Incremental value of automatically segmented perirenal adipose tissue for pathological grading of clear cell renal cell carcinoma: a multicenter cohort study.

OBJECTIVES: Accurate preoperative prediction of the pathological grade of clear cell renal cell carcinoma (ccRCC) is crucial for optimal treatment planning and patient outcomes. This study aims to develop and validate a deep-learning (DL) algorithm to automatically segment renal tumours, kidneys, and perirenal adipose tissue (PRAT) from computed tomography (CT) images and extract radiomics features to predict the pathological grade of ccRCC. METHODS: In this cross-ethnic retrospective study, a total of 614 patients were divided into a training set (383 patients from the local hospital), an internal validation set (88 patients from the local hospital), and an external validation set (143 patients from the public dataset). A two-dimensional TransUNet-based DL model combined with the train-while-annotation method was trained for automatic volumetric segmentation of renal tumours, kidneys, and visceral adipose tissue (VAT) on images from two groups of datasets. PRAT was extracted using a dilation algorithm by calculating voxels of VAT surrounding the kidneys. Radiomics features were subsequently extracted from three regions of interest of CT images, adopting multiple filtering strategies. The least absolute shrinkage and selection operator (LASSO) regression was used for feature selection, and the support vector machine (SVM) for developing the pathological grading model. Ensemble learning was used for imbalanced data classification. Performance evaluation included the Dice coefficient for segmentation and metrics such as accuracy and area under curve (AUC) for classification. The WHO/International Society of Urological Pathology (ISUP) grading models were finally interpreted and visualized using the SHapley Additive exPlanations (SHAP) method. RESULTS: For automatic segmentation, the mean Dice coefficient achieved 0.836 for renal tumours and 0.967 for VAT on the internal validation dataset. For WHO/ISUP grading, a model built with features of PRAT achieved a moderate AUC of 0.711 (95% CI, 0.604-0.802) in the internal validation set, coupled with a sensitivity of 0.400 and a specificity of 0.781. While model built with combination features of the renal tumour, kidney, and PRAT showed an AUC of 0.814 (95% CI, 0.717-0.889) in the internal validation set, with a sensitivity of 0.800 and a specificity of 0.753, significantly higher than the model built with features solely from tumour lesion (0.760; 95% CI, 0.657-0.845), with a sensitivity of 0.533 and a specificity of 0.767. CONCLUSION: Automated segmentation of kidneys and visceral adipose tissue (VAT) through TransUNet combined with a conventional image morphology processing algorithm offers a standardized approach to extract PRAT with high reproducibility. The radiomics features of PRAT and tumour lesions, along with machine learning, accurately predict the pathological grade of ccRCC and reveal the incremental significance of PRAT in this prediction.

An inner mitochondrial membrane microprotein from the SLC35A4 upstream ORF regulates cellular metabolism.

Upstream open reading frames (uORFs) are cis-acting elements that can dynamically regulate the translation of downstream ORFs by suppressing downstream translation under basal conditions and, in some cases, increasing translation under stress conditions. Computational and empirical methods have identified uORFs in the 5'-UTRs of approximately half of all mouse and human transcripts, making uORFs one the largest regulatory elements known. Because the prevailing dogma was that eukaryotic mRNAs produce a single functional protein, the peptides and small proteins, or microproteins, encoded by uORFs are under studied. We hypothesized that a uORF in the SLC35A4 mRNA is producing a functionalmicroprotein (SLC35A4-MP) because of its conserved amino acid sequence. Through a series of biochemical and cellular experiments, we find that the 103-amino acid SLC35A4-MP is a single-pass transmembrane inner mitochondrial membrane (IMM) microprotein. The IMM contains the protein machinery crucial for cellular respiration and ATP generation, and loss of function studies with SLC35A4-MP significantly diminish maximal cellular respiration, indicating a vital role for this microprotein in cellular metabolism. The findings add to the growing list of functional microproteins and, more generally, indicate that uORFs that encode conserved microproteins are an untapped reservoir of functional microproteins.

Patient-Controlled Subcutaneous Analgesia with Hydromorphone versus Oral Oxycontin for Opioid Titration of Cancer Pain: A Prospective Multicenter Randomized Trial.

Background: Studies have shown that oral oxycontin tablets can be used for opioid titration. The European Society for Medical Oncology (ESMO) guidelines for adult cancer pain recommend opioid titration through the parenteral route, usually the intravenous or subcutaneous route. Patient-controlled subcutaneous analgesia (PCSA) with hydromorphone needs further evaluation for opioid titration. This prospective multicenter study was designed to compare the efficacy and safety of hydromorphone PCSA with oral oxycontin tablets for opioid titration of cancer pain. Patients and Methods: Eligible patients with cancer pain were randomly assigned in a 1:1 ratio to the PCSA group or the oxycontin group for dose titration. Different titration methods were given in both groups depending on whether the patient had an opioid tolerance. The primary endpoint of this study was time to successful titration (TST). Results: A total of 256 patients completed this study. The PCSA group had a significantly lower TST compared with the oxycontin group (median [95% confidence interval (CI)], 5.5[95% CI:2.5-11.5] hours vs.16.0 [95% CI:11.5-22.5] hours; p<0.001). The frequency (median; interquartile) of breakthrough pain (Btp) over 24 hours was significantly lower in the PCSA group (2.5;2.0-3.5) than in the oxycontin group.(3.0; 2.5-4.5) (p=0.04). The pain was evaluated by numeric rating scale (NRS) score at 12 hours after the start of titration. The pain score (median; interquartile) was significantly lower in the PCSA versus the oxycontin group (2.5;1.5-3.0) vs 4.5;3.0-6.0) (p=0.02). The equivalent dose of oral morphine (EDOM) for a successful titration was similar in both groups (p=0.29), but there was a significant improvement in quality of life (QoL) in both groups (p=0.03). No between-group difference in the incidence of opioid-related adverse effects was observed (p=0.32). Conclusion: Compared with oral oxycontin tablet, the use of PCSA with hydromorphone achieved a shorter titration duration for patients with cancer pain (p<0.001), without significantly increasing adverse events (p=0.32).

Biological characteristics and clinical treatment of pulmonary sarcomatoid carcinoma: a narrative review.

Background and Objective: Pulmonary sarcomatoid carcinoma (PSC) is a subset of non-small cell lung cancer (NSCLC) with highly malignant, aggressive, and heterogeneous features. Patients with this disease account for approximately 0.1-0.4% of lung cancer cases. The absence of comprehensive summaries on the basic biology and clinical treatments for PSC means there is limited systematic awareness and understanding of this rare disease. This paper provides an overview of the biological characteristics of PSC and systematically summarizes various treatment strategies available for patients with this disease. Methods: For this narrative review, we have searched literature related to the basic biology and clinical treatment approaches of PSC by searching the PubMed database for articles published from July 16, 1990 to August 29, 2023. The following keywords were used: "pulmonary sarcomatoid carcinoma", "genetic mutations", "immune microenvironment", "hypoxia", "angiogenesis", "overall survival", "surgery", "radiotherapy", "chemotherapy", and "immune checkpoint inhibitors". Key Content and Findings: Classical PSC comprises epithelial and sarcomatoid components, with most studies suggesting a common origin. PSC exhibits a higher tumor mutational burden (TMB) and mutation frequency than other types of NSCLC. The tumor microenvironment (TME) of PSC is characterized by hypoxia, hypermetabolism, elevated programmed cell death protein 1/programmed cell death-ligand 1 expression, and high immune cell infiltration. Treatment strategies for advanced PSC are mainly based on traditional NSCLC treatments, but PSC exhibits resistance to chemotherapy and radiotherapy. The advancement of genome sequencing has introduced targeted therapies as an option for mutation-positive PSC cases. Moreover, due to the characteristics of the immune microenvironment of PSC, many patients positively respond to immunotherapy, demonstrating its potential for the management of PSC. Conclusions: Although several studies have examined and assessed the TME of PSC, these are limited in quantity and quality, presenting challenges for research into the clinical treatment strategies for PSC. With the emergence of new technologies and the advancement of clinical research, for example, savolitinib's clinical study for MET exon 14 skipping mutations positive PSC patients have shown promising outcomes, more in-depth studies on PSC are eagerly anticipated.

Deep reinforcement learning identifies personalized intermittent androgen deprivation therapy for prostate cancer.

The evolution of drug resistance leads to treatment failure and tumor progression. Intermittent androgen deprivation therapy (IADT) helps responsive cancer cells compete with resistant cancer cells in intratumoral competition. However, conventional IADT is population-based, ignoring the heterogeneity of patients and cancer. Additionally, existing IADT relies on pre-determined thresholds of prostate-specific antigen to pause and resume treatment, which is not optimized for individual patients. To address these challenges, we framed a data-driven method in two steps. First, we developed a time-varied, mixed-effect and generative Lotka-Volterra (tM-GLV) model to account for the heterogeneity of the evolution mechanism and the pharmacokinetics of two ADT drugs Cyproterone acetate and Leuprolide acetate for individual patients. Then, we proposed a reinforcement-learning-enabled individualized IADT framework, namely, I$^{2}$ADT, to learn the patient-specific tumor dynamics and derive the optimal drug administration policy. Experiments with clinical trial data demonstrated that the proposed I$^{2}$ADT can significantly prolong the time to progression of prostate cancer patients with reduced cumulative drug dosage. We further validated the efficacy of the proposed methods with a recent pilot clinical trial data. Moreover, the adaptability of I$^{2}$ADT makes it a promising tool for other cancers with the availability of clinical data, where treatment regimens might need to be individualized based on patient characteristics and disease dynamics. Our research elucidates the application of deep reinforcement learning to identify personalized adaptive cancer therapy.

Atroposelective Synthesis of Axially Chiral Diaryl Ethers by N-Heterocyclic-Carbene-Catalyzed Sequentially Desymmetric/Kinetic Resolution Process.

We describe herein an N-heterocyclic-carbene-catalyzed atroposelective synthesis of axially chiral diaryl ethers. Through a sequentially enantioselective desymmetric process and a kinetic resolution process, the products could be constructed in good yields with excellent enantiopurities. Both alcohols and phenols were compatible with this catalytic system. The axially chiral carboxylic acids derived from the esters were proven to be potential chiral ligands for asymmetric synthesis, for example, Rh(III)-catalyzed enantioselective C-H functionalization.

Dietary elaidic acid boosts tumoral antigen presentation and cancer immunity via ACSL5.

Immunomodulatory effects of long-chain fatty acids (LCFAs) and their activating enzyme, acyl-coenzyme A (CoA) synthetase long-chain family (ACSL), in the tumor microenvironment remain largely unknown. Here, we find that ACSL5 functions as an immune-dependent tumor suppressor. ACSL5 expression sensitizes tumors to PD-1 blockade therapy in vivo and the cytotoxicity mediated by CD8+ T cells in vitro via regulation of major histocompatibility complex class I (MHC-I)-mediated antigen presentation. Through screening potential substrates for ACSL5, we further identify that elaidic acid (EA), a trans LCFA that has long been considered harmful to human health, phenocopies to enhance MHC-I expression. EA supplementation can suppress tumor growth and sensitize PD-1 blockade therapy. Clinically, ACSL5 expression is positively associated with improved survival in patients with lung cancer, and plasma EA level is also predictive for immunotherapy efficiency. Our findings provide a foundation for enhancing immunotherapy through either targeting ACSL5 or metabolic reprogramming of antigen presentation via dietary EA supplementation.

The association of genomic alterations with PD-L1 expression in Chinese patients with EGFR/ALK wild-type lung adenocarcinoma and potential predictive value of Hippo pathway mutations to immunotherapy.

BACKGROUND: The study focuses on PD-L1 expression as an essential biomarker for gauging the response of EGFR/ALK wild-type NSCLC patients to FDA-approved immune checkpoint inhibitors (ICIs). It aims to explore clinical, molecular, and immune microenvironment characteristics associated with PD-L1 expression in EGFR/ALK wild-type lung adenocarcinoma patients eligible for ICI therapy. METHODS: In this retrospective study, tumor samples from 359 Chinese EGFR/ALK wild-type lung adenocarcinoma patients underwent comprehensive evaluations for PD-L1 expression and NGS-targeted sequencing. The investigation encompassed the analysis and comparison of clinical traits, gene mutations, pathways, and immune signatures between two groups categorized by PD-L1 status: negative (TPS < 1%) and positive (TPS ≥ 1%). Additionally, the study explored the link between genomic changes and outcomes following immunotherapy. RESULTS: High tumor mutational burden correlated significantly with PD-L1 positivity in patients with EGFR/ALK wild-type lung adenocarcinoma. Gene alterations, including TP53, KRAS, and others, were more pronounced in the PD-L1 positive group. Pathway analysis highlighted higher frequencies of alterations in pathways like RTK/RAS, p53, and Hippo in PD-L1-positive patients. The Hippo pathway's relevance was confirmed in separate immunotherapy cohorts, associated with better outcomes. In terms of immune cell infiltration, Hippo mutants exhibited higher levels of CD68+ PD-L1+ macrophages, CD8+ T cells, and CD8+ PD-1- T cells. CONCLUSIONS: This study offers insights into genomic features of Chinese EGFR/ALK wild-type lung adenocarcinoma patients based on PD-L1 expression. Notably, Hippo pathway alterations were linked to improved immunotherapy outcomes. These findings suggest connections between the Hippo pathway and PD-L1 expression, warranting further clinical and functional investigations. The research advances our understanding of PD-L1 expression's genomic context and immunotherapy response in EGFR/ALK wild-type lung adenocarcinoma.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer.

BACKGROUND: Cadonilimab is a bispecific antibody that simultaneously targets programmed cell death receptor-1 and cytotoxic T lymphocyte-associated antigen-4. This study aimed to assess the safety and efficacy of cadonilimab plus anlotinib for the first-line treatment of advanced non-small cell lung cancer (NSCLC) without sensitizing EGFR/ALK/ROS1 mutations. METHODS: Patients received cadonilimab 15 mg/kg and 10 mg/kg every three weeks (Q3W) plus anlotinib at doses of 10 or 12 mg once daily for two weeks on a one-week-off schedule. The primary endpoints included safety and objective response rate (ORR). RESULTS: Sixty-nine treatment-naïve patients received cadonilimab 15 mg/kg Q3W combination (n = 49) and 10 mg/kg Q3W combination (n = 20). Treatment-related adverse events (TRAEs) were reported in 48 (98.0%) and 19 (95.0%) patients, with grade ≥3 TRAEs occurring in 29 (59.2%) and five (25.0%) patients, respectively. TRAEs leading to cadonilimab discontinuation occurred in eight (16.3%) and one (5.0%) patients in the cadonilimab 15 mg/kg Q3W and 10 mg/kg Q3W dosing groups. The confirmed ORRs were 51.0% (25/49) and 60.0% (12/20) accordingly. CONCLUSIONS: Cadonilimab 10 mg/kg Q3W plus anlotinib showed manageable safety and promising efficacy as a first-line chemo-free treatment for advanced NSCLC. GOV IDENTIFIER: NCT04646330.

Baseline C-reactive protein predicts efficacy of the first-line immune checkpoint inhibitors plus chemotherapy in advanced lung squamous cell carcinoma: a retrospective, multicenter study.

AIMS: To investigate the predictive value of baseline C-reactive protein (CRP) levels on the efficacy of chemotherapy plus immune checkpoint inhibitors (ICI) in patients with advanced lung squamous cell carcinoma (LSCC). MATERIALS AND METHODS: In this retrospective multicenter study spanning from January 2016 to December 2020, advanced LSCC patients initially treated with chemotherapy or a combination of chemotherapy and ICI were categorized into normal and elevated CRP subgroups. The relationship between CRP levels and treatment outcomes was analyzed using multivariate Cox proportional hazards models and multivariate logistic regression, focusing primarily on the progression-free survival (PFS) endpoint, and secondarily on overall survival (OS) and objective response rate (ORR) endpoints. Survival curves were generated using the Kaplan-Meier method, with the log-rank test used for comparison between groups. RESULTS: Of the 245 patients evaluated, the 105 who received a combination of chemotherapy and ICI with elevated baseline CRP levels exhibited a significant reduction in PFS (median 6.5 months vs. 11.8 months, HR, 1.78; 95% CI: 1.12-2.81; p = 0.013) compared to those with normal CRP levels. Elevated CRP was identified as an independent risk factor for poor PFS through multivariate-adjusted analysis. However, among the 140 patients receiving chemotherapy alone, baseline CRP levels did not significantly influence PFS. Furthermore, within the combination therapy group, there was a notable decrease in the ORR (51% vs. 71%, p = 0.035), coupled with a significantly shorter OS (median 20.9 months vs. 31.5 months, HR, 2.24; 95% CI: 1.13-4.44; p = 0.033). CONCLUSION: In patients with advanced LSCC, elevated baseline CRP levels were identified as an independent predictive factor for the efficacy of combination therapy with chemotherapy and ICI, but not in chemotherapy alone. This suggests that CRP may be a valuable biomarker for guiding treatment strategies.

Stabilized cyclic peptides as modulators of protein-protein interactions: promising strategies and biological evaluation.

Protein-protein interactions (PPIs) control many essential biological pathways which are often misregulated in disease. As such, selective PPI modulators are desirable to unravel complex functions of PPIs and thus expand the repertoire of therapeutic targets. However, the large size and relative flatness of PPI interfaces make them challenging molecular targets for conventional drug modalities, rendering most PPIs "undruggable". Therefore, there is a growing need to discover innovative molecules that are able to modulate crucial PPIs. Peptides are ideal candidates to deliver such therapeutics attributed to their ability to closely mimic structural features of protein interfaces. However, their inherently poor proteolysis resistance and cell permeability inevitably hamper their biomedical applications. The introduction of a constraint (i.e., peptide cyclization) to stabilize peptides' secondary structure is a promising strategy to address this problem as witnessed by the rapid development of cyclic peptide drugs in the past two decades. Here, we comprehensively review the recent progress on stabilized cyclic peptides in targeting challenging PPIs. Technological advancements and emerging chemical approaches for stabilizing active peptide conformations are categorized in terms of α-helix stapling, ß-hairpin mimetics and macrocyclization. To discover potent and selective ligands, cyclic peptide library technologies were updated based on genetic, biochemical or synthetic methodologies. Moreover, several advances to improve the permeability and oral bioavailability of biologically active cyclic peptides enable the de novo development of cyclic peptide ligands with pharmacological properties. In summary, the development of cyclic peptide-based PPI modulators carries tremendous promise for the next generation of therapeutic agents to target historically "intractable" PPI systems.

Susceptibility Genes Associated with Multiple Primary Cancers.

With advancements in treatment and screening techniques, we have been witnessing an era where more cancer survivors harbor multiple primary cancers (MPCs), affecting approximately one in six patients. Identifying MPCs is crucial for tumor staging and subsequent treatment choices. However, the current clinicopathological criteria for clinical application are limited and insufficient, making it challenging to differentiate them from recurrences or metastases. The emergence of next-generation sequencing (NGS) technology has provided a genetic perspective for defining multiple primary cancers. Researchers have found that, when considering multiple tumor pairs, it is crucial not only to examine well-known essential mutations like MLH1/MSH2, EGFR, PTEN, BRCA1/2, CHEK2, and TP53 mutations but also to explore certain pleiotropic loci. Moreover, specific deleterious mutations may serve as regulatory factors in second cancer development following treatment. This review aims to discuss these susceptibility genes and provide an explanation of their functions based on the signaling pathway background. Additionally, the association network between genetic signatures and different tumor pairs will be summarized.

Impact of prophylactic dexamethasone on the efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy in patients with advanced Non-Squamous Non-Small-Cell lung cancer.

BACKGROUND: Baseline corticosteroids exposure is associated with inferior clinical outcomes in patients with non-small-cell lung cancer (NSCLC) treated with programmed cell death-1 (PD-1) axis blockade. Dexamethasone is a potent corticosteroid used in the prevention of chemotherapy-associated adverse events (CAAEs). OBJECTIVE: Since dexamethasone has immunosuppressive properties, this study attempted to elucidate its effects on the efficacy of immunotherapy plus chemotherapy in patients with non-squamous NSCLC. METHODS: The study retrospectively analyzed the medical records of 254 advanced non-squamous NSCLC patients who received front-line treatment with a PD-1 pathway inhibitor and platinum-based chemotherapy at three academic institutions. The average dosage of prophylactic dexamethasone per chemotherapy cycle was calculated. Patients were divided into three groups based on the dose of dexamethasone: High-d (≥24 mg), Moderate-d (12-24 mg), and Low-d (<12 mg). Spearman's rank correlation was used to assess the correlation between the dosage of dexamethasone and progression-free survival (PFS). Logistic regression was used to assess the correlation between dexamethasone dosage and the occurrence of immune related adverse effects (irAE). Univariate and multivariate Cox proportional hazards regression models were used to analyze the differences in survival among the different dexamethasone dosage groups. RESULT: The dosage of prophylactic dexamethasone was not significantly correlated with PFS (Spearman's rho = -0.103, P = 0.098). Results from the univariate [hazard ratio (HR)Low-d/High-d, 1.00; P = 0.997; HRModerate-d/High-d, 0.85; P = 0.438] and multivariate (HRLow-d/High-d, 0.71; P = 0.174; HRModerate-d/High-d, 0.87; P = 0.512) analyses showed no significant association between dexamethasone and PFS. Dexamethasone did not have significant effect on the objective response rate, disease control rate or overall survival. The toxicity profiles of irAE were similar across all three groups. CONCLUSION: The results of this study suggest that the use of prophylactic dexamethasone does not have an adverse effect on the clinical outcomes of non-squamous NSCLC patients treated with PD-1 blockade therapy and chemotherapy. Routine use of dexamethasone for preventing CAAEs should be recommended for patients undergoing combined immunotherapy and chemotherapy.

Clinical definition of secondary resistance to immunotherapy in non-small cell lung cancer.

Immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 blockade) have revolutionized the treatment landscape in non-small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO-IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Exploiting innate immunity for cancer immunotherapy.

Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.

Efficacy, safety and dose selection of AZD3759 in patients with untreated EGFR-mutated non-small-cell lung cancer and central nervous system metastases in China (CTONG1702-Arm 8): a multi-center, single-arm, phase 2 trial.

Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. Methods: We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR-mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon's minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Findings: Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. Interpretation: AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Funding: Chinese Thoracic Oncology Group (CTONG).

Biochemistry and Protein Interactions of the CYREN Microprotein.

Over the past decade, advances in genomics have identified thousands of additional protein-coding small open reading frames (smORFs) missed by traditional gene finding approaches. These smORFs encode peptides and small proteins, commonly termed micropeptides or microproteins. Several of these newly discovered microproteins have biological functions and operate through interactions with proteins and protein complexes within the cell. CYREN1 is a characterized microprotein that regulates double-strand break repair in mammalian cells through interaction with Ku70/80 heterodimer. Ku70/80 binds to and stabilizes double-strand breaks and recruits the machinery needed for nonhomologous end join repair. In this study, we examined the biochemical properties of CYREN1 to better understand and explain its cellular protein interactions. Our findings support that CYREN1 is an intrinsically disordered microprotein and this disordered structure allows it to enriches several proteins, including a newly discovered interaction with SF3B1 via a distinct short linear motif (SLiMs) on CYREN1. Since many microproteins are predicted to be disordered, CYREN1 is an exemplar of how microproteins interact with other proteins and reveals an unknown scaffolding function of this microprotein that may link NHEJ and splicing.

Expert consensus on the diagnosis and treatment of RET gene fusion non-small cell lung cancer in China.

The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell-surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non-small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second-generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first-generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET-targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.