Bronchioalveolar organoids: A preclinical tool to screen toxicity associated with antibody-drug conjugates.

Despite extensive preclinical testing, cancer therapeutics can result in unanticipated toxicity to non-tumor tissue in patients. These toxicities may pass undetected in preclinical experiments due to modeling limitations involving poor biomimicry of 2-dimensional in vitro cell cultures and due to lack of interspecies translatability in in vivo studies. Instead, primary cells can be grown into miniature 3-dimensional structures that recapitulate morphological and functional aspects of native tissue, termed "organoids." Here, human bronchioalveolar organoids grown from primary alveolar epithelial cells were employed to model lung epithelium and investigate off-target toxicities associated with antibody-drug conjugates (ADCs). ADCs with three different linker-payload combinations (mafodotin, vedotin, and deruxtecan) were tested in bronchioalveolar organoids generated from human, rat, and nonhuman primate lung cells. Organoids demonstrated antibody uptake and changes in viability in response to ADC exposure that model in vivo drug sensitivity. RNA sequencing identified inflammatory activation in bronchioalveolar cells in response to deruxtecan. Future studies will explore specific cell populations involved in interstitial lung disease and incorporate immune cells to the culture.

Fractional CO2 laser treatment as adjunctive therapy to topical steroids for managing vulvar lichen sclerosus.

OBJECTIVES: Uncontrolled vulvar lichen sclerosus (VLS) is often associated with distressful symptoms of genital itch, irritation, and pain and can lead to a pathological process including anatomical changes, scarring, and an elevated risk of cancer in the genital area. First-line topical corticosteroid as monotherapy is frequently not adequate to fully suppress disease activity and control symptoms. This study evaluated the efficacy of fractional CO2 laser treatments as adjunctive therapy where recalcitrant VLS had been improved, but not adequately controlled, with topical corticosteroid treatment. Outcomes were evaluated up to 12 months after a series of CO2 laser treatments delivered via a fractional handpiece. MATERIALS AND METHODS: Women with a diagnosis of VLS supported by histologic findings on biopsy and/or clinical signs on physical examination received up to five monthly laser treatments. Subjects maintained existing topical corticosteroid and any exogenous hormone treatment during the study. Investigators assessed severity (0 = not present, 1 = mild, 2 = moderate, or 3 = severe) of clinical signs and architectural changes present before adjunctive study interventions and at follow-up visits. Subjects reported the presence of clinical symptoms and impact on quality of life on 4- or 5-point Likert scales. The validated Female Sexual Function Index (FSFI) was used to assess changes in sexual function. Four subjects were biopsied before adjunctive laser treatment and at follow-up. RESULTS: Twelve females, 11 postmenopausal, with a mean age of 57 ± 10 years received three to five monthly CO2 laser treatments. Significant improvement in all prominent clinical signs and architectural changes were reported at the 3- and 6-month follow-ups after the treatment series. Significant improvement was maintained at the 12-month follow-up, with 89% of subjects showing at least one-point improvement in elasticity compared to baseline; 86% in lichenification; 88% in sclerosis; and 80% in whitening and parchment-like skin. Labial fusion and the extent of disease improved in 50% of patients. Ulcerations present in three subjects at baseline resolved after treatment. Subjects reported 86% improvement in dyspareunia and 83% in skin tearing. Quality of life improved significantly after treatment (p < 0.01). The 6-month follow-up FSFI showed significant improvement in sexual function compared to baseline (p < 0.05), with a mean point improvement of 4.5. Histology findings after treatment showed some positive improvement, as a decrease in dermal hyalinized zone thickness. There were no treatment complications or adverse events related to the treatment. CONCLUSIONS: Fractional CO2 laser treatment outcomes showed improvement in predominant clinical signs and architectural changes in VLS recalcitrant to topical corticosteroid treatment. Adjunctive laser treatment relieved symptoms and improved quality of life as well as sexual function. Fractional CO2 laser treatment may provide an advanced treatment modality for the management of recalcitrant VLS with improved patient care and sustainable outcomes. Further study in a larger population and with CO2 laser treatment to both vulvar tissue and the vaginal canal should be explored.

A Clinical Approach to Vulvar Ulcers.

This article discusses the differential diagnosis of vulvar ulcers and describes a general clinical approach to this common but nonspecific examination finding. The differential diagnosis includes sexually and nonsexually transmitted infections, dermatitides, trauma, neoplasms, hormonally induced ulcers, and drug reactions. Patient history and physical examination provide important clues to the cause of a vulvar ulcer. However, laboratory testing is usually required for accurate diagnosis because the clinical presentation is often nonspecific and may be atypical due to secondary conditions.

Challenging Ulcerative Vulvar Conditions: Hidradenitis Suppurativa, Crohn Disease, and Aphthous Ulcers.

This article discusses the clinical evaluation and approach to patients with 3 complex ulcerative vulvar conditions: hidradenitis suppurativa, metastatic Crohn disease of the vulva, and aphthous ulcers. These conditions are particularly challenging to medical providers because, although each is known to present with nonspecific examination findings that vary in morphology, the predominance of the diagnosis is based on clinical examination and exclusion of a wide variety of other conditions. Care of patients with these conditions is further complicated by the lack of therapeutic data and the significant impact these conditions have on quality of life.