Lazertinib in EGFR-Variant Non-Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors: A Nonrandomized Controlled Trial.

Importance: EGFR-variant non-small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Objective: To investigate CNS activity with lazertinib, a third-generation EGFR TKI. Design, Setting, and Participants: This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR-variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022. Exposure: Lazertinib, 240 mg, once daily. Main Outcomes and Measures: The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety. Results: Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2. Conclusions and Relevance: In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR-variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT05326425.

Personalized Biomarker-Based Umbrella Trial for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: KCSG HN 15-16 TRIUMPH Trial.

PURPOSE: A precise oncologic approach for head and neck squamous cell carcinoma (HNSCC) is necessary. We performed a genomic profile-based umbrella trial for the patients with platinum-refractory recurrent and/or metastatic HNSCC. METHODS: In this multicenter, open-label, single-arm phase II trial, we performed targeted next-generation sequencing (NGS). Patients were assigned to each treatment arm on the basis of their matching genomic profiles: arm 1, alpelisib, a PIK3CA inhibitor; arm 2, poziotinib, an epidermal growth factor receptor/HER2 inhibitor; arm 3, nintedanib, an fibroblast growth factor receptor inhibitor; and arm 4, abemaciclib, a CDK4/6 inhibitor. If there was no matching target, patients were allocated to arm 5, duvalumab ± tremelimumab, anti-PD-L1/cytotoxic T-cell lymphocyte-4 inhibitor. When progressive disease (PD) occurred in arms 1-4, cross over to arm 5 was allowed. The primary end point was disease control rate (DCR) in arm 1 and overall response rate (ORR) in arms 2-5 by investigator assessment. RESULTS: Between October 2017 and August 2020, 203 patients were enrolled, including crossover. In arm 1, the ORR was 21.2% and DCR was 65.6%. The ORR was 0% for arm 2, 42.9% for arm 3, 0% for arm 4, and 15.6% for arm 5. In the case of PD with durvalumab, tremelimumab was added, and the ORR for durvalumab + tremelimumab was 2.2%. The median progression-free survival was 3.4, 3.2, 5.6, 1.6, and 1.7 months for each arm, respectively. The median overall survival was 12.4, 6.1, 11.1, 9.1, and 12.7 months, respectively. Overall, the toxicity profiles were manageable, and there were no treatment-related deaths. CONCLUSION: To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable.

Analysis of low-level somatic mosaicism reveals stage and tissue-specific mutational features in human development.

Most somatic mutations that arise during normal development are present at low levels in single or multiple tissues depending on the developmental stage and affected organs. However, the effect of human developmental stages or mutations of different organs on the features of somatic mutations is still unclear. Here, we performed a systemic and comprehensive analysis of low-level somatic mutations using deep whole-exome sequencing (average read depth ~500×) of 498 multiple organ tissues with matched controls from 190 individuals. Our results showed that early clone-forming mutations shared between multiple organs were lower in number but showed higher allele frequencies than late clone-forming mutations [0.54 vs. 5.83 variants per individual; 6.17% vs. 1.5% variant allele frequency (VAF)] along with less nonsynonymous mutations and lower functional impacts. Additionally, early and late clone-forming mutations had unique mutational signatures that were distinct from mutations that originated from tumors. Compared with early clone-forming mutations that showed a clock-like signature across all organs or tissues studied, late clone-forming mutations showed organ, tissue, and cell-type specificity in the mutation counts, VAFs, and mutational signatures. In particular, analysis of brain somatic mutations showed a bimodal occurrence and temporal-lobe-specific signature. These findings provide new insights into the features of somatic mosaicism that are dependent on developmental stage and brain regions.

A Prospective, Split-Face, Comparative Study of Combined Treatment With Fractional Microneedle Radiofrequency and Nonablative 1927-nm Fractional Thulium Fiber Laser for Wrinkle Treatment.

BACKGROUND: Fractional microneedle radiofrequency (FMR) and nonablative 1927-nm fractional thulium fiber laser (TFL) are widely used for skin rejuvenation treatment. OBJECTIVES: To investigate the efficacy and safety of combined treatment with both devices for wrinkles. PATIENTS AND METHODS: Twenty-five patients with wrinkles were enrolled. One side of the face was treated with FMR alone, while the other side was treated with a combination of FMR and TFL. Each treatment consisted of 3 sessions at four-week intervals and patients were followed up 12 weeks after the last treatment. Overall improvement was assessed by patient global assessment (PGA) and investigator global assessment (IGA). Depression scores for the evaluation of wrinkles were objectively assessed by Antera 3D system. RESULTS: Both sides of the face led to clinical improvement in both mean PGA and IGA. Combination treatment demonstrated a greater improvement in both mean PGA and IGA compared with FMR alone. In addition, wrinkle grading scales and depression scores showed greater improvement in the combination group than in FMR alone. CONCLUSION: This study demonstrated that FMR and TFL comprise a good combination treatment for the treatment of wrinkles because both treatments have a synergistic effect on wrinkle improvement.

Non-Ablative 1927 nm Fractional Thulium Fiber Laser: New, Promising Treatment Modality for Riehl's Melanosis.

BACKGROUND AND OBJECTIVES: The treatment of Riehl's melanosis, also known as pigmented contact dermatitis, is highly challenging. Intense pulsed light (IPL) and 1064 nm Q-switched Nd:Yag (QS-Nd:YAG) laser are reported to have some efficacy. However, no single effective treatment has yet been identified. In this study, we demonstrated the efficacy and safety of the non-ablative 1927 nm fractional thulium fiber laser (TFL, LASEMD™; Lutronic Corp., Goyang, Korea) for patients with Riehl's melanosis. STUDY DESIGN/MATERIALS AND METHODS: A retrospective chart and photographic review of nine patients with Riehl's melanosis, who had received at least three sessions of TFL treatment, was performed. Before the start of TFL treatment, combination treatment with a topical cream containing hydroquinone, low-fluence QS-Nd:YAG laser, pulsed dye laser, and IPL was used with variable and discouraging effects. Seven patients were treated on the face and two patients on the neck with three to seven sessions at 1-month intervals. Clinical improvement was assessed using clinical photos taken before and after every treatment session according to dermal pigmentation area and severity index (DPASI) and a quartile grading scale by two blinded dermatologists. RESULTS: Patients underwent three to seven sessions of TFL treatment depending on severity of pigmentation. Of nine patients, six demonstrated a clinical improvement of 51%-75%, one demonstrated an improvement of 76%-100%, and two showed an improvement of 26%-50% after treatment. The DPASI was significantly decreased from 9.55 to 5.25 on average. Melanin index was decreased after treatment in two patients whose melanin index were measured at initial visits. Treatment-related adverse events, such as scarring or postinflammatory hyperpigmentation (PIH), were not observed in all patients except for transient erythema and swelling. CONCLUSIONS: This report suggests that TFL could be an alternative and/or additive treatment option for hyperpigmentation in intractable Riehl's melanosis and might be a promising treatment for PIH caused by any reason including Riehl's melanosis. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

ATP-P2X7-Induced Inflammasome Activation Contributes to Melanocyte Death and CD8+ T-Cell Trafficking to the Skin in Vitiligo.

Extracellular adenosine 5'-triphosphate (ATP) is a well-known inflammasome-activating signal. Emerging evidence demonstrates a critical role for inflammasome activation in vitiligo pathogenesis. However, the specific molecular mechanism of inflammasome-dependent melanocyte degeneration in vitiligo is still not clear. This study presents how extracellular ATP, released from keratinocytes by oxidative stress, affects melanocyte survival in vitiligo skin. H2O2-induced oxidative injury increased ATP release from keratinocytes and skin tissues. The high concentration of extracellular ATP induced both ROS production and cell death in melanocytes. Treatment with ATP caused the activation of caspase-1 as well as the production of active forms of IL-1ß and IL-18 via P2X7 receptor in keratinocytes and melanocytes. Lesional and perilesional skin of vitiligo showed higher levels of ATP as well as upregulation of active caspase-1 compared with nonlesional skin, suggesting its possible role in inflammasome activation in vitiligo. Moreover, the elevated expression of CXCL9 in keratinocytes, mediated through ATP/P2X7 receptor-dependent inflammasome activation, was responsible for CLA+CD8+ T-cell chemotaxis into the skin. These results demonstrate that extracellular ATP as a danger signal activates the inflammasome pathway and increases cutaneous chemotaxis of CD8+ T cells via CXCL9 in vitiligo. Therefore, targeting ATP-P2X7 signaling may be a potential strategy for vitiligo treatment.

Autophagy induction can regulate skin pigmentation by causing melanosome degradation in keratinocytes and melanocytes.

Autophagy regulates cellular turnover by disassembling unnecessary or dysfunctional constituents. Recent studies demonstrated that autophagy and its regulators play a wide variety of roles in melanocyte biology. Activation of autophagy is known to induce melanogenesis and regulate melanosome biogenesis in melanocytes. Also, autophagy induction was reported to regulate physiologic skin color via melanosome degradation, although the downstream effectors are not yet clarified. To determine the role of autophagy as a melanosome degradation machinery, we administered several autophagy inducers in human keratinocytes and melanocytes. Our results showed that the synthetic autophagy inducer PTPD-12 stimulated autophagic flux in human melanocytes and in keratinocytes containing transferred melanosomes. Increased autophagic flux led to melanosome degradation without affecting the expression of MITF. Furthermore, the color of cell pellets of both melanocytes and keratinocytes was visibly lightened. Inhibition of autophagic flux by chloroquine resulted in marked attenuation of PTPD-12-induced melanosome degradation, whereas the expression of melanogenesis pathway genes and proteins remained unaffected. Taken together, our results suggest that the modulation of autophagy can contribute to the regulation of melanocyte biology and skin pigmentation.

Critical Role of ATP-P2X7 Axis in UV-Induced Melanogenesis.

Purinergic signaling participates in skin physiology and pathology, such as hair growth, wound healing, inflammation, pain, and skin cancer. However, few studies have investigated the involvement of purinergic signaling in skin pigmentation. This study demonstrated that extracellular adenosine 5'-triphosphate (ATP) released from keratinocytes by UVB radiation promotes melanin production in primary human epidermal melanocytes and ex vivo skin cultures. Intracellular calcium ion and protein kinase C/CREB signaling contributed to ATP-mediated melanogenesis. Also, P2X7 receptor was proven to play a pivotal role in ATP-mediated melanogenesis because P2X7 receptor blockade abrogated ATP-induced melanin production. In addition, MNT1 cells with P2X7 receptor knockout using CRISPR/Cas9 system did not show any increase in MITF expression when co-cultured with UV-irradiated keratinocytes compared to MNT1 cells with intact P2X7 receptor, which showed increased expression of MITF. In conclusion, our results indicate that the extracellular ATP-P2X7 signaling axis is an adjunctive mechanism in UV-induced melanogenesis. Furthermore, ATP-induced purinergic signaling in melanocytes may alter skin pigmentation.

Asymptomatic Hyperpigmentation without Preceding Inflammation as a Clinical Feature of Citrus Fruits-Induced Phytophotodermatitis.

Phytophotodermatitis is a condition that occurs by contact with plants containing phototoxic agents such as furocoumarins and psoralens with subsequent ultraviolet exposure. Phytophotodermatitis typically presents as sharply defined erythematous patches with occasional blistering, sometimes accompanied with pain or itching sensation. In some cases, however, sudden appearance of asymptomatic hyperpigmentation can be the only clinical finding of phytophotodermatitis. Here, we present two patients with sudden development of asymptomatic pigmentation on their hand without preceding inflammation by the contact with citrus fruits containing photosensitizers and subsequent exposure to strong sunlight. As like these patients, phytophotodermatitis can present with only pigmentation without noticeable inflammation especially in dark skinned people. In such cases, physician can sometimes have difficulty in diagnosis of phytophotodermatitis. Therefore, it is important to consider the possibility of phytophotodermatitis through careful history taking, especially in patients who have abruptly developed well-defined hyperpigmentation on sun-exposed areas, to avoid unnecessary test and treatment.

Intramuscular triamcinolone acetonide: An undervalued option for refractory alopecia areata.

Severe alopecia areata (AA) can have an unpredictable clinical course and become refractory to contact immunotherapy. Novel treatment options include low-dose interleukin-2 and Janus kinase inhibitors; however, these treatments are still under investigation. Therefore, we evaluated the efficacy and safety of intramuscular (i.m.) triamcinolone acetonide (TAC) as a rescue therapy for refractory AA. We retrospectively analysed efficacy, adverse effects and relapse rate of i.m. TAC monthly in 27 patients with refractory AA. We defined AA as refractory if the patient showed an unsatisfactory response to both systemic treatment (not i.m. TAC) and the consecutive diphenylcyclopropenone immunotherapy. The initial systemic treatment of other forms of corticosteroids and/or cyclosporin was used to control extensive AA involving more than 25% of the scalp. Administration of i.m. TAC for 3-6 months resulted in a 63.0% response rate, and all patients showed inactive disease after treatment. Final hair regrowth negatively correlated with initial scalp involvement (Spearman r = -0.595, P = 0.001). All patients showed complete recovery of adrenocortical reserve within 3 months after the last injection. Adverse effects of systemic steroid therapy were observed only in female patients (dysmenorrhea and osteoporosis). i.m. TAC may provide a valuable therapeutic option to manage active hair loss and facilitate hair regrowth in refractory AA, especially in male patients.