Despite the lack of predictive biomarkers and a prognostic stratification strategy, immune checkpoint inhibitor (ICI) has shown promise in improving outcomes for patients with limited-stage small cell lung cancer (LS-SCLC). We evaluated the potential of circulating tumor DNA (ctDNA) to dynamically predict outcomes in patients with LS-SCLC receiving concurrent chemoradiotherapy (CCRT) with or without consolidation ICI. We analyzed 490 serial samples collected from 144 LS-SCLC patients at baseline (t0), post-induction chemotherapy and pre-thoracic radiotherapy (t1), post-radiotherapy (t2), and progressive disease (t3). For 44 patients receiving consolidation ICI with serplulimab, an investigational PD-1 inhibitor, ctDNA dynamics during consolidation ICI were also assessed at multiple time points. Patients with undetectable ctDNA after CCRT had good outcomes with or without consolidation ICI, whereas ctDNA-positive patients at t2, indicating poor response to CCRT, derived survival benefit from consolidation ICI. Notably, ctDNA status at t1 appeared more predictive than at t2. A three-level risk stratification strategy integrating t1 ctDNA status with radiological tumor shrinkage identified a high-risk subgroup of patients who achieved significantly improved progression-free survival (PFS) (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.08-0.75; p = 0.014) and overall survival (OS) (HR, 0.06; 95% CI, 0.00-0.42; p = 0.001) from consolidation ICI, prioritizing CCRT plus consolidation ICI. Furthermore, maintaining ctDNA negativity during consolidation ICI was associated with favorable outcomes. These data provide valuable insights into the individualized management of LS-SCLC in the era of immunotherapy.

Purpose Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). However, reliable biomarkers for predicting response to immunotherapy remain limited. Among circulating immune cells, PD-1⁺CD8⁺ T cells represent an activated subset that directly responds to PD-1 blockade. Profiling the T-cell receptor (TCR) repertoire within this population may reflect antitumor immune activity and holds promise as noninvasive, blood-based biomarker. Methods and Materials We prospectively enrolled 63 patients with unresectable LA-NSCLC who underwent chemoradiation therapy. Peripheral blood PD-1⁺CD8⁺ T cells were isolated from peripheral blood mononuclear cells obtained by density gradient centrifugation at 3 time points: before radiation therapy, during radiation therapy (on-RT, approximately at the 20th fraction), and after radiation therapy (post-RT), yielding a total of 141 blood samples. TCR sequencing was performed to assess repertoire diversity. Dynamic changes in TCR diversity metrics across time points were analyzed and correlated with progression-free survival (PFS). Results A higher D50 index on-RT was significantly associated with improved median PFS (not reached vs 21.95 months; P = .0246), regardless of the timing of immunotherapy. Patients with more stable TCR diversity and clonality on-RT experienced significantly longer PFS. Specifically, patients with low D50 index variation between on-RT and post-RT had a median PFS that was not reached (95% CI, 30.72-NA), compared with 21.95 months (95% CI, 17.84-NA; P = .018) in the high-variation group. Similarly, patients with low clonality variation demonstrated longer PFS from pre-RT to on-RT (30.72 vs 21.95 months; P = .0425) and from on-RT to post-RT (not reached vs 22.21 months; P = .0331). Clonal tracking analyses revealed that patients with short-PFS exhibited a higher proportion of markedly decreased TCR clones, particularly among high-frequency clones, suggesting impaired antitumor immune responses. Conclusions Peripheral PD-1⁺CD8⁺ TCR diversity and its dynamic changes on-RT are associated with PFS in patients with LA-NSCLC. These findings suggest that TCR repertoire profiling of circulating PD-1⁺CD8⁺ T cells may serve as a noninvasive biomarker to identify patients less likely to benefit from consolidation immunotherapy. Further validation in larger, prospective cohorts is warranted.

Background Various devices are used for facial wrinkle treatment, but comparative data on their efficacy and safety are limited. Objective To compare the efficacy and safety of a temperature-controlled bipolar fractional radiofrequency microneedling device (Profound) with a skin treatment system (EndyMed Pro) for facial wrinkle treatment. Methods A prospective, randomized controlled trial was conducted at three sites in China from February 2022 to May 2023. A total of 140 healthy adults (age >= 20, Fitzpatrick skin Type III-IV) were randomized to receive either a single Profound treatment or three EndyMed Pro treatments. Results No significant differences in wrinkle scores (Fitzpatrick, crow's feet, and nasolabial folds) were observed between the two groups at 24 weeks. However, Profound showed superior results for wrinkles at the corner of the lips and the mandibular margin at 20 and 24 weeks (p < 0.05). Conclusion Profound provided similar or superior improvements in wrinkle reduction compared to EndyMed Pro, particularly for wrinkles at the corner of the lips and the mandibular margin.

Importance Biologic agents are commonly used with conventional immunosuppressants for treatment of immune-mediated dermatologic diseases, raising concerns about tuberculosis (TB) risk, particularly in high-burden geographic regions. Previous studies have shown inconsistent results across biologic classes, with most focusing on active TB and limited data on latent TB infection (LTBI) conversion. Objectives To evaluate the incidence of active TB and LTBI conversion in dermatologic patients receiving systemic therapy and to explore differences by biologic class and regional TB burden. Data Sources PubMed/MEDLINE, Embase, Web of Science Core Collection, and the Cochrane Library were searched from database inception to October 1, 2025. Controlled vocabulary and free-text terms were used for dermatologic diseases, systemic therapies, and tuberculosis-related outcomes. Clinical trial registries and reference lists were also screened. Study Selection Randomized clinical trials, cohort studies, case-control studies, and cross-sectional studies reporting active TB or LTBI conversion in dermatologic patients receiving systemic therapy were included. Two reviewers independently screened records and performed full-text assessment. Data Extraction and Synthesis Data extraction and risk-of-bias assessment (Newcastle–Ottawa Scale and Cochrane Risk of Bias tool) were conducted independently by 2 reviewers following PRISMA guidelines. Single-arm incidence rates were pooled using random-effects models with logit transformation. Prespecified subgroup analyses were conducted by biologic class and regional TB burden. Main Outcomes and Measures Primary outcomes were incidence of LTBI conversion (among patients with negative baseline results of tuberculin skin test or interferon-gamma release assay) and active TB during follow-up. Results Of 4726 records identified, 31 studies comprising a total of 15 005 patients met inclusion criteria and were included in the analysis. The pooled incidence of LTBI conversion was 4.3%, highest with tumor necrosis factor inhibitors, followed by interleukin (IL)-17 and ustekinumab (IL-12/23 p40 inhibitor). The overall incidence of active TB was 1.0% and it was more frequent in high-burden regions. Conclusions and Relevance In this systematic review and meta-analysis, TB-related risk varied by biologic mechanism and epidemiologic context. Risk assessment and monitoring should integrate dermatologic treatment class and regional TB burden to guide clinical decision-making.

Melasma is a persistent and recurrent condition that remains difficult to manage effectively. Both fractional 1064 nm picosecond Nd:YAG (PSNY) and low-fluence Q-switched Nd:YAG (QSNY) lasers have been applied in treatment, yet there is currently insufficient data to compare their efficacy and safety. This retrospective study evaluated 99 female patients with melasma, including 54 treated with PSNY laser and 45 with QSNY laser. Each patient received two to five laser sessions at 2-4-week intervals. Clinical efficacy was evaluated by the modified Melasma Area and Severity Index (mMASI) at baseline, as well as four weeks following the second and fifth treatment sessions, with adverse events carefully documented. The PSNY laser produced a mean mMASI reduction of 23.7% and 40.7% after two and five sessions, respectively, while QSNY treatment achieved reductions of 9.8% and 29.5%. Although both modalities were safe and effective, PSNY laser demonstrated faster clinical improvement and required lower energy fluence. Post-inflammatory hyperpigmentation occurred in 7.4% of PSNY-treated patients and 13.3% of QSNY-treated patients, with no significant difference between groups. In conclusion, fractional PSNY laser therapy provides a rapid, safe, and effective alternative to QSNY laser for managing melasma.

Importance:Biologic agents are commonly used with conventional immunosuppressants for treatment of immune-mediated dermatologic diseases, raising concerns about tuberculosis (TB) risk, particularly in high-burden geographic regions. Previous studies have shown inconsistent results across biologic classes, with most focusing on active TB and limited data on latent TB infection (LTBI) conversion. Objectives:To evaluate the incidence of active TB and LTBI conversion in dermatologic patients receiving systemic therapy and to explore differences by biologic class and regional TB burden. Data Sources:PubMed/MEDLINE, Embase, Web of Science Core Collection, and the Cochrane Library were searched from database inception to October 1, 2025. Controlled vocabulary and free-text terms were used for dermatologic diseases, systemic therapies, and tuberculosis-related outcomes. Clinical trial registries and reference lists were also screened. Study Selection:Randomized clinical trials, cohort studies, case-control studies, and cross-sectional studies reporting active TB or LTBI conversion in dermatologic patients receiving systemic therapy were included. Two reviewers independently screened records and performed full-text assessment. Data Extraction and Synthesis:Data extraction and risk-of-bias assessment (Newcastle-Ottawa Scale and Cochrane Risk of Bias tool) were conducted independently by 2 reviewers following PRISMA guidelines. Single-arm incidence rates were pooled using random-effects models with logit transformation. Prespecified subgroup analyses were conducted by biologic class and regional TB burden. Main Outcomes and Measures:Primary outcomes were incidence of LTBI conversion (among patients with negative baseline results of tuberculin skin test or interferon-gamma release assay) and active TB during follow-up. Results:Of 4726 records identified, 31 studies comprising a total of 15 005 patients met inclusion criteria and were included in the analysis. The pooled incidence of LTBI conversion was 4.3%, highest with tumor necrosis factor inhibitors, followed by interleukin (IL)-17 and ustekinumab (IL-12/23 p40 inhibitor). The overall incidence of active TB was 1.0% and it was more frequent in high-burden regions. Conclusions and Relevance:In this systematic review and meta-analysis, TB-related risk varied by biologic mechanism and epidemiologic context. Risk assessment and monitoring should integrate dermatologic treatment class and regional TB burden to guide clinical decision-making.

BACKGROUND:Checkpoint inhibitor pneumonitis (CIP) is the leading cause of treatment-related deaths for immune checkpoint inhibitor (ICI) combination therapies. CIP is problematic to diagnose and differentiate, particularly from radiation pneumonitis (RP), due to the lack of mechanistic distinctions between them. METHODS:Using single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq), we characterize the cellular landscape of bronchoalveolar lavage fluid (BALF) and peripheral blood from a discovery cohort (seven CIP, six RP, and six treatment-naive controls) and a validation cohort (five patients receiving combined ICI and radiotherapy who were diagnosed with RP). FINDINGS:We report a striking accumulation of alveolar CD8+ exhausted T cells (Texs) in CIP. The alveolar CD8+ Texs of CIP primarily differentiate from tissue-resident ZNF683hi CD8+ T cells, whereas those of RP predominantly originate from peripherally related GZMKhi CD8+ T cells. These findings were further validated in a prospectively enrolled validation cohort and ultimately guided successful clinical decisions regarding ICI rechallenge. CONCLUSIONS:These results highlight distinct cellular and molecular features in CIP and RP, thereby providing insights into clinical decision-making regarding ICI rechallenge in lung cancer patients. FUNDING:This study was supported by the National Natural Science Foundation of China.

Background:Vitiligo is an acquired depigmentary disorder caused by the loss of functional melanocytes. Increasing evidence suggests that competing endogenous RNA (ceRNA) interactions participate in this process, yet their global architecture in vitiligo remains unclear. Objective:To delineate a long non-coding RNA (lncRNA)-microRNA (miRNA)-mRNA ceRNA network associated with vitiligo and to identify blood-borne RNA markers with diagnostic potential. Methods:miRNA, mRNA, and lncRNA expression data from vitiligo patients and healthy controls were obtained from the GEO database (GSE141655 and GSE186928). Differentially expressed (DE) mRNAs, miRNAs and lncRNAs were screened (|log2 FC| > 0.5, adj. p< 0.05). Functional enrichment, STRING-based protein-protein interaction (PPI) mapping, and lncRNA-mRNA co-expression analysis (Pearson r > 0.9) was performed. miRNA-mRNA pairs were predicted with miRWalk 3.0, and miRNA-lncRNA pairs with miRanda v3.3a (score ≥ 140, energy ≤-20 kcal mol-¹). Triplets that shared the same miRNA, displayed positive lncRNA--mRNA correlation, and showed inverse expression relative to the miRNA were combined into a ceRNA network; hub nodes were ranked by degree centrality. Candidate lncRNAs were validated by RT-qPCR in peripheral blood from 20 vitiligo patients and 20 matched controls. Results:A total of 454 DE-mRNAs (341 down-, 113 up-regulated), 22 DE-miRNAs (6 down-, 16 up-regulated), and 281 DE-lncRNAs (112 down-, 169 up-regulated) were identified. Enrichment analysis highlighted pathways linked to melanogenesis, oxidative stress, PI3K-Akt, JAK-STAT and IL-17 signalling. The ceRNA network comprised 33 lncRNAs, 12 miRNAs and 58 mRNAs; SLC32A1, GRIA2, PRKACG and WNT1 were top hub proteins in the PPI sub-network. Blood validation confirmed up-regulation of CASC19, NUCB1-AS1 and LINC01485 and down-regulation of VAV3-AS1, SPATA13-AS1, ZNF350-AS1 and LINC00677 (all p< 0.05). Conclusion:Our findings map a vitiligo-related ceRNA landscape and pinpoints seven circulating lncRNAs with diagnostic promise. The results provide a foundation for probing non-coding RNA-mediated mechanisms and developing targeted therapies for vitiligo.

Melasma is a recurrent and treatment-resistant hyperpigmentation disorder characterized by a complex and multifactorial pathogenesis. However, the lack of a stable and reliable animal model has hindered systematic investigations into its onset and progression. In this study, we established a melasma-like model in C57BL/6J mice by combining broadband UVB irradiation, intramuscular progesterone administration, and induced emotional stress. The affected skin areas exhibited irregular, brown hyperpigmented patches. Histopathological analysis revealed an accumulation of melanin granules in the epidermis and superficial dermis, elevated levels of tyrosinase (TYR) in both skin and plasma, systemic oxidative stress imbalance, and reduced autophagic activity in the lesional skin. Furthermore, this model displayed distinct differences from a UV-induced post-inflammatory hyperpigmentation (PIH) model. Notably, the melasma-like mice responded to tranexamic acid treatment in a manner that closely resembled clinical outcomes observed in human patients. Collectively, these findings establish a stable, reproducible, and clinically relevant mouse model of melasma, providing a valuable platform for future research into its pathogenesis and treatment.

Several studies have demonstrated the inhibitory effect of metformin on pigmentation. However, the effect of metformin on melanosome transfer remains unknown. The goals of this study were to elucidate the effects of metformin on melanogenesis and melanosome transfer and explore the related mechanisms. We determined that, compared with those in the control zebrafish, the area occupied by pigment granules, melanin content, tyrosinase activity, and the expression levels of melanogenesis genes and melanosome transfer-related genes were reduced in metformin-treated zebrafish. In human primary melanocytes, MNT1 cells/B16F10 cells, metformin also plays a negative role in melanin synthesis regardless of health status and α-MSH-induced pigmentation. Unlike arbutin, metformin inhibited the formation of dendrites and filopodia-like structures and suppressed melanosome transfer. After treatment with metformin, the cAMP content was reduced, the expression of MITF and downstream molecules was downregulated, and the expression of Rho GTPases was changed. Metformin partially abrogated the changes in genes regulating melanin synthesis, melanosome transfer and the cytoskeleton induced by a cAMP activator. Furthermore, the Nrf2 expression was decreased upon metformin intervention, and metformin partially abrogated the changes in genes regulating melanogenesis caused by a Nrf2 activator. Our study revealed that metformin can serve as a candidate depigmentation agent.

Skin aging is a complex process driven by intrinsic genetic factors and extrinsic environmental influences. In this study, sequestosome1 (SQSTM1/p62) was identified as a key regulator of senescence, the senescence-associated secretory phenotype (SASP), and skin aging. Notably, p62 expression is reduced in senescent cells and aging skin of both humans and mice. The depletion of p62 in the epidermis was found to be positively associated with accelerated aging and the initiation of SASP. Mechanistically, p62 inhibits the accumulation of ubiquitin-specific protease 7 (USP7) during senescence induction by orchestrating its degradation through specific binding interactions. In particular, the Tyr-67 residue within the PB1 domain or Gln-418 within the UBA domain of p62 forms a hydrogen bond with Ala-993 in the Ubl5 domain of USP7. Mutations in either Tyr-67 or Gln-418 of p62, or Ala-993 of USP7, resulted in the induction of cellular senescence, highlighting the critical role of these molecular interactions in the regulation of aging processes.

Background: Liquid biopsy-based biomarkers, including circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB), are recognized as promising predictors of prognoses and responses to immune checkpoint inhibitors (ICIs), despite insufficient sensitivity of single biomarker detection. This research aims to determine whether the combinatorial utility of longitudinal ctDNA with bTMB analysis could improve the prognostic and predictive effects. Methods: This prospective two-center cohort trial, consisting of discovery and validation datasets, enrolled unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) patients and assigned them to chemoradiotherapy (CRT) or CRT + consolidation ICI cohorts from 2018 to 2022. Blood specimens were collected pretreatment, 4 weeks post-CRT, and at progression to assess bTMB and ctDNA using 486-gene next-generation sequencing. Dynamic ∆bTMB was calculated as post-CRT bTMB minus baseline bTMB levels. Decision curve analyses were performed to calculate Concordance index (C-index). Results: One hundred twenty-eight patients were enrolled. In the discovery dataset (n = 73), patients treated with CRT and consolidation ICI had significantly longer overall survival (OS; median not reached [NR] vs 20.2 months; P < 0.001) and progression-free survival (PFS; median 25.2 vs 11.4 months; P = 0.011) than those without ICI. Longitudinal analysis demonstrated a significant decrease in ctDNA abundance post-CRT (P < 0.001) but a relative increase with disease progression. Post-CRT detectable residual ctDNA correlated with significantly shorter OS (median 18.3 months vs NR; P = 0.001) and PFS (median 7.3 vs 25.2 months; P < 0.001). For patients with residual ctDNA, consolidation ICI brought significantly greater OS (median NR vs 14.8 months; P = 0.005) and PFS (median 13.8 vs 6.2 months; P = 0.028) benefit, but no significant difference for patients with ctDNA clearance. Dynamic ∆bTMB was predictive of prognosis. Patients with residual ctDNA and increased ∆bTMB (∆bTMB > 0) had significantly worse OS (median 9.0 vs 23.0 months vs NR; P < 0.001) and PFS (median 3.4 vs 7.3 vs 25.2 months; P < 0.001). The combinatorial model integrating post-CRT ctDNA with ∆bTMB had optimal predictive effects on OS (C-index = 0.723) and PFS (C-index = 0.693), outperforming individual features. In the independent validation set, we confirmed residual ctDNA predicted poorer PFS (median 50.8 vs 14.3 months; P = 0.026) but identified more consolidation ICI benefit (median NR vs 8.3 months; P = 0.039). The combined model exhibited a stable predictive advantage (C-index = 0.742 for PFS). Conclusions: The multiparameter assay integrating qualitative residual ctDNA testing with quantitative ∆bTMB dynamics improves patient prognostic risk stratification and efficacy predictions, allowing for personalized consolidation therapy for LA-NSCLC.

B-cell Chronic Lymphocytic Leukemia (B-CLL) is a malignancy caused by the clonal expansion of mature B lymphocytes bearing a CD5+CD19+ (B1) phenotype. However, the origin of B-CLL remains controversial. We showed previously that STYK1/NOK transgenic mice develop a CLL-like disease. Using this model system in this study, we attempt to define the stage of CLL initiation. Here, we show that the phenotype of STYK1/NOK-induced B-CLL is heterogeneous. The expanded B1 lymphocyte pool was detected within peripheral lymphoid organs and was frequently associated with the expansions of memory B cells. Despite this immunophenotypic heterogeneity, suppression of B cell development at an early stage consistently occurred within the bone marrow (BM) of STYK1/NOK-tg mice. Overall, we suggest that enforced expression of STYK1/NOK in transgenic mice might significantly predispose BM hematopoietic stem cells (HSCs) towards the development of B-CLL.

BackgroundFew reports have confirmed whether exosomes derived from fibroblasts can regulate the process of melanogenesis. We wondered whether exosomes derived from fibroblasts could have a potent regulatory effect on melanogenesis and explored the underlying mechanisms.ObjectiveThis study aimed to find the role of fibroblasts in melanocytes and revealed the related mechanisms.MethodsRT-qPCR, Western blot analysis were conducted to measure the RNA and protein expression level of various related genes. miRNA sequencing, mass spectrum analysis and subsequent bioinformatics analysis were employed to find the underlying targets. Zebrafish were employed to measure the melanin synthesis related process in vivo. Furthermore, electron microscopy, ROS measurement and dual-luciferase reporter assay were adopted to investigate the relationship between these processes.ResultsWe found that exosomes derived from human primary dermal fibroblasts were internalized by human primary melanocytes and MNT1 cells and that the melanin content and the expression of melanin synthesis-related proteins TYR and MITF was inhibited by exosomes derived from UVB-induced human primary dermal fibroblasts. The miRNA expression profile in secreted exosomes changed significantly, with miR-25-5p identified as capable of regulating TSC2 expression via the CDS region. The miR-25-5p-TSC2 axis could affect the melanin content through subsequent cellular organelle dysfunction, such as mitochondrial dysfunction, endoplasmic reticulum stress and dysregulation of lysosomal cysteine proteases.ConclusionWe unveiled a novel regulatory role of fibroblasts in melanocytes, facilitated by the secretion of exosomes. miR-25-5p within exosomes plays a pivotal role in regulating melanogenesis via TSC2-induced cellular organelle dysfunction.

BACKGROUND:Melasma is a common and chronic pigmentary disorder with complex pathogenesis, and the relationship between melasma and metabolic syndrome remains elusive. Thus, metabolomics might contribute to the early detection of potential metabolic abnormalities in individuals with melasma. OBJECTIVE:The present study aims to analyze changes in plasma metabolites of female melasma patients and identify disease markers as well as explore potential therapeutic targets. METHODS:Plasma samples from 20 female patients with melasma and 21 healthy female controls that were comparable in terms of age and body mass index were collected for untargeted metabolomics investigations. Ultra-high performance liquid chromatography-mass spectrometry was used to analyze metabolites in the plasma. Metabolic pathway analyses were employed to identify significantly differentially expressed metabolites in melasma patients. Receiver operating characteristic curves were constructed, and correlation analyses were performed using the modified Melasma Area and Severity Index and oxidative stress levels. RESULTS:In contrast to healthy subjects, melasma patients showed significant alterations in 125 plasma metabolites, including amino acids, lipids, and carbohydrate-related metabolites. KEGG pathway analysis suggested that primary pathways associated with the development of melasma include tryptophan metabolism, as well as the biosynthesis of phenylalanine, tyrosine, and tryptophan. Importantly, based on receiver operating characteristic curves and correlation analyses, several metabolites were identified as robust biomarkers for melasma. CONCLUSION:Collectively, this study identified significant changes in plasma metabolites in melasma patients, providing new insights into the pathogenesis of melasma and opening novel therapeutic avenues.

Chemical peels are widely used to treat various skin diseases and photoaging. Their rational, effective, and safe use has become an important issue in clinical practice. To standardize the clinical use of chemical peels, a group of experts developed this consensus based on the latest research and discussions. This consensus provides specific guidance to clinicians on chemical peels with respect to their classification, peeling agents, mechanisms, indications, contraindications, peeling techniques, and complications.

Dear Editor, Responses to consolidation immune checkpoint inhibitor (ICI) in locally advanced non-small-cell lung cancer (LA-NSCLC) are heterogeneous, and current decision-making procedures have little accuracy.1 This prospective cohort study provided the first evidence for dynamic circulating tumour DNA (ctDNA) predicting failure patterns in LA-NSCLC patients receiving chemoradiotherapy (CRT), allowing the early identification of the potentially curable population with radical CRT and different therapeutic benefits from consolidation ICI. Exploring effective biomarkers to guide personalized consolidation immunotherapy, avoid overtreatment, and reduce the potential risk of immune-related toxicities is of clinical importance.1-3 In this prospective multicenter trial (NCT04014465), 105 patients with unresectable LA-NSCLC were assigned to CRT or CRT plus consolidation ICI cohorts, with balanced baseline characteristics (Figure 1A and Table S1). As expected, patients undergoing consolidation ICI had significantly improved overall and progression-free survival (PFS) (Figure 1B,C). All patients have collected blood samples at baseline, on-CRT (radiotherapy reached 40 Gy/4 weeks), post-CRT (1 month after CRT), and progressive timepoints, subjected to 486-gene next-generation sequencing to analyze longitudinal ctDNA. Detailed information about ctDNA assay techniques and study procedures is attached as the Supporting Information. No significant difference in ctDNA abundance across cohorts at any time point (Figure 1D). Notably, quantitative ctDNA could reflect tumour burden,4 since ctDNA levels significantly decreased with effective CRT but increased at disease progression, and baseline ctDNA positively correlated with the clinical stage (Figure 1E–G). We further explored the prognostic value of ctDNA at longitudinal landmark timepoints. Post-CRT detectable ctDNA, rather than baseline or on-CRT ctDNA, was associated with significantly worse survival (Figure 2A–C). In patients with detectable ctDNA post-CRT, 75% of non-progression patients received consolidation ICI, while 63.3% of non-progression patients used ICI in the undetectable population (Figure 2D,E). Survival analyses were confirmed in patients with detectable ctDNA post-CRT, those receiving consolidation ICI had significantly longer PFS than those without ICI, yet no significant difference in patients with ctDNA clearance (Figure 2F,G). According to post-CRT ctDNA minus baseline ctDNA levels, the dynamic change pattern of longitudinal ctDNA included decreased (n = 54), stably undetectable (n = 30), and increased (n = 19; Figure 2H). Strikingly, the majority of patients with increased ctDNA (73.7%) developed disease progression (Figure 2I). Next, we investigated the predictive effect of longitudinal ctDNA on first failure patterns, which were categorized as local-regional, distant, or both, as presented in Figure 3A. The primary failure pattern for patients with decreased ctDNA in the CRT cohort was distant metastasis (51.9%), and consolidation ICI significantly reduced the incidence of distant metastasis (18.5%; p = .019). However, in the stably undetectable ctDNA group, the incidence of local-regional failure (21.4% vs. 37.5%) and distant metastasis (28.6% vs. 31.3%) was both similar between patients with and without consolidation ICI (p = .592). In the increased ctDNA group, simultaneously local-regional and distant failure was the most predominant failure pattern (36.4%) for patients with CRT, and consolidation ICI brought a tendency (p = .583) of a reduced proportion of local-regional (18.2% vs. 12.5%), distant (27.3% vs. 25.0%), and simultaneously local-regional and distant (36.4% vs. 12.5%) failure. For patients with decreased ctDNA post-CRT, although consolidation ICI brought significant PFS benefit (p = .046; Figure 3B), a more obvious distant metastasis-free survival (DMFS) benefit was observed (p = .003; Figure 3C). In the increased ctDNA population (Figure 3D,E), patients with consolidation ICI had significantly improved PFS (p = .005) and DMFS (p = .020). In contrast, in the stably undetectable ctDNA group (Figure 3F,G), no significant difference in PFS (p = .427) or DMFS (p = .773) between patients with and without ICI. These data suggest that dynamic ctDNA could identify different failure patterns and therapeutic responses to ICI: 1) Decreased ctDNA dynamics predict a higher risk of distant metastasis but more DMFS benefit from ICI, presumably because effective radiotherapy could cause localized tumour cell death and accordingly decreased release of tumour-derived products into the peripheral blood, whereas it is difficult for local radiotherapy to completely eradicate disseminated ctDNA pre-existed in the circulation.5 Consolidation ICI as a potent systemic treatment would effectively reduce the risk of overt metastases and micrometastases, thereby bringing DMFS benefit to this patient subset; 2) Increased ctDNA, reflecting resistance to definitive CRT, is associated with a higher risk of distant and local-regional failure, and subsequent ICI improves DMFS as well as PFS. In the clinical setting, for patients with solitary lesions of suspected metastasis,6 dynamic ctDNA testings may contribute to differential diagnosis between primary and metastatic diseases, as increased ctDNA indicates the hematogenous spread of tumour cells in the peripheral circulation7 3) Stably undetectable ctDNA predicts excellent outcomes irrespective of consolidation ICI, suggesting the potentially curable population with CRT.2 Cox regression analysis demonstrated consolidation ICI, post-CRT ctDNA, and dynamic ctDNA changes were significant variables in predicting PFS (Table S2 and Figure S1). Lastly, we compared the prediction effects and clinical decision-making benefits of single-time ctDNA detection with longitudinal ctDNA dynamics. Time-dependent receiver operating characteristic curves indicated that post-CRT ctDNA was the optimal predictor of PFS (Figure 4A,B). In terms of dynamic ctDNA assessments, as shown in Figure 4C,D, patients with increased ctDNA had the significantly worst PFS and DMFS, and patients with stably undetectable ctDNA had the longest survival. Furthermore, decision curve analysis suggested the combined model integrating qualitative post-CRT ctDNA detection with quantitative ctDNA dynamics had superior usefulness in predicting PFS and DMFS, compared to individual features (Figure 4E,F). Based on this combinatorial model, patients with decreased ctDNA were further divided into two groups, and patients with post-CRT detectable/decreased ctDNA had significantly worse PFS and DMFS than those with undetectable/decreased ctDNA (Figure 4G-H), in both CRT and CRT + consolidation ICI cohorts (Figure S2). In conclusion, we determined that the multiparameter assay integrating qualitative with quantitative ctDNA metrics could improve patient risk stratification, consistent with previous findings.8-10 Moreover, we innovatively discovered dynamic ctDNA could predict failure patterns, potential curability with CRT, and different responses to consolidation ICI, thereby serving as a robust prognostic and predictive model with improved usefulness to facilitate ctDNA-guided treatment personalization. Our findings warrant independent validation in a larger-scale clinical cohort. The ongoing randomized, phase II trial (InTRist, NCT05888402) will further validate the predictive value of longitudinal ctDNA dynamics and provide high-quality evidence for translational application of ctDNA in LA-NSCLC. Yu Wang and Tao Zhang performed data analysis and interpretation, investigation, as well as manuscript drafting. Yin Yang, Jianyang Wang, Canjun Li, Xin Xu, Yuqi Wu, Ying Jiang and Jinghao Duan assisted with data acquisition and curation, project administration, and independent validation. Luhua Wang and Nan Bi supervised this study, provided resources, acquired funding, and critically revised the manuscript. All authors contributed to the study conceptualization and approved the final version. We thank the patients, caregivers, and their families for participating in this study. The authors declare no conflict of interest. This work was founded by the National Natural Sciences Foundation Key Program (No. 82173348), CAMS Innovation Fund for Medical Sciences (No. 2021-1-I2M-1-012), and the Special Research Fund for Central Universities, Peking Union Medical College (No. 3332023133). This study was approved by the institutional review board of the Chinese Academy of Medical Sciences (No. 19/098-1883). All patients provided written informed consent. 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Background . Becker’s nevus (BN) severely affects a patient’s appearance and can lead to depression, especially when it involves the face or neck. Currently, there is no effective treatment. Laser therapy has become popular, but its efficacy has not been confirmed. We evaluated the efficacy and safety of lasers in treating BN. Methods . This retrospective study involved 49 patients exposed to different laser treatments who completed at least one treatment session and follow-up. Results . The patients treated with the 755-nm alexandrite picosecond laser and Q-switched 694-nm ruby laser gained relatively good results: 3.07 ± 1.09 and 2.87 ± 1.14 on the five-point scale and 3.47 ± 0.73 and 3.40 ± 0.85 on the GAIS, respectively. However, the results of the 755-nm alexandrite picosecond laser with a diffractive focus lens array and the fractionated 1064-nm neodymium-doped: yttrium aluminum garnet picosecond laser were poor. Furthermore, there were marked differences between the number of treatment sessions and treatment effects, both for the five-point grading score for pigment clearance ( F = 15.246, p < 0.001) and GAIS ( F = 15.469, p < 0.001). Concerning different lasers and efficacy, there were no marked differences between the five-point grading scale and the GAIS ( p > 0.05). Conclusions . Although the efficacy of various lasers for BN is not satisfactory and there are no marked differences between picosecond and Q-switched lasers, they can help in selecting an appropriate laser for slight-to -moderate pigment removal. The 755-nm alexandrite picosecond laser is a new option, whereas nonablative fractional picosecond lasers for BN are not recommended. Increasing the number of treatment sessions can improve the curative effect slightly.

Progression occurs in approximately two-thirds of patients with locally advanced non-small cell lung cancer (LANSCLC) receiving chemoradiation and consolidation immunotherapy. Molecular indicators for outcome prediction are under development. A novel metric, the ratio of mean to max variant allele frequency (mmVAF), was derived from 431 pre-treatment tissue biopsies from The Cancer Genome Atlas and evaluated in serial circulating tumor DNA (ctDNA) from 70 LA-NSCLC patients receiving definitive radiotherapy/chemoradiotherapy (RT/CRT) with/without immunotherapy. High mmVAFs in pre-treatment tissue biopsies, indicating clonal predominant tumors (P < 0.01), were associated with inferior overall survival [OS, hazard ratio (HR): 1.48, 95 % confidence interval (CI): 1.11-1.98]. Similar associations of mmVAF with clonality (P < 0.01) and OS (HR: 2.24, 95 % CI: 0.71-7.08) were observed in pre-treatment ctDNA. At 1-month post-RT, ctDNA mmVAF-high patients receiving consolidation immunotherapy exhibited improved progression-free survival (PFS) compared to those who did not (HR: 0.14, 95 % CI: 0.03-0.67). From the baseline to week 4 of RT and/or 1-month post-RT, survival benefits from consolidation immunotherapy were exclusively observed in ctDNA mmVAF-increased patients (PFS, HR: 0.39, 95 % CI: 0.14-1.15), especially in terms of distant metastasis (HR: 0.11, 95 % CI: 0.01-0.95). In summary, our longitudinal data demonstrated the applicability of ctDNA-defined clonality for prognostic stratification and immunotherapy benefit prediction in LA-NSCLC.