Dual-source dual-energy CT and deep learning for equivocal lymph nodes on CT images for thyroid cancer.

OBJECTIVES: This study investigated the diagnostic performance of dual-energy computed tomography (CT) and deep learning for the preoperative classification of equivocal lymph nodes (LNs) on CT images in thyroid cancer patients. METHODS: In this prospective study, from October 2020 to March 2021, 375 patients with thyroid disease underwent thin-section dual-energy thyroid CT at a small field of view (FOV) and thyroid surgery. The data of 183 patients with 281 LNs were analyzed. The targeted LNs were negative or equivocal on small FOV CT images. Six deep-learning models were used to classify the LNs on conventional CT images. The performance of all models was compared with pathology reports. RESULTS: Of the 281 LNs, 65.5% had a short diameter of less than 4 mm. Multiple quantitative dual-energy CT parameters significantly differed between benign and malignant LNs. Multivariable logistic regression analyses showed that the best combination of parameters had an area under the curve (AUC) of 0.857, with excellent consistency and discrimination, and its diagnostic accuracy and sensitivity were 74.4% and 84.2%, respectively (p < 0.001). The visual geometry group 16 (VGG16) based model achieved the best accuracy (86%) and sensitivity (88%) in differentiating between benign and malignant LNs, with an AUC of 0.89. CONCLUSIONS: The VGG16 model based on small FOV CT images showed better diagnostic accuracy and sensitivity than the spectral parameter model. Our study presents a noninvasive and convenient imaging biomarker to predict malignant LNs without suspicious CT features in thyroid cancer patients. CLINICAL RELEVANCE STATEMENT: Our study presents a deep-learning-based model to predict malignant lymph nodes in thyroid cancer without suspicious features on conventional CT images, which shows better diagnostic accuracy and sensitivity than the regression model based on spectral parameters. KEY POINTS: Many cervical lymph nodes (LNs) do not express suspicious features on conventional computed tomography (CT). Dual-energy CT parameters can distinguish between benign and malignant LNs. Visual geometry group 16 model shows superior diagnostic accuracy and sensitivity for malignant LNs.

Phase Ib study of anlotinib in combination with anti-PD-L1 antibody (TQB2450) in patients with advanced acral melanoma.

BACKGROUND: Acral melanoma, the most common subtype of melanoma in Asians, is often diagnosed at an advanced stage and responds poorly to current programmed cell death protein 1 (PD-1) inhibitors. OBJECTIVES: To evaluate the safety and efficacy of TQB2450 and anlotinib in patients with advanced acral melanoma in a phase Ib study (NCT03991975). METHODS: Patients received TQB2450 (1200 mg every 3 weeks) and anlotinib (10 mg or 12 mg once daily, 2-week on/1-week off) in the dose-escalation and dose-expansion phases. The primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and objective response rate (ORR). RESULTS: Nineteen patients were enrolled between June 2019 and June 2022. The majority of patients (16 of 19 patients) received anlotinib and TQB2450 as first-line treatment. No DLTs were observed, and MTD was not reached. Eighteen (94.7%) out of 19 patients experienced treatment-related adverse events (TRAEs), but most were grade 1 or 2. Grade 3 or greater TRAEs occurred in seven patients (36.8%). The ORR was 26.3% (two complete responses and three partial responses). The disease control rate was 73.7%. The median duration of response was 30.3 months [95% confidence interval (CI): 5.8-NA]. The median progression-free survival (PFS) was 5.5 months (95% CI: 2.8-NA), and median overall survival was 20.3 months (95% CI: 14.8-NA). Whole-exome sequencing suggested that acquired drug resistance might be attributed to activation of the MAPK signalling pathway and transformation to an immunosuppressive tumour environment. CONCLUSIONS: TQB2450 combined with anlotinib showed favourable tolerance and promising anti-tumour activity with a prolonged PFS compared with anti-PD1 monotherapy in patients with advanced acral melanoma.

Novel Topological Motifs and Superconductivity in Li-Cs System.

In this work, we determined the phase diagram and electronic properties of the Li-Cs system by using an evolutionary crystal structure prediction algorithm coupled with first-principles calculations. We found that Li-rich compounds are more easily formed in a wide range of pressures, while the only predicted Cs-rich compound LiCs3 is thermodynamically stable at pressures above 359 GPa. A topological analysis of crystal structures concludes that both Li6Cs and Li14Cs have a unique topology that has not been reported in existing intermetallics. Of particular interest is the fact that four Li-rich compounds (Li14Cs, Li8Cs, Li7Cs, and Li6Cs) are found to be superconductors with a high critical temperature (∼54 K for Li8Cs at 380 GPa), due to their peculiar structural topologies and notable charge transfer from Li to Cs atoms. Our results not only extend an in-depth understanding of the high-pressure behavior of intermetallic compounds but also provide a new route to design new superconductors.

An Evidence-Based Staging System for Mucosal Melanoma: A Proposal.

BACKGROUND: There is no widely employed staging system for mucosal melanoma (MuM) that incorporates all anatomic sites. We hypothesized that MuM patients arising from different anatomical sites could be staged using a common approach. METHODS: A prospective database contained 1814 MuM patients with a median follow-up of 5.14 years was employed. Overall survival (OS) was calculated from the time of pathological diagnosis to the date of death from any cause. Multivariate analyses of prognostic variables and OS were performed using the Cox proportional hazard model. RESULTS: For localized MuM, the most significant median OS differences were primary tumors invading submucosa (i.e., T1) versus deeper (i.e., T2/T3/T4): 4.3 versus 3.4, 3.1, and 2.9 years, respectively (p < 0.001). For patients only with regional node metastasis at presentation, the most significant were: 1 versus ≥ 2 regional nodes (N1 vs. N2, 2.5 vs. 2.1 years, p < 0.001). For patients with distant metastasis at presentation, the median OS was 1.5, 1.2, 0.8, and 0.6 years respectively for skin/subcutaneous tissue/distant lymph nodes (M1a), lung metastasis (M1b), all other visceral sites except brain (M1c), and brain (M1d) (p < 0.001). Based on these results, the staging system for MuM is proposed: (1) Stage I: T1N0M0 (median OS, 4.3 years); (2) Stage II: T2-4N0M0 (3.1 years); (3) Stage IIIA: T1-4N1M0 (2.5 years), Stage IIIB: T1-4N2M0 (2.1 years); (4) Stage IV: TanyNanyM1 (0.9 years) (p < 0.001). CONCLUSIONS: A single, unified, staging system for mucosal melanoma inclusive of all anatomical primary tumor sites can harmonize staging of MuM and the design of clinical trials.

Safety, activity, and pharmacokinetics of camrelizumab in advanced Asian melanoma patients: a phase I study.

BACKGROUND: Anti-programmed cell death receptor-1 (PD-1) monotherapy is the standard treatment for metastatic melanoma in current. Camrelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody whose safety and efficacy have not been reported in advanced Asian melanoma patients. METHODS: This phase I study investigated the safety, activity, and pharmacokinetics of camrelizumab in Chinese patients with advanced melanoma. The study included two phases, the dose-escalation phase ("3 + 3" design at 60 mg, 200 mg, and 400 mg) and the dose-expansion phase. RESULTS: No dose-limiting toxicities were recorded over the dose-escalation phase, and the maximum tolerated dose was not reached. The most common treatment-related adverse events (TRAEs) in 36 patients were reactive cutaneous capillary endothelial proliferation, followed by rash, fever, hypothyroidism, hyperthyroidism, vitiligo, and fatigue. Five grade 3 or above TRAEs were reported (13.9%), including two cases of elevated γ-glutamyltransferase and blood triglycerides without clinical symptoms, and one liver injury recovered after symptomatic treatment. The confirmed overall response rate was 13.9% (95%CI: 4.7, 29.5%) and disease control rate was 38.9% (95%CI: 23.1, 56.5%). The median progression-free survival was 1.8 months (95%CI: 1.1, 2.4) and the median overall survival was 11.1 months (95%CI: 6.8, 15.4). CONCLUSIONS: Camrelizumab had acceptable tolerability and similar anti-tumor activity compared with other anti-PD-1 antibodies in advanced Asian melanoma patients. TRIAL REGISTRATION: ClinicalTrials.gov identification: NCT02738489. Registered on 14/04/2016, prospectively registered.

Prognostic value of ulceration varies across Breslow thicknesses and clinical stages in acral melanoma: a retrospective study.

BACKGROUND: Ulceration is regarded as an adverse prognostic factor and is used together with tumour thickness to subcategorize patients with cutaneous melanoma. However, the prognostic impact of ulceration in acral melanoma (AM) is controversial. OBJECTIVES: To assess the prognostic impact of ulceration in AM and the variability across different Breslow thicknesses and clinical stages. METHODS: A multicentre retrospective study of patients diagnosed with AM between January 2000 and December 2017. Differences in melanoma-specific survival (MSS) between patients with and without ulceration were assessed using the multivariable Cox proportional hazards model and log-rank test. RESULTS: Among 1053 enrolled patients, 62.6% had ulceration. After a median follow-up of 61 months, patients with ulceration had a lower median MSS than those without: 66.1 months, 95% confidence interval (CI) 60.0-86.0 vs. not reached; hazard ratio 1.41, 95% CI 1.09-1.82; P = 0.012. Among patients with thin (≤ 1 mm) melanoma, the survival curves of patients with vs. without ulceration clearly separated over time (P < 0.001). No association between ulceration and MSS was observed for melanomas of thickness > 1 mm (subgroups of T2, T3 and T4; all P-values > 0.05) or patients with stage III disease (hazard ratio 1.09, 95% CI 0.71-1.68, P = 0.39). CONCLUSIONS: Ulceration is an independent negative prognostic factor for patients with AM, but the impact varies across Breslow thicknesses and clinical stages. Ulceration has a significant effect on prognosis for patients with thin (≤ 1 mm) melanoma, but there was no association between ulceration and survival in intermediate/thick AM or stage III AM. What is already known about this topic? Ulceration status is used together with Breslow tumour thickness to subcategorize patients into different stages according to the America Joint Committee on Cancer melanoma staging system. As one distinctive subtype of cutaneous melanoma, acral melanoma (AM) is characterized by poor survival outcomes due to delayed diagnosis and a high prevalence of negative prognostic and genetic features. The prognostic impact of ulceration in AM is still controversial. What does this study add? This was the first large-scale study to assess the prognostic and staging values of ulceration in patients with AM. Ulceration has a significant effect on prognosis for patients with thin (≤1 mm) melanoma, but no association between ulceration and survival was found in intermediate/thick or stage III AM. These findings should be considered when using ulceration-based staging systems.

Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study.

BACKGROUND: Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African. OBJECTIVES: To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups. METHODS: Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal. RESULTS: In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50-57% vs. 20%, 95% CI 13-28%; adjusted P < 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7-20·3 vs. 5·4 months, 95% CI 4·5-7·0; adjusted P < 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48-6·81; adjusted P < 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46-0·74; adjusted P < 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes. CONCLUSIONS: Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.

Prognostic impact of Breslow thickness in acral melanoma: A retrospective analysis.

BACKGROUND: Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited. OBJECTIVE: The objective of the study was to determine the prognostic impact of Breslow thickness in AM. METHODS: This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4 mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression. RESULTS: A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The median follow-up time was 60.1 months. The median MSS in patients with T1-T4 disease was not reached, 111.0, 92.8, and 67.1 months, respectively. MSS differed significantly among cN0 patients with T1-T3 AM (log-rank P = .004, .012, <0.001 for T1 vs T2, T2 vs T3, and T1 vs T3, respectively); however, there was no significant difference between T3 and T4 AM (hazard ratio = 0.82, 95% CI, 0.62-1.09). Six-subgroup analyses confirmed that survival outcomes were similar between different subgroups with tumor thickness >2 mm. LIMITATIONS: The limitations were retrospective design and some missing variables. CONCLUSIONS: There was no association between tumor thickness and survival in AM patients with a Breslow thickness >2 mm.

The Clinicopathological and Survival Profiles Comparison Across Primary Sites in Acral Melanoma.

BACKGROUND: The clinicopathological and survival profiles across primary sites in acral melanoma (AM) are still controversial and unclear. METHODS: This is a multi-center retrospective study. Clinicopathological data of AM patients diagnosed between 1 January 2000 and 31 December 2017 from 6 large tertiary hospitals in China were extracted. Chi square tests were used to compare basic characteristics between primary sites of sole, palm and nail bed. Melanoma-specific survival (MSS) differences based on primary sites were compared by log-rank tests and multivariate Cox regressions were used to identify prognostic factors for MSS. RESULTS: In total, 1157 AM patients were included. The sole group had a more advanced initial stage, deeper Breslow thickness, higher recurrence rate and distant metastases risk (all P < 0.05). The proportion of age < 65 years and ulceration were statistically lower in nail bed and palm groups, respectively. A total of 294 patients underwent sentinel lymph node biopsy and rates of positive SLN status had no statistical difference across primary sites. Among 701 patients with genetic profiles, the mutational frequency of BRAF, C-KIT, and PDGFRA were similar except for NRAS (higher in sole group, P = 0.0102). The median MSS of sole, nail bed and palm patients were 65.0 months, 112.0 months, and not reached, respectively (log-rank P = 0.0053). In multivariate analyses, primary site, initial stage, ulceration and recurrence were the prognostic factors for MSS in overall population, but the statistical significance varied over primary sites. CONCLUSIONS: Substantial clinicopathological and survival heterogeneities exist across different primary sites in the AM population. Sole melanoma has worse prognosis compared with palm and nail bed subtypes.

Isolation, Characterization, and Bioinformatic Analyses of Lytic Salmonella Enteritidis Phages and Tests of Their Antibacterial Activity in Food.

Salmonella Enteritidis remains a major threat for food safety. To take efforts to develop phage-based biocontrol for S. Enteritidis contamination in food, in this study, the phages against S. Enteritidis were isolated from sewage samples, characterized by host range assays, DNA restriction enzyme pattern analyses, and transmission electron microscope observations, and tested for antibacterial activity in food; some potent phages were further characterized by bioinformatic analyses. Results showed that based on the plaque quality and host range, seven lytic phages targeting S. Enteritidis were selected, considered as seven distinct phages through DNA physical maps, and classified as Myoviridae or Siphoviridae family by morphologic observations; the combined use of such seven strain phages as a "food additive" could succeed in controlling the artificial S. Enteritidis contamination in the different physical forms of food at a range of temperatures; by bioinformatic analyses, both selected phage BPS11Q3 and BPS15Q2 seemed to be newfound obligate lytic phage strains with no indications for any potentially harmful genes in their genomes. In conclusion, our results showed a potential of isolated phages as food additives for controlling S. Enteritidis contamination in some salmonellosis outbreak-associated food vehicles, and there could be minimized potential risk associated with using BPS11Q3 and BPS15Q2 in food.

Clinicopathological features, current status, and progress of primary central nervous system melanoma diagnosis and treatment.

Primary central nervous system (CNS) melanoma is an extremely rare condition, with an incidence rate of 0.01 per 100,000 individuals per year. Despite its rarity, the etiology and pathogenesis of this disease are not yet fully understood. Primary CNS melanoma exhibits highly aggressive biological behavior and presents clinically in a distinct manner from other types of melanomas. It can develop at any age, predominantly affecting the meninges as the primary site, with clinical symptoms varying depending on the neoplasm's location. Due to the lack of specificity in its presentation and the challenging nature of imaging diagnosis, distinguishing primary CNS melanoma from other CNS diseases. The combination of challenges in early detection, heightened tumor aggressiveness, and the obscured location of its origin contribute to an unfavorable prognostic outcome. Furthermore, there has been currently no consensus on a standardized treatment approach for primary CNS melanoma. Despite recent advancements in targeted therapy and immunotherapy for CNS melanoma, patients with primary CNS melanoma have limited treatment options due to their inadequate response to these therapies. Here, we provided a comprehensive summary of the epidemiology, clinical features, molecular pathological manifestations, and available diagnostic and therapeutic approaches of primary CNS melanoma. Additionally, we proposed potential therapeutic strategies for it.

Different microbial functional traits drive bulk and rhizosphere soil phosphorus mobilization in an alpine meadow after nitrogen input.

Enhanced nitrogen (N) input is expected to influence the soil phosphorus (P) cycling through biotic and abiotic factors. Among these factors, soil microorganisms play a vital role in regulating soil P availability. However, the divergent contribution of functional microorganisms to soil P availability in the rhizosphere and bulk soil under N addition remains unclear. We conducted an N addition experiment with four N input rates (0, 5, 10, and 15 g N m-2 year-1) in an alpine meadow over three years. Metagenomics was employed to investigate the functional microbial traits in the rhizosphere and bulk soil. We showed that N addition had positive effects on microbial functional traits related to P-cycling in the bulk and rhizosphere soil. Specifically, high N addition significantly increased the abundance of most microbial genes in the bulk soil but only enhanced the abundance of five genes in the rhizosphere soil. The soil compartment, rather than the N addition treatment, was the dominant factor explaining the changes in the diversity and network of functional microorganisms. Furthermore, the abundance of functional microbial genes had a profound effect on soil available P, particularly in bulk soil P availability driven by the ppa and ppx genes, as well as rhizosphere soil P availability driven by the ugpE gene. Our results highlight that N addition stimulates the microbial potential for soil P mobilization in alpine meadows. Distinct microbial genes play vital roles in soil P availability in bulk and rhizosphere soil respectively. This indicates the necessity for models to further our knowledge of P mobilization processes from the bulk soil to the rhizosphere soil, allowing for more precise predictions of the effects of N enrichment on soil P cycling.

Effects of interaction of multiple large-scale atmospheric circulations on precipitation dynamics in China.

Different scenarios of precipitation, that lead to such phenomena as droughts and floods are influenced by concurrent multiple teleconnection factors. However, the multivariate relationship between precipitation indices and teleconnection factors, including large-scale atmospheric circulations and sea surface temperature signals in China, is rarely explored. Understanding this relationship is crucial for drought early warning systems and effective response strategies. In this study, we comprehensively investigated the combined effects of multiple large-scale atmospheric circulation patterns on precipitation changes in China. Specifically, Pearson correlation analysis and Partial Wavelet Coherence (PWC) were used to identify the primary teleconnection factors influencing precipitation dynamics. Furthermore, we used the cross-wavelet method to elucidate the temporal lag and periodic relationships between multiple teleconnection factors and their interactions. Finally, the multiple wavelet coherence analysis method was used to identify the dominant two-factor and three-factor combinations shaping precipitation dynamics. This analysis facilitated the quantification and determination of interaction types and influencing pathways of teleconnection factors on precipitation dynamics, respectively. The results showed that: (1) the Atlantic Multidecadal Oscillation (AMO), EI Niño-Southern Oscillation (ENSO), East Asia Summer Monsoon (EASM), and Indian Ocean Dipole (IOD) were dominant teleconnection factors influencing Standardized Precipitation Index (SPI) dynamics; (2) significant correlation and leading or lagging relationships at different timescales generally existed for various teleconnection factors, where AMO was mainly leading the other factors with positive correlation, while ENSO and Southern Oscillation (SO) were mainly lagging behind other factors with prolonged correlations; and (3) the interactions between teleconnection factors were quantified into three types: enhancing, independent and offsetting effects. Specifically, the enhancing effect of two-factor combinations was stronger than the offsetting effect, where AMO + NAO (North Atlantic Oscillation) and AMO + AO (Atlantic Oscillation) had a larger distribution area in southern China. Conversely, the offsetting effect of three-factor combinations was more significant than that of the two-factor combinations, which was mainly distributed in northeast and northwest regions of China. This study sheds new light on the mechanisms of modulation and pathways of influencing various large-scale factors on seasonal precipitation dynamics.

IBI310 (anti-CTLA-4 antibody) monotherapy or in combination with sintilimab in advanced melanoma or urothelial carcinoma.

IBI310 is a recombinant fully human IgG1 antibody against cytotoxic T lymphocyte antigen 4. This study was conducted to evaluate IBI310 monotherapy or combination therapy with sintilimab in the patients with advanced melanoma or urothelial carcinoma (UC). Patients in phase 1a received IBI310 at 0.3/1/2/3 mg/kg intravenously (IV) every 3 weeks (Q3W) following the accelerated titration and 3 + 3 escalation design. Patients in phase 1b received IBI310 (1/2/3 mg/kg IV, Q3W) plus sintilimab (200 mg IV, Q3W) for four cycles, followed by sintilimab maintenance therapy. The phase 1b expansion of IBI310 plus sintilimab was performed in patients with advanced melanoma or UC. Overall, 53 patients were enrolled, including 10 patients with melanoma in phase 1a, 34 with melanoma, and 9 with UC in phase 1b. Overall, 94.3% of patients (50/53) experienced at least one treatment-related adverse event (TRAE) with most being grade 1-2; 26.4% of patients (14/53) experienced grade 3 or higher TRAEs. In phase 1a, the disease control rate (DCR) was 50.0% (95% confidence interval [CI], 18.7%-81.3%). In phase 1b, the objective response rate (ORR) and DCR were 17.6% (95% CI, 6.8%-34.5%) and 44.1% (95% CI, 27.2%-62.1%), respectively, for melanoma, and were 22.2% (95% CI, 2.8%-60.0%) and 66.7% (95% CI, 29.9%-92.5%), respectively, for UC. IBI310 monotherapy or combination therapy with sintilimab was well tolerated with favorable antitumor activity across patients with advanced melanoma and UC.

Natural history of bone-only metastasis in renal cell carcinoma.

BACKGROUND: Bone metastasis (BM) is considered a poor prognostic factor of renal cell carcinoma (RCC). Confusion exists regarding how to deal with RCC patients with bone-only metastasis. PATIENTS AND METHODS: The clinical data of consecutive RCC patients with bone-only metastasis at Peking University Cancer Hospital between 2006 and 2018 were retrospectively collected and analyzed. RESULTS: Fifty-four eligible patients were screened from an RCC database of 1,878 metastatic patients. After a median follow-up of 43.6 m, 61.1% of the patients were presented with progression of prior BM or new BM. The progression-free survival (PFS) and overall survival (OS) was 16.2 m (95%CI: 11.4-21.0) and 65.2 m, respectively. For the 30 patients with oligo-metastasis (≤3 loci) and 24 ones with multiple-metastasis (>3 loci), the median OS was not reached and 42.0m (95%CI: 12.7-71.2) with statistical difference (P < 0.001). In the oligo-metastasis group, the median PFS of the 15 patients treated with local therapy and of the 13 patients treated with systemic therapy was 14.2 m (95%CI: 5.3-23.3) and 18.0 m (95%CI:15.4-20.6), respectively. In the multiple-metastasis group, the median PFS and OS of the 18 patients treated with systemic therapy was 16.6 m (95%CI: 7.5-25.7) and 63.9 m (95%CI: 21.8-106.0), respectively. Univariate analysis and multivariate analysis showed that the number of metastatic sites (oligo/multiple) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score, RCC pathological subtype were significantly associated with prognosis (P < 0.05). CONCLUSION: RCC patients with bone-only metastases have a favorable prognosis. The number of metastatic sites, IMDC, RCC pathological subtype could serve as survival predictors, which might provide clue of treatment modality.

Soil properties and fungal community jointly explain N2O emissions following N and P enrichment in an alpine meadow.

Nutrient enrichment, such as nitrogen (N) and phosphorus (P), typically affects nitrous oxide (N2O) emissions in terrestrial ecosystems, predominantly via microbial nitrification and denitrification processes in the soil. However, the specific impact of soil property and microbial community alterations under N and P enrichment on grassland N2O emissions remains unclear. To address this, a field experiment was conducted in an alpine meadow of the northeastern Qinghai-Tibetan Plateau. This study aimed to unravel the mechanisms underlying N and P enrichment effects on N2O emissions by monitoring N2O fluxes, along with analyzing associated microbial communities and soil physicochemical properties. We observed that N enrichment individually or in combination with P enrichment, escalated N2O emissions. P enrichment dampened the stimulatory effect of N enrichment on N2O emissions, indicative of an antagonistic effect. Structural equation modeling (SEM) revealed that N enrichment enhanced N2O emissions through alterations in fungal community composition and key soil physicochemical properties such as pH, ammonium nitrogen (NH4+-N), available phosphorus (AP), microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN)). Notably, our findings demonstrated that N2O emissions were significantly more influenced by fungal activities, particularly genera like Fusarium, rather than bacterial processes in response to N enrichment. Overall, the study highlights that N enrichment intensifies the role of fungal attributes and soil properties in driving N2O emissions. In contrast, P enrichment exhibited a non-significant effect on N2O emissions, which highlights the critical role of the fungal community in N2O emissions responses to nutrient enrichments in alpine grassland ecosystems.

Comparative Epigenetic Profiling Reveals Distinct Features of Mucosal Melanomas Associated with Immune Cell Infiltration and Their Clinical Implications.

Mucosal melanoma exhibits limited responsiveness to anti-PD-1 therapy. However, a subgroup of mucosal melanomas, particularly those situated at specific anatomic sites like primary malignant melanoma of the esophagus (PMME), display remarkable sensitivity to anti-PD-1 treatment. The underlying mechanisms driving this superior response and the DNA methylation patterns in mucosal melanoma have not been thoroughly investigated. We collected tumor samples from 50 patients with mucosal melanoma, including 31 PMME and 19 non-esophageal mucosal melanoma (NEMM). Targeted bisulfite sequencing was conducted to characterize the DNA methylation landscape of mucosal melanoma and explore the epigenetic profiling differences between PMME and NEMM. Bulk RNA sequencing and multiplex immunofluorescence staining were performed to confirm the impact of methylation on gene expression and immune microenvironment. Our analysis revealed distinct epigenetic signatures that distinguish mucosal melanomas of different origins. Notably, PMME exhibited distinct epigenetic profiling characterized by a global hypermethylation alteration compared with NEMM. The prognostic model based on the methylation scores of a 7-DMR panel could effectively predict the overall survival of patients with PMME and potentially serve as a prognostic factor. PMME displayed a substantial enrichment of immune-activating cells in contrast to NEMM. Furthermore, we observed hypermethylation of the TERT promoter in PMME, which correlated with heightened CD8+ T-cell infiltration, and patients with hypermethylated TERT were likely to have improved responses to immunotherapy. Our results indicated that PMME shows a distinct methylation landscape compared with NEMM, and the epigenetic status of TERT might be used to estimate prognosis and direct anti-PD-1 treatment for mucosal melanoma. SIGNIFICANCE: This study investigated the intricate epigenetic factor of mucosal melanomas contributed to the differential immune checkpoint inhibitor response, and found that PMME exhibited a global hypermethylation pattern and lower gene expression in comparison to NEMM. TERT hypermethylation may contribute to the favorable responses observed in patients with mucosal melanoma undergoing immunotherapy.

Pembrolizumab Versus High-Dose Interferon-α2b as Adjuvant Therapy for Pediatric Melanoma: A Retrospective Study.

INTRODUCTION: Pembrolizumab is well-tolerated in pediatric patients with advanced tumors, consistent with results in adults. However, information on the safety and efficacy of adjuvant pembrolizumab in children and adolescents with melanoma is lacking. OBJECTIVES: To compare pembrolizumab versus high-dose interferon-α2b (HDI) as adjuvant therapy in pediatric patients with melanoma. METHODS: We performed a retrospective study of pediatric patients diagnosed with melanoma between January 2008 and April 2022. Relapse-free survival (RFS) and the 1-year RFS rate were compared between patients receiving adjuvant pembrolizumab or HDI. RESULTS: Seventy-five pediatric patients with melanoma were screened from a database of 6,013 patients. Twenty-four patients were finally enrolled, of whom 9 received pembrolizumab and 15 received HDI as adjuvant therapy. By August 31, 2022, the median follow-up times were 23.6 months and 98.7 months in the pembrolizumab and HDI groups, respectively. There was no significant difference in median RFS between two groups (not reached versus 38.7 months, P = 0.11). The median overall survival was not reached in either group. The 1-year RFS rates were 88.9% and 66.7% in the pembrolizumab and HDI groups, respectively. All adverse events in the pembrolizumab group were grade 1 or 2, but grade 3-5 adverse events occurred in two (13%) patients receiving HDI. CONCLUSIONS: RFS was similar in pediatric patients with melanoma receiving adjuvant pembrolizumab or HDI, but pembrolizumab was associated with a reduced risk of recurrence and a more favorable safety profile. However, due to the small sample size and differences in follow-up time, larger and prospective studies are still warranted to explore better adjuvant therapies for pediatric melanoma.

A phase II study of efficacy and safety of the MEK inhibitor tunlametinib in patients with advanced NRAS-mutant melanoma.

BACKGROUND: NRAS-mutant melanoma is an aggressive subtype with poor prognosis; however, there is no approved targeted therapy to date worldwide. METHODS: We conducted a multicenter, single-arm, phase II, pivotal registrational study that evaluated the efficacy and safety of the MEK inhibitor tunlametinib in patients with unresectable, stage III/IV, NRAS-mutant melanoma (NCT05217303). The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response(DOR), overall survival (OS) and safety. FINDINGS: Between November 2, 2020 and February 11, 2022, a total of 100 patients were enrolled. All (n = 100) patients received at least one dose of tunlametinib (safety analysis set [SAS]) and 95 had central laboratory-confirmed NRAS mutations (full analysis set [FAS]). In the FAS, NRAS mutations were observed at Q61 (78.9%), G12 (15.8%) and G13 (5.3%). The IRRC-assessed ORR was 35.8%, with a median DOR of 6.1 months. The median PFS was 4.2 months, DCR was 72.6% and median OS was 13.7 months. Subgroup analysis showed that in patients who had previously received immunotherapy, the ORR was 40.6%. No treatment-related deaths occurred. INTERPRETATION: Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.