Lanolina

Lanolin-induced contact dermatitis

Authors of a study published in Dermatitis sought to determine characteristics, detection, and prevalence of lanolin-induced contact dermatitis. Lanolin, the 2023 contact allergen of the year, is a weak sensitizer with an estimated 0.4% of the European population demonstrating contact allergy to it. Despite this low prevalence, certain patients are more susceptible to lanolin contact allergy, including the young and elderly and those with stasis dermatitis, leg ulcers, perianal/genital dermatitis, or atopic dermatitis. Lanolin may produce a false-negative patch test in these patients when tested on normal skin.

Pediatric dermatologists share clues for distinguishing contact dermatitis from atopic dermatitis and discuss noteworthy allergens. Read more in DermWorld.

Related content:

• Aluminum: Contact allergen of the year 2022 – DermWorld Insights and Inquiries (June 2022)

• What challenges and barriers exist when patch testing children? – DermWorld (June 2021)

• Parabens — A common allergen with lots of hype and no real harm – DermWorld Insights and Inquiries (September 2019)

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The following text is written by Immunocore: Harnessing the power of T cells against cancer



Over the past two decades, significant advances have been made in immuno-oncology, but restrictions such as the reliance on antibody-based targeting of cell-surface proteins have limited the applicability of existing approaches. T cell receptor (TCR) therapy is a new branch of immuno-oncology that is able to overcome the limitation associated with antibody-based therapeutics by targeting intracellular antigens, in theory unlocking the entire proteome. Immunocore has innovated a novel form of T cell receptor technology, engineering and developing a modular molecule that combines a target-identifying TCR and an immune-activating effector function. The company launched the world's first bispecific TCR therapy in 2022, for metastatic uveal melanoma, and has trials ongoing in cutaneous melanoma.

Initiating an effective anti-cancer immune response is the central goal of cancer immuno-oncology. However, there are mechanisms of resistance that preclude immune recognition and include, but are not limited to, very low number of acquired mutations within the cancer cell, deletion or exhaustion of T cells capable of recognizing tumor antigens, an immuno-suppressive microenvironment around the tumor, and down-regulation of antigen presentation machinery. Cancer cells can also deactivate (or exhaust) cancer-specific T cells by overexpressing ligands for immune checkpoint receptors, such as CTLA4 and PD1 (Jiang, Li & Zhu, 2015). Checkpoint inhibitors like anti-CTLA4 and anti-PD1/-PDL1 antibodies can block these interactions, but their effects are limited if the tumor has a low mutational burden or there is an absence of pre-existing tumor-specific T cells (Morad et al., 2021).     Redirecting T cells can potentially bypass the absence or exhaustion of tumor-specific T cells regardless of their intrinsic (or natural) specificity and can be achieved by chimeric antigen receptor T cells (CAR-T cells) or bispecific antibody-based T cell engagers (Barrett et al., 2014; Laskowski & Rezvani, 2020). However, all antibody-targeted recognition of tumor cells has the limitation of only recognizing proteins presented on the cell surface. This presents a challenge for the treatment of solid tumors due to the limited number of cancer-specific antigens on the cell surface, which also tend to be present in low numbers (Lowe et al., 2019; Berman & Bell, 2022). Therefore, finding new cancer-specific intracellular antigens and approaches to target them is a major hurdle for cancer immunotherapy.   In contrast to antibodies, T cell receptors (TCRs) can specifically recognise intracellular proteins as processed peptides bound to human leukocyte antigen (HLA) proteins presented on the cell surface. A new class of bispecific biologics called immune mobilising monoclonal TCRs against cancer (ImmTAC), has the potential to recognize >90% of the proteome, including intracellular proteins, with high sensitivity to as few as 10 peptide-HLA complexes per cell (Liddy et al., 2012). ImmTAC molecules are soluble bispecific fusion proteins, comprised of an affinity-enhanced TCR fused to an antibody fragment targeting CD3 (cluster of differentiation 3). The TCR arm recognizes and binds with high affinity and specificity to a peptide presented in the context of an HLA molecule on the cell surface of tumor cells. The effector arm binds to CD3, an activating receptor expressed on the surface of all T cells, resulting in redirection and activation of T cells regardless of their native TCR specificity. Once activated, T cells release inflammatory cytokines and chemokines that stimulate the local immune response and cytolytic proteins for direct killing of tumor cells (Damato et al., 2019).

Compared to a natural TCR, the highly engineered TCR arm of an ImmTAC molecule has a 106-fold increased affinity for its target peptide-HLA complex. In contrast to the TCR arm, the anti-CD3 arm is designed to bind CD3 with a 1000-fold lower affinity. This differential affinity allows the ImmTAC to stay bound to the target for a sufficient time, while ImmTAC-redirected T cells can disengage and re-engage multiple times (i.e., serial triggering) (Berman & Bell, 2022). In addition to cytotoxic CD8+ cells, ImmTAC molecules can activate other T cell subsets including CD4+ T cells, which can enhance cytotoxic CD8+ T effector functions and protect the cells from exhaustion (Boudousquie et al., 2017).   Given all T cell receptors are restricted to a specific allelic variant of HLA, ImmTAC molecules are similarly restricted to a single allelic variant of the HLA, currently limited to A*02:01 (Damato et al., 2019; González-Galarza et al., 2015). Research is ongoing to develop new ImmTAC molecules targeting additional HLA alleles as well as pursuing strategies to overcome HLA restriction altogether.   Tebentafusp (IMCgp100) was the first ImmTAC molecule to enter the clinic and to be subsequently approved for the treatment of adult patients with HLA-A*02:01+ with unresectable or metastatic uveal melanoma. Tebentafusp recognises a peptide derived from the melanocyte lineage specific antigen gp100 (gp100280-288) in complex with HLA-A*02:01. Gp100 is expressed in melanocytes and overexpressed in melanoma. To date, tebentafusp was evaluated in phase I/II (IMCgp100-102) and phase III (IMCgp100-202) clinical trials for treatment of metastatic uveal melanoma. Additionally, tebentafusp is being investigated as either monotherapy or in combination with pembrolizumab in a global randomized phase II/III trial in patients with advanced cutaneous melanoma (IMCgp100-203; NCT05549297).   With the approval of tebentafusp across more than 30 countries, Immunocore is the only commercial-stage TCR company in the world and is pioneering the development of off-the-shelf soluble TCR bispecific fusion proteins. With multiple clinical-stage programs in development, Immunocore is keen to engage with healthcare professionals who want to learn more about our novel platform technology, take part in our sponsored clinical trials, as well as explore potential scientific collaborations to understand better the potential applications of the ImmTAC platform.     References:   Barrett DM, Grupp SA, June CH. Chimeric Antigen Receptor- and TCR-Modified T Cells Enter Main Street and Wall Street. J Immunol. 2015 Aug 1;195(3):755-61. doi: 10.4049/jimmunol.1500751. PMID: 26188068; PMCID: PMC4507286. Berman DM, Bell JI. Redirecting Polyclonal T cells Against Cancer with Soluble T Cell Receptors. Clin Cancer Res. 2022 Oct 18:CCR-22-0028. doi: 10.1158/1078-0432.CCR-22-0028. Epub ahead of print. PMID: 36255733. Boudousquie C, Bossi G, Hurst JM, Rygiel KA, Jakobsen BK, Hassan NJ. Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells. Immunology. 2017 Nov;152(3):425-438. doi: 10.1111/imm.12779. Epub 2017 Aug 2. PMID: 28640942; PMCID: PMC5629433. Damato BE, Dukes J, Goodall H, Carvajal RD. Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma. Cancers (Basel). 2019 Jul 11;11(7):971. doi: 10.3390/cancers11070971. PMID: 31336704; PMCID: PMC6679206. González-Galarza FF, Takeshita LY, Santos EJ, Kempson F, Maia MH, da Silva AL, Teles e Silva AL, Ghattaoraya GS, Alfirevic A, Jones AR, Middleton D. Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations. Nucleic Acids Res. 2015 Jan;43(Database issue):D784-8. doi: 10.1093/nar/gku1166. Epub 2014 Nov 20.PMID: 25414323; PMCID: PMC4383964. Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015 Jun 18;6(6):e1792. doi: 10.1038/cddis.2015.162. PMID: 26086965; PMCID: PMC4669840. Laskowski T, Rezvani K. Adoptive cell therapy: Living drugs against cancer. J Exp Med. 2020 Dec 7;217(12):e20200377. doi: 10.1084/jem.20200377. PMID: 33227136; PMCID: PMC7686916. Liddy N, Bossi G, Adams KJ, Lissina A, Mahon TM, Hassan NJ, Gavarret J, Bianchi FC, Pumphrey NJ, Ladell K, Gostick E, Sewell AK, Lissin NM, Harwood NE, Molloy PE, Li Y, Cameron BJ, Sami M, Baston EE, Todorov PT, Paston SJ, Dennis RE, Harper JV, Dunn SM, Ashfield R, Johnson A, McGrath Y, Plesa G, June CH, Kalos M, Price DA, Vuidepot A, Williams DD, Sutton DH, Jakobsen BK. Monoclonal TCR-redirected tumor cell killing. Nat Med. 2012 Jun;18(6):980-7. doi: 10.1038/nm.2764. PMID: 22561687. Lowe KL, Cole D, Kenefeck R, OKelly I, Lepore M, Jakobsen BK. Novel TCR-based biologics: mobilising T cells to warm 'cold' tumours. Cancer Treat Rev. 2019 Jul;77:35-43. doi: 10.1016/j.ctrv.2019.06.001. Epub 2019 Jun 12. PMID: 31207478. Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2022 Feb 3;185(3):576. doi: 10.1016/j.cell.2022.01.008. Erratum for: Cell. 2021 Oct 14;184(21):5309-5337. PMID: 35120665. Oates J, Hassan NJ, Jakobsen BK. ImmTACs for targeted cancer therapy: Why, what, how, and which. Mol Immunol. 2015 Oct;67(2 Pt A):67-74. doi: 10.1016/j.molimm.2015.01.024. Epub 2015 Feb 21. PMID: 25708206. Robinson J, Barker DJ, Georgiou X, Cooper MA, Flicek P, Marsh SGE. IPD-IMGT/HLA Database. Nucleic Acids Res. 2020 Jan 8;48(D1):D948-D955. doi: 10.1093/nar/gkz950. PMID: 31667505; PMCID: PMC7145640. Robinson RA, McMurran C, McCully ML, Cole DK. Engineering soluble T-cell receptors for therapy. FEBS J. 2021 Nov;288(21):6159-6173. doi: 10.1111/febs.15780. Epub 2021 Mar 10. PMID: 33624424; PMCID: PMC8596704.

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Neoadjuvant immunotherapy for melanoma is now ready for clinical practice

 Data are now available from a prospective randomized trial showing a survival benefit with neoadjuvant therapy in stage III compared to classical adjuvant therapy in stage III with pembrolizumab. These results were first presented at ESMO Congress 2022 and recently published in the New England Journal of Medicine. In the SWOG S1801 trial, one arm received primary lymphadenectomy followed by classical adjuvant therapy with 18 cycles of 200 mg pembrolizumab (a flat dose) every three weeks. In the comparator arm, three cycles of pembrolizumab were initially administered as neoadjuvant therapy, followed by surgery, and then an additional 15 cycles of pembrolizumab postoperatively. There was a remarkable improvement in prognosis in the neoadjuvant therapy arm. Here, the two-year estimated event-free survival was 72% in the neoadjuvant arm and 49% in the adjuvant group (HR=0.58, p=0.004). With only 36 deaths to date, there was still no clear advantage for overall survival (HR=0.63, p=0.18).¹

 

Given the clear advantage of event-free survival, the question for our patients is whether we can use this regimen of neoadjuvant treatment for lymph node metastasis. This treatment is not associated with increased toxicity for patients, nor is it associated with increased costs. However, there has been no approval for this type of use by regulatory agencies such as the FDA or EMA. It is also not clear whether the pharmaceutical companies in question are planning and will undertake studies relevant to approval.

 

Against this background, EADO has taken the initiative and initiated a statement on this topic. Leading dermatologists and oncologists worldwide were involved in the discussion. The statement is clear: Neoadjuvant immunotherapy for melanoma is now ready for clinical practice. This should be incorporated into standard care. The statement was published in Nature Medicine on May 16, 2023 and can be downloaded here.²

 

 

¹) Patel, S.P., et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med 388, 813-823 (2023).

²) Garbe, C., et al. Neoadjuvant immunotherapy for melanoma is now ready for clinical practice. Nat Med (2023).

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A Retrospective Analysis of Risk Factors for Atopic Dermatitis Severity

• Min Luo, 
• Huichun C. Su, 
• Jinger E. Lin, 
• Changhua H. Zhu, 
• Lihang H. Lin, and 
• Yue Han

Published Online: 26 Apr 2023Doi: https://doi.org/10.1089/derm.2023.0037

Article

Abstract: Background: Atopic dermatitis (AD) has the highest burden of any skin disease; however, the severity-associated factors remain unclear.

Objective: To evaluate potential severity-associated factors of AD and to design and validate a severity prediction model to inform the management of AD patients.

Methods: A cross-sectional study of 900 AD patients was conducted from December 2021 to October 2022 at our hospital. The primary outcome was disease severity, categorized as mild, moderate, or severe using the scoring atopic dermatitis index. Ordinal logistic regression and bootstrapped validation were used to derive and internally validate the model.

Results: Increasing age, elevated eosinophil level, higher economic status, and urban residence were associated with severe AD. Breastfeeding, disinfectants and topical emollients use, and short duration of bathing were associated with mild AD. In the prediction model, predictors included age, eosinophil and economic status, residence, feeding, disinfectants and emollients use, and duration of bathing. Prediction models demonstrated good discrimination (bias-corrected concordance index [c-index] = 0.72) and good calibration.

Conclusion: Risk factors for the severity of AD were identified that could aid the early prediction of AD progression. The predictive model included variables that are easily evaluated and could inform personalized prevention and therapy.

Capsule Summary

• Data on the atopic dermatitis severity-associated factors are limited.

• This cross-sectional study of 900 AD patients was conducted to explore 31 factors on AD severity. We successfully designed and validated a severity prediction model. The predictive model included variables that are easily evaluated and could inform personalized prevention and therapy.

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Allogeneic Transplantation in Patients With Advanced Cutaneous T-Cell Lymphomas

The Lancet

TAKE-HOME MESSAGE

• This prospective trial of 99 patients with advanced-stage cutaneous T-cell lymphomas in full or partial remission reported significantly longer progression-free survival among patients who underwent allogeneic haematopoietic stem cell transplantation (HSCT) compared with those who underwent treatment other than HSCT (9 months vs 3 months). In addition, significantly fewer patients experienced disease relapse in the HSCT group than in the non-HSCT group. Excluding graft-versus-host disease, the most common serious adverse event in both groups was infections.
• Patients with advanced-stage cutaneous T-cell lymphomas in partial or full remission who received allogeneic HSCT experienced significantly longer progression-free survival compared with those who received non-HSCT treatment.

–  Lillian Sun, MD

Abstract

BACKGROUND

Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs.

METHODS

In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18-70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting.

FINDINGS

From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0-35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6-30·5]) than in the non-HSCT group (3·0 months [2·0-6·3]), with a hazard ratio of 0·38 (95% CI 0·21-0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group.

INTERPRETATION

Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission.

FUNDING

French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.

The Lancet

Allogeneic transplantation in advanced cutaneous T-cell lymphomas (CUTALLO): a propensity score matched controlled prospective study

Lancet 2023 Apr 24;[EPub Ahead of Print], A de Masson, M Beylot-Barry, C Ram-Wolff, JB Mear, S Dalle, M d'Incan, S Ingen-Housz-Oro, C Orvain, J Abraham, O Dereure, A Charbonnier, J Cornillon, C Longvert, S Barete, S Boulinguez, E Wierzbicka-Hainaut, F Aubin, MT Rubio, M Bernard, A Schmidt-Tanguy, R Houot, A Pham-Ledard, D Michonneau, P Brice, H Labussière-Wallet, JD Bouaziz, F Grange, H Moins-Teisserenc, K Jondeau, L Michel, S Mourah, M Battistella, E Daguindau, M Loschi, A Picard, N Franck, N Maillard, A Huynh, S Nguyen, A Marçais, G Chaby, P Ceballos, Y Le Corre, S Maury, JO Bay, H Adamski, E Bachy, E Forcade, G Socié, M Bagot, S Chevret, R Peffault de Latour 

Dress tx topico

• Original Research Article
• Published: 03 May 2023

Systemic Versus Topical Corticosteroids in the Treatment of DRESS: A Retrospective Cohort Study Followed by a Meta-Analysis

• Bertrand ShengYang Lian, 
• Judy H. Ha, 
• …
• Haur Yueh Lee 

American Journal of Clinical Dermatology(2023)Cite this article

• 54 Accesses

• 2 Altmetric

• Metrics details

Abstract

Background

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe systemic drug hypersensitivity syndrome with significant risks of mortality and long-term sequelae. Management is challenging; whilst systemic corticosteroids are generally regarded as standard of care, there is a suggestion that topical corticosteroids may be a safe alternative.

Objective

We aimed to compare the clinical outcomes of patients with DRESS treated with systemic corticosteroids and topical corticosteroids in an academic medical center.

Methods

The medical records of patients diagnosed with DRESS at the Singapore General Hospital between 2009 and 2017 were retrospectively reviewed. A secondary systematic review and meta-analysis were performed to further clarify the outcomes.

Results

Out of 94 patients with DRESS, 41 (44%) were treated with topical corticosteroids and 53 (56%) were treated with systemic corticosteroids. Patients receiving systemic corticosteroids were more likely to develop infective complications (32.1 vs 12.2%, p = 0.02). One-month and 12-month mortality, length of hospital stay, flares of DRESS, and viral reactivation were similar between the two groups. In our meta-analysis (six studies, n = 292), there were no significant differences in mortality or length of stay between patients treated with systemic or topical corticosteroids.

Limitations

This study was a non-controlled retrospective cohort study and the allocation of treatment may have been influenced by the severity of disease. Results of the secondary meta-analysis are limited by the quality of included studies.

Conclusions

Topical corticosteroids may be a safe and efficacious alternative to systemic corticosteroids in the treatment of mild-to-moderate DRESS.

Clinical Trial Registration

PROSPERO registration CRD42021285691.

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Yana Kost, BA1; Alexandra K. Rzepecki, MD1; Alana Deutsch, MD1; et al Mathew R. Birnbaum, MD1; Nitin Ohri, MD, MS2; H. Dean Hosgood, PhD3; Juan Lin, PhD3; Johanna P. Daily, MD, MS4; Kosaku Shinoda, PhD5,6; Beth N. McLellan, MD1 Author Affiliations JAMA Oncol. Published online May 4, 2023. doi:10.1001/jamaoncol.2023.0454

Nasal Colonization With Staph Bacteria Linked to Acute Radiation Dermatitis

FRIDAY, May 12, 2023 (HealthDay News) -- Nasal colonization with Staphylococcus aureus(SA) before radiation therapy (RT) is associated with acute radiation dermatitis (ARD) severity, and bacterial decolonization (BD) is effective for ARD prophylaxis, according to two studies published online May 4 in JAMA Oncology.

Yana Kost, from the Albert Einstein College of Medicine in Bronx, New York, and colleagues conducted a prospective cohort study to examine whether nasal colonization with SA before RT is associated with ARD severity in patients with breast or head and neck cancer. Data were included for 76 patients, all of whom developed ARD: 61.8, 28.9, and 9.2 percent had grade 1, 2, and 3, respectively. The researchers found that patients who developed grade 2 or higher versus grade 1 ARD had a greater prevalence of baseline nasal SA colonization (34.5 versus 12.8 percent).

In a second study, Kost and colleagues conducted a phase 2/3 randomized clinical trial involving patients with breast cancer or head and neck cancer (75 and two, respectively) receiving RT with curative intent. Participants were randomly assigned to receive BD or standard of care (39 and 38 patients, respectively). The researchers found that none of the patients treated with BD and 23.7 percent treated with standard of care developed grade 2 or higher ARD with moist desquamation. The results were similar for the 75 patients with breast cancer (none and 21.6 percent, respectively). The mean ARD grade was significantly lower for patients treated with BD versus standard of care (1.2 versus 1.6).

"The results of this randomized clinical trial suggest that BD is effective for ARD prophylaxis, specifically for patients with breast cancer, and support the further investigation of BD for ARD prophylaxis," the authors write.

Two authors disclosed financial ties to the pharmaceutical industry.

Abstract/Full Text 1 (subscription or payment may be required)

Abstract/Full Text 2 (subscription or payment may be required)

Association of Staphylococcus aureus Colonization With Severity of Acute Radiation Dermatitis in Patients With Breast or Head and Neck Cancer

Key Points

Question  Is Staphylococcus aureus (SA) colonization associated with acute radiation dermatitis (ARD) severity in patients with breast or head and neck cancer?

Findings  This cohort study of 76 patients with breast or head and neck cancer found that nasal SA colonization prior to radiation therapy was present in 35% of patients who developed grade 2 or higher ARD compared with 13% of patients who developed grade 1 ARD, a significant difference.

Meaning  The findings suggest that SA colonization may be associated with grade 2 or higher ARD development in patients with breast or head and neck cancer.

Abstract

Importance  Pathogenesis of acute radiation dermatitis (ARD) is not completely understood. Pro-inflammatory cutaneous bacteria may contribute to cutaneous inflammation after radiation therapy.

Objective  To evaluate whether nasal colonization with Staphylococcus aureus (SA) before radiation therapy is associated with ARD severity in patients with breast or head and neck cancer.

Design, Setting, and Participants  This prospective cohort study with observers blinded to colonization status was conducted from July 2017 to May 2018 at an urban academic cancer center. Patients aged 18 years or older with breast or head and neck cancer and plans for fractionated radiation therapy (≥15 fractions) with curative intent were enrolled via convenience sampling. Data were analyzed from September to October 2018.

Exposures  Staphylococcus aureus colonization status before radiation therapy (baseline).

Main Outcomes and Measures  The primary outcome was ARD grade using the Common Terminology Criteria for Adverse Event Reporting, version 4.03.

Results  Among 76 patients analyzed, mean (SD) age was 58.5 (12.6) years and 56 (73.7%) were female. All 76 patients developed ARD: 47 (61.8%) with grade 1, 22 (28.9%) with grade 2, and 7 (9.2%) with grade 3. The prevalence of baseline nasal SA colonization was higher among patients who developed grade 2 or higher ARD compared with those who developed grade 1 ARD (10 of 29 [34.5%] vs 6 of 47 [12.8%]; P = .02, by χ² test).

Conclusions and Relevance  In this cohort study, baseline nasal SA colonization was associated with development of grade 2 or higher ARD in patients with breast or head and neck cancer. The findings suggest that SA colonization may play a role in the pathogenesis of ARD.

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NECROBIOSIS LIPOIDICA IN A WINK

---

By Warren R. Heymann, MD, FAAD
May 3, 2023
Vol. 5, No. 18

Ninety years have transpired since Urbach coined the term necrobiosis lipoidica diabeticorum (NLD) for the granulomatous disorder first described by Oppenheim in 1929 as dermatitis atrophicans lipoidica diabetica. (1) Early authors observed sclerotic plaques with erythematous, violaceous borders, yellowish centers, and telangiectasias, predominantly on the lower extremities. Although subsequent case reports of NLD were published, in 1960, Rollins and Winkelmann recognized that many patients with NLD are not diabetic; the authors defined the clinical and histological differences between the two groups. (2) Their observation spearheaded the change to refer to the disorder as necrobiosis lipoidica (NL) instead of NLD. This commentary focuses on newer literature about NL. 

NL is observed mostly in female patients, representing up to 75% of all cases. The disorder is characteristically observed in middle age, with an earlier average age of onset in diabetic patients (25 years) compared to nondiabetic individuals (46 years). (3,4) There have been multiple reports in the pediatric literature, an example being a 13-year-old girl with type I diabetes presenting with a morphologically characteristic lesion in an uncommon location (her left arm). (4) Lesions classically involve the pretibial region, usually commencing as small, firm red-brown papules that enlarge, becoming centrally atrophic. Lesions may Koebnerize. Uncommonly, lesions may affect other sites such as the arms, face, and scalp. (1) In a literature review encompassing 81 NL patients, the incidence of ulceration was found to occur between 15-35% of cases. Diabetes was observed in 65.4% and hypertension in 11%. (5) In a cross-sectional analysis of 236 patients with NL, associations with diabetes, obesity, hypertension, hyperlipidemia, and thyroid disease were confirmed. (6) Other reported associations include inflammatory bowel disease (Crohn and ulcerative colitis), rheumatoid arthritis, and sarcoidosis. (1)

The complications of NL are secondary infection, scarring, and the development of cutaneous malignancies. In their retrospective review of 328 cases of NL at the Mayo Clinic, Harvey et al identified 6 cutaneous cancers within NL lesions: 6 were squamous cell carcinoma (SCC), 1 basal cell carcinoma, and 1 melanoma. All malignancies were in ulcerated NL; the authors surmise that the ulceration itself may be predispose lesions toward malignancy, akin to patients with ulcerative lichen planus and lichen sclerosus. (7) In this context, it must be recognized that distinguishing pseudocarcinomatous hyperplasia from true SCC is challenging and requires careful clinicopathologic correlation. (8)

Image from JAAD 2013; 69: 783-91.

Tian and Coulson eloquently summarize the management of NL: "Smoking cessation and avoiding trauma to the affected shins are key factors to avoid transformation from an unsightly plaque into a painful, recalcitrant ulcer. The progression of new lesions may be halted by intralesional or occluded potent topical corticosteroids applied to the margins of the lesions. Topical tacrolimus can also be effective. Once atrophy has developed, there is little that will reverse this, although topical retinoids may be tried. Telangiectasia is often marked and has been treated with pulsed dye laser. Extensive lesions may justify trials of nicotinamide or prednisolone.Antiplatelet therapy in the form of aspirin or dipyridamole has its enthusiasts, though responses are inconclusive. Phototherapies such as topical psoralen and ultraviolet (UV) A (PUVA) and UVA-1, as well as photodynamic therapy,have received recent interest and may arrest progression and improve the appearance. A variety of systemic antiinflammatory and immunosuppressive agents have been tried with some success, including mycophenolate mofetil, fumaric acid esters, ciclosporin, antimalarials, thalidomide, and pentoxifylline. Biologics, especially anti-TNFs (adalimumab, infliximab, and etanercept), and more recently ustekinumab, have also been proposed. Platelet-rich plasma has some evidence of efficacy. The chronically ulcerated lesion is a challenge; antibiotics deal with secondary infection, appropriate dressings may be required, and growth factors such as becaplermin and granulocyte–macrophage colony-stimulating factor (GM-CSF) may accelerate healing. Because diabetics may have coexisting large vessel atherosclerosis that may contribute to ulceration, non-invasive arterial studies or angiography needs to be considered if clinically indicated. Excision and grafting including punch grafting may transform the patient's quality of life and improve cosmesis. Work with the diabetologist to optimize diabetic control." (9) Given the accumulating evidence for benefit of JAK inhibitors in granulomatous disorders, the initial report of tofacitinib efficacy in a recalcitrant case of ulcerated NL (10) is a likely prelude to many future reports of other JAK inhibitors for treating NL. 

The etiology of NL remains an enigma. The association of NL with diabetes points toward microangiopathy. Glucose transporter 1 is expressed in fibroblasts of sclerotic collagen; abnormal collagen fibrils with increased cross-linking could be etiologic. The pathogenic contributions of impaired neutrophilic migration, tumor necrosis factor-alpha, and deposition of other immunoreactants require further definition. (1,3)

The classical histological appearance of NL demonstrates a "layer cake" of horizontal granulomatous dermatitis with dermal fibrosis admixed with necrobiosis and lymphoplasmacytic infiltration. In their study, Rollins and Winkelmann demonstrated that NL in diabetic versus nondiabetics is different — with the classical appearance in the former and epithelioid granulomatous appearance resembling sarcoidosis in the latter. (2) This observation has been confirmed (again from the Mayo Clinic) by Johnson et al, in a retrospective histological review of 97 NL patients, finding a statistically significant difference with naked (sarcoidal/tuberculoid) granulomas being more frequently observed in nondiabetic NL patients (22.7%) compared to diabetic NL patients (3.2%). (11)

This commentary was written on Father's Day 2022. I never met Richard K. Winkelmann, MD, PhD, but anyone practicing dermatology and dermatopathology has been influenced by this founding father of the American Society of Dermatopathology. I encourage you to read the enlightening tribute to him by Perniciaro in which he notes that Dr. Winkelmann insisted that colleagues, friends, and family address him as "Wink." (12) I dedicate this commentary to Wink, who has indirectly taught me so much throughout my career. 

Point to Remember: Necrobiosis lipoidica is usually associated with diabetes, but may also be accompanied by thyroid disease, hypertension, hyperlipidemia, and other disorders. JAK inhibitors are on the horizon in treating the granulomatous component of the disorder.

Our expert's viewpoint

Aaron R. Mangold, MD, FAAD
Associate Professor of Dermatology, Mayo Clinic
Scottsdale, Arizona

Necrobiosis lipoidica (NL) is a chronic granulomatous disease often associated with ulceration, pain, and scarring. Although up to half of cases are associated with poorly controlled diabetes, average HbA1c of 8.6%, the underlying metabolic and inflammatory drivers remain unclear. Newer gene expression data in both NL as well as other granulomatous diseases found a key role of immune pathways and pathogenic, interferon gamma secreting T-cells as well as metabolically active macrophages. Our team's recent phase 2 trial using topical ruxolitinib in NL has confirmed the key role of interferon signaling as well as the therapeutic potential with an overall response rate of 82%. 

There are limited clinical practice guidelines for the management of NL and it is challenging to draw conclusions on evidence-based treatment recommendations. In those with diabetes, improved glucose control may reduce the risk of developing comorbidities and improve lesions of NL. Additional management of chronic wounds as well as venous insufficiency may be beneficial. For indurated, tender plaque of NL, topical, intralesional, and systemic anti-inflammatories can be effective. Although there are no comparative studies, biologics (95%), classic immunosuppressants (89%), and topical therapies (79%) seems to be the most effective treatments followed by light-based modalities including ultraviolet A (54%) and photodynamic therapies (80%).

1. Lepe K, Riley CA, Salazar FJ. Necrobiosis Lipoidica. 2021 Aug 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29083569

2. ROLLINS TG, WINKELMANN RK. Necrobiosis lipoidica granulomatosis. Necrobiosis lipoidica diabeticorum in the nondiabetic. Arch Dermatol. 1960 Oct;82:537-43. doi: 10.1001/archderm.1960.01580040055010. PMID: 13742950.

3. Berman HS, Shabihkhani M, Hogeling M. Pediatric necrobiosis lipoidica: case report and review of the literature. Dermatol Online J. 2021 Jul 15;27(7). doi: 10.5070/D327754363. PMID: 34391328.

4. Alhameedy MM. Necrobiosis Lipoidica: Atypical Presentation in a Diabetic Girl. Case Rep Dermatol. 2021 Nov 30;13(3):547-552. doi: 10.1159/000520588. PMID: 35082617; PMCID: PMC8739632.

5. Di Bartolomeo L, Macca L, Motolese A, Guarneri C, Guarneri F. Ulcerative necrobiosis lipoidica: case report of an atypical presentation and literature review. Eur Rev Med Pharmacol Sci. 2021 Oct;25(19):6047-6050. doi: 10.26355/eurrev_202110_26882. PMID: 34661264.

6. Hashemi DA, Brown-Joel ZO, Tkachenko E, Nelson CA, Noe MH, Imadojemu S, Vleugels RA, Mostaghimi A, Wanat KA, Rosenbach M. Clinical Features and Comorbidities of Patients With Necrobiosis Lipoidica With or Without Diabetes. JAMA Dermatol. 2019 Apr 1;155(4):455-459. doi: 10.1001/jamadermatol.2018.5635. PMID: 30785603; PMCID: PMC6523472.

7. Harvey JA, Severson KJ, Brumfiel CM, Patel MH, Butterfield RJ, Nelson SA, Sekulic A, Pittelkow MR, Mangold AR. Necrobiosis lipoidica-associated cutaneous malignancy. J Am Acad Dermatol. 2022 Jun;86(6):1428-1429. doi: 10.1016/j.jaad.2021.06.848. Epub 2021 Jun 18. PMID: 34153393.

8. Xie CB, Ring N, Damsky W, McNiff JM, Olino K, Odell I. Squamous cell carcinoma arising in long-standing necrobiosis lipoidica treated with radical resection and split-thickness skin graft. JAAD Case Rep. 2021 Nov 17;19:90-93. doi: 10.1016/j.jdcr.2021.11.005. PMID: 35024397; PMCID: PMC8724883.

9. Tian TM, Coulson IH. Necrobiosis Lipoidica, in Lebwohl MG, Heymann WR, Coulson IM, Murrell DF, Treatment of Skin Disease, Sixth Edition, Elsevier, 2022. Accessed online June 19th, 2022.

10. Janßen S, Jansen TM. Ulcerated necrobiosis lipoidica successfully treated with tofacitinib. Int J Dermatol. 2022 Jun;61(6):739-741. doi: 10.1111/ijd.15960. Epub 2021 Nov 16. PMID: 34783006.

11. Johnson E, Patel MH, Brumfiel CM, Severson KJ, Bhullar P, Boudreaux B, Butterfield RJ, DiCaudo DJ, Nelson SA, Pittelkow MR, Mangold AR. Histopathologic features of necrobiosis lipoidica. J Cutan Pathol. 2022 Apr 11. doi: 10.1111/cup.14238. Epub ahead of print. PMID: 35403265. 

12. Perniciaro C. Richard K. "Wink" Winkelmann, MD, PhD (July 12, 1925 to August 16, 2012). Am J Dermatopathol 2013; 35: 281-282. 

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