplan-Meier curve analysis showed a significant difference between curves when stratified by patient-reported ethnicity. Cox regression analysis demonstrated after accounting for age, gender, BMI, smoking and Hurley stage, the significance of ethnicity in influencing time to secondary loss of response disappears. CONCLUSIONS: Caucasian or Asian ethnicity does not influence response to adalimumab treatment on patients with hidradenitis suppurativa.

Resident cutaneous memory T cells: a clinical review of their role in chronic inflammatory dermatoses and potential as therapeutic targets.

Resident memory T cells (T-RMs) remain in epithelial barrier tissues after antigen exposure and the initial effector phase. These T-RMs provide effective antimicrobial and anticancer immunity; however, pathogenic T-RMs have been shown to mediate various chronic inflammatory disorders in a variety of tissue types. In the skin, T-RMs are referred to as resident cutaneous memory T cells (cT-RMs). Understanding the mechanisms leading to the development and establishment of these cT-RMs populations may allow for targeted treatments that provide durable responses in chronic immune-mediated skin diseases, even after cessation. In this review, we summarize the evidence on cT-RMs as drivers of chronic inflammatory dermatoses, including psoriasis, vitiligo, atopic dermatitis, cutaneous lupus erythematosus and alopecia areata, among others. Data from in vitro, animal model and ex vivo human studies are presented, with a focus on the potential for cT-RMs to trigger acute disease flares, as well as recurrent disease, by establishing an immune 'memory' in the skin. Furthermore, the available data on the potential for existing and novel treatments to affect the development or survival of cT-RMs in the skin are synthesized. The data suggest a dynamic and rapidly growing area in the field of dermatology; however, we also discuss areas in need of greater research to allow for optimal treatment selection for long-term disease control.

Chemotherapy in Cutaneous Melanoma: Is There Still a Role?

PURPOSE OF REVIEW: In the preceding decade, the management of metastatic cutaneous melanoma has been revolutionised with the development of highly effective therapies including immune checkpoint inhibitors (specifically CTLA-4 and PD-1 inhibitors) and targeted therapies (BRAF and MEK inhibitors). The role of chemotherapy in the contemporary management of melanoma is undefined. RECENT FINDINGS: Extended analyses highlight substantially improved 5-year survival rates of approximately 50% in patients with metastatic melanoma treated with first-line therapies. However, most patients will progress on these first-line treatments. Sequencing of chemotherapy following failure of targeted and immunotherapies is associated with low objective response rates and short progression-free survival, and thus, meaningful benefits to patients are minimal. Chemotherapy has limited utility in the contemporary management of cutaneous melanoma (with a few exceptions, discussed herein) and should not be the standard treatment sequence following failure of first-line therapies. Instead, enrolment onto clinical trials should be standard-of-care in these patients.

The nutritional impact of CD19-targeted CAR-T therapy versus BEAM chemotherapy for adult patients with lymphoma.

BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapy demonstrating durable remissions in patients with refractory or relapsing non-Hodgkin's B-cell lymphoma. Maintaining a patient's nutritional status has been demonstrated to improve outcomes in cancer treatment. However, no studies have investigated how CAR-T therapy affects nutritional status, nor compared its impact with other cancer treatments for this patient group. The primary aim of the present study was to investigate the effect of CAR-T therapy on the prevalence of nutrition impact symptoms (NIS) and nutritional status within 30 days post-treatment of patients with lymphoma compared to a conditioning regimen for autologous haematopoetic stem cell transplant (carmustine/BCNU, Etoposide, cytarabine/Ara-C, Melphalan [BEAM] auto-haematopoetic stem cell transplant [HSCT]). METHODS: Clinical notes of patients with lymphoma who underwent either CAR-T therapy or BEAM auto-HSCT between 2018 and 2021 were reviewed. Data extracted included body weight measurements and NIS, including decreased appetite, nausea, vomiting, diarrhoea, constipation, mucositis, cytokine release syndrome (CRS) and neurotoxicity at baseline and 30 ± 7 days post-treatment. RESULTS: In total, 129 adults with lymphoma (n = 88 CAR-T vs. n = 41 BEAM) were included. Nutritional status was assessed in both groups at baseline prior to treatment. Mean absolute weight change was significantly different between groups (3.05 kg in CAR-T, -5.9 kg in BEAM, p ≤ 0.001). This was also significant when weight loss was categorised into percentage weight loss (p = 0.01). CAR-T patients experienced a significantly lower prevalence of decreased appetite (52.3% vs. 97.6%) nausea (25% vs. 78%,) vomiting (10.2% vs. 53.7%), diarrhoea (43.2% vs. 96.7%) and mucositis (5.7% vs. 75.6%) combined across all levels of severity compared to BEAM chemotherapy (all p ≤ 0.01). CRS and neurotoxicity, which are specific side effects of CAR-T therapy, were moderately positively associated with weight loss. CONCLUSIONS: Weight loss, percentage weight loss and NIS were significantly reduced in CAR-T compared to BEAM treatment. However, patients who experienced neurotoxicity during treatment did have significant weight loss.

Academic dermatology in Australia and New Zealand between 2017 and 2022: A cross-sectional bibliometric analysis.

INTRODUCTION: Academic dermatologists in Australia and New Zealand provide high-quality and meaningful contributions to the understanding of disease and therapeutic translational research. Concerns have been raised by the Australian Medical Association regarding the decline of clinical academics in Australia as a whole, however, such trends in scholarly output have not previously been analysed for Australasian dermatologists. METHODS: A bibliometric analysis of dermatologists in Australia and New Zealand was conducted in January and February 2023. Available Scopus profiles for all dermatologists were used to measure lifetime H index, scholarly output, citation counts and field-weighted citation impact (FWCI) in the last 5 years (2017-2022). Trends in output over time were measured using non-parametric tests. Differences in output between subgroups stratified by gender and academic leadership positions (associate professor or professor) were measured using Wilcoxon rank-sum and one-way ANOVA tests. The scholarly output of recent College graduates was also analysed as a subgroup, comparing the same bibliographic variables in the 5 years preceding and 5 years following awarding of their fellowships. RESULTS: From the 463 practising dermatologists in Australia and New Zealand, 372 (80%) were successfully matched to Scopus researcher profiles. Of these dermatologists, 167 were male (45%) and 205 (55%) were female, and 31 (8%) held academic leadership positions. Most dermatologists (67%) published at least one paper in the last 5 years. The median lifetime H index was 4, and between 2017 and 2022 median scholarly output was 3, the median citations were 14 and the median FWCI was 0.64. There was a non-significant trend towards fewer publications per year, however, citation count and FWCI decreased significantly. By subgroups, female dermatologists published significantly more papers between 2017 and 2022, and other bibliographic variables were comparable to male dermatologists. However, women were underrepresented in positions of academic leadership-comprising only 32% of this cohort despite representing 55% of dermatologists. Professors were also significantly more likely to have higher bibliographic outcomes than associate professors. Finally, analysis of recent College graduates highlighted a significant decline in bibliometric outcomes pre- and post-fellowship. CONCLUSION: Overall, our analysis identifies a trend towards decreased research output by dermatologists in Australia and New Zealand in the last 5 years. Strategies to support dermatologists in research endeavours, particularly women and recent graduates, will be essential in maintaining strong scholarly output among Australasian dermatologists and thereby sustaining optimal evidence-based patient care.

BRAF inhibition and the spectrum of granulomatous reactions.

V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors have emerged as a promising targeted therapy for malignancies with BRAF mutations, particularly metastatic melanoma. However, granulomatous reactions (GRs), including sarcoidosis and sarcoid-like reactions, have been reported as a consequence of BRAF inhibition. It is important to adequately characterize these GRs, including cutaneous manifestations and systemic involvement, in order to guide investigations and management. A literature review was conducted to characterize the spectrum of GRs associated with BRAF inhibitors, identifying 55 reactions affecting 51 patients, with 37 reactions limited to cutaneous involvement. Further, a possible correlation with cancer response, mechanisms of granuloma formation, and a proposed workup and management approach for these GRs are presented.

The global regulatory architecture of transcription during the Caulobacter cell cycle.

Each Caulobacter cell cycle involves differentiation and an asymmetric cell division driven by a cyclical regulatory circuit comprised of four transcription factors (TFs) and a DNA methyltransferase. Using a modified global 5' RACE protocol, we globally mapped transcription start sites (TSSs) at base-pair resolution, measured their transcription levels at multiple times in the cell cycle, and identified their transcription factor binding sites. Out of 2726 TSSs, 586 were shown to be cell cycle-regulated and we identified 529 binding sites for the cell cycle master regulators. Twenty-three percent of the cell cycle-regulated promoters were found to be under the combinatorial control of two or more of the global regulators. Previously unknown features of the core cell cycle circuit were identified, including 107 antisense TSSs which exhibit cell cycle-control, and 241 genes with multiple TSSs whose transcription levels often exhibited different cell cycle timing. Cumulatively, this study uncovered novel new layers of transcriptional regulation mediating the bacterial cell cycle.