Metastatic Small-Cell Lung Carcinoma Infiltrating the Heart: A Rare Case Diagnosed Using Imaging Data.

Small-cell lung carcinoma is a high-grade aggressive disease that occurs most commonly in bronchial lung cancer, and metastasis to the heart is extremely rare. The diagnosis of metastatic small-cell lung carcinoma infiltrating the heart remains challenging because of the variability of its clinical presentation. Hereinafter, we reported a case of a 41-year-old man who suffered from small-cell lung cancer that invaded the pulmonary artery. The patient presented with chest tightness, dry cough, and deterioration in exercise tolerance and diagnosed at his imaging data, who had an uneventful recovery after surgical resection of the masses.

Incomplete Unilateral Horner's Syndrome Due to Superior Vena Cava Compression Syndrome Caused by Small Cell Lung Carcinoma.

Incomplete unilateral Horner's syndrome due to central small cell lung cancer (SCLC) with consecutive compression of the superior vena cava has not been reported before. A 56-year-old woman with stage T4,N3(cerv),M1a metastatic central SCLC treated with carboplatin and etoposide developed incomplete Horner's syndrome before receiving the first cycle of chemotherapy. Investigation for ptosis ruled out myasthenic syndrome, myasthenia, primary myopathy, facial palsy, and mitochondrial disorders. After congestion developed in the upper inflow area and compression of the superior vena cava was noted, Horner's syndrome was attributed to superior vena cava compression syndrome (SVCCS). Stenting of the stenosis did not result in a complete resolution of Horner's syndrome. In summary, SVCCS can lead to congestion of the jugular veins and subsequent impairment of the centripetal sympathetic fibers that run along the carotid artery. Compression of the sympathetic fibers can lead to incomplete Horner's syndrome with non-fluctuating and non-exercise-induced ptosis. Clinicians should be aware that Horner's syndrome associated with SCLC may be due not only to a myasthenic syndrome but also, in rare cases, to a focal affection of sympathetic fibers.

Prophylactic cranial irradiation in patients with resected small-cell lung cancer: A systematic review and meta-analysis.

Prophylactic cranial irradiation (PCI) was recommended for limited-stage small-cell lung cancer (SCLC) patients with complete or partial response to primary chemoradiotherapy. But it is still controversial regarding its role in SCLC patients who have had radical resection. This meta-analysis aims to evaluate the efficacy of PCI in resected SCLC patients. We searched PubMed, EMBASE, Web of Science, CENTRAl, and ClinicalTrials for controlled trials and cohort studies regarding PCI in postoperative SCLC patients. The correlation between PCI and post-operative outcomes in SCLC patients, including survival and brain metastasis rate (BMR), was examined using hazard ratios (HRs) and risk ratios with corresponding 95% confidence intervals. Quality of studies was assessed by the Newcastle-Ottawa Scale (NOS), and publication bias was assessed by Begg's test. Meta-analysis of eight studies with 2688 patients in total showed PCI was associated with improved overall survival (OS) for resected SCLC (HR: 0.65, 95% CI: 0.57-0.75, p < 0.01). In addition, subgroup analysis on three studies including 923 patients confirmed the protective role of postoperative PCI in N0 SCLC patients (HR: 0.79, 95% CI: 0.61-0.97, p < 0.05). There was also a significant reduction in BMR in the PCI group pooled from six studies (HR: 0.58, 95% CI: 0.40-0.85, p < 0.01). The use of PCI delayed brain recurrence and improved OS in patients with resected, stage I-III SCLC. Importantly, patients with N0 SCLC can also benefit from postoperative PCI. In future studies, PCI's role in patients with resected N0 SCLC at different T stage may need to be explored.

Deep learning to estimate response of concurrent chemoradiotherapy in non-small-cell lung carcinoma.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is a crucial treatment for non-small cell lung carcinoma (NSCLC). However, the use of deep learning (DL) models for predicting the response to CCRT in NSCLC remains unexplored. Therefore, we constructed a DL model for estimating the response to CCRT in NSCLC and explored the associated biological signaling pathways. METHODS: Overall, 229 patients with NSCLC were recruited from six hospitals. Based on contrast-enhanced computed tomography (CT) images, a three-dimensional ResNet50 algorithm was used to develop a model and validate the performance in predicting response and prognosis. An associated analysis was conducted on CT image visualization, RNA sequencing, and single-cell sequencing. RESULTS: The DL model exhibited favorable predictive performance, with an area under the curve of 0.86 (95% confidence interval [CI] 0.79-0·92) in the training cohort and 0.84 (95% CI 0.75-0.94) in the validation cohort. The DL model (low score vs. high score) was an independent predictive factor; it was significantly associated with progression-free survival and overall survival in both the training (hazard ratio [HR] = 0.54 [0.36-0.80], P = 0.002; 0.44 [0.28-0.68], P < 0.001) and validation cohorts (HR = 0.46 [0.24-0.88], P = 0.008; 0.30 [0.14-0.60], P < 0.001). The DL model was also positively related to the cell adhesion molecules, the P53 signaling pathway, and natural killer cell-mediated cytotoxicity. Single-cell analysis revealed that differentially expressed genes were enriched in different immune cells. CONCLUSION: The DL model demonstrated a strong predictive ability for determining the response in patients with NSCLC undergoing CCRT. Our findings contribute to understanding the potential biological mechanisms underlying treatment responses in these patients.

Metabolomic Profiling of Pulmonary Neuroendocrine Neoplasms.

BACKGROUND/OBJECTIVES: Pulmonary neuroendocrine neoplasms (NENs) account for 20% of malignant lung tumors. Their management is challenging due to their diverse clinical features and aggressive nature. Currently, metabolomics offers a range of potential cancer biomarkers for diagnosis, monitoring tumor progression, and assessing therapeutic response. However, a specific metabolomic profile for early diagnosis of lung NENs has yet to be identified. This study aims to identify specific metabolomic profiles that can serve as biomarkers for early diagnosis of lung NENs. METHODS: We measured 153 metabolites using liquid chromatography combined with mass spectrometry (LC-MS) in the plasma of 120 NEN patients and compared them with those of 71 healthy individuals. Additionally, we compared these profiles with those of 466 patients with non-small-cell lung cancers (NSCLCs) to ensure clinical relevance. RESULTS: We identified 21 metabolites with consistently altered plasma concentrations in NENs. Compared to healthy controls, 18 metabolites were specific to carcinoid tumors, 5 to small-cell lung carcinomas (SCLCs), and 10 to large-cell neuroendocrine carcinomas (LCNECs). These findings revealed alterations in various metabolic pathways, such as fatty acid biosynthesis and beta-oxidation, the Warburg effect, and the citric acid cycle. CONCLUSIONS: Our study identified biomarker metabolites in the plasma of patients with each subtype of lung NENs and demonstrated significant alterations in several metabolic pathways. These metabolomic profiles could potentially serve as biomarkers for early diagnosis and better management of lung NENs.

POU4F3 is a Sensitive and Specific Marker of Merkel Cell Carcinoma.

Although of therapeutic importance, a single sensitive and specific immunostain to distinguish Merkel cell carcinoma (MCC) from mimics is not currently available. In addition, single tumor cells are difficult to detect in sentinel lymph node biopsy. Leveraging publicly available data sets of 9264 solid tumors and over 600,000 single-cell transcriptomes, we identified POU4F3 to be a specific marker of MCC. Analyses of Pan-Cancer RNA bulk sequencing data of 24 tumor types from Tumor Cancer Genomic Atlas (TCGA) datasets as well as non-TCGA SCLC and MCC datasets confirmed POU4F3 specificity for MCC. Single-cell RNA sequencing analyses also confirmed lack of POU4F3 expression in lung small cell carcinoma as well as a variety of normal tissues. Nuclear POU4F3 immunohistochemical expression was noted in 98.7% of 153 MCCs and in only 1.7% of mimics (3 of 180 cases, including 95 small cell carcinomas of which 55 from lung and the remainder from other sites). Three POU4F3-positive non-MCC cases were from lung (2 cases) and vagina (1 case). All 153 tested MCC cases were negative for ASCL1, a key transcriptional regulator highly expressed in SCLC. NeuroD1 was seen in a subset of MCC cases (20.9%, 32/153). POU4F3 immunostain was performed on 29 sentinel lymph nodes and strong POU4F3 nuclear expression facilitated ease of metastasis detection, even single tumor cells. Our study built on prior works shows that POU4F3 to be a sensitive and specific clinical marker of MCC.

Recent treatment patterns and real-world survival following first-line anti-PD-L1 treatment for extensive-stage small cell lung cancer.

BACKGROUND: The landscape of small cell lung cancer (SCLC) has changed since the 2019 and 2020 approvals of anti-PD-L1 atezolizumab and durvalumab for first-line (1L) treatment in combination with chemotherapy. We studied treatment patterns and real-world overall survival (rwOS) following 1L-3L therapy. PATIENTS AND METHODS: A nationwide electronic health record (EHR)-derived de-identified database was used to describe treatment patterns, characteristics, and survival of patients with extensive-stage (ES)-SCLC by 1L anti-PD-L1 treatment. Patients with ES-SCLC who initiated ≥1 line of systemic therapy from 2013 to 2021, with potential follow-up through 2022, were included. RESULTS: Among 9952 patients with SCLC, there were 4308 patients with ES-SCLC treated during the study period who met eligibility criteria. Etoposide + platinum (EP) chemotherapy was most common in the 1L, with addition of anti-PD-L1 therapy to most regimens by 2019. Second-line regimens varied by platinum sensitivity status and shifted from topotecan to lurbinectedin over time. Median rwOS following 1L therapy was 8.3 months (95% CI, 7.9-8.8) in those treated with 1L anti-PD-L1 and 8.0 months (95% CI, 7.8-8.2) in those who were not. Following 2L and 3L, median rwOS was 5.6 (95% CI, 4.9-6.3) and 4.9 months (95% CI, 3.4-6.0), respectively, among 1L anti-PD-L1-treated, and 4.5 (95% CI, 4.2-4.9) and 4.0 months (95% CI, 3.7-4.5), respectively, among those who were not. CONCLUSION: Despite the introduction of frontline anti-PD-L1 therapy, survival remains dismal among patients with ES-SCLC treated in the real-world setting.

The expression of YAP1 and other transcription factors contributes to lineage plasticity in combined small cell lung carcinoma.

Lineage plasticity in small cell lung carcinoma (SCLC) causes therapeutic difficulties. This study aimed to investigate the pathological findings of plasticity in SCLC, focusing on combined SCLC, and elucidate the involvement of YAP1 and other transcription factors. We analysed 100 surgically resected SCLCs through detailed morphological observations and immunohistochemistry for YAP1 and other transcription factors. Component-by-component next-generation sequencing (n = 15 pairs) and immunohistochemistry (n = 35 pairs) were performed on the combined SCLCs. Compared with pure SCLCs (n = 65), combined SCLCs (n = 35) showed a significantly larger size, higher expression of NEUROD1, and higher frequency of double-positive transcription factors (p = 0.0009, 0.04, and 0.019, respectively). Notably, 34% of the combined SCLCs showed morphological mosaic patterns with unclear boundaries between the SCLC and its partner. Combined SCLCs not only had unique histotypes as partners but also represented different lineage plasticity within the partner. NEUROD1-dominant combined SCLCs had a significantly higher proportion of adenocarcinomas as partners, whereas POU2F3-dominant combined SCLCs had a significantly higher proportion of squamous cell carcinomas as partners (p = 0.006 and p = 0.0006, respectively). YAP1 expression in SCLC components was found in 80% of combined SCLCs and 62% of pure SCLCs, often showing mosaic-like expression. Among the combined SCLCs with component-specific analysis, the identical TP53 mutation was found in 10 pairs, and the identical Rb1 abnormality was found in 2 pairs. On immunohistochemistry, the same abnormal p53 pattern was found in 34 pairs, and Rb1 loss was found in 24 pairs. In conclusion, combined SCLC shows a variety of pathological plasticity. Although combined SCLC is more plastic than pure SCLC, pure SCLC is also a phenotypically plastic tumour. The morphological mosaic pattern and YAP1 mosaic-like expression may represent ongoing lineage plasticity. This study also identified the relationship between transcription factors and partners in combined SCLC. Transcription factors may be involved in differentiating specific cell lineages beyond just 'neuroendocrine'.

Complexities in the Diagnosis and Management of Anti-Hu Antibody-Associated Paraneoplastic Syndrome.

Anti-Hu is the most commonly associated antibody in paraneoplastic syndromes (PNS) - mainly secondary to small cell lung cancer (SCLC), breast cancer, thymoma, and lymphoma. This case is about a 65-year-old female patient presenting with slurred speech, headache, and loss of balance for one day. On examination, she was found to have downbeat and bilateral gaze-evoked nystagmus, dysarthria, and bilateral intention tremors. The rest of the neurological examination was unremarkable. Upon investigation, a CT scan showed a pre-sacral mass and a PET scan showed a lobulated soft tissue mesenteric mass at L5/S1, thought to possibly be a gastrointestinal stromal tumour, and mediastinal lymph nodes including right lower pre-tracheal, subcarinal and right hilar lymph nodes. Additionally, paraneoplastic antibody testing was positive for anti-Hu antibodies. She was given a five-day course of intravenous immunoglobulin without significant clinical improvement. The patient was discharged on a fast-track pathway and did not undergo chemotherapy, radiotherapy or surgical resection as the primary tumour could not be diagnosed.  Paraneoplastic antibodies are a family of autoantibodies occurring as a result of malignancy that act to recognize antigens in the brain, resulting in a variety of neurological manifestations. Despite well-known literature on this entity, PNS is notoriously difficult to diagnose and manage. The first step in the management of PNS is to treat the underlying malignancy. Beyond this, the other key component of PNS treatment is immune modulation which may involve immunosuppression with high-dose corticosteroids, IV immunoglobulins, plasma exchange or plasmapheresis. It is therefore important for PNS to be diagnosed early and to adopt a comprehensive multidisciplinary approach to improve the outcomes of those presenting with PNS.

Five-year survival in patients with extensive-stage small cell lung cancer treated with atezolizumab in the Phase III IMpower133 study and the Phase III IMbrella A extension study.

OBJECTIVES: IMbrella A is a Phase III extension study that allowed rollover from Roche/Genentech-sponsored atezolizumab trials, including IMpower133, a Phase I/III trial of first-line atezolizumab or placebo plus carboplatin/etoposide in extensive-stage small cell lung cancer. We report outcomes from an exploratory analysis of IMpower133 with extended time-to-event data for patients who rolled over to IMbrella A. MATERIALS AND METHODS: IMpower133 patients could roll over to IMbrella A to receive atezolizumab 1200 mg intravenously every three weeks if they continued to receive atezolizumab at IMpower133 closure or were in survival follow-up after atezolizumab discontinuation. Overall survival and safety were assessed; only serious adverse events and AEs of special interest were collected in IMbrella A. RESULTS: Eighteen of 26 eligible patients rolled over to IMbrella A. At clinical cutoff (March 16, 2023), median follow-up in the atezolizumab plus carboplatin/etoposide arm (IMpower133 and IMbrella A) was 59.4 months. The three-, four-, and five-year overall survival (95 % CI) estimates were 16 % (11 %-21 %), 13 % (8 %-18 %), and 12 % (7 %-17 %), respectively. In IMbrella A, serious adverse events occurred in three patients (16.7 %), and one adverse event of special interest was reported (grade two hypothyroidism). CONCLUSION: This long-term analysis of patients from IMbrella A previously enrolled in IMpower133 provides the first report of five-year overall survival outcomes in patients with extensive-stage small cell lung cancer treated with first-line cancer immunotherapy and chemotherapy. While limited by small patient numbers and lack of long-term data for the IMpower133 control arm, exploratory overall survival analyses in patients treated with atezolizumab plus carboplatin/etoposide compared favorably with historical data with chemotherapy alone. NCT03148418.

Cytomorphological Features as a Subtyping Tool of Non-Small-Cell Lung Cancer in Brushing Bronchoscopic Samples.

Background and Objective: Nowadays, the separation of adenocarcinomas (ADCs) and squamous cell carcinomas (SCCs) is crucial given that there are new specific targeted therapies. So, the aim of this study was to examine the differences in cytomorphological features between ADC and SCC in bronchoscopic brush samples. Material and Methods: The retrospective study was conducted over a 3-year period at Western Balkan University Hospital. All brushing samples were analysed. According to the histopathological report, patients were classified into ADC and SCC groups. The cytomorphological features analysed in 95 samples were presence of necrosis, cell distribution, nuclear atypia, size of nuclei, and visibility of nucleoli. Statistical analysis was performed in JASP, and P values <0.05 were considered significant. Results: The necrotic background was more frequent in SCC samples. Small clusters sized ≤200 µm were found in 17.95% of samples from the SCC group and 53.57% in the ADC group. Large clusters sized >400 µm were found in 43.59% in the SCC group, while in the ADC group, it was found in 5.36%. There were no differences in nuclear atypia between groups. Nuclei that were >5x lymphocyte size were found more often in samples from ADC than in the SCC group (37.50 vs 10.25%). In 89.75% of samples from the SCC group, nuclei were ≤5x lymphocyte sizes, while in the ADC group, the percentage was 63.5%. Nucleoli were more often visible in samples from the ADC group compared to the SCC group (92.86% vs 64.10%, P < 0,05). Conclusions: Small clusters, large nuclei, and visible nucleoli were more frequent in the ADC group (P < 0.05), while large clusters, small nuclei, and invisible nucleoli were more frequent in the SCC group (P < 0.05).

Methodological and TNM Focus-Based Comparison of EGFR Mutation Status in Non-Small-Cell Lung Carcinomas.

Background: Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung carcinomas (NSCLC) are a frequent class of driver mutations, and tyrosine kinase inhibitor (TKI) therapy provides considerable clinical benefits. Using the most effective and also easiest method for EGFR analysis is cost-effective and time-saving. In this study, we aimed to determine which method could be more effective by comparing the incidences of EGFR mutations in cytological and histological samples which were obtained by different methods also, whether there was a difference in the incidences of EGFR mutations between the primary foci, mediastinal lymph nodes, and distant metastatic foci. Materials and Methods: We retrospectively reviewed 420 cases of cytological materials, small biopsies, and surgical samples reported as NSCLC underwent EGFR analysis in our department between 2016 and 2022. We collected the data and interpreted the results from two different perspectives. Results: We identified 36 EGFR mutations in 362 biopsies (9.94%) and 17 in 58 cytology samples (29.31%). There is a significant difference between the two methods (P = 0.01*). We observed 38 EGFR mutations in 320 primary foci (11.87%), 7 EGFR mutations in 36 mediastinal or subcarinal lymph nodes (19.44%), and 8 EGFR mutations in 64 distant metastatic foci (12.50%). A significant difference was also observed in pleural samples (P = 0.005*). Conclusion: We observed more successful results with cell blocks obtained from liquid-based cytological specimens than with formalin-fixed, paraffin-embedded tissues obtained from resection or otherwise in our clinical routine. Our study results highlight the benefits of cytological specimens in molecular treatments and current therapy modalities.

Correlation between Periostin Expression and Pro-Angiogenic Factors in Non-Small-Cell Lung Carcinoma.

The role of periostin (POSTN) in remodeling the microenvironment surrounding solid tumors and its effect on the tumor cells in non-small-cell lung carcinoma (NSCLC) have not yet been fully understood. The aim of this study was to determine the relationship between POSTN expression (in tumor cells [NSCLC cells] and the tumor stroma) and pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and microvascular density (MVD) in NSCLC. In addition, these associations were analyzed in individual histological subtypes of NSCLC (SCC, AC, and LCC) and their correlations with clinicopathological factors and prognosis were examined. Immunohistochemistry using tissue microarrays (TMAs) was used to assess the expression of POSTN (in tumor cells and cancer-associated fibroblasts [CAFs]) and the pro-angiogenic factors. A significant positive correlation was found between the expression of POSTN (in cancer cells/CAFs) and the expression of the analyzed pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and MVD in the entire population of patients with NSCLC and individual histological subtypes (AC, SCC). In addition, this study found that POSTN expression (in tumor cells/CAFs) increased with tumor size (pT), histopathological grade (G), and lymph-node involvement (pN). In addition, a high expression of POSTN (in tumor cells and CAFs) was associated with shorter survival among patients with NSCLC. In conclusion, a high expression of POSTN (in cancer cells and CAFs) may be crucial for angiogenesis and NSCLC progression and can constitute an independent prognostic factor for NSCLC.

Epidermal growth factor receptor-mutated lung carcinomas with insufficient response to epidermal growth factor receptor inhibitors.

Administration of single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a standard treatment option for metastatic non-small cell lung carcinomas with EGFR exon 19 deletions (ex19del) and L858R substitutions. However, there is a significant interpatient heterogeneity with regard to the degree of the response and its duration. Patients with EGFR ex19del mutation, TP53 wild-type, good performance status, low tumor burden and no circulating tumor DNA (ctDNA) at baseline have the best chances to derive pronounced benefit from TKI therapy. In contrast, subjects with EGFR L858R substitution, mutated TP53, poor overall condition, high tumor volume and detectable ctDNA are generally poor responders to EGFR inhibitors. ctDNA dynamics in the first days or weeks of treatment allows reliable identification of patients, who are very unlikely to derive clinically meaningful benefit from single-agent TKIs. These patients are candidates for clinical trials, which may involve the addition of chemotherapy and antiangiogenic drugs to patients, who failed to achieve immediate benefit from TKI monotherapy.

[Box: see text].

Real-world overall survival after alternative dosing for pembrolizumab in the treatment of non-small cell lung cancer: A nationwide retrospective cohort study with a non-inferiority primary objective.

BACKGROUND: High and increasing expenses on pembrolizumab ask for more cost-effective and sustainable treatment strategies to improve affordability of healthcare. Therefore, a part of the Dutch hospitals implemented an alternative, partially lower, weight-based dosing protocol for pembrolizumab. This provided the unique opportunity to compare the overall survival (OS) of the alternative pembrolizumab dosing protocol to standard dosing using a nationwide registry in non-small cell lung cancer (NSCLC) patients. METHODS: This is a retrospective cohort study with a non-inferiority primary objective. Forty hospitals in the Dutch Medication Audit and Dutch Lung Cancer Audit treated 1966 patients with NSCLC with first line pembrolizumab (mono- or combination therapy) between Jan 1st 2021, and Mar 31st, 2023. Alternative weight-based pembrolizumab dosing (100/150/200 mg Q3W or 200/300/400 mg Q6W) was administered to 604 patients, and 1362 patients received standard pembrolizumab dosing (200 mg Q3W or 400 mg Q6W). A Cox proportional hazard model with selected covariates was used to compare the OS between alternative and standard dosing protocols. The non-inferiority margin was set at a hazard ratio (HR) of 1.2 for OS. Non-inferiority is established by showing that the upper limit of the 95 % confidence interval (CI) of the HR of OS is smaller or equal to 1.2. RESULTS: Distribution of age (66.7 years +/-9.4), sex (45 % female) and treatment combinations were similar for both groups, comorbidity score was higher in the standard group. Median daily dose in the alternative dosing group was 22 % lower compared to the standard dosing group, 7.14 mg/day (interquartile range (IQR):5.48-8.04 mg/day) vs. 9.15 mg/day (IQR:8.33-9.52 mg/day), respectively. Alternative dosing was non-inferior to standard dosing regarding overall survival (adjusted HR 0.83, 95 %CI:0.69-1.003). CONCLUSION: This large, retrospective real-world analysis supports the hypothesis that the alternative, partially lower pembrolizumab dosing protocol in NSCLC maintains treatment effectiveness while reducing treatment costs.

Tetraspanin 3 promotes NSCLC cell proliferation via regulation of ß1 integrin intracellular recycling.

BACKGROUND: The involvement of tetraspanins in cancer development has been widely implicated. In this study, the function and molecular mechanisms of tetraspanin 3 (TSPAN3) in non-small cell lung cancer (NSCLC) cells were explored. METHODS: Tissue samples from patients diagnosed with NSCLC were analyzed by immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) to indicate the involvement of TSPAN3 in cancer progression. In the meantime, we also performed exhaustive mechanistic studies using A549 and H460 cells in vitro through a variety of methods including western blotting, real-time PCR, immunofluorescent staining, coimmunoprecipitation, cell proliferation assay, and nocodazole (NZ) washout assay. Proper statistical analysis was implemented wherever necessary in this study. RESULTS: TSPAN3 was found to be highly expressed in lung cancer cells and tissues. Moreover, high levels of TSPAN3 positively correlated with poor differentiation, lymph node involvement, advanced pathological tumor-node-metastasis stage, and poor prognosis in patients with NSCLC. TSPAN3 showed potential to promote the proliferation of NSCLC cells in vitro and in vivo. Specifically, TSPAN3 was found to interact with ß1 integrin via the LEL domain, thereby facilitating the sorting of ß1 integrin into Rab11a endosomes and promoting ß1 integrin recycling and upregulation. CONCLUSIONS: Our findings reveal TSPAN3 may represent a potentially valuable therapeutic target for NSCLC.

Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial.

BACKGROUND: We report 5-year efficacy and safety outcomes from CheckMate 9LA in patients with metastatic non-small cell lung cancer (mNSCLC) and exploratory analyses in key patient subgroups. METHODS: Adults with stage IV/recurrent NSCLC and no sensitizing EGFR/ALK alterations were randomized to receive nivolumab plus ipilimumab with chemotherapy (n = 361) or chemotherapy (n = 358). Outcomes were assessed in all randomized patients and subgroups. RESULTS: With 57.3 months' minimum follow-up, patients continued to derive overall survival (OS) benefit with nivolumab plus ipilimumab with chemotherapy over chemotherapy (HR, 0.73; 95% CI, 0.62-0.85; 5-year OS rates, 18% vs. 11%), regardless of tumor programmed death ligand 1 (PD-L1) expression (PD-L1 < 1%, 22% vs. 8%; PD-L1 ≥ 1%, 18% vs. 11%), histology (squamous, 18% vs. 7%; non-squamous, 19% vs. 12%), or presence of baseline brain metastases (20% vs. 6%). Five-year duration of response (DOR) rates were 19% versus 8% with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, with consistent benefit across subgroups. Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five-year progression-free survival and DOR rates in 5-year survivors were 55% versus 38% and 59% versus 46%, respectively. No new safety signals were observed in 5-year survivors, regardless of the number of ipilimumab doses received. CONCLUSION: This 5-year update supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy over chemotherapy in patients with mNSCLC, regardless of tumor PD-L1 expression or histology. GOV REGISTRATION: NCT03215706.

Incorporation of whole-body metabolic tumor burden into current prognostic models for non-small cell lung cancer patients with spine metastasis.

BACKGROUND CONTEXT: Numerous prognostic models are utilized for surgical decision and prognostication in metastatic spine tumors. However, these models often fail to consider the whole-body tumor burden into account, which may be crucial for the prognosis of metastatic cancers. A potential surrogate marker for tumor burden, whole-body metabolic tumor burden (wMTB), can be calculated from total lesion glycolysis (TLG) obtained from 18F-Fludeoxyglucose positive emission tomography (18F-FDG PET) images. PURPOSE: We aimed to improve prognostic power of current models by incorporating wMTB for non-small cell lung cancer (NSCLC) patients with spine metastases. DESIGN: Retrospective analysis using a review of electrical medical records and survival data. PATIENT SAMPLE: In this study, we included 74 NSCLC patients with image proven spine metastases. OUTCOME MEASURES: Increase in Integrated Discrimination Improvement (IDI) index after incorporation of wMTB into prognostic scores. METHODS: Enrolled patients' baseline data, cancer characteristics and survival status were retrospectively collected. Five widely used prognostic scores (Tomita, Katagiri, Tokuhashi, Global Spine Tumor Study Group [GSTSG], New England Spine Metastasis Score [NESMS]), and TLG indexes were calculated for all patients. The relationships among survival time, prognostic models and TLG values were analyzed. Improvement of prognostic power was validated by incorporating significant TLG index into significant current models. RESULTS: Among current prognostic models, Tomita (EGFR wild-type), Katagiri, GSTSG and Tokuhashi were significantly related to patient survival. Among TLG indexes, LogTLG3 was significantly related to survival. Incorporation of LogTLG3 into significant prognostic models resulted in positive IDI index until 3 years in all models. CONCLUSION: This study showed that incorporation of wMTB improved prognostic power of current prognostic models of metastatic spine tumors.

Are 19del and L858R really different disease entities?

Clinicians have recognized the similarities and differences between the two subtypes of common epidermal growth factor receptor (EGFR) mutations, but actual treatment strategies have not yet changed. The L858R mutation can be understood by considering the pharmacological conformational plasticity of the receptor protein and the presence of other co-occurring mutations, whether subtypes of EGFR or non-EGFR mutations and differences in downstream signaling pathways. As long as we know that molecular differences lead to biological differences, it is a challenge for all of us that our treatment strategies must change.

[Box: see text].

Diagnostic accuracy of CT and PET/CT radiomics in predicting lymph node metastasis in non-small cell lung cancer.

OBJECTIVES: This study evaluates the accuracy of radiomics in predicting lymph node metastasis in non-small cell lung cancer, which is crucial for patient management and prognosis. METHODS: Adhering to PRISMA and AMSTAR guidelines, we systematically reviewed literature from March 2012 to December 2023 using databases including PubMed, Web of Science, and Embase. Radiomics studies utilizing computed tomography (CT) and positron emission tomography (PET)/CT imaging were included. The quality of studies was appraised with QUADAS-2 and RQS tools, and the TRIPOD checklist assessed model transparency. Sensitivity, specificity, and AUC values were synthesized to determine diagnostic performance, with subgroup and sensitivity analyses probing heterogeneity and a Fagan plot evaluating clinical applicability. RESULTS: Our analysis incorporated 42 cohorts from 22 studies. CT-based radiomics demonstrated a sensitivity of 0.84 (95% CI: 0.79-0.88, p < 0.01) and specificity of 0.82 (95% CI: 0.75-0.87, p < 0.01), with an AUC of 0.90 (95% CI: 0.87-0.92), indicating no publication bias (p-value = 0.54 > 0.05). PET/CT radiomics showed a sensitivity of 0.82 (95% CI: 0.76-0.86, p < 0.01) and specificity of 0.86 (95% CI: 0.81-0.90, p < 0.01), with an AUC of 0.90 (95% CI: 0.87-0.93), with a slight publication bias (p-value = 0.03 < 0.05). Despite high clinical utility, subgroup analysis did not clarify heterogeneity sources, suggesting influences from possible factors like lymph node location and small subgroup sizes. CONCLUSIONS: Radiomics models show accuracy in predicting lung cancer lymph node metastasis, yet further validation with larger, multi-center studies is necessary. CLINICAL RELEVANCE STATEMENT: Radiomics models using CT and PET/CT imaging may improve the prediction of lung cancer lymph node metastasis, aiding personalized treatment strategies. RESEARCH REGISTRATION UNIQUE IDENTIFYING NUMBER (UIN): International Prospective Register of Systematic Reviews (PROSPERO), CRD42023494701. This study has been registered on the PROSPERO platform with a registration date of 18 December 2023. https://www.crd.york.ac.uk/prospero/ KEY POINTS: The study explores radiomics for lung cancer lymph node metastasis detection, impacting surgery and prognosis. Radiomics improves the accuracy of lymph node metastasis prediction in lung cancer. Radiomics can aid in the prediction of lymph node metastasis in lung cancer and personalized treatment.