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Ivonescimab is a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor, yielding promising clinical outcomes for patients with advanced non-small cell lung cancer in early-phase studies. We compared the efficacy and safety of ivonescimab with pembrolizumab in patients with programmed cell death ligand-1 (PD-L1)-positive advanced non-small cell lung cancer. HARMONi-2 is a randomised, double-blind, phase 3 trial across 55 hospitals in China. Eligible patients were aged 18 years or older and had locally advanced or metastatic PD-L1-positive non-small cell lung cancer without sensitising epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations and an Eastern Cooperative Oncology Group performance-status of 0 or 1. Patients were randomly assigned (1:1) to receive 20 mg/kg ivonescimab or 200 mg pembrolizumab intravenously every 3 weeks. Randomisation was stratified by histology, clinical stage, and PD-L1 expression. The primary endpoint was progression-free survival (PFS) assessed by a masked independent radiographic review committee per RECIST v1.1 in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05499390; recruitment is complete, with the trial ongoing and final analysis to be reported later. Between Nov 9, 2022, and Aug 26, 2023, 398 (45%) of 879 screened patients were randomly assigned to receive ivonescimab (n=198) or pembrolizumab (n=200). At the preplanned interim analysis, median PFS was significantly longer with ivonescimab than with pembrolizumab (11·1 vs 5·8 months; stratified hazard ratio [HR] 0·51 [95% CI 0·38–0·69]; one-sided p<0·0001). The PFS benefit of ivonescimab over pembrolizumab was broadly consistent within prespecified subgroups, including patients with PD-L1 tumour proportion score (TPS) 1–49% (HR 0·54 [95% CI 0·37–0·78]) and PD-L1 TPS of 50% of higher (HR 0·48 [0·29–0·79]). Grade 3 or higher treatment-related adverse events occurred in 58 (29%) patients with ivonescimab and 31 (16%) patients with pembrolizumab. Immune-related adverse events of grade 3 or higher were observed in 14 (7%) of 197 patients on ivonescimab and 16 (8%) of 199 patients on pembrolizumab. Ivonescimab demonstrated a manageable safety profile in patients with both squamous and non-squamous non-small cell lung cancer. In patients with squamous cell carcinoma, grade 3 or higher treatment-related adverse events were comparable between the two groups. Ivonescimab significantly improved PFS compared with pembrolizumab in previously untreated patients with advanced PD-L1 positive non-small cell lung cancer. Therefore, ivonescimab might represent another treatment option in the first-line setting for PD-L1-positive advanced non-small cell lung cancer. Akeso Biopharma.

Neoadjuvant chemoimmunotherapy has been successfully used in patients with resectable non-small-cell lung cancer (NSCLC). However, its application to potentially resectable IIIA/IIIB NSCLC remains controversial. This retrospective study aims to evaluate the efficacy and safety of neoadjuvant chemoimmunotherapy followed by conversion surgery in patients with potentially resectable stage III NSCLC, focusing on conversion rate and survival benefits. Patients with ‘potentially resectable’ stage IIIA/IIIB NSCLC who were deemed unsuitable for complete (R0) resection at initial diagnosis were retrospectively identified. After 2–4 cycles of treatment, all patients were reevaluated for surgical resectability. Data on patient characteristics, radiological and pathological responses, and survival outcomes were collected. In total, 148 patients were included in the final analysis. Upon the completion of neoadjuvant therapy, 105 patients were considered suitable for conversion surgery. Three patients refused surgery, and 102 patients ultimately underwent surgery, yielding a conversion rate of 70.9% and a resection rate of 68.9%. The rate of complete (R0) resection was 100%, with a major pathological response (MPR) of 64.7% and a pathologic complete response (pCR) of 41.2%. Postoperative complications were observed in nine patients (8.8%), and there was no surgery-related mortality within 30 days. The median progression-free survival (PFS) was 19.1 months in the non-surgery group, and the overall survival (OS) was not reached. In the 102 patients who underwent conversion surgery, both the median PFS and OS were not reached, accompanied by 2-year OS and PFS rates of 87.3% and 78.4%, respectively. Our findings showed that neoadjuvant chemoimmunotherapy expanded the opportunities for conversion surgery in potentially resectable cases. Subsequent conversion surgery is safe and has the potential for significant survival benefits.

Background No definite conclusion has yet to be reached for immunotherapy beyond progression(IBP) of first-line immunotherapy as the second-line treatment for advanced NSCLC patients with negative driver genes. Therefore a retrospective study was conducted to evaluate the efficacy of IBP in this population and investigated whether the cycles best response and progressive mode of first-line immunotherapy could affect the results. Patients and methods The clinical data of patients with advanced NSCLC whose response was evaluated as progressive disease (PD) after receiving a PD-1/PD-L1 inhibitors as first-line therapy were retrospectively collected and the patients were assigned to the IBP and non-IBP groups. The overall survival (OS), progression-free survival (PFS) were evaluated between the two groups. The survival effects of cycles best response and progressive mode of first-line immunotherapy were also evaluated. Results Between January 2019 and January 2022, a total of 121 patients was evaluated as PD after first-line immunotherapy in our institution; 53 (43.8%) patients were included in the IBP group and 68 (56.2%) patients were included in the non-IBP group. The OS and PFS were no significantly different between the two groups in whole population. Further analysis revealed the OS was prolonged with the prolongation of first-line medication cycle. The median OS was 15.4m (15.4 vs 10.8 p =0.047) 16.1m (16.1 vs 10.8 p =0.039), 16.3m (16.3 vs 10.9 p =0.029) for patients with ≥4, ≥6, ≥8 cycles in first-line immunotherapy, respectively. The advantages of OS and PFS were also seen in the subgroup of PR (best response) and oligo progression of first-line immunotherapy. Conclusions The clinical outcomes of IBP were similar to those of non-IBP in patients with PD after first-line immnuotherapy in advanced NSCLC. But more cycles, PR as best response and oligo progression in first-line was benefit.

Background. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease in China, caused by SFTS virus (SFTSV). Severe SFTS patients can quickly proceed to multiorgan dysfunction and death; however, underlying pathogenic mechanisms remain unclear. Methods. Serum samples from 15 fatal and 44 nonfatal SFTS cases were subjected to multiplex-microbead immunoassays to detect a broad spectrum of cytokines. The viral load and virus-specific IgG titers were also tested by real-time PCR and ELISA, respectively. Results. Cytokines IL-IRA, IL-6, IL-10, G-CSF, IP-10, and MCP-1 were elevated in SFTS patients and produced at robust levels in fatal cases. In contrast, cytokines PDGF-BB and RANTES decreased in SFTS patients. These cytokines reverted to normal ranges during the convalescent phase of SFTSV infection. Cytokines IL-1β, IL-8, MIP-1α, and MIP-1β showed a unique pattern of elevation in fatal cases but not in nonfatal cases. However, these cytokines increased in the convalescent phase of nonfatal SFTS cases. Our regression analysis revealed that the serum viral load correlated with these cytokines. Moreover, levels of these cytokines correlated with various clinical parameters and virus-specific IgG titers. Conclusion. The study demonstrates that SFTSV infection induces a cytokine storm with abnormally expressed cytokine profiles, which are associated with the disease severity.

Background RET fusions are rare oncogenic drivers in non-small cell lung cancer (NSCLC). While activating RET rearrangements are found in NSCLC patients harboring epidermal growth factor receptor ( EGFR ) genetic alterations at resistance to EGFR inhibitors, the extent to which co-occurring genomic alterations exist and how they might affect prognosis or therapy response is poorly understood. Methods Targeted next-generation sequencing (NGS) was used to assess 380 baseline patients with primary RET fusions and 71 EGFR -mutated NSCLC patients who acquired RET fusions after developing resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Results Primary RET fusions were more likely associated with females and younger age, with KIF5B being the predominant fusion partner. In baseline patients, both SMAD4 (5.3% vs. 0.0%, P  = 0.044) and MYC copy-number gain variants (6.9% vs. 0.0%, P  = 0.009) were more frequently co-mutated with KIF5B-RET than CCDC6-RET . By contrast, CDKN2A (11.3% vs. 2.4%, P  = 0.003) mutations were significantly enriched in CCDC6-RET -rearranged baseline patients. A significant increase in the proportion of CCDC6-RET was observed in acquired RET -rearranged patients (47.3% vs. 22.5%, P  < 0.001). The median progression-free survival (PFS) of patients harboring RB1 and TP53 double-mutations (5.5 vs. 10.0 months, P  = 0.020) or ERBB2 amplification (5.6 vs. 10.0 months, P  = 0.041) was significantly shorter than the wild-type counterparts. Moreover, we identified that RET fusions were more likely associated with acquired resistance (AR) to third-generation EGFR-TKIs than previous generations of EGFR-TKIs. Conclusions In conclusion, we depicted the mutational profiles of NSCLC patients who harbor RET fusions at baseline or after resistance to EGFR-TKIs. Furthermore, our results suggest that RET fusions mediate secondary resistance to third-generation EGFR-TKIs and might be associated with poor prognosis in patients with NSCLC.

Objective To investigate the role of consolidative thoracic radiation (TRT) in extensive-stage small-cell lung cancer (ES-SCLC) receiving first-line chemo-immunotherapy followed by immunotherapy maintenance. Patients and methods Outcomes of patients without disease progression after first-line chemotherapy were retrospectively reviewed (January 2020 to December 2021). Based on TRT or not, patients were allocated to TRT group or non-TRT group. Progression-free survival (PFS), overall survival (OS) and local-recurrence free survival (LRFS) were calculated by the Kaplan–Meier method and compared by log-rank test. Results Of 100 patients, 47 received TRT and 53 non-TRT. The median follow-up was 20.3 months. The median PFS and OS in TRT were 9.1 months and 21.8 months, versus 8.8 months ( p  = 0.93) and 24.3 months ( p  = 0.63), respectively, in non-TRT. The median LRFS time in TRT was not reached, but significantly longer than 10.8 months in non-TRT (HR = 0.27, p  < 0.01). Second-line chemotherapy significantly prolonged survival compared to that with chemo-free patients (mOS: 24.5 vs. 21.4 months, p  = 0.026). The subgroup analysis showed a trend of patients with brain metastases benefit from TRT (21.8 versus 13.7 months, HR 0.61, p  = 0.38) while liver metastases did not. Of 47 patients with TRT, only 10.6% of patients experienced grade 3 radiation-induced pneumonitis, while no grade 4 or 5 adverse events occurred. Conclusion Consolidative TRT in the period of immunotherapy maintenance followed first-line chemo-immunotherapy did not prolong OS and PFS but associated with improved LRFS in ES-SCLC.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with an increasing annual incidence rate. In this case report, we presented two patients infected with the SFTS virus, suggesting a potential direct transmission route from camels to humans through blood contact. Both patients developed symptoms after engaging in the slaughtering of one sick camel, while their family members living in the same environment or co-diners remained unaffected. Subsequent detection revealed a high viral load of SFTS virus, reaching 10 viral RNA copies/ml, in the sample obtained from the sick camel. Metagenomic sequencing did not identify any other pathogens. The SFTS virus was successfully isolated from both patient and camel samples. The complete nucleotide sequences obtained from the infected patients demonstrated a remarkable 100% similarity to those found in the camel, and genetic evolution analysis classified the virus as genotype A. Additionally, partial sequences of the SFTS virus were identified in ticks captured from the camel rearing environment, however, these sequences showed only 95.9% similarity to those found in camel and humans. Furthermore, immunoglobulin M and immunoglobulin G antibodies were detected in serum samples collected from the patient. Our findings provide evidence that camel may serve as a competent reservoir for transmitting the SFTS virus to humans. Further investigations into SFTS virus infections in large animals are warranted to understand their role in viral maintenance and transmission.

The first locally acquired case in the Chinese mainland was reported on May 31, 2023, lagging behind other countries. In this study, we aimed to examine the early clinical and epidemiological characteristics of the earliest cases of Mpox in Beijing, China. Additionally, we investigated the sequence and transmission patterns of the Mpox virus (MPXV). We analyzed 37 reported cases of Mpox in Beijing from May 31, 2023 to June 21, 2023. The age range of the subjects was 24-51 years. Thirty-six cases (97.3%) were identified in men who have sex with men (MSM), and 19 cases (51.4%) tested positive for the human immunodeficiency virus. Thirty-three cases were symptomatic, while four were asymptomatic. Skin lesions were observed in 32 cases (97.0%), fever in 26 (78.8%), and swollen lymph nodes in 17 (51.5%). Rash typically appeared in the genital or perianal area 1-3 days before fever onset, with a minimum incubation period of 2 days. For individuals with skin rashes, the skin lesion samples showed 100% positivity and low Ct values. There were high oropharyngeal swab (75.8%) and blood (84.6%) positivity rates. All MPXV strains belonged to the B.1.3 branch of the West African lineage. These strains carried 76-86 nucleotide substitutions compared with the reference human MPXV genome, and genetic diversity was observed. Our findings provide the first insights into the landscape of early transmission of Mpox in Beijing and help inform policy formulation in the Chinese mainland.

Can thoracic radiotherapy provide additional survival benefits for elderly patients with extensive-stage small cell lung cancer receiving chemotherapy combined with immunotherapy? A multicenter study Why was this study conducted? Extensive-stage small cell lung cancer is a highly malignant type of lung cancer, often presenting with distant metastases at diagnosis. While chemotherapy combined with immunotherapy has become the standard first-line regimen, the role of thoracic radiotherapy at this stage—particularly its value in elderly patients (⩾70 years)—remains unclear. What did the researchers do? This retrospective study analyzed patients aged ⩾70 years with extensive-stage small cell lung cancer receiving first-line chemotherapy plus immunotherapy from three cancer centers. Patients were divided into radiotherapy (RT) and non-RT groups based on whether they received consolidation thoracic RT, and overall survival (OS) and progression-free survival (PFS) were compared between groups. What did the researchers find? Results showed that patients receiving thoracic radiotherapy had a median overall survival prolonged by approximately 4 months (18.43 months vs 14.39 months, P = 0.008) and a median progression-free survival prolonged by approximately 2.3 months (10.56 months vs. 8.30 months, P = 0.034). Even after adjusting for time bias using stricter statistical methods, radiotherapy conferred a clear survival benefit. Additionally, patients with baseline liver metastases had poorer outcomes. Regarding safety, no significant increase in severe adverse events was observed among radiotherapy recipients. What do these findings mean? This study demonstrates that adding chest consolidation radiotherapy to first-line chemotherapy plus immunotherapy in elderly patients with extensive-stage small cell lung cancer who respond to the initial regimen further prolongs survival with manageable adverse effects. This finding provides new clinical guidance for the treatment of elderly lung cancer patients.

Introduction The PKHD1 (Polycystic Kidney and Hepatic Disease 1) gene is essential for producing fibrocystin or polyductin, which is crucial in various cellular functions. Mutations in PKHD1 have been found to be involved in the development and progression of colorectal cancer (CRC). Along with APC, TP53, and KRAS, PKHD1 is one of the most frequently mutated genes in CRC. PKHD1 expression is governed by the Wnt/PCP pathway, often dysregulated in CRC. Targeting this pathway, crucial for CRC progression, could unveil potential therapeutic strategies for colon cancer treatment. Methods This study examined an in‐house dataset of 3702 colon cancer samples, analyzing mutation landscapes, clinical features, tumor mutational burden (TMB), microsatellite instability (MSI), and chromosomal instability (CIN) score. For the survival analysis of PKHD1 patients, survival data of 436 colon adenocarcinoma samples were obtained from TCGA dataset. Additionally, 433 samples from TCGA with RNA‐seq data were used for the assessment of immune cell infiltration and gene set enrichment analysis. Results Polycystic Kidney and Hepatic Disease 1 mutation was detected in 424 colon cancer patients from our in‐house cohort and was associated with increased TMB, higher MSI, and lower CIN score. Importantly, within the TCGA dataset, PKHD1 mutations were identified as an independent prognostic factor, not merely correlated with established prognostic biomarkers, and were associated with poorer overall survival outcomes. In terms of immune response, these mutations correlated with increased enrichment scores for 12 immune cell types, including B cell plasma, macrophages, and naive CD4+ T cells. Additionally, interferon alpha and interferon‐gamma gene sets were significantly down‐regulated in patients with PKHD1 mutations (FDA q‐value < 0.1). Conclusions Overall, these findings suggest that PKHD1 may be a potential biomarker for the prognosis of colon cancer and provide some insight for personalized immunotherapy. In this study of 3702 samples, mutations in the PKHD1 gene, frequently observed in colorectal cancer (CRC), were correlated with increased tumor mutational burden and microsatellite instability, but decreased chromosomal instability. These mutations also serve as an independent prognostic biomarker, associated with poorer overall survival outcomes in TCGA COAD patients. These critical findings reinforce the potential of PKHD1 as a pivotal biomarker for colon cancer prognosis and may facilitate the emergence of personalized immunotherapy strategies.