Background: The global burden of lung cancer (LC) is increasing. Quantitative projections of the future LC burden in different world regions could help optimize the allocation of resources and provide a benchmark for evaluating LC prevention and control interventions. Objective: We aimed to predict the future incidence of LC in 40 countries by 2035, with an emphasis on country- and sex-specific disparities. Methods: Data on LC incidence from 1978 to 2012 were extracted from 126 cancer registries of 40 countries in Cancer Incidence in Five Continents Volumes V-XI and used for the projection. Age-standardized incidence rates (ASRs) per 100,000 person-years and the number of incident cases were predicted through 2035, using the NORDPRED age-period-cohort model. Results: Global ASRs of the 40 studied countries were predicted to decrease by 23% (8.2/35.8) among males, from 35.8 per 100,000 person-years in 2010 to 27.6 in 2035, and increase by 2% (0.3/16.8) among females, from 16.8 in 2010 to 17.1 in 2035. The ASRs of LC among females are projected to continue increasing dramatically in most countries by 2035, with peaks after the 2020s in most European, Eastern Asian, and Oceanian countries, whereas the ASRs among males will continue to decline in almost all countries. The ASRs among females are predicted to almost reach those among males in Ireland, Norway, the United Kingdom, the Netherlands, Canada, the United States, and New Zealand in 2025 and in Slovenia in 2035 and even surpass those among males in Denmark in 2020 and in Brazil and Colombia in 2025. In 2035, the highest ASRs are projected to occur among males in Belarus (49.3) and among females in Denmark (36.8). The number of new cases in 40 countries is predicted to increase by 65.32% (858,000/1,314,000), from 1.31 million in 2010 to 2.17 million in 2035. China will have the largest number of new cases. Conclusions: LC incidence is expected to continue to increase through 2035 in most countries, making LC a major public health challenge worldwide. The ongoing transition in the epidemiology of LC highlights the need for resource redistribution and improved LC control measures to reduce future LC burden worldwide.

Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment. We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells. The CLL-1 CAR-T cells specifically lysed CLL-1+ cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1+ myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression. CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.

Notch signaling represents a key mechanism mediating cancer metastasis and stemness. To understand how Notch signaling is overactivated to couple tumor metastasis and self-renewal in NSCLC cells, we performed the current study and showed that RFC4, a DNA replication factor amplified in more than 40% of NSCLC tissues, directly binds to the Notch1 intracellular domain (NICD1) to competitively abrogate CDK8/FBXW7-mediated degradation of NICD1. Moreover, RFC4 is a functional transcriptional target gene of Notch1 signaling, forming a positive feedback loop between high RFC4 and NICD1 levels and sustained overactivation of Notch signaling, which not only leads to NSCLC tumorigenicity and metastasis but also confers NSCLC cell resistance to treatment with the clinically tested drug DAPT against NICD1 synthesis. Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis. Therefore, our study characterizes the pivotal roles of the positive feedback loop between RFC4 and NICD1 in coupling NSCLC metastasis and stemness properties and suggests its therapeutic and diagnostic/prognostic potential for NSCLC therapy.

Background: Lymph node (LN) dissection is a common procedure for non-small cell lung cancer (NSCLC) to ascertain disease severity and treatment options. However, murine studies have indicated that excising tumor-draining LNs diminished immunotherapy effectiveness, though its applicability to clinical patients remains uncertain. Hence, the authors aim to illustrate the immunological implications of LN dissection by analyzing the impact of dissected LN (DLN) count on immunotherapy efficacy, and to propose a novel ‘immunotherapy-driven’ LN dissection strategy. Materials and methods: The authors conducted a retrospective analysis of NSCLC patients underwent anti-PD-1 immunotherapy for recurrence between 2018 and 2020, assessing outcomes based on DLN count stratification. Results: A total of 144 patients were included, of whom 59 had a DLN count less than or equal to 16 (median, IQR: 11, 7–13); 66 had a DLN count greater than 16 (median, IQR: 23, 19–29). With a median follow-up time of 14.3 months (95% CI: 11.0–17.6), the overall median progression-free survival (PFS) was 7.9 (95% CI: 4.1–11.7) months, 11.7 (95% CI: 7.9–15.6) months in the combination therapy subgroup, and 4.8 (95% CI: 3.1–6.4) months in the immunotherapy alone subgroup, respectively. In multivariable Cox analysis, DLN count less than or equal to 16 is associated with an improved PFS in all cohorts [primary cohort: HR=0.26 (95% CI: 0.07–0.89), P=0.03]; [validation cohort: HR=0.46 (95% CI: 0.22–0.96), P=0.04]; [entire cohort: HR=0.53 (95% CI: 0.32–0.89), P=0.02]. The prognostic benefit of DLN count less than or equal to 16 was more significant in immunotherapy alone, no adjuvant treatment, pN1, female, and squamous carcinoma subgroups. A higher level of CD8+ central memory T cell (Tcm) within LNs was associated with improved PFS (HR: 0.235, 95% CI: 0.065–0.845, P=0.027). Conclusions: An elevated DLN count (cutoff: 16) was associated with poorer immunotherapy efficacy in recurrent NSCLC, especially pronounced in the immunotherapy alone subgroup. CD8+Tcm proportions in LNs may also impact immunotherapy efficacy. Therefore, for patients planned for adjuvant immunotherapy, a precise rather than expanded lymphadenectomy strategy to preserve immune-depending LNs is recommended.