Molecular classification of small cell lung cancer subtypes: Characteristics, prognostic factors, and clinical translation.

ABSTRACT: Small cell lung cancer (SCLC) is a highly malignant tumor with a very poor prognosis; therefore, more effective treatments are urgently needed for patients afflicted with the disease. In recent years, emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology, metastasis, immune microenvironment, and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes. Additionally, advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease. Herein, we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.

MRD-directed and risk-adapted individualized stratified treatment of AML.

Measurable residual disease (MRD) has been widely recognized as a biomarker for deeply evaluating complete remission (CR), predicting relapse, guiding pre-emptive interventions, and serving as an endpoint surrogate for drug testing. However, despite the emergence of new technologies, there remains a lack of comprehensive understanding regarding the proper techniques, sample materials, and optimal time points for MRD assessment. In this review, we summarized the MRD methods, sample sources, and evaluation frequency according to the risk category of the European Leukemia Net (ELN) 2022. Additionally, we emphasize the importance of properly utilizing and combining these technologies. We have also refined the flowchart outlining each time point for pre-emptive interventions and intervention paths. The evaluation of MRD in acute myeloid leukemia (AML) is sophisticated, clinically applicable, and technology-dependent, and necessitates standardized approaches and further research.

Association Between Visceral Fat Area and Cancer Prognosis: A Population-Based Multicenter Prospective Study.

BACKGROUND: Diverse indicators have been used to represent adipose tissue, while the relationship between body adipose mass and the prognosis of patients with cancer remains controversial. OBJECTIVE: This study aimed to explore the indicators of optimal body composition that represent body fat mass to predict risk of cancer-related mortality. METHODS: We conducted a population-based multicenter prospective cohort study of patients with initial cancer between February 2012 and September 2020. Clinical information, body composition indicators, hematologic test results, and follow-up data were collected. Body composition indicators were analyzed using principal component analysis to select the most representative indicators, and the cutoff value was set according to the optimal stratification method. The hazard ratio (HR) for mortality was calculated using Cox proportional hazards regression models. RESULTS: Among 14,018 patients with complete body composition data, visceral fat area (VFA) is a more optimal indicator for body fat content (principal component index: 0.961) than body mass index (principal component index: 0.850). The cutoff points for VFA in terms of time to mortality were 66 cm2 and 102 cm2 for gastric/esophageal cancer and other cancers, respectively. Among the 2788 patients treated systemically, multivariate analyses demonstrated that a lower VFA was associated with a higher risk of death in patients with cancer of diverse types (HR: 1.33; 95% CI: 1.08, 1.64; P = 0.007), especially gastric cancer (HR: 2.13; 95% CI: 1.3, 3.49; P = 0.003), colorectal cancer HR: 1.81; 95% CI: 1.06, 3.08; P = 0.030) and nonsmall-cell lung cancer (HR: 1.27; 95% CI: 1.01, 1.59; P = 0.040). CONCLUSION: VFA is an independent prognostic indicator of muscle mass in patients with diverse types of cancer, particularly gastric, colorectal, and nonsmall-cell lung cancers. TRIAL REGISTRATION NUMBER: ChiCTR1800020329.

Epidermal growth factor receptor compound and concomitant mutations: advances in precision treatment strategies.

ABSTRACT: Epidermal growth factor receptor ( EGFR ) mutations are common oncogenic driver mutations in patients with non-small cell lung cancer (NSCLC). The application of EGFR-tyrosine kinase inhibitors (TKIs) is beneficial for patients with advanced and early-stage NSCLC. With the development of next-generation sequencing technology, numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation; however, the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown. Thus, we review the incidence, prognosis, and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.

Clonal evolution characteristics and reduced dimension prognostic model for non-metastatic metachronous bilateral breast cancer.

Background: How to evaluate the prognosis and develop overall treatment strategies of metachronous bilateral breast cancer (MBBC) remains confused in clinical. Here, we investigated the correlation between clonal evolution and clinical characteristics of MBBC; we aim to establish a novel prognostic model in these patients. Methods: The data from Surveillance, Epidemiology, and End Results (SEER) database and the First Hospital of Jilin University were analyzed for breast cancer-specific cumulative mortality (BCCM) by competing risk model. Meanwhile, whole-exome sequencing was applied for 10 lesions acquired at spatial-temporal distinct regions of five patients from our own hospital to reconstruct clonal evolutionary characteristics of MBBC. Then, dimensional-reduction (DR) cumulative incidence function (CIF) curves of MBBC features were established on different point in diagnostic interval time, to build a novel DR nomogram. Results: Significant heterogeneity in genome and clinical features of MBBC was widespread. The mutational diversity of contralateral BC (CBC) was significantly higher than that in primary BC (PBC), and the most effective prognostic MATH ratio was significantly correlated with interval time (R 2 = 0.85, p< 0.05). In SEER cohort study (n = 13,304), the interval time was not only significantly affected the BCCM by multivariate analysis (p< 0.000) but determined the weight of clinical features (T/N stage, grade and ER status) on PBC and CBC in prognostic evaluation. Thus, clinical parameters after DR based on interval time were incorporated into the nomogram for prognostic predicting BCCM. Concordance index was 0.773 (95% CI, 0.769-0.776) in training cohort (n = 8,869), and 0.819 (95% CI, 0.813-0.826) in validation cohort (n = 4,435). Conclusions: Bilateral heterogeneous characteristics and interval time were determinant prognostic factors of MBBC. The DR prognostic nomogram may help clinicians in prognostic evaluation and decision making.

Anaplastic lymphoma kinase-special immunity and immunotherapy.

Alterations in the anaplastic lymphoma kinase (ALK) gene play a key role in the development of various human tumors, and targeted therapy has transformed the treatment paradigm for these oncogene-driven tumors. However, primary or acquired resistance remains a challenge. ALK gene variants (such as gene rearrangements and mutations) also play a key role in the tumor immune microenvironment. Immunotherapy targeting the ALK gene has potential clinical applications. Here, we review the results of recent studies on the immunological relevance of ALK-altered tumors, which provides important insights into the development of tumor immunotherapies targeting this large class of tumors.

Cost-Effectiveness Analyses of Home Parenteral Nutrition for Incurable Gastrointestinal Cancer Patients.

Background: Appropriate nutritional support, including supplemental home parenteral nutrition (sHPN), may improve prognosis and quality of life (Qol) of malnourished cancer patients. We aimed to explore the cost-effectiveness of sHPN for incurable gastrointestinal cancer patients from the Chinese healthcare perspective. Method: Clinical data were extracted from a randomized controlled trial (NCT02066363). Patients were randomized into the sHPN group or the non-sHPN group (receiving best practice nutritional care). A Markov model was established with a 6-week cycle length. Costs were acquired from local hospitals, effect parameters included quality-adjusted life year (QALY), Qol, body mass index, fat-free mass (FFM), FFM index, handgrip strength, and a 6-min walking test. Sensitivity analyses were conducted with a willingness-to-pay (WTP) set at 3 per capita gross domestic product ($29,307/QALY). Results: When considering QALY as a utility, the incremental cost-effectiveness ratio (ICER) was $24,289.17, with an incremental cost of $2,051.18 and an incremental QALY of 0.0844 between the sHPN group and the non-sHPN group. Furthermore, we explored the cost-effectiveness of sHPN from multidimensions, where we analyzed various effect parameters at different visits; the results showed a superior benefit for patients in the sHPN group except for the handgrip parameter at visit 2. Sensitivity analysis demonstrated the influence of utilities in the sHPN group, but the sHPN group was still cost-effective with a WTP of $2,500/QALY. Conclusion: In China, sHPN was cost-effective for patients with incurable gastrointestinal cancer, which suggested further applications in clinical practice and provided references for clinical decisions and pricing.

The Role of Graphene Oxide Nanocarriers in Treating Gliomas.

Gliomas are the most common primary malignant tumors of the central nervous system, and their conventional treatment involves maximal safe surgical resection combined with radiotherapy and temozolomide chemotherapy; however, this treatment does not meet the requirements of patients in terms of survival and quality of life. Graphene oxide (GO) has excellent physical and chemical properties and plays an important role in the treatment of gliomas mainly through four applications, viz. direct killing, drug delivery, immunotherapy, and phototherapy. This article reviews research on GO nanocarriers in the treatment of gliomas in recent years and also highlights new ideas for the treatment of these tumors.

A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice.

Clinical treatment is challenging for elderly patients with lung cancer who cannot tolerate chemotherapy, do not have cancer driver genes, and have low expression of PD-L1. Since these patients are usually excluded from clinical studies, evidence-based medicine supporting the use of immunotherapy is lacking. Considering the potentially limited clinical benefits and high associated risk of hyperprogressive disease, determining an appropriate treatment is an urgent clinical challenge. We report a 71 year-old male patient diagnosed with advanced lung adenocarcinoma lacking key driving genes (EGFR, ALK, and ROS-1), and low expression of PD-L1 on tumor cells (10-15%). The tumor tissue showed a low level of microsatellite instability, low tumor mutational burden, and no DNA mismatch repair deficiency on whole-exome sequencing (WES). However, a high blood tumor mutational burden was detected. After considering the biomarkers of therapeutic effect and ruling out the risk of hyperprogressive disease, pembrolizumab 200 mg was administered every 3 weeks for a year (17 cycles). The disease remained stable for >39 months, and adverse effects were mild and well-tolerated. Therefore, a comprehensive biomarker evaluation, especially in elderly patients lacking driving genes, is essential. Liquid biopsy technology and WES may be useful for overcoming the limitations of tissue biopsy.

Coexisting opportunities and challenges: In which scenarios can minimal/measurable residual disease play a role in advanced non-small cell lung cancer?

Curative therapy was not previously available for patients with advanced non-small cell lung cancer (NSCLC); thus, the concept of minimal/measurable (or molecular) residual disease (MRD) was not applicable to these patients. However, advances in targeted and immunotherapy have revolutionized the treatment landscape for patients with advanced NSCLC, with emerging evidence of long-term survival and even the hope of complete remission (CR) by imaging examination. The latest research shows that patients with oligometastatic lung cancer can benefit from local treatment. After removing the lesions, the choice of follow-up therapy and monitoring of the lesions could remain uncertain. MRD plays a role in identifying early-stage NSCLC patients with high risks of recurrence and determining adjuvant therapy after radical treatment. In recent years, evidence has been accumulating regarding the use of circulating cell-free tumor DNA (ctDNA) to assess MRD in solid tumors. This study discussed the possible applications of ctDNA-based MRD monitoring in advanced NSCLC and described the current challenges and unresolved problems in the application of MRD in advanced NSCLC.

Research Progress and Challenges in the Treatment of Central Nervous System Metastasis of Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors and has high morbidity and mortality rates. Central nervous system (CNS) metastasis is one of the most frequent complications in patients with NSCLC and seriously affects the quality of life (QOL) and overall survival (OS) of patients, with a median OS of untreated patients of only 1-3 months. There are various treatment methods for NSCLC CNS metastasis, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, which do not meet the requirements of patients in terms of improving OS and QOL. There are still many problems in the treatment of NSCLC CNS metastasis that need to be solved urgently. This review summarizes the research progress in the treatment of NSCLC CNS metastasis to provide a reference for clinical practice.

Focused evaluation of the roles of macrophages in chimeric antigen receptor (CAR) T cell therapy associated cytokine release syndrome.

Cytokine release syndrome (CRS) is a major obstacle to the widespread clinical application of chimeric antigen receptor (CAR) T cell therapies. CRS can also be induced by infections (such as SARS-CoV-2), drugs (such as therapeutic antibodies), and some autoimmune diseases. Myeloid-derived macrophages play key roles in the pathogenesis of CRS, and participate in the production and release of the core CRS cytokines, including interleukin (IL)-1, IL-6, and interferon-γ. In this review, we summarize the roles of macrophages in CRS and discuss new developments in macrophage activation and the related mechanisms of cytokine regulation in CRS.

The promising role of antibody drug conjugate in cancer therapy: Combining targeting ability with cytotoxicity effectively.

INTRODUCTION: Traditional cancer therapy has many disadvantages such as low selectivity and high toxicity of chemotherapy, as well as insufficient efficacy of targeted therapy. To enhance the cytotoxic effect and targeting ability, while reducing the toxicity of antitumor drugs, an antibody drug conjugate (ADC) was developed to deliver small molecular cytotoxic payloads directly to tumor cells by binding to specific antibodies via linkers. METHOD: By reviewing published literature and the current progress of ADCs, we aimed to summarize the basic characteristics, clinical progress, and challenges of ADCs to provide a reference for clinical practice and further research. RESULTS: ADC is a conjugate composed of three fundamental components, including monoclonal antibodies, cytotoxic payloads, and stable linkers. The mechanisms of ADC including the classical internalization pathway, antitumor activity of antibodies, bystander effect, and non-internalizing mechanism. With the development of new drugs and advances in technology, various ADCs have achieved clinical efficacy. To date, nine ADCs have received US Food and Drug Administration (FDA) approval in the field of hematologic tumors and solid tumors, which have become routine clinical treatments. CONCLUSION: ADC has changed traditional treatment patterns for cancer patients, which enable the same treatment for pancreatic cancer patients and promote individualized precision treatment. Further exploration of indications could focus on early-stage cancer patients and combined therapy settings. Besides, the mechanisms of drug resistance, manufacturing techniques, optimized treatment regimens, and appropriate patient selection remain the major topics.

Clinical challenges in neoadjuvant immunotherapy for non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs), a type of immunotherapy, have become one of the most important therapeutic options for first- and second-line treatment of advanced non-small cell lung cancer (NSCLC). Recent clinical studies have shown that immunotherapy can offer substantial survival benefits to patients with early-stage or resectable advanced NSCLC. However, considering the importance of timing when using ICIs and their associated adverse events (AEs), the advantages and disadvantages of using these agents need to be weighed carefully when deciding the use of a combined treatment. In addition, the inconsistency between imaging assessment and pathological results poses further challenges to the evaluation of efficacy of neoadjuvant immunotherapy. It is also important to develop new methodologies and discover suitable biomarkers that can be used to evaluate survival outcomes of immunotherapy and identify patients who would benefit the most from this treatment. In this review, we aimed to summarize previous results of ongoing clinical trials on neoadjuvant immunotherapy for lung cancer and discuss the challenges and future perspectives of this therapeutic approach in the treatment of resectable NSCLC.

Comprehensive Comparison Between Adjuvant Targeted Therapy and Chemotherapy for EGFR-Mutant NSCLC Patients: A Cost-Effectiveness Analysis.

BACKGROUND: Chemotherapy has been the current standard adjuvant treatment for early-stage non-small-cell lung cancer (NSCLC) patients, while recent studies showed benefits of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We conducted a cost-effectiveness analysis to comprehensively evaluate the benefit of EGFR-TKI compared with chemotherapy for early-stage EGFR-mutant NSCLC patients after resection from the perspective of the Chinese health care system. METHOD: A Markov model was established. Clinical data were based on the phase 3, ADJUVANT trial, where stage II-IIIA, EGFR-mutant NSCLC patients were randomized into gefitinib group or chemotherapy group after resection. Cost parameters mainly included costs of drugs, examinations, and adverse events (AEs). Effect parameters were evaluated by quality-adjusted life year (QALY). Outcomes contained incremental cost-effective ratio (ICER), average cost-effective ratio (ACER), and net benefit. The willingness-to-pay threshold was set as 3 times per capita gross domestic product ($30,828/QALY). Sensitivity analyses were also conducted to verify the stability of the model. RESULTS: Patients who received gefitinib had both a higher cost ($12,057.98 vs. $11,883.73) and a higher QALY (1.55 vs. 1.42) than patients who received chemotherapy. With an ICER of $1,345.62/QALY, adjuvant gefitinib was of economic benefit compared with chemotherapy. The ACER and net benefit were also consistent (gefitinib vs. chemotherapy, ACER: $7,802.30/QALY vs. $8,392.77/QALY; net benefit: $35,584.85 vs. $31,767.17). Sensitivity analyses indicated the stability of the model and the impact of utility. CONCLUSION: Adjuvant EGFR-TKI application for early-stage EGFR-mutant NSCLC patients was cost-effective compared with chemotherapy, which might provide a reference for clinical decision-making and medical insurance policy formulation in China.

The Role of the Transcription Factor EGR1 in Cancer.

Early growth response factor 1 (EGR1) is a transcription factor that is mainly involved in the processes of tissue injury, immune responses, and fibrosis. Recent studies have shown that EGR1 is closely related to the initiation and progression of cancer and may participate in tumor cell proliferation, invasion, and metastasis and in tumor angiogenesis. Nonetheless, the specific mechanism whereby EGR1 modulates these processes remains to be elucidated. This review article summarizes possible mechanisms of action of EGR1 in tumorigenesis and tumor progression and may serve as a reference for clinical efficacy predictions and for the discovery of new therapeutic targets.

Precision Detection Technology: Equipping Precision Oncology with Wings.

In recent years, precision medical detection techniques experienced a rapid transformation from low-throughput to high-throughput genomic sequencing, from multicell promiscuous detection to single-cell precision sequencing. The emergence of liquid biopsy technology has compensated for the many limitations of tissue biopsy, leading to a tremendous transformation in precision detection. Precision detection techniques contribute to monitoring disease development more closely, evaluating therapeutic effects more scientifically, and developing new targets and new drugs. In the future, the role of precision detection and the joint detection in epigenetics, rare gene detection, individualized targeted therapy, and multigene targeted drug combination therapy should be extensively explored. This article reviews the changes in precision medical detection technology in the era of precision medicine, as well as the development, clinical application, and future challenges of liquid biopsy.

Advances and challenges in immunotherapy of small cell lung cancer.

Small cell lung cancer (SCLC) is a highly lethal disease, characterized by early metastasis and rapid growth, and no effective treatment after relapse. Etoposide-platinum (EP) combination has been the backbone therapy of SCLC over the past 30 years. It is extremely urgent and important to seek new therapies for SCLC. In the past 5 years, immunotherapy, such as immune checkpoint inhibitors programmed cell death protein-1 (PD-1), cytotoxic T lymphocyte associatedprotein-4 (CTLA-4), has made remarkable achievements in the treatment of patients with SCLC, and it has become the first-line option for the treatment of some patients. Some traditional chemotherapeutic drugs or targeted drugs, such as alkylating agent temozolomide and transcription inhibitor lurbinectedin, have been found to have immunomodulatory effects and are expected to become new immunotherapeutic agents. In this study, we aimed to review the efficacy of new treatments for SCLC and discuss the current challenges and application prospect in the treatment of SCLC patients.

[Advances in Combination Therapy of Immune Checkpoint Inhibitors for Lung Cancer].

Immune checkpoint inhibitors (ICIs) therapy is the most commonly used immunotherapy regimen at present. It has been approved for clinical treatment of melanoma, kidney cancer, head and neck cancer, bladder cancer and other tumors. It has made a breakthrough in the treatment of lung cancer and become a new pillar of comprehensive treatment of lung cancer. However, ICIs alone is less effective in non-selective patients, and combination therapy has become a hot topic of exploration. This article focuses on the development of combined immune checkpoint inhibitors and describes how immunotherapy can be used to treat early stage cancer.

Development status and clinical applications of precision detection technology in the times of precision oncology / 中国肿瘤生物治疗杂志

@#Precision detection techniques have promoted the development of individualized diagnosis and treatment of tumors in the era of precision medicine. At the same time, clinical demands of precision treatments have further driven the development and application of precision detection techniques. In recent years, precision medical detection techniques realized rapid transformations from low-throughput to high-throughput genomic sequencing, from tissue biopsies to liquid biopsies, and from multicell promiscuous detection to single cell precision sequencing. All these changes have promoted the emergence and development of new technologies, new targets, and new drugs in the era of precision oncology medicine. In the future, multi-dimensional combined detection could help to improve the accuracy of precision medicine; ctDNA methylation detection analysis could broaden the research field of precision medicine; and the transformation of clinical trial design could also contribute to promote the in-depth development of precision medicine.