Skin Cancer Induction by the Antimycotic Drug Voriconazole is Caused by Impaired DNA Damage Detection Due to Chromatin Compaction.

Phototoxicity and skin cancer are severe adverse effects of the anti-fungal drug voriconazole (VOR). These adverse effects resemble those seen in xeroderma pigmentosum, caused by defective DNA nucleotide excision repair (NER), and we show that VOR decreases NER capacity. We show that VOR treatment does not perturb the expression of NER, or other DNA damage-related genes, but that VOR localizes to heterochromatin, in complexes containing histone acetyltransferase general control of amino-acid synthesis 5-like 2. Impairment of general control of amino-acid synthesis 5-like 2 binding to histone H3 reduced acetylation of H3, restricting damage-dependent chromatin unfolding, thereby reducing NER initiation. Restoration of H3 histone acetylation using histone deacetylase inhibitors, rescued VOR-induced NER repression, thus offering a preventive therapeutic option. These findings underline the importance of DNA damage-dependent chromatin remodeling as an important prerequisite of functional DNA repair.

Successful serial plasmapheresis for solar urticaria, a case report and literature review.

BACKGROUND/PURPOSE: Amidst the emergence of new therapeutic options, traditional therapeutic plasmapheresis (TPE) used in diseases involving a toxic substance in the plasma, remains a viable alternative for cases of recalcitrant solar urticaria (SU). We emphasize the importance of documenting successful experience with repeated plasmapheresis to increase awareness amongst physicians and dermatologists regarding this effective treatment option. MATERIAL AND METHOD: We reported a case of recalcitrant SU that had not responded to a combination of H1-antihistamines, immunosuppressants, omalizumab and intravenous immunoglobulin. We introduced serial TPE, which involved two consecutive days of procedures for each course was introduced. We detailed the regimen and highlighted the clinical and objective benefits observed with multiple treatments. Additionally, we compared this to other plasmapheresis regimens and their treatment responses previously reported for solar urticaria. RESULTS: Our patient underwent serial TPE, totaling 42 procedures over five years. Following the last TPE session, phototesting showed a sustained prolongation of minimal urticating doses (MUDS), which exceeded the maximum tested doses across nearly all ultraviolet (UV) and visible light ranges, with the exception of the two short ultraviolet B (UVB) wavelengths. MUDs increased to 25 from 6 mj/cm2 at 307.5± 5nm, and to 500 from 15 mj/cm2 at 320 ± 10nm, before the initial TPE. In our review, we included five articles covering eight SU patients who received TPE. Of these, the five patients with positive intradermal tests responded particularly well immediately after treatment. However, the condition relapsed within two weeks in one patient and within two months in another. In contrast, the other three patients with negative intradermal tests, showed no significant benefits from the treatment. No serious side effects from TPE were reported amongst the patients. CONCLUSIONS: This review underscores the efficacy of serial plasmapheresis procedures in treating refractory cases of SU, high3lighting the robust results observed.

Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system.

Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We show substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.

Neurological disease in xeroderma pigmentosum: prospective cohort study of its features and progression.

Xeroderma pigmentosum (XP) results from biallelic mutations in any of eight genes involved in DNA repair systems, thus defining eight different genotypes (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XP variant or XPV). In addition to cutaneous and ophthalmological features, some patients present with XP neurological disease. It is unknown whether the different neurological signs and their progression differ among groups. Therefore, we aim to characterize the XP neurological disease and its evolution in the heterogeneous UK XP cohort. Patients with XP were followed in the UK National XP Service, from 2009 to 2021. Age of onset for different events was recorded. Cerebellar ataxia and additional neurological signs and symptoms were rated with the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS) and the Activities of Daily Living questionnaire (ADL). Patients' mutations received scores based on their predicted effects. Data from available ancillary tests were collected. Ninety-three XP patients were recruited. Thirty-six (38.7%) reported neurological symptoms, especially in the XPA, XPD and XPG groups, with early-onset and late-onset forms, and typically appearing after cutaneous and ophthalmological symptoms. XPA, XPD and XPG patients showed higher SARA scores compared to XPC, XPE and XPV. SARA total scores significantly increased over time in XPD (0.91 points/year, 95% confidence interval: 0.61, 1.21) and XPA (0.63 points/year, 95% confidence interval: 0.38, 0.89). Hyporeflexia, hypopallesthaesia, upper motor neuron signs, chorea, dystonia, oculomotor signs and cognitive impairment were frequent findings in XPA, XPD and XPG. Cerebellar and global brain atrophy, axonal sensory and sensorimotor neuropathies, and sensorineural hearing loss were common findings in patients. Some XPC, XPE and XPV cases presented with abnormalities on examination and/or ancillary tests, suggesting underlying neurological involvement. More severe mutations were associated with a faster progression in SARA total score in XPA (0.40 points/year per 1-unit increase in severity score) and XPD (0.60 points/year per 1-unit increase), and in ADL total score in XPA (0.35 points/year per 1-unit increase). Symptomatic and asymptomatic forms of neurological disease are frequent in XP patients, and neurological symptoms can be an important cause of disability. Typically, the neurological disease will be preceded by cutaneous and ophthalmological features, and these should be actively searched in patients with idiopathic late-onset neurological syndromes. Scales assessing cerebellar function, especially walking and speech, and disability can show progression in some of the groups. Mutation severity can be used as a prognostic biomarker for stratification purposes in clinical trials.

Retrospective study of efficacy and adverse events of immune checkpoint inhibitors in 22 xeroderma pigmentosum patients with metastatic or unresectable cancers.

Background: Xeroderma pigmentosum (XP), a rare disease with defects in DNA repair genes, has >1,000-fold increased risk of ultraviolet-induced skin cancers. Immune checkpoint inhibitors (ICIs) are used for treating cancers with large numbers of mutations but may also promote adverse events (AEs). Deficient DNA repair in XP patients may lead to increased numbers of mutations, leading to enhanced efficacy of cancer response or, alternatively, to increased AE in response to ICI. We sought to compare the efficacy and AE of ICI in XP patients with metastatic or unresectable cancers to that of ICI-treated patients in the general population. Methods: In this retrospective study, we reviewed medical records of XP patients treated in the United States and in London (UK). We also reviewed published reports of ICI-treated XP patients and patients in the general population. Results: Metastatic or unresectable cancers in all 22 (100%) XP patients showed regression or remission in response to ICI. The types and frequencies of AE in XP patients were similar to those reported among ICI-treated patients in the general population. However, two XP patients had concurrent additional cancers that did not respond to ICI, two XP patients had cancer recurrence or progression after initial response, and eight XP patients developed new skin cancers during or after ICI treatment. Conclusion: In this retrospective study with small sample size, XP patients demonstrated positive responses to ICI and the treatment was well tolerated but some patients developed new skin cancers while being treated. ICIs can be considered in treating metastatic or unresectable cancers in XP patients.

Acceptability and influence of a complex personalized intervention on changes in photoprotection behaviours among people with xeroderma pigmentosum.

OBJECTIVES: Rigorous photoprotection is the only means to prevent skin cancer in people with the rare condition of xeroderma pigmentosum (XP). We conducted a qualitative process evaluation of patient experiences and responses to a highly personalized, multi-component intervention, 'XPAND', designed to influence the psychosocial determinants of inadequate photoprotection among adults with XP. DESIGN: Qualitative study of 15 patients following participation in a RCT. METHODS: Semi-structured interviews explored acceptability, changes in photoprotection and attributions for behavioural changes. Analysis followed a framework approach. RESULTS: Participants were overwhelmingly positive in their views of the quality and range of components of XPAND and the relevance to their personal photoprotection barriers. All participants reported improved adherence to at least one photoprotection activity and nearly two-thirds of participants noted improvements across multiple activities. Participants believed improvements in their photoprotection behaviours were influenced by different change mechanisms. Sunscreen application, was mainly facilitated by habit formation, prompted by text messages, whereas the wearing of a photoprotective face buff was influenced by strategies, learnt during one-to-one sessions, to overcome worry about looking different. Enhancement of general self-confidence and perceived support from XPAND described by participants facilitated change more broadly. CONCLUSIONS: Exploration of responses to XPAND is required in the international XP population, followed by adaptation and evaluation to see if it could benefit other patient groups at higher risk of skin cancer. Implications for approaches to behaviour change include the acceptability of complex multidimensional interventions, the importance of dynamic personalization and the interactive nature of behaviour change mechanisms.