Guselkumab for Pityriasis Rubra Pilaris and Dysregulation of IL-23/IL-17 and NFkB Signaling: A Nonrandomized Trial.

Importance: There is no US Food and Drug Administration-approved treatment for pityriasis rubra pilaris (PRP), and it is common for patients to fail to experience improvement with several systemic options. Involvement of interleukin (IL) 23 suggests a potential therapeutic target. Objective: To determine whether guselkumab, an IL-23p19 inhibitor, provides clinical improvement for participants with PRP and better understand gene and protein dysregulation in PRP. Design, Setting, and Participants: This single-arm, investigator-initiated nonrandomized trial was conducted from October 2019 to August 2022 at a single-center academic university with participants from 8 states in the US. In total, 14 adults with moderate to severe PRP were enrolled; 12 completed the trial. Age-matched and sex-matched healthy controls provided skin and blood for proteomic and transcriptomic studies. The primary outcome was observed at 24 weeks, and additional follow-up occurred at 36 weeks. Intervention: Guselkumab is a fully human immunoglobulin G1 λ monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23. Subcutaneous injections were given at the US Food and Drug Administration-approved dosing schedule for psoriasis over a 24-week period. Main Outcomes and Measures: The primary outcome was the mean change in the Psoriasis Area Severity Index (PASI) score at week 24. Secondary outcomes included pruritus, Dermatology Life Quality Index score, clinical response at week 36, and association with transcriptomics and proteomics expression. Results: A per-protocol analysis was performed for the cohort of 4 female and 8 male patients who had a mean (SD) age of 56.5 (18.7) years. The mean improvement in PASI score, pruritus, and Dermatology Life Quality Index score was 61.8% (P < .001), 62.3% (P = .001), and 60.2% (P < .001), respectively. Nine participants (75%) achieved a 50% improvement in PASI. Among these clinical responders, at week 36, 8 of 9 achieved PASI75, and 6 of 9 achieved PASI90. No participants had pathogenic CARD14 gene variations. There was 1 serious adverse event that was not associated with the study drug. Proteomics and gene expression profiles identified dysregulation of a predominance of inflammatory pathways (such as T helper 17 and nuclear factor κ B) in participants with PRP who later responded well to treatment with guselkumab and stronger dysregulation of keratinocyte development pathways in individuals who did not respond to guselkumab. Conclusion and Relevance: The results of this nonrandomized trial suggest that guselkumab has efficacy in treating refractory moderate to severe adult PRP. Trial Registration: ClinicalTrials.gov Identifier: NCT03975153.

Low accuracy of self-reported family history of melanoma in high-risk patients.

Family history of melanoma is a major melanoma risk factor. However, self-reported family histories for some cancers, including melanoma, are commonly inaccurate. We used a unique database, the Utah Population Database (UPDB), as well as the Utah Cancer Registry to determine the accuracy of self-reported family history of melanoma in a large cohort of high-risk patients. Patient charts were reviewed and compared to records in the UPDB and the UCR to confirm personal and family history of melanoma in 1780 patients enrolled in a total body photography monitoring program. Self-reported family history of melanoma in first-degree relatives had an overall sensitivity of 71%, specificity of 79%, PPV of 31%, and NPV of 95%, with decreased accuracy (PPV) for second-degree relatives. A personal history of melanoma was the only factor significantly associated with accuracy in self-reported family history of melanoma. Patient age, sex, estimated nevus count, and number of prior personal melanomas were not significant predictors. Dermatologists should educate patients on the differences between melanomas, keratinocyte carcinomas, and pre-cancers. Confirming self-reported family history of melanoma may improve risk assessment for patients undergoing screening.

Dupilumab-Associated Ocular Surface Disease: Clinical Characteristics, Treatment, and Follow-Up.

PURPOSE: A consecutive case series of patients with dupilumab-associated ocular surface disease (DAOSD) that describes common ocular symptoms and signs, proposes a symptom disease severity grading system, and describes treatment strategies of DAOSD patients was evaluated. METHODS: A retrospective chart review of patients with concomitant dupilumab-treated atopic dermatitis and DAOSD with ophthalmic evaluation between January 2014 and May 2019 was conducted. RESULTS: Twenty-nine patients (mean age 46 years, M/F: 12/17) with 57 ophthalmic exams were identified. The most common ocular symptoms included irritation/pain (n = 28, 97%), redness (n = 24, 83%), pruritus (n = 18, 62%), discharge (n = 18, 62%), and light sensitivity (n = 6, 21%). The most frequent signs included conjunctival injection (n = 18, 62%), superficial punctate keratitis (n = 16, 55%), and papillary reaction (n = 8, 28%). Topical corticosteroids (TCS) (n = 23, 79%), tacrolimus (n = 6, 21%), and artificial tears (n = 7, 24%) were the most commonly used therapies. Of those with follow-up documentation (n = 21), 20 were noted to have partial or complete response with TCS based on symptoms and reduction of signs. Using our proposed symptom-based grading scale, scaled 1 to 5 based on the presence of common symptoms listed above, 66% (n = 19) requiring topical immunomodulating therapy were found in the 'severe' group (≥3 symptoms) and 17% (n = 5) were found in the 'mild' group (≤2 symptoms). CONCLUSIONS: This study provides insight into the commonly presenting ocular signs and symptoms associated with DAOSD and highlights the efficacy of TCS and other immunomodulators in improving symptoms associated with DAOSD. Based on our findings, we propose a symptom-based grading system that can guide nonophthalmic physicians regarding ophthalmology consult.

Synergistic induction of IL-23 by TNFα, IL-17A, and EGF in keratinocytes.

IL-23 is an inflammatory cytokine that plays an essential role in Th17 immunity by enhancing Th17 cell proliferation and survival, and Th17 cytokine production. IL-23 has pathogenic roles in the development of Th17-mediated inflammatory diseases including psoriasis. Despite successful treatment of psoriasis by blocking IL-23, the regulation of IL-23 expression in psoriasis patients is largely unknown. Dendritic cells are generally considered to be the primary source of IL-23 in psoriasis. While high levels of IL-23 are found in psoriatic epidermis, IL-23 expression in psoriatic keratinoctyes remains a controversial issue. In this study, we demonstrated that IL-23 production is induced by a combination of TNFα and IL-17A in human keratinocytes. Additionally, this IL-23 induction by TNFα and IL-17A is further increased in psoriatic keratinocytes and is enhanced by EGFR signaling. Although IL-23 is also robustly induced by toll-like receptor agonists in dendritic cells and macrophages, IL-23 expression in these cell types is not regulated by TNFα, IL-17A, and EGFR signaling. Given that IL-23 is essential for maintaining Th17 activation, IL-23 induction by TNFα, IL-17A, and EGF in keratinocytes could play an important pathological role in psoriasis pathogenesis as well as the cutaneous rash associated with EGFR inhibition therapy.

Evaluation of Ixekizumab Treatment for Patients With Pityriasis Rubra Pilaris: A Single-Arm Trial.

Importance: Pityriasis rubra pilaris is a rare and disabling cutaneous disease that is frequently recalcitrant to conventional therapies and appears to involve interleukin (IL)-17 overexpression. Objective: To investigate the clinical response and safety of ixekizumab in treating pityriasis rubra pilaris. Design, Setting, and Participants: Single-arm, investigator-initiated trial conducted in adult patients with moderate to severe pityriasis rubra pilaris at a single-center academic university from June 2018 to January 2020. A total of 41 patients were screened, 12 were enrolled, and 11 completed the full duration of therapy. A referred, consecutive sample was used during participant selection. The treatment period and primary outcome occurred over 24 weeks with additional patient follow-up through 36 weeks. Intervention: Subcutaneous administration of ixekizumab, a humanized IgG4 antibody that binds IL-17A, at the US Food and Drug Administration-approved dosing schedule for treatment of psoriasis for 24 weeks. Main Outcomes and Measures: The primary outcome was the mean change in Psoriasis Area and Severity Index at 24 weeks. Secondary outcomes included change in affected body surface area, quality of life, induction of sustained remission, and association of improvement with CARD14 genetic variations and cutaneous cytokine expression. Results: A total of 12 white patients (mean [SD] age, 49.8 [15.1] years; 8 male [67%]) were enrolled between June 2018 and April 2019, with 11 completing the full course of intervention. The mean (SEM) improvements in Psoriasis Area and Severity Index, affected body surface area, and Dermatology Life Quality Index were 15.2 (2.1) (P < .0001), 29.8% (9.3%) (P = .009), and 9.5 (2.5) (P = .004), respectively. The 4 participants with the most improvement in Psoriasis Area and Severity Index at week 24 stayed in remission at week 36 (defined as lack of increase in Psoriasis Area and Severity Index from week 24 through week 36), off therapy. Relative dermal IL-17A expression decreased by a 1.9 log-fold change. No participants had known pathogenic CARD14 variations. There were no serious adverse events. Conclusions and Relevance: In this single-armed trial, ixekizumab was associated with reduced clinical signs and symptoms of pityriasis rubra pilaris in a subset of patients, including those in whom other systemic therapies have failed. Trial Registration: ClinicalTrials.gov Identifier: NCT03485976.

Improved melanoma outcomes and survival in patients monitored by total body photography: A natural experiment.

Total body photography (TBP) facilitates early melanoma detection, but long-term outcomes have not been well studied. Our objectives were to examine melanoma diagnoses, role of TBP-associated follow-up visits, and survival in patients monitored by TBP. A total of 1955 patients meeting inclusion criteria received TBP from 2004-2013 at a single academic center. We compared the melanoma diagnoses and overall survival of 1253 patients with any follow-up visits (median, three visits; range, 1-18) and 702 patients with no follow-up visits. Use of TBP photographs influenced decision to biopsy 66 of 121 (54.5%) melanomas diagnosed after TBP. Lower invasive melanoma Breslow depth was significantly associated with having one or more follow-up visit (median, 0.83 vs 0.33 mm; P = .002) and photographic review (median, 0.31 vs 0.48 mm; P = 0.02). In multivariable analyses, greater overall survival was significantly associated with having one or more follow-up visit after TBP (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.14-0.91; P < 0.032) and having more than 100 nevi (HR, 0.37; 95% CI, 0.22-0.64; P = 0.004). Worse overall survival was significantly associated with increasing age (HR per year, 1.06; 95% CI, 1.04-1.08; P < 0.001) and male sex (HR, 2.65; 95% CI, 1.48-4.73; P = 0.001). Thus, monitoring by TBP was associated with subsequent melanoma diagnoses of lower stage and depth and greater overall survival.

Current controversies in early-stage melanoma: Questions on incidence, screening, and histologic regression.

In the first article in this continuing medical education series we review controversies and uncertainties relating to the epidemiology and initial diagnosis of localized cutaneous melanoma (ie, stage 0, I, or II). Many of these issues are unsettled because of conflicting evidence. Melanoma incidence appears to be increasing, yet its basis has not been fully explained. Despite the advantages of early detection, the US Preventive Services Task Force does not recommend skin screening for the general population. Occasionally, biopsy specimens of melanoma will show histologic regression, but the prognostic importance of this phenomenon is uncertain. Some practitioners recommend obtaining a sentinel lymph node biopsy specimen for thin melanomas showing regression, although this histologic finding is not part of the staging system for thin melanomas. Our goal is to provide the clinician who cares for patients with (or at risk for) melanoma with up-to-date contextual knowledge to appreciate the multiple sides of each controversy so that they will be better informed to discuss these issues with their patients and their families.

Capillary hemangioma associated with dermal atrophy masquerading as a deep fungal infection.

Hemangiomas are benign vascular neoplasms which arise in early adulthood. Herein we present a 79-year-old woman with a hemangioma of the lower flank masquerading as a cutaneous manifestation of a systemic fungal infection upon initial histological analysis. Decreased elastin and collagen within the lesion likely accounted for the clumping and splaying of the capillaries into "hyphae-like" structures. Loss of dermal elastic tissue and collagen apparently concentrated the capillary proliferation into an unusual morphology mimicking the hyphal structures. Through additional staining methods the lesion was confirmed to be an unusual presentation of a capillary hemangioma.

Evaluating Casama: Contextualized semantic maps for summarization of lung cancer studies.

OBJECTIVE: It is crucial for clinicians to stay up to date on current literature in order to apply recent evidence to clinical decision making. Automatic summarization systems can help clinicians quickly view an aggregated summary of literature on a topic. Casama, a representation and summarization system based on "contextualized semantic maps," captures the findings of biomedical studies as well as the contexts associated with patient population and study design. This paper presents a user-oriented evaluation of Casama in comparison to a context-free representation, SemRep. MATERIALS AND METHODS: The effectiveness of the representation was evaluated by presenting users with manually annotated Casama and SemRep summaries of ten articles on driver mutations in cancer. Automatic annotations were evaluated on a collection of articles on EGFR mutation in lung cancer. Seven users completed a questionnaire rating the summarization quality for various topics and applications. RESULTS: Casama had higher median scores than SemRep for the majority of the topics (p≤ 0.00032), all of the applications (p≤ 0.00089), and in overall summarization quality (p≤ 1.5e-05). Casama's manual annotations outperformed Casama's automatic annotations (p = 0.00061). DISCUSSION: Casama performed particularly well in the representation of strength of evidence, which was highly rated both quantitatively and qualitatively. Users noted that Casama's less granular, more targeted representation improved usability compared to SemRep. CONCLUSION: This evaluation demonstrated the benefits of a contextualized representation for summarizing biomedical literature on cancer. Iteration on specific areas of Casama's representation, further development of its algorithms, and a clinically-oriented evaluation are warranted.

Non-small cell lung cancer clinical trials requiring biopsies with biomarker-specific results for enrollment provide unique challenges.

BACKGROUND: Clinical trials in lung cancer increasingly require patients to provide fresh tumor tissue as a prerequisite to enrollment. The effects of this requirement on enrollment rates, enrollment durations, and patient selection have not been fully elucidated. METHODS: The authors retrospectively reviewed data generated by patients who consented to 1 or more interventional lung cancer clinical trials at the University of California-Los Angeles Jonsson Comprehensive Cancer Center between January 2013 and December 2014. Trials were considered to require a biopsy when enrollment was conditional on the procurement of tissue without intervening therapy between procurement and enrollment. RESULTS: In total, 311 patients underwent 368 screening incidents for 1 or more of 19 trials. Trials that required a new biopsy had a longer median screening duration (34 vs 14 days) than trials that did not require a biopsy (P < .001). Trials that required a biopsy had a greater screen failure rate (49.1% vs 26.5%; P < .001), which was largely driven by patients who did not undergo the required biopsy or lacked the required biomarker. Worsening performance status led to the majority of screen failures (56.5%) among biomarker-eligible patients. CONCLUSIONS: Although the scientific benefits of obtaining a new biopsy and requiring specific results for trial enrollment are clear, these requirements lead to a lengthening of the screening period, which, in some patients, is associated with clinical decline before enrollment. Implications for the interpretation of data from studies of this design should be explored. Cancer 2017;123:4800-7. © 2017 American Cancer Society.

Primary lung metastasis of glioblastoma multiforme with epidural spinal metastasis: Case report.

Extracranial metastasis of glioblastoma multiforme (GBM) is rare, but has recently been reported with increasing frequency. GBM metastases typically present after a biopsy or resection of the primary tumor. An otherwise healthy 54year-old woman presented with recurring pleural effusions originally believed to be from a primary lung malignancy. The patient subsequently experienced a generalized tonic clonic seizure and a right temporal brain mass was discovered. The patient later developed weakness and radiculopathy, and an extramedullary extradural mass spreading from C7 to T6 was discovered. She underwent resection of both central nervous system lesions as well as a lung biopsy, and all pathologic specimens were consistent with GBM. The case presented is unique in that the patient's initial symptoms were related to her metastasis. Furthermore, a purely epidural spread of GBM that respects the leptomeninges and intramedullary parenchyma is highly unusual.

Clinical Trials in Non-Small Cell Lung Cancer with Biomarker-Driven Treatment Allocation: Ready or Not, Here We Come.

Lung cancer is the leading cause of cancer mortality. Great advances in non-small cell lung cancer therapy have been seen in the last decade, beginning with the success in treating lung cancer harboring EGFR mutations and ALK-gene rearrangements. The potential of these biomarker-driven therapies has propelled research in biomarker targeted approaches to the forefront of lung cancer research. The successful development of immunotherapeutic agents targeting PD-L1 and PD-1 with an associated non-genomic biomarker has opened a new front in the effort for targeted approaches. Although early-phase lung cancer studies have hinted at the potential to use biomarkers to select patients for allocation to treatment in the conduct of clinical trials, data from late-phase studies have tempered expectations. The data leave unclear the wisdom of routinely restricting enrollment on lung cancer clinical trials to biomarker restricted populations, particularly non-genomic biomarkers.