Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

Real-World Survival Comparisons Between Radiotherapy and Surgery for Metachronous Second Primary Lung Cancer and Predictions of Lung Cancer-Specific Outcomes Using Machine Learning: Population-Based Study.

BACKGROUND: Metachronous second primary lung cancer (MSPLC) is not that rare but is seldom studied. OBJECTIVE: We aim to compare real-world survival outcomes between different surgery strategies and radiotherapy for MSPLC. METHODS: This retrospective study analyzed data collected from patients with MSPLC between 1988 and 2012 in the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) analyses and machine learning were performed to compare variables between patients with MSPLC. Survival curves were plotted using the Kaplan-Meier method and were compared using log-rank tests. RESULTS: A total of 2451 MSPLC patients were categorized into the following treatment groups: 864 (35.3%) received radiotherapy, 759 (31%) underwent surgery, 89 (3.6%) had surgery plus radiotherapy, and 739 (30.2%) had neither treatment. After PSM, 470 pairs each for radiotherapy and surgery were generated. The surgery group had significantly better survival than the radiotherapy group (P<.001) and the untreated group (563 pairs; P<.001). Further analysis revealed that both wedge resection (85 pairs; P=.004) and lobectomy (71 pairs; P=.002) outperformed radiotherapy in overall survival for MSPLC patients. Machine learning models (extreme gradient boosting, random forest classifier, adaptive boosting) demonstrated high predictive performance based on area under the curve (AUC) values. Least absolute shrinkage and selection operator (LASSO) regression analysis identified 9 significant variables impacting cancer-specific survival, emphasizing surgery's consistent influence across 1 year to 10 years. These variables encompassed age at diagnosis, sex, year of diagnosis, radiotherapy of initial primary lung cancer (IPLC), primary site, histology, surgery, chemotherapy, and radiotherapy of MPSLC. Competing risk analysis highlighted lower mortality for female MPSLC patients (hazard ratio [HR]=0.79, 95% CI 0.71-0.87) and recent IPLC diagnoses (HR=0.79, 95% CI 0.73-0.85), while radiotherapy for IPLC increased mortality (HR=1.31, 95% CI 1.16-1.50). Surgery alone had the lowest cancer-specific mortality (HR=0.83, 95% CI 0.81-0.85), with sublevel resection having the lowest mortality rate among the surgical approaches (HR=0.26, 95% CI 0.21-0.31). The findings provide valuable insights into the factors that influence cumulative cancer-specific mortality. CONCLUSIONS: Surgical resections such as wedge resection and lobectomy confer better survival than radiation therapy for MSPLC, but radiation can be a valid alternative for the treatment of MSPLC.

CDK4/6 inhibitor abemaciclib combined with low-dose radiotherapy enhances the anti-tumor immune response to PD-1 blockade by inflaming the tumor microenvironment in Rb-deficient small cell lung cancer.

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown significant activity against several solid tumors by reducing the phosphorylation of the canonical CDK4/6 substrate retinoblastoma (Rb) protein, while the anti-tumor effect of CDK4/6 inhibitors on Rb-deficient tumors is not clear. Most small cell lung cancers (SCLCs) are Rb-deficient and show very modest response to immune checkpoint blockade (ICB) despite recent advances in the use of immunotherapy. Here, we aimed to investigate the direct effect of CDK4/6 inhibition on SCLC cells and determine its efficacy in combination therapy for SCLC. Methods: The immediate impact of CDK4/6 inhibitor abemaciclib on cell cycle, cell viability and apoptosis in four SCLC cell lines was initially checked. To explore the effect of abemaciclib on double-strand DNA (ds-DNA) damage induction and the combination impact of abemaciclib coupled with radiotherapy (RT), western blot, immunofluorescence (IF) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. An Rb-deficient immunocompetent murine SCLC model was established to evaluate efficacy of abemaciclib in combination therapy. Histological staining, flow cytometry analysis and RNA sequencing were performed to analyze alteration of infiltrating immune cells in tumor microenvironment (TME). Results: Here, we demonstrated that abemaciclib induced increased ds-DNA damage in Rb-deficient SCLC cells. Combination of abemaciclib and RT induced more cytosolic ds-DNA, and activated the STING pathway synergistically. We further showed that combining low doses of abemaciclib with low-dose RT (LDRT) plus anti-programmed cell death protein-1 (anti-PD-1) antibody substantially potentiated CD8+ T cell infiltration and significantly inhibited tumor growth and prolonged survival in an Rb-deficient immunocompetent murine SCLC model. Conclusions: Our results define previously uncertain DNA damage-inducing properties of CDK4/6 inhibitor abemaciclib in Rb-deficient SCLCs, and demonstrate that low doses of abemaciclib combined with LDRT inflame the TME and enhance the efficacy of anti-PD-1 immunotherapy in SCLC model, which represents a potential novel therapeutic strategy for SCLC.

Lifetime risks of second primary malignancies after pediatric Hodgkin lymphoma and non-Hodgkin lymphoma.

OBJECTIVES: Survivors after pediatric Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) are with lifetime risk for second primary malignancy (SPM). This necessitates a thorough analysis to better understand the potential long-term health implications for these individuals. METHODS: We used a US-wide population-based cancer registry data to quantify the SPM risk and identify its incidence patterns among pediatric lymphoma patients. RESULTS: We observed 4.74-fold (95% CI 4.27-5.25) and 3.40-fold (95% CI 2.78-4.10) increased risks of SPM in survivors after pediatric HL and NHL, respectively. Through over 40 years' follow-up, the cumulative incidence of SPM for pediatric lymphoma was persistently increasing, and here we firstly report the high 40-year cumulative incidence rates of SPM, 22.2% for HL and 12.6% for NHL, suggesting that SPM accounts for a great proportion of deaths among survivors. Of 6805 pediatric lymphomas, 462 (6.36%) developed a SPM, especially second breast and thyroid cancer, followed by hematologic neoplasms including leukemia and NHL. The competing risk analysis demonstrated gender, lymphoma subtype and radiotherapy were significantly associated with SPM. Different risk patterns of SPM were identified between pediatric HL and NHL. Chemotherapy accelerated SPM development but did not increase its incidence risk. CONCLUSION: Overall, patients after pediatric lymphoma can be with high lifetime risk of SPM, and more attention should be paid to SPM-related signs for early detection and intervention.

Innovating Healthcare: The Role of ChatGPT in Streamlining Hospital Workflow in the Future.

ChatGPT is revolutionizing hospital workflows by enhancing the precision and efficiency of tasks that were formerly the exclusive domain of healthcare professionals. Additionally, ChatGPT can aid in administrative duties, including appointment scheduling and billing, which enables healthcare professionals to allocate more time towards patient care. By shouldering some of these responsibilities, ChatGPT has the potential to advance the quality of patient care, streamline departmental efficiency, and lower healthcare costs. Nevertheless, it is crucial to strike a balance between the advantages of ChatGPT and the necessity of human interaction in healthcare to guarantee optimal patient care. While ChatGPT may assume some of the duties of physicians in particular medical domains, it cannot replace human doctors. Tackling the challenges and constraints associated with the integration of ChatGPT into the healthcare system is critical for its successful implementation.

Enhancing Diabetes Self-management and Education: A Critical Analysis of ChatGPT's Role.

ChatGPT, an advanced natural language processing model, holds significant promise in diabetes self-management and education. ChatGPT excels in providing personalized educational experiences by tailoring information to meet individual patient needs and preferences. It aids patients in developing self-management skills and strategies, fostering proactive disease management. Additionally, ChatGPT addresses healthcare access disparities by enabling patients to access educational resources irrespective of their geographic location or physical limitations. However, it is important to acknowledge and address the deficiencies of ChatGPT, such as its limited medical expertise, contextual understanding, and emotional support capabilities. Strategies for optimizing ChatGPT include regular training and updating, integration of healthcare professionals' expertise, improvement in contextual comprehension, and enhancing emotional support. By addressing these limitations and striking a balance between the benefits and limitations, ChatGPT can play a significant role in empowering patients to better understand and manage diabetes. Further research and development are needed to refine ChatGPT's capabilities and address ethical considerations, but its integration in patient education holds the potential to transform healthcare delivery and create a more informed and engaged patient population.

Lung Cancer Stem Cell Markers as Therapeutic Targets: An Update on Signaling Pathways and Therapies.

Cancer stem cells, a relatively small group of self-renewing cancer cells, were first isolated from acute myeloid leukemia. These cells can play a crucial role in tumor metastasis, relapse, and therapy resistance. The cancer stem cell theory may be applied to lung cancer and explain the inefficiency of traditional treatments and eventual recurrence. However, because of the unclear accuracy and illusive biological function of cancer stem cells, some researchers remain cautious about this theory. Despite the ongoing controversy, cancer stem cells are still being investigated, and their biomarkers are being discovered for application in cancer diagnosis, targeted therapy, and prognosis prediction. Potential lung cancer stem cell markers mainly include surface biomarkers such as CD44, CD133, epithelial cell adhesion molecule, and ATP-binding cassette subfamily G member 2, along with intracellular biomarkers such as aldehyde dehydrogenase, sex-determining region Y-box 2, NANOG, and octamer-binding transcription factor 4. These markers have different structures and functions but are closely associated with the stem potential and uncontrollable proliferation of tumor cells. The aberrant activation of major signaling pathways, such as Notch, Hedgehog, and Wnt, may be associated with the expression and regulation of certain lung cancer stem cell markers, thus leading to lung cancer stem cell maintenance, chemotherapy resistance, and cancer promotion. Treatments targeting lung cancer stem cell markers, including antibody drugs, nanoparticle drugs, chimeric antigen receptor T-cell therapy, and other natural or synthetic specific inhibitors, may provide new hope for patients who are resistant to conventional lung cancer therapies. This review provides comprehensive and updated data on lung cancer stem cell markers with regard to their structures, functions, signaling pathways, and promising therapeutic target approaches, aiming to elucidate potential new therapies for lung cancer.

Efficient Generation of an Fah/Rag2 Dual-Gene Knockout Porcine Cell Line Using CRISPR/Cas9 and Adenovirus.

The shortage of human hepatocytes continues to be a significant limitation for the widespread application of hepatocyte transplantation and bioartificial liver (BAL) support therapy. Recombinant activation gene 2 (Rag2) and fumarylacetoacetate hydrolase (Fah)-deficient mice could be highly repopulated with human hepatocytes. However, Fah/Rag2-deficient mice can only produce up to 1 × 108 human hepatocytes per mouse. We hypothesized that 2-10 × 1010 human hepatocytes can be produced per Fah/Rag2-deficient pig, which is an adequate supply for hepatocyte transplantation and BAL therapy. In a novel approach, we used stably transfected Cas9 cells and single-guide RNA adenoviruses containing fluorescent reporters to enrich porcine cells with Fah/Rag2 dual gene mutations. This resulted in the construction of Fah/Rag2 double knockout porcine iliac artery endothelial cells, which were subsequently used for generating Fah/Rag2-deficient pigs.