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BACKGROUND: Superior outcomes have been obtained for neoadjuvant treatment with immune checkpoint inhibitors (ICI) plus chemotherapy over neoadjuvant chemotherapy alone, especially in patients with high programmed cell death ligand 1 (PD-L1) expression. However, it is not always possible to obtain sufficient tumor specimens for biomarker testing before surgery. In this study, we explored clinical factors that can predict high PD-L1 expression. METHODS: We retrospectively enrolled 340 lung cancer patients who received pulmonary resection between 2014 and 2023 and who had PD-L1 expression data. Chi-squared tests and logistic regression analyses were used to identify clinical factors associated with high PD-L1 status. RESULTS: Univariable and multivariable analyses revealed that smoking, high maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT), and high plasma fibrinogen are independent predictors of high PD-L1 expression. A predictive score for high PD-L1 expression (ranging from 0 to 3) was developed based on these parameters. Notably, only 5% of patients with a score of 0 exhibited high PD-L1 expression, whereas this proportion increased to 53% for patients with a score of 3. CONCLUSION: These results showed that plasma fibrinogen, smoking history, and SUVmax are predictors of high PD-L1 expression, providing a basis for identifying patients expected to benefit from neoadjuvant ICI treatment.

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The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS(OFF)). The KRASG12C mutation results in the accumulation of KRASG12C(OFF), promoting cell cycle survival and proliferation primarily through the canonical MAPK and PI3K pathways. The KRASG12C mutation is found in 13% of lung adenocarcinomas. Previously considered undruggable, sotorasib and adagrasib are the first available OFF-state KRASG12C inhibitors, but treatment resistance is frequent. In this review, after briefly summarizing the KRAS pathway and the mechanism of action of OFF-state KRASG12C inhibitors, we discuss primary and acquired resistance mechanisms. Acquired resistance is the most frequent, with "on-target" mechanisms such as a new KRAS mutation preventing inhibitor binding; and "off-target" mechanisms leading to bypass of KRAS through gain-of-function mutations in other oncogenes such as NRAS, BRAF, and RET; or loss-of-function mutations in tumor suppressor genes such as PTEN. Other "off-target" mechanisms described include epithelial-to-mesenchymal transition and histological transformation. Multiple co-existing mechanisms can be found in patients, but few cases have been published. We highlight the lack of data on non-genomic resistance and the need for comprehensive clinical studies exploring histological, genomic, and non-genomic changes at resistance. This knowledge could help foster new treatment initiatives in this challenging context.

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The 24 claudin (CLDN) genes in the human genome encode 26 representative CLDN family proteins. CLDNs are tetraspan­transmembrane proteins at tight junctions. Because several CLDN isoforms, such as CLDN6 and CLDN18.2, are specifically upregulated in human cancer, CLDN­targeting monoclonal antibodies (mAbs), antibody­drug conjugates (ADCs), bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells have been developed. In the present review, CLDN1­, 4­, 6­ and 18.2­targeting investigational drugs in clinical trials are discussed. CLDN18.2­directed therapy for patients with gastric and other types of cancer is the most advanced area in this field. The mouse/human chimeric anti­CLDN18.2 mAb zolbetuximab has a single­agent objective response rate (ORR) of 9%, and increases progression­free and overall survival in combination with chemotherapy. The human/humanized anti­CLDN18.2 mAb osemitamab, and ADCs AZD0901, IBI343 and LM­302, with single­agent ORRs of 28­60%, have been tested in phase III clinical trials. In addition, bsAbs, CAR T cells and their derivatives targeting CLDN4, 6 or 18.2 are in phase I and/or II clinical trials. AZD0901, IBI343, zolbetuximab and the anti­CLDN1 mAb ALE.C04 have been granted fast track designation or priority review designation by the US Food and Drug Administration.

Asunto(s)

Claudinas , Neoplasias , Humanos , Claudinas/metabolismo , Claudinas/genética , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Animales , Isoformas de Proteínas/genética , Terapia Molecular Dirigida/métodos , Claudina-4/metabolismo , Claudina-4/genética , Claudina-1/metabolismo , Claudina-1/genética , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico

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Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the Transwell cell migration and invasion assay data shown in Fig. 3B were strikingly similar to data appearing in different form in a pair of other articles written by different authors at different research institutes, one of which had already been published elsewhere prior to the submission of this paper to International Journal of Molecular Medicine, and one of which was under consideration for publication at around the same time. In view of the fact that the abovementioned data had already apparently been published previously, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 48: 147, 2021; DOI: 10.3892/ijmm.2021.4980].

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Lung cancer is increasingly recognized as a leading cause of cancer­related mortality. Immunotherapy has emerged as a promising therapeutic approach for lung cancer, particularly non­small cell lung cancer (NSCLC). Nonetheless, the response rate to programmed cell death 1 (PD­1) inhibitors remains less than optimal. It has been suggested that protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in the development and progression of cancer by facilitating T cell expansion and cytotoxicity. Our previous research demonstrated that the combination of tumor necrosis factor receptor 2 (TNFR2) with immune activity treatments synergistically suppresses tumor growth. This insight led to exploring the efficacy of a combined treatment strategy involving PD­1 inhibitors, PTP1B inhibitors and TNFR2 antibodies (triple therapy) in NSCLC. In this context, the therapeutic effectiveness of these combination immunotherapies was validated in mouse models with NSCLC by analyzing the expansion and function of immune cells, thereby assessing their impact on tumor growth. The results indicated that inhibiting PTP1B decreases the expression of PD­L1 and TNFR2 on LLC cells, along with an increase in the proportion of CD4+T and CD8+T cells. Compared with other treatment groups, the triple therapy significantly reduced tumor volume in mice with NSCLC and extended their survival. Moreover, this combination therapy altered the distribution of myeloid­derived suppressor cells, dendritic cells, B cells and M1 macrophages, while increasing the proportion of CD8+T cells and reducing the proportion of Treg cells in the spleens, lymph nodes, and tumors of NSCLC models. The triple therapy also resulted in a decrease in PD­L1, PTP1B and TNFR2 expression within NSCLC tumor tissues in mice. Overall, the triple therapy effectively suppressed tumor growth and improved outcomes in mice with NSCLC by modulating immune cell distribution and reducing levels of target immune proteins.

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Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Receptor de Muerte Celular Programada 1 , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Receptores Tipo II del Factor de Necrosis Tumoral , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Ratones , Receptores Tipo II del Factor de Necrosis Tumoral/antagonistas & inhibidores , Receptores Tipo II del Factor de Necrosis Tumoral/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Humanos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Inmunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología

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BACKGROUND: Small cell lung cancer (SCLC) is the most aggressive neuroendocrine lung cancer, with a dismal 5-year survival rate. No reliable biomarkers or imaging are available for early SCLC detection. In a search for a specific marker of SCLC, this study identified that hepatocyte cell adhesion molecule 2 (HEPACAM2), a member of the immunoglobulin-like superfamily, is highly and specifically expressed in SCLC. METHODS: This study investigated HEPACAM2 expression in patients with SCLC via RNA sequencing and evaluated its relationship to progression-free survival (PFS) and overall survival (OS). Immunofluorescence microscopy was used to assess the cellular location of HEPACAM2 and to conduct in vitro and in vivo studies to understand its expression and functional significance. These findings were integrated with databases of patients with SCLC. RESULTS: HEPACAM2 is highly expressed and specific to SCLC. HEPACAM2 levels are inversely correlated with PFS and OS in patients with SCLC and are expressed at all stages. Moreover, HEPACAM2 messenger RNA and its peptides can be detected in the secretomes in cell lines. Positively correlated with ASCL1 expression in SCLC tumors, HEPACAM2 is localized primarily to the plasma membrane and linked to extracellular matrix signaling and cellular migration. A loss of HEPACAM2 in SCLC cells attenuated ASCL1 and MYC expression. Consistent with clinical data, in vitro and in vivo studies suggested that HEPACAM2 promotes cancer cell growth. CONCLUSIONS: With its remarkable specificity, high expression, presence in early disease, and extracellular secretion, HEPACAM2 could be a potential diagnostic cell surface biomarker for early SCLC detection. These findings warrant further investigation into its role in the pathobiology of SCLC.

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OBJECTIVE: To explore the survival effect of thoracic gross tumor volume (GTV) in three-dimensional (3D) radiotherapy for stage IV non-small cell lung cancer (NSCLC). METHODS: The data cases were obtained from a single-center retrospective analysis. From May. From 2008 to August 2018, 377 treatment criteria were enrolled. GTV was defined as the volume of the primary lesion and the hilus as well as the mediastinal metastatic lymph node. Chemotherapy was a platinum-based combined regimen of two drugs. The number of median chemotherapy cycles was 4 (2-6), and the cut-off value of the planning target volume (PTV) dose of the primary tumor was 63 Gy (30-76.5 Gy). The cut-off value of GTV volume was 150 cm3 (5.83-3535.20 cm3). RESULTS: The survival rate of patients with GTV <150 cm3 is better than patients with GTV ≥150 cm3. Multivariate Cox regression analyses suggested that peripheral lung cancer, radiation dose ≥63 Gy, GTV <150 cm3, 4-6 cycles of chemotherapy, and CR + PR are good prognostic factors for patients with stage IV non-small cell lung cancer. The survival rate of patients with GTV <150 cm3 was longer than patients with ≥150 cm3 when they underwent 2 to 3 cycles of chemotherapy concurrent 3D radiotherapy (p < 0.05). When performing 4 to 6 cycles of chemotherapy concurrent 3D radiotherapy, there was no significant difference between <150 cm3 and ≥150 cm3. CONCLUSIONS: The volume of stage IV NSCLC primary tumor can affect the survival of patients. Appropriate treatment methods can be opted by considering the volume of tumors to extend patients' lifetime to the utmost.

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Carcinoma de Pulmón de Células no Pequeñas , Quimioradioterapia , Neoplasias Pulmonares , Estadificación de Neoplasias , Carga Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Femenino , Quimioradioterapia/métodos , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Pronóstico , Tasa de Supervivencia

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Non-small cell lung cancer (NSCLC) that is operable still carries a high risk of recurrence, approaching 50% of all operable cases despite adding adjuvant chemotherapy. However, the utilization of immunotherapy and targeted therapy moving beyond the metastatic NSCLC setting and into early-stage perioperative management has generated tremendous enthusiasm and has been practice-changing. Adjuvant atezolizumab in NSCLC first demonstrated a clinical benefit with an immune checkpoint inhibitor. Then, with studies studying a significant benefit in major pathologic response in surgical patients treated preoperatively with immunotherapy compared to only chemotherapy, neoadjuvant nivolumab and chemotherapy were evaluated and showed significant event-free survival benefit leading to subsequent studies evaluating perioperative immunotherapy and chemotherapy. Meanwhile, with regards to targeted therapies, adjuvant osimertinib in EGFR-mutated NSCLC and adjuvant alectinib in ALK-rearranged NSCLC have both received regulatory approvals following demonstrated clinical benefit in clinical trials. With rapidly evolving changes in the field, new combinations such as multiple immunotherapy agents and antibody-drug conjugates in development, perioperative NSCLC management has quickly become complicated with different pathways to perioperative treatment. Furthermore, circulating tumor DNA and studies looking at better tools to prognosticate immunotherapy response will help with decision-making regarding which patients should receive immunotherapy and if so, either only pre-operatively or both pre- and post-operatively. In this review, we look at the evolution of systemic therapy in the perioperative setting from adjuvant chemotherapy to adjuvant immunotherapy to perioperative immunotherapy and look at perioperative targeted therapy while looking ahead to future considerations.

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Objective: To compare and analyze the clinical effects of thoracoscopic lobectomy and segmentectomy in stage I non-small cell lung cancer (NSCLC). Method: This was a retrospective study. Eighty patients with stage I NSCLC treated in Cangzhou People's Hospital from December 2019 to January 2022 were randomly divided into the segmentectomy group and lobectomy group, with 40 cases in each group. Further comparative analysis was carried out focusing on perioperative indexes, maximum ventilation volume (MVV), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), VAS score of postoperative pain and complications. Result: There was no significant difference in the number of dissected lymph nodes and extubation time between the two groups (p>0.05). The operation time was longer, while intraoperative blood loss was less and the stay of stay in hospital was shorter in the segmentectomy group significantly than those in the lobectomy group (p<0.05). Furthermore, no significant difference was observed in MVV%, FVC% and FEV1% between the two groups before operation (p>0.05). Meanwhile, the segmentectomy group had evidently lower VAS scores at 1 d, 3 d and 5 d postoperatively than those in the lobectomy group (p<0.05). Besides, there was a much lower total incidence of complications in the segmentectomy group than that in the lobectomy group (p<0.05). Conclusion: Compared with lobectomy, thoracoscopic segmentectomy is more effective in the treatment of stage I NSCLC, with less bleeding and mild pain, which can alleviate pulmonary function injury and reduce postoperative complications that is conducive to the improved prognosis of patients.

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Objective: To evaluate the efficacy and safety of Apatinib combined with epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) in the treatment of patients with non-small cell lung cancer (NSCLC) and acquired EGFR-TKI resistance. Methods: Clinical records of 106 patients with NSCLC at Shanxi Tumor Hospital of the Chinese Academy of Medical Sciences Cancer Hospital from January 2017 to October 2020, with acquired drug resistance after EGFR-TKI treatment were retrospectively analyzed. Among them, 52 patients received Apatinib combined with EGFR-TKI (Apatinib group), and 54 patients received a standard chemotherapy (pemetrexed combined with platinum) (chemotherapy group). Clinical efficacy indicators, follow-up results, and adverse reactions in both groups were compared. Results: There was no significant difference in the objective response rate and disease control rate between the two groups (P>0.05). The progression free survival (PFS) of the Apatinib group was significantly longer than that of the chemotherapy group (10.5 months vs. 5.7 months; P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). Conclusions: Compared with standard chemotherapy, Apatinib combined with EGFR-TKI has the same efficacy in treating NSCLC patients with EGFR-TKI resistance, and was associated with longer PFS with no significant increase in adverse reactions.

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Acute generalized exanthematous pustulosis, an infrequent adverse drug reaction, mainly results from drugs. Clinically, acute generalized exanthematous pustulosis manifests as a high fever, with skin lesions of small monomorphic subcorneal sterile pustules on an erythematous that presents at 1-4 days after medication exposure. The incidence of acute generalized exanthematous pustulosis varies from 3/1, 000, 000 to 5/1, 000, 000, while the mortality rate is typically around 5%. We present a case of a 69-year-old female who developed a diffuse, erythematous, pustular rash over the entire body and exhibited a fever of 38.3°C after 4 days of icotinib therapy. Considering her medication history and the appearance of the lesions, she was diagnosed with acute generalized exanthematous pustulosis and received appropriate treatment. We also conducted a literature review through PubMed to compare similarities and differences between our case and those reported in the literature.

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Introduction: Osimertinib, a third-generation EGFR-TKI, is known for its high efficacy against brain metastases (BM) in non-small cell lung cancer (NSCLC) due to its ability to penetrate the blood-brain barrier. This study aims to evaluate the use of brain MRI radiomics in predicting the intracranial efficacy to osimertinib in NSCLC patients with BM. Materials and methods: This study analyzed 115 brain metastases from NSCLC patients with the EGFR-T790M mutation treated with second-line osimertinib. The primary endpoint was intracranial response, and the secondary endpoint was intracranial progression-free survival (iPFS). We performed tumor delineation, image preprocessing, and radiomics feature extraction. Using a 5-fold cross-validation strategy, we built radiomic models with eight feature selectors and eight machine learning classifiers. The models' performance was evaluated by the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis. Results: The dataset of 115 brain metastases was divided into training and validation sets in a 7:3 ratio. The radiomic model utilizing the mRMR feature selector and stepwise logistic regression classifier showed the highest predictive accuracy, with AUCs of 0.879 for the training cohort and 0.786 for the validation cohort. This model outperformed a clinical-MRI morphological model, which included age, ring enhancement, and peritumoral edema (AUC: 0.794 for the training cohort and 0.697 for the validation cohort). The radiomic model also showed strong performance in calibration and decision curve analyses. Using a radiomic-score threshold of 199, patients were classified into two groups with significantly different median iPFS (3.0 months vs. 15.4 months, p < 0.001). Conclusion: This study demonstrates that MRI radiomics can effectively predict the intracranial efficacy of osimertinib in NSCLC patients with brain metastases. This approach holds promise for assisting clinicians in personalizing treatment strategies.

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Background: Few research has explored the risk of distant metastasis dynamically changes with age in non-small cell lung cancer patients. The objective of this study was to explore the risk factors of developing distant metastasis with changing age. Methods: This retrospective cohort study was based on a large population of patients with non-small cell lung cancer from the SEER database. Logistic regression was applied to identify risk factors for distant metastasis. The clinicopathological features were compared between the young group (≤50 years old) and the old group (>50 years old). Dose-response analyses were conducted to explore risk of distant metastasis changes with age. Results: A total of 18,711 patients were studied in this study. According to the univariate and multivariate logistic regression analyses, ten factors were found to be risk factors for distant metastasis. Young patients have a greater incidence of each pattern of metastasis. However, the survival time of younger patients was longer. Dose-response analyses indicated that the risks of pleural or pericardial metastasis and overall distant metastasis gradually decreased with age at younger ages, but they intend to increase at older ages. Conclusions: Age, sex, ethnicity, histology, T category, N category, differentiation grade, primary site of the tumor, ipsilateral metastases are factors associated with distant metastasis in NSCLC patients. Young patients have a greater risk of distant metastasis. The distant metastasis may decrease with the increasing age in patients younger than 70 years, but increase with the climb of age for patients older than 70 years.

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Purpose: There exists a dearth of research concerning non-small cell lung cancer (NSCLC) patients experiencing overall progressive disease concomitant with shrinking lesions after immunotherapy. This is a special type of mixed response. We aim to evaluate the clinical characteristics and treatment options of these patients during immunotherapy. Patients and Methods: We categorized patients into two groups: Progressive Disease with Mixed Responses (PDMR) (n = 31) and Progressive Disease with None Mixed Responses (PDNMR) (n = 144), depending on whether at least one target lesion had shrunk by ≥30% at the point of overall progression. Computed tomography scans and magnetic resonance imaging were utilized to evaluate the clinicopathological significance of these patients, and a multivariate analysis was conducted to scrutinize the clinical characteristics and prognosis-influencing factors in these patients. Results: Patients in the PDMR group had worse staging and a greater proportion of previous radiotherapy. The median overall survival (mOS 22 vs 36.4 months; P = 0.019) and median progression-free survival (mPFS 5.83 vs 9.03 months; P = 0.031) of the PDMR group were shorter than PDNMR group. Longer subsequent OS with continued immunotherapy after PDMR compared with patients who do not continue with immunization after PDMR (mOS 23.9 vs 6.5 months; P = 0.024). Conclusion: PDMR was primarily observed in stage IV patients and previously irradiated patients. OS and PFS were inferior in patients with PDMR compared to patients with PDNMR. The continuation of immunotherapy in PDMR patients could extend their survival.

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Background: Sasanlimab (PF-06801591), a humanized immunoglobulin G4 monoclonal antibody, binds to programmed cell death protein-1 (PD-1), preventing ligand (PD-L1) interaction. Objectives: To evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of two subcutaneous sasanlimab dosing regimens. Design: An open-label study consisting of phases Ib and II. Phase Ib: non-randomized, dose escalation, and expansion study in Asian participants with advanced malignancies. Phase II: conducted globally in participants with non-small-cell lung cancer with PD-L1 positive or PD-L1 status unknown tumors; participants were randomized 1:2 to receive subcutaneous sasanlimab 300 mg once every 4 weeks (300 mg-Q4W) or 600 mg once every 6 weeks (600 mg-Q6W). Methods: Primary endpoint in phase Ib: dose-limiting toxicity (DLT) occurring in first treatment cycle; in phase II: C trough and AUC. Results: A total of 155 participants (phase Ib, n = 34; phase II, n = 121) received sasanlimab. Phase Ib: no DLT reported. Phase II: ratio of adjusted geometric mean for AUCtau was 231.2 (90% CI, 190.1-281.2) and C trough was 111.5 (90% CI, 86.3-144.0) following 600 mg-Q6W (test) versus 300 mg-Q4W (reference). Phase Ib: grade 3 treatment-related adverse events (TRAEs) occurred in 1/4 (25%) and 3/12 (25%) participants treated in 300 mg-Q4W dose escalation and expansion cohorts, respectively. Phase II: grade 3 TRAEs occurred in 3/41 (7.3%) and 3/80 (3.8%) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively; no grade 4/5 TRAEs. Phase II: confirmed objective response was observed in 11/41 (26.8% (95% CI, 14.2-42.9)) and 12/80 (15.0% (95% CI, 8.0-24.7)) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively. Conclusions: Phase Ib regimens were considered safe with no DLTs reported. In phase II, 600 mg-Q6W regimen criteria were met for AUCtau and C trough metrics to support PK-based extrapolation of efficacy of alternative regimen. Regimens were well tolerated, showing anti-tumor activity in participants with advanced solid tumors. Administration of sasanlimab at a dose of 600 mg-Q6W subcutaneously may serve as a convenient alternative to 300 mg-Q4W administration. Trial registration: NCT04181788 (ClinicalTrials.gov); 2019-003818-14 (EudraCT).

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Objective: PIK3CA-mutant non-small-cell lung cancer (NSCLC) is associated with other genetic mutations and may influence treatment strategies and clinical outcomes. We aimed to characterize PIK3CA mutations co-occurring with several major driver mutations using data from published cohorts and our medical center. Materials and Methods: We analyzed NSCLC patients harboring PIK3CA mutations from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering (MSK) databases and retrospectively identified NSCLC patients with PIK3CA-mutants at a single medical center from our electronic records. The Log rank test was used to determine the association between PIK3CA mutations and overall survival (OS) in NSCLC patients. Results: Common hotspot mutations in PIK3CA were found in exon 9 (c.1633G > A, E545K, and c.1624G > A, E542K) and exon 20 (c.3140A > G, H1047R) in all cohorts. Co-occurring mutations of PIK3CA with EGFR, KRAS, and TP53 have been frequently observed in patients with NSCLC, with different percentages in these datasets generated by different background. PIK3CA mutations were observed to be significantly associated with poor OS in lung adenocarcinomas patients in the MSKCC cohort (hazard ratio [HR] = 0.519, 95% confidence interval [CI] = 0.301-0.896; P <0.05). Conclusion: PIK3CA co-occurring mutations in other genes may represent distinct subsets of NSCLC. Further elucidation of the roles of PIK3CA hotspot mutations combined with other driver mutations, including EGFR and KRAS, is needed to guide effective treatment in patients with advanced NSCLC.

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Cauda equina syndrome (CES) is a rare condition describing the constellation of symptoms resulting from the compression of the cauda equina. Metastatic lesions are a common cause of CES, with lung lesions often implicated as the primary source. A particularly rare cause of CES is leptomeningeal metastasis (LM) from primary solid tumors. In this case, a 63-year-old male presented with urinary and fecal retention, as well as altered sensation in the genitalia. The clinical diagnosis of CES was based on the constellation of symptoms. Computed tomography (CT) imaging demonstrated a metastatic lesion in the S2 and S3 sacral vertebral bodies, with extension into the right piriformis muscle. Magnetic resonance imaging (MRI) revealed an intramedullary lesion at L2 and leptomeningeal enhancement, indicative of metastasis. Further imaging identified a primary lesion in the right lower lobe of the lung, with additional metastases to the brain and liver. A pathological diagnosis of metastatic neuroendocrine carcinoma (NEC) was confirmed following a supraclavicular lymph node biopsy. The patient received steroid therapy, chemotherapy, and radiation to the pelvis. This case provides an important perspective on CES evaluation due to the scarcity of literature highlighting spinal metastases as the primary presentation in patients with NEC of the lung. The clinical diagnosis of CES should raise suspicion for metastasis and warrant further investigation.

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Background: Liquid biopsy-based biomarkers, including circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB), are recognized as promising predictors of prognoses and responses to immune checkpoint inhibitors (ICIs), despite insufficient sensitivity of single biomarker detection. This research aims to determine whether the combinatorial utility of longitudinal ctDNA with bTMB analysis could improve the prognostic and predictive effects. Methods: This prospective two-center cohort trial, consisting of discovery and validation datasets, enrolled unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) patients and assigned them to chemoradiotherapy (CRT) or CRT + consolidation ICI cohorts from 2018 to 2022. Blood specimens were collected pretreatment, 4 weeks post-CRT, and at progression to assess bTMB and ctDNA using 486-gene next-generation sequencing. Dynamic ∆bTMB was calculated as post-CRT bTMB minus baseline bTMB levels. Decision curve analyses were performed to calculate Concordance index (C-index). Results: One hundred twenty-eight patients were enrolled. In the discovery dataset (n = 73), patients treated with CRT and consolidation ICI had significantly longer overall survival (OS; median not reached [NR] vs 20.2 months; P < 0.001) and progression-free survival (PFS; median 25.2 vs 11.4 months; P = 0.011) than those without ICI. Longitudinal analysis demonstrated a significant decrease in ctDNA abundance post-CRT (P < 0.001) but a relative increase with disease progression. Post-CRT detectable residual ctDNA correlated with significantly shorter OS (median 18.3 months vs NR; P = 0.001) and PFS (median 7.3 vs 25.2 months; P < 0.001). For patients with residual ctDNA, consolidation ICI brought significantly greater OS (median NR vs 14.8 months; P = 0.005) and PFS (median 13.8 vs 6.2 months; P = 0.028) benefit, but no significant difference for patients with ctDNA clearance. Dynamic ∆bTMB was predictive of prognosis. Patients with residual ctDNA and increased ∆bTMB (∆bTMB > 0) had significantly worse OS (median 9.0 vs 23.0 months vs NR; P < 0.001) and PFS (median 3.4 vs 7.3 vs 25.2 months; P < 0.001). The combinatorial model integrating post-CRT ctDNA with ∆bTMB had optimal predictive effects on OS (C-index = 0.723) and PFS (C-index = 0.693), outperforming individual features. In the independent validation set, we confirmed residual ctDNA predicted poorer PFS (median 50.8 vs 14.3 months; P = 0.026) but identified more consolidation ICI benefit (median NR vs 8.3 months; P = 0.039). The combined model exhibited a stable predictive advantage (C-index = 0.742 for PFS). Conclusions: The multiparameter assay integrating qualitative residual ctDNA testing with quantitative ∆bTMB dynamics improves patient prognostic risk stratification and efficacy predictions, allowing for personalized consolidation therapy for LA-NSCLC.

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Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. Despite advances in treatment, prognosis remains poor, necessitating the identification of reliable prognostic biomarkers. Costimulatory molecules (CMs) have shown to enhance antitumor immune responses. We aimed to explore their prognostic signals in NSCLC. Methods: This study is a combination of bioinformatics analysis and laboratory validation. Gene expression profiles from The Cancer Genome Atlas (TCGA), GSE120622, and GSE131907 datasets were collected. NSCLC samples in TCGA were clustered based on CMs using consensus clustering. We used LASSO regression to identify CMs-related signatures and constructed nomogram and risk models. Differences in immune cells and checkpoint expressions between risk models were evaluated. Enrichment analysis was performed for differentially expressed CMs between NSCLC and controls. Key results were validated using qRT-PCR and flow cytometry. Results: NSCLC samples in TCGA were divided into two clusters based on CMs, with cluster 1 showing poor overall survival. Ten CMs-related signatures were identified using LASSO regression. NSCLC samples in TCGA were stratified into high- and low-risk groups based on the median risk score of these signatures, revealing differences in survival probability, drug sensitivity, immune cell infiltration and checkpoints expression. The area under the ROC curve values (AUC) for EDA, ICOS, PDCD1LG2, and VTCN1 exceeded 0.7 in both datasets and considered as hub genes. Expression of these hub genes was significance in GSE131907 and validated by qRT-PCR. Macrophage M1 and T cell follicular helper showed high correlation with hub genes and were lower in NSCLC than controls detected by flow cytometry. Conclusion: The identified hub genes can serve as prognostic biomarkers for NSCLC, aiding in treatment decisions and highlighting potential targets for immunotherapy. This study provides new insights into the role of CMs in NSCLC prognosis and suggests future directions for clinical research and therapeutic strategies.

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BACKGROUND: Gastrointestinal tract metastasis from lung cancer is rare and compared to small cell lung cancer (SCLC), non-SCLC (NSCLC) is even less likely to metastasize in this manner. Additionally, small intestinal tumors can also present with diverse complications, some of which require urgent intervention. CASE SUMMARY: In this report, we detail a unique case of stage IV lung cancer, where the presence of small intestine tumors led to intussusception. Subsequent to a small intestine resection, pathology confirmed that all three tumors within the small intestine were metastases from adenocarcinoma of the lung. The postoperative follow-up period extended beyond 14 mo. CONCLUSION: In patients with stage IV NSCLC, local tumor control can be achieved with various treatments. However, if small intestinal metastasis occurs, surgical intervention remains necessary, as it may improve survival.