Pathological complete response to neoadjuvant lorlatinib in a patient with stage IIIA ALK-positive non-small cell lung cancer: a case report.

Background: Given the promising efficacy of targeted therapies in patients with advanced non-small cell lung cancer (NSCLC) harboring oncogenic drivers, its use in adjuvant and even neoadjuvant therapy is increasing. Lorlatinib is a potent brain-penetrating third-generation anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) tyrosine kinase inhibitors (TKIs) with broad ALK mutation coverage. Currently, there is a limited evidence regarding the efficacy of lorlatinib as neoadjuvant therapy in locally advanced NSCLC in the presence of ALK rearrangements. The aim of this case report is to describe a rare case of pathological complete response (pCR) to neoadjuvant lorlatinib in a patient with stage IIIA ALK-positive NSCLC, providing evidence for neoadjuvant targeted therapy. Case Description: A 35-year-old male was pathologically diagnosed with locally advanced stage IIIA (cT2bN2M0) ALK-positive NSCLC. Clinically, the patient had pulmonary nodules in the left inferior lobe, which were enlarged progressively with follow-up, with the largest measuring approximately 4.6 cm × 2.8 cm by computed tomography (CT) scan and we found that the lymph nodes (stations 4L, 7, and 8) were invaded by metastasis. Following a 3-month neoadjuvant treatment with lorlatinib at 100 mg daily, his CT scan demonstrated a partial response (PR). This patient then underwent a left inferior lobectomy with mediastinal lymph node dissection (MLD) and mediastinal cyst resection via video-assisted thoracoscopic surgery (VATS). Postoperative pathology revealed a pCR. This patient continued to receive lorlatinib and remained disease free at his 10-month follow-up. Conclusions: Herein we reported the case of a pCR in stage IIIA ALK-positive NSCLC patient treated with neoadjuvant lorlatinib. Our findings underscore the potential of lorlatinib as a neoadjuvant treatment for resectable ALK-positive NSCLC.

Reduction in Marine Primary Productivity in the Early Cambrian Nanhua Basin, South China.

The Cambrian explosion is represented by a rapid diversification of early animals in which the role of marine primary productivity remains obscure. In this study, we analyzed multiple geochemical data, including TOC, major, and trace elements, in the basinal Yuanjia section, South China. Covariations among TOC, P/Al, CuEF, and NiEF suggest that they could be taken as effective marine productivity proxies in the early Cambrian Nanhua Basin. The similarities of CdEF and Cd/Mo in the Nanhua Basin and modern upwelling settings suggest that they might be effective to track upwelling, where Cd and Mo were mainly controlled by plankton biomass and redox conditions, respectively. Our results indicate that CoEF and Co × Mn were invalid in evaluating upwelling because of the significant effects of water-column redox conditions on Co enrichments in the Nanhua Basin. The decreased TOC, P/Al, CuEF, and NiEF reflect a long-term decline in marine productivity from late age 2 to age 3. In comparison with the published results in the outer shelf (Jinsha, TZS drill core, YJK drill core, and GDM-1 well) and slope areas (TX-1 well), the fall in marine productivity might be common in the early Cambrian Nanhua Basin. Our results exhibit that the reduced marine productivity was accompanied by weakened upwelling, quiet hydrothermal activities, and enhanced local terrestrial fluxes, indicating that variations in marine productivity might be mainly driven by the development of upwelling in the early Cambrian Nanhua Basin. Comparison of marine productivity with fossil records suggests that food availability was sufficient to sustain the Cambrian explosion in the Nanhua Basin. We infer that marine productivity might indirectly stimulate early animal evolution through its significant impact on water-column oxygen levels in the early Cambrian Nanhua Basin.

ADGRE5-centered Tsurv model in T cells recognizes responders to neoadjuvant cancer immunotherapy.

Background: Neoadjuvant immunotherapy with anti-programmed death-1 (neo-antiPD1) has revolutionized perioperative methods for improvement of overall survival (OS), while approaches for major pathologic response patients' (MPR) recognition along with methods for overcoming non-MPR resistance are still in urgent need. Methods: We utilized and integrated publicly-available immune checkpoint inhibitors regimens (ICIs) single-cell (sc) data as the discovery datasets, and innovatively developed a cell-communication analysis pipeline, along with a VIPER-based-SCENIC process, to thoroughly dissect MPR-responding subsets. Besides, we further employed our own non-small cell lung cancer (NSCLC) ICIs cohort's sc data for validation in-silico. Afterward, we resorted to ICIs-resistant murine models developed by us with multimodal investigation, including bulk-RNA-sequencing, Chip-sequencing and high-dimensional cytometry by time of flight (CYTOF) to consolidate our findings in-vivo. To comprehensively explore mechanisms, we adopted 3D ex-vivo hydrogel models for analysis. Furthermore, we constructed an ADGRE5-centered Tsurv model from our discovery dataset by machine learning (ML) algorithms for a wide range of tumor types (NSCLC, melanoma, urothelial cancer, etc.) and verified it in peripheral blood mononuclear cells (PBMCs) sc datasets. Results: Through a meta-analysis of multimodal sequential sc sequencing data from pre-ICIs and post-ICIs, we identified an MPR-expanding T cells meta-cluster (MPR-E) in the tumor microenvironment (TME), characterized by a stem-like CD8+ T cluster (survT) with STAT5-ADGRE5 axis enhancement compared to non-MPR or pre-ICIs TME. Through multi-omics analysis of murine TME, we further confirmed the existence of survT with silenced function and immune checkpoints (ICs) in MPR-E. After verification of the STAT5-ADGRE5 axis of survT in independent ICIs cohorts, an ADGRE5-centered Tsurv model was then developed through ML for identification of MPR patients pre-ICIs and post-ICIs, both in TME and PBMCs, which was further verified in pan-cancer immunotherapy cohorts. Mechanistically, we unveiled ICIs stimulated ADGRE5 upregulation in a STAT5-IL32 dependent manner in a 3D ex-vivo system (3D-HYGTIC) developed by us previously, which marked Tsurv with better survival flexibility, enhanced stemness and potential cytotoxicity within TME. Conclusion: Our research provides insights into mechanisms underlying MPR in neo-antiPD1 and a well-performed model for the identification of non-MPR.

Clinicopathological characteristics and treatment outcomes of advanced SMARCA4-deficient thoracic tumors.

PURPOSE: SMARCA4-deficient thoracic tumors, characterized by distinct clinicopathological, morphological, immunohistochemical, and genetic features, differ significantly from conventional non-small-cell lung carcinomas (NSCLCs). This group encompasses both SMARCA4-deficient NSCLCs (SMARCA4-NSCLCs) and SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs). The efficacy of PD-1 inhibitors in treating SMARCA4-deficient thoracic tumors remains uncertain. METHODS: Medical records of 36 patients diagnosed with stage IIIB, IIIC, or IV SMARCA4-deficient thoracic tumors were analyzed. We assessed the clinical, pathological, and genetic features of these patients through immunohistochemistry (IHC) and a 68-gene panel next-generation sequencing (NGS). We compared the differences between SMARCA4-NSCLCs and SMARCA4-UTs, and evaluated the impact of chemotherapy and immunotherapy on patient outcomes. RESULTS: The majority of patients with SMARCA4-deficient thoracic tumors were heavy-smoking males, averaging 64.6 years in age. IHC predominantly showed weak or negative staining for markers such as TTF-1, CK5/6, p40, synaptophysin, chromogranin A, and CD56, which are often associated with adenocarcinoma, squamous cell carcinoma, and neuroendocrine tumors. The most common genetic mutations identified via NGS included TP53, CDKN2A, KRAS, STK11, NF1, and PTEN. No significant overall survival (OS) difference was observed between SMARCA4-NSCLCs and SMARCA4-UTs (p = 0.366). The median OS for patients treated with chemotherapy (n = 9) was 447 days, while the median OS for patients undergoing PD-1-inhibitor-based therapy (n = 16) was not reached (p = 0.105). CONCLUSION: SMARCA4-deficient thoracic tumors exhibit distinct characteristics from conventional NSCLCs, and PD-1 inhibitors show promise in treating advanced SMARCA4-deficient thoracic tumors.

Neoadjuvant Chemoimmunotherapy Increases Tumor Immune Lymphocytes Infiltration in Resectable Non-small Cell Lung Cancer.

BACKGROUND: Neoadjuvant chemoimmunotherapy treatment (NCIT) has achieved great success for non-small cell lung cancer (NSCLC); however, the intrinsic mechanism underlying this treatment remains unclear. METHODS: Thirty-two patients with stage IIA-IIIC NSCLC who underwent surgery after NCIT were included in this retrospective study. Multiplex immunofluorescence (mIF) staining and image analysis assays were performed on the samples collected before and after NCIT for each patient. RNA analyses was applied to confirm the mIF results. RESULTS: Among the enrolled patients, 14 achieved major pathological response or pathological complete response (pCR) and were defined as the 'response' group, whereas 18 patients did not respond well to NCIT and were defined as the 'nonresponse' group. The results of the mIF assays revealed an overall increase in tumor immune lymphocytes (TILs) after NCIT in the stroma area (p = 0.03) rather than the tumor area (p = 0.86). The percentage of CD8+ T cells and tertiary lymphoid structure counts in both the response and nonresponse groups increased significantly after NCIT compared with before NCIT. CD3+ T cells and FOXP3+ cells decreased significantly in the response group but remained unchanged or increased in the nonresponse group. A comparison of the response and nonresponse groups showed that CD3, FOXP3+ and CD8+/PD-1+ cells before NCIT may serve as predictors of the response to neoadjuvant immunotherapy. The RNA analyses confirmed the mIF results that TILs were elevated after NCIT. CONCLUSIONS: The infiltration of immune cells before NCIT was correlated with pathologic complete response, which enhanced the TILs as a promising predictor for selecting patients who were more likely to benefit from NCIT.