Advanced Stage Lung Cancer Patients Research Articles

IL-33/NF-κB/ST2L/Rab37 positive-feedback loop promotes M2 macrophage to limit chemotherapeutic efficacy in lung cancer

IL-33 is a danger signal that binds to its receptor ST2L to promote tumor progression. This study identifies the IL-33/ST2L positive-feedback loop and the trafficking of ST2L membrane presentation in macrophages that contribute to lung tumor progression. Mechanistically, IL-33 induces ST2L upregulation by activating NF-κB, which binds to the promoter region of the ST2L gene. Moreover, Rab37, a small GTPase involved in membrane trafficking, mediates ST2L trafficking to the plasma membrane of M2 macrophages. This IL-33/NF-κB/ST2L/Rab37 axis promotes positive-feedback loops that enhance ST2L expression and membrane trafficking in M2 macrophages. Notably, neutralizing antibodies against IL-33 or ST2L block NF-κB activity, suppress M2 macrophage polarization, and synergistically inhibit tumor growth when combined with cisplatin treatment in vitro/vivo. Clinically, Rab37+/ST2L+/CD206+ tumor-infiltrating M2 macrophages correlate with advanced-stage lung cancer patients with poor response to chemotherapy. These findings unveil a positive-feedback mechanism and provide a basis for IL-33/ST2L-targeting therapy for cancer.

Factors Associated with Procedure-related Tumor Seeding in Advanced Stage Lung Cancer Patients with Malignant Pleural Effusions

Objective: Pleural procedure-related tumor seeding detected by computed tomography (CT) is common in lung cancer patients with malignant pleural effusion. This study aimed to identify the incidence of tumor seeding and the associated factors among lung cancer patients with malignant pleural effusions. Material and Methods: This retrospective cohort study was conducted on 146 lung cancer patients with malignant pleural effusions, diagnosed between 2010 and 2017, who underwent at least 1 pleural procedure and had at least 2 series of CT images. The potential factors were categorized into clinical characteristics, pleural characteristics, treatment factors, and pleural procedures. Incidence rate ratios (IRR) were analyzed by Poisson regression to identify factors that were independently associated with tumor seeding. Results: The incidence of procedure-related tumor seeding was 26%. Significantly increased IRRs of tumor seeding were found in relation to 1 time (IRR 5.653, 95% confidence interval [CI] 2.549 to 12.538) and ≥2 times of conventional intercostal chest drainage (ICD) insertion (IRR 5.837, 95% CI 1.768 to 19.266), 1 time (IRR 8.924, 95% CI 3.181 to 25.033) and ≥2 times of pleural biopsy (IRR 6.485, 95% CI 1.372 to 30.660), adenocarcinoma (IRR 8.329, 95% CI 2.804 to 24.747), and pleural thickening (IRR 12.458, 95% CI 1.360 to 114.152). Conclusion: Patients who had at least one pleural biopsy or ICD insertion, pleural fluid cytology positive or suspicious for malignancy, adenocarcinoma, or pleural thickening were found to be significantly at risk for tumor seeding.

Myeloid-derived suppressor cells from tumour-bearing mice induce the population expansion of CD19hiFcγRIIbhi regulatory B cells via PD-L1.

Myeloid-derived suppressor cells (MDSCs) increase in number and gain immunosuppressive functions in tumours and many other pathological conditions. MDSCs are characterized by their strong T-cell immunosuppressive capacity. The effects that MDSCs may have on B cells, especially within the tumour microenvironment, are less well understood. Here, we report that either monocytic MDSCs or polymorphonuclear MDSCs can promote increases in interleukin (IL)-10-expressing CD19hiFcγRIIbhi regulatory B cells in vitro and in vivo. Splenic transitional-1, -2, and -3 cells and marginal zone B cells, but not follicular B cells, differentiate into IL-10-expressing CD19hiFcγRIIbhi regulatory B cells. The adoptive transfer of CD19hiFcγRIIbhi regulatory B cells via tail vein injection can promote subcutaneous 3LL tumour growth in mice. The expression of programmed death-ligand 1 on MDSCs was found to be strongly associated with CD19hiFcγRIIbhi regulatory B cell population expansion. Furthermore, the frequency of circulating CD19+FcγRIIhi regulatory B cells was significantly increased in advanced-stage lung cancer patients. Our results unveil a critical role of MDSCs in regulatory B-cell differentiation and population expansion in lung cancer patients.

Differentially Expressed Genes Involved in Primary Resistance to Immunotherapy in Patients with Advanced-Stage Pulmonary Cancer.

In the last few years, nivolumab has become the standard of care for advanced-stage lung cancer patients. Unfortunately, up to 60% of patients do not respond to this treatment. In our study, we identified variations in gene expression related to primary resistance to immunotherapy. Bronchoscopy biopsies were obtained from advanced non-small cell lung cancer (NSCLC) patients previously characterized as responders or non-responders after nivolumab treatment. Ten tumor biopsies (from three responders and seven non-responders) were analyzed by the differential expression of 760 genes using the NanoString nCounter platform. These genes are known to be involved in the response to anti-PD1/PD-L1 therapy. All the patients were treated with nivolumab. Examining the dysregulated expression of 24 genes made it possible to predict the response to nivolumab treatment. Supervised analysis of the gene expression profile (GEP) revealed that responder patients had significantly higher levels of expression of CXCL11, NT5E, KLRK1, CD3G, GZMA, IDO1, LCK, CXCL9, GNLY, ITGAL, HLA-DRB1, CXCR6, IFNG, CD8A, ITK, B2M, HLA-B, and HLA-A than did non-responder patients. In contrast, PNOC, CD19, TP73, ARG1, FCRL2, and PTGER1 genes had significantly lower expression levels than non-responder patients. These findings were validated as predictive biomarkers in an independent series of 201 patients treated with nivolumab (22 hepatocellular carcinomas, 14 non-squamous cell lung carcinomas, 5 head and neck squamous cell carcinomas, 1 ureter/renal pelvis carcinoma, 120 melanomas, 4 bladder carcinomas, 31 renal cell carcinomas, and 4 squamous cell lung carcinomas). ROC curve analysis showed that the expression levels of ITK, NT5E, ITGAL, and CD8A were the best predictors of response to nivolumab. Further, 13/24 genes showed an adverse impact on overall survival (OS) in an independent, large series of patients with NSCLC (2166 cases). In summary, we found a strong association between the global GEP of advanced NSCLC and the response to nivolumab. The classification of NSCLC patients based on GEP enabled us to identify those patients who genuinely benefited from treatment with immune checkpoint inhibitors (ICIs). We also demonstrated that abnormal expression of most of the markers comprising the genomic signature has an adverse influence on OS, making them significant markers for therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these biomarkers.

Piloting a Patient Tool to Aid Palliative Care Referrals during Advanced Lung Cancer Treatment

ContextPatient misperceptions are a strong barrier to early palliative care discussions and referrals during advanced lung cancer treatment. ObjectivesWe developed and tested the acceptability of a web-based patient-facing palliative care education and screening tool intended for use in a planned multilevel intervention (i.e., patient, clinician, system-level targets). MethodsWe elicited feedback from advanced lung cancer patients (n = 6), oncology and palliative care clinicians (n = 4), and a clinic administrator (n = 1) on the perceived relevance of the intervention. We then tested the prototype of a patient-facing tool for patient acceptability and preliminary effects on patient palliative care knowledge and motivation. ResultsPartners agreed that the intervention—clinician palliative care education and an electronic health record-integrated patient tool—is relevant and their feedback informed development of the patient prototype. Advanced stage lung cancer patients (n = 20; age 60 ± 9.8; 40% male; 70% with a technical degree or less) reviewed and rated the prototype on a five-point scale for acceptability (4.48 ± 0.55), appropriateness (4.37 ± 0.62), and feasibility (4.43 ± 0.59). After using the prototype, 75% were interested in using palliative care and 80% were more motivated to talk to their oncologist about it. Of patients who had or were at risk of having misperceptions about palliative care (e.g., conflating it with hospice), 100% no longer held the misperceptions after using the prototype. ConclusionThe palliative care education and screening tool is acceptable to patients and may address misperceptions and motivate palliative care discussions during treatment.

Hierarchical superstructure aerogels for in situ biofluid metabolomics.

High-throughput biofluid metabolomics analysis for screening life-threatening diseases is urgently needed. However, the high salt content of biofluid samples, which introduces severe interference, can greatly limit the analysis throughput. Here, a new 3-D interconnected hierarchical superstructure, namely a "plasmonic gold-on-silica (Au/SiO2) double-layered aerogel", integrating distinctive features of an upper plasmonic gold aerogel with a lower inert silica aerogel was successfully developed to achieve in situ separation and storage of inorganic salts in the silica aerogel, parallel enrichment of metabolites on the surface of the functionalized gold aerogel, and direct desorption/ionization of enriched metabolites by the photo-excited gold aerogel for rapid, sensitive, and comprehensive metabolomics analysis of human serum/urine samples. By integrating all these unique advantages into the hierarchical aerogel, multifunctional properties were introduced in the SALDI substrate to enable its effective utilization in clinical metabolomics for the discovery of reliable metabolic biomarkers to achieve unambiguous differentiation of early and advanced-stage lung cancer patients from healthy individuals. This study provides insight into the design and application of superstructured nanomaterials for in situ separation, storage, and photoexcitation of multi-components in complex biofluid samples for sensitive analysis.

Prognostic Factors and Outcomes in Advanced Stage Lung Cancer Patients with COVID-19 Omicron Variant Infection.

We study the characteristics and outcomes in lung cancer patients with COVID-19 Omicron variant infection. Hospitalized lung cancer patients with advanced-stage disease and laboratory-confirmed COVID-19 Omicron infection were included. Pneumonitis involving at least 25% of lung parenchyma on CT scans, accompanied by symptoms and oxygen saturation below 93%, were criteria for enrollment. Pneumonitis severity was graded using CTCAE v5.0. Treatment included Paxlovid, prednisolone, anticoagulation, and ventilation. Initial data, radiographic findings, and outcomes were compared. Logistic regression was employed to determine risk factors for in-hospital mortality. Fifteen patients (median age: 65 years; 80.0% males) were included. 73.3% improved and were discharged, 20.0% died, and 6.7% remained intubated. Initial symptoms included cough (100.0%), fever (73.3%), and shortness of breath (53.3%). Symptoms resolved in discharged patients. Median fever duration was 3.5 days, and respiratory symptom recovery took 26 days. Three patients died due to respiratory failure from Omicron pneumonia. Lower oxygen saturation, reduced lymphocyte/neutrophil ratio on day 7, and diffuse bilateral lung lesions were poor prognostic factors. This study underscores the importance of prompt intervention and early diagnosis for lung cancer patients infected with the COVID-19 Omicron variant. Lower oxygen saturation, decreased lymphocyte/neutrophil ratio on day 7, and diffuse lung lesions on CT scans were associated with worse outcomes. Clinicians should prioritize timely and comprehensive management to improve survival rates in this population.

Evaluating the Potential of Delta Radiomics for Assessing Tyrosine Kinase Inhibitor Treatment Response in Non-Small Cell Lung Cancer Patients.

Our study aimed to harness the power of CT scans, observed over time, in predicting how lung adenocarcinoma patients might respond to a treatment known as EGFR-TKI. Analyzing scans from 322 advanced stage lung cancer patients, we identified distinct image-based patterns. By integrating these patterns with comprehensive clinical information, such as gene mutations and treatment regimens, our predictive capabilities were significantly enhanced. Interestingly, the precision of these predictions, particularly related to radiomics features, diminished when data from various centers were combined, suggesting that the approach requires standardization across facilities. This novel method offers a potential pathway to anticipate disease progression in lung adenocarcinoma patients treated with EGFR-TKI, laying the groundwork for more personalized treatments. To further validate this approach, extensive studies involving a larger cohort are pivotal.

Effect of Exercise Training on Quality of Life, Symptoms, and Functional Status in Advanced-Stage Lung Cancer Patients: A Systematic Review.

Advanced-stage lung cancer (LC) causes significant morbidity and impacts patients' quality of life (QoL). Exercise has been proven to be safe, feasible, and beneficial for symptom reduction and QoL improvement in many types of cancers, but research is limited in advanced-stage LC patients. This systematic review evaluates the effect of exercise interventions on the symptoms and QoL in patients with advanced-stage LC. Twelve prospective studies (744 participants) were included, evaluating different combinations of exercises and training such as aerobics, tai chi, strength, inspiratory muscle training, and relaxation. Studies found outcomes including but not limited to improved QoL, symptom burden, psychosocial health, functional status, and physical function. The results of this review support that exercise is safe and feasible with evidence supporting improved QoL and symptom mitigation. Integration of exercise should be considered in the individualized management of advanced-stage LC patients under the guidance of their healthcare providers.

Correlation of drug susceptibility testing on short term cultures of CTCs positively with clinical outcomes in non-small cell lung cancer.

e21177 Background: Enumeration of circulating tumor cells (CTCs) is rapidly emerging as a minimally invasive and reliable technique for monitoring disease progression and patient’s response to treatment. However, its utility beyond enumeration in clinical management of cancer remains scarcely explored. Being biologically similar to both primary and secondary tumors, CTCs may help in identification of most efficacious therapies. In this study, we propose a method for short term culture of CTCs thereby allowing to evaluate the drug susceptibility testing in individual patients. Methods: We obtained peripheral blood samples from 20 advanced stage lung cancer patients undergoing treatment at Kidwai Memorial Institute of Oncology, Bangalore, India. These blood samples were processed and cultured on ellipsoidal microwells maintained at hypoxic conditions (1% O2). The CTC clusters were seeded onto 96 well plates coated with Matrigel and treated with the same drug regimen as the respective patients. The viability of the cells was measured using CellTitre-Glo. Results: Of the 20 samples, tight cluster formation was observed in four samples and drug susceptibility testing was performed. Based on clinical treatment received, we treated CTCs with combination of pemetrexed and carboplatin at respective Cmax concentrations of 5.68 and 3.68 µg/ml. The combination drug treatment resulted in decreased viability of CTCs to 30.7%. Notably, the CT scan images demonstrated significant reduction of pleural effusion in patient following treatment with carboplatin and pemetrexed, thus correlating with our in vitro drug susceptibility finding. Conclusions: In this proof of concept study, we demonstrate the feasibility of utilizing in vitro drug susceptibility testing on CTCs as an approach to guide patient specific chemotherapeutic treatment approaches, thus opening avenues for personalized treatments.

Comprehensive plasma genotyping reveals mutational signatures that confer resistance to tyrosine kinase inhibitors (TKI) in patients with advanced lung cancer.

e20505 Background: Targeting actionable mutations with TKI has altered the treatment paradigm for progressive lung cancers. Significant fraction of patients remain unresponsive to TKI due to cooccurrence of activating EGFR mutations (mEGFR) with other driver mutations. Biopsy of the advanced patients is challenging and is often inconclusive due to tumor heterogeneity. Plasma genotyping using a comprehensive gene panel poses a viable alternative to obtain a broad mutational landscape for Tx decisions. Here we demonstrate the clinical utility of our comprehensive gene panel for detecting actionable mutations and novel alterations from advanced lung cancer patients. Methods: Mutational landscape of 82 advanced-stage lung cancer patients was monitored longitudinally using target-hybridization enrichment of ctDNA and FFPE derived genomic DNA (tDNA). Libraries prepared using a custom designed comprehensive gene panel OncoIndx, targeting 600 cancer relevant exons including MSI and HRR pathway genes, sequenced on Illumina platform. Variant calling was performed using an in-house developed bioinformatics pipeline. Results: Cumulatively, 551 mutations from ctDNA (n = 70) and tDNA (n = 12) samples with pathogenic, likely pathogenic and unknown significance were detected. This included SNVs (31.64 %), truncations (44.73%), splice variants (8.73%), frameshift (6 %), CNVs (4.18 %) and indels (2.9 %). Genome-wide alterations conceded low TMB (10-18) and high average HRD (43-45%) scores in ctDNA and tDNA respectively. mEGFR was the most frequently detected alteration (45.12 %), and had comparable occurrence in ctDNA and tDNA. 28 % ctDNA samples with mEGFR co-occurred with targetable ATM, RAD54 or TP53 mutations and had high HRD scores. Other actionable variants of RAS, ALK, ROS, BRAF and MET were primarily detected in ctDNA samples, albeit at low frequency. Surprisingly, 10 % patients with MET alterations that potentiate TKI resistance were concomitant with mEGFR, and showed high genome instability. Single or multiple mutations in HRR pathway genes were detected in 45 % ctDNA samples. Alterations likely to lead therapy resistance were principally observed in ctDNA samples suggesting that liquid biopsy provides elaborate cancer mutation landscape. Conclusions: Monitoring patients longitudinally for the Tx response is highly implicated. Targeted gene profiling of ctDNA detected multiple variants that were inconspicuous in tDNA. We observed a significant enrichment of variants co-occurring with mEGFR, a new finding on ctDNA mutational analysis. Further investigation into this may suggest better treatment strategies to benefit from TKI resistance. Comprehensive plasma genotyping suggests that patients positive for TKI blunting MET, RAS, BRAF mutations with or without mEGFR co-occurrence may benefit from HRD inhibitors in combination with TKI. Clinical trial information: CTRI/2016/08/007149 .

An association of epidermal growth factor receptor mutation subtypes with prognostic prediction and site-specific recurrence in advanced stage lung cancer patients.

Concerning the different clinical behavior of epidermal growth factor receptor (EGFR) subtypes in advanced-stage lung cancer patients, the current study aimed to evaluate the clinical, pathological, and prognostic significance of EGFR mutation subtypes, and treatment response in patients with advanced-stage lung cancer. A retrospective study enrolled a total of 346 patients with advanced-stage lung cancer tested for EGFR mutation. EGFR mutation was analyzed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Statistical analysis was performed using SPSS version 20.0. EGFR mutation was evident in 38% of patients with the highest prevalence of exon 19 deletions. A higher incidence of 19-deletions and 20-insertions were observed in young patients, while a higher incidence of L858R was noted in old age patients. Patients with de-novo T790M failed to improve their OS by any of the treatment modalities. Patients with de-novo T790M mutation have a higher risk of developing lung, liver, and multiple site metastases while patients with L858R mutation have a higher risk of developing brain metastasis. Additionally, patients with 19 deletion mutation did not improve their OS after receiving conventional chemotherapy hence, they demonstrate better survival only after EGFR-TKIs. Multivariate survival analysis predicted chemotherapy as an independent predictor of OS. Besides clinicopathological and prognostic consequences of EGFR mutation and mutation subtypes, patients harboring TKI sensitive, or insensitive mutations reveal different secondary disease development and hence should be treated accordingly for better survival. Current findings may provide the basis for a better treatment strategy.

Surgery is a promising strategy for improving overall survival for stage III-N2 non-small cell lung cancer patients.

Surgery is commonly used to treat stage I lung cancer patients, whereas radiotherapy is applied to treat stage III lung cancer patients. However, few advanced-stage lung cancer patients benefit from surgery. This study aimed to investigate the efficacy of surgery for stage III-N2 non-small cell lung cancer (NSCLC) patients. A total of 204 patients with stage III-N2 NSCLC were included and divided into surgery (n=60) and radiotherapy (n=144) groups. The clinical characteristics [tumor node metastasis (TNM) stage, and adjuvant chemotherapy] and basic information (gender, age, and smoking/family history) of the included patients were evaluated. Furthermore, the patients' Eastern Cooperative Oncology Group (ECOG) scores and comorbidities were also evaluated, and the Kaplan-Meier approach was utilized to analyze their overall survival (OS). A multivariate Cox proportional hazards model was generated to analyze OS. There was a significant difference in disease stages (IIIa and IIIb) between the surgery and radiotherapy groups (P<0.001). Compared with the surgery group, there were more patients with ECOG scores of 1 and 2 and fewer patients with ECOG scores of 0 in the radiotherapy group (P<0.001). Moreover, there was a significant difference in comorbidities between the stage III-N2 NSCLC patients in the two groups (P=0.011). The OS rate was higher significantly in stage III-N2 NSCLC patients in the surgery group compared to that in the radiotherapy group (P<0.05). Kaplan-Meier analysis demonstrated that the OS of III-N2 NSCLC was markedly better in the surgery group compared to the radiotherapy group (P<0.05). The multivariate proportional hazards model showed that age, T stage, surgery, disease stage, and adjuvant chemotherapy were independent prognostic predictors for OS in stage III-N2 NSCLC patients. Surgery is associated with improved OS in stage III-N2 NSCLC patients and is recommended to treat these patients.

Palliative care use and utilization determinants among patients treated for advanced stage lung cancer care in the community and academic medical setting.

Despite clinical guidelines, palliative care is underutilized during advanced stage lung cancer treatment. To inform interventions to increase its use, patient-level barriers and facilitators (i.e., determinants) need to be characterized, especially among patients living in rural areas or those receiving treatment outside academic medical centers. Between 2020 and 2021, advanced stage lung cancer patients (n = 77; 62% rural; 58% receiving care in the community) completed a one-time survey assessing palliative care use and its determinants. Univariate and bivariate analyses described palliative care use and determinants and compared scores by patient demographic (e.g., rural vs. urban) and treatment setting (e.g., community vs. academic medical center) factors. Roughly half said they had never met with a palliative care doctor (49.4%) or nurse (58.4%) as part of cancer care. Only 18% said they knew what palliative care was and could explain it; 17% thought it was the same as hospice. After palliative care was distinguished from hospice, the most frequently cited reasons patients stated they would not seek palliative care were uncertainty about what it would offer (65%), concerns about insurance coverage (63%), difficulty attending multiple appointments (60%), and lack of discussion with an oncologist (59%). The most common reasons patients stated they would seek palliative care were a desire to control pain (62%), oncologist recommendation (58%), and coping support for family and friends (55%). Interventions should address knowledge and misconceptions, assess care needs, and facilitate communication between patients and oncologists about palliative care.

The impact of chemotherapy on quality of life in advanced-stage lung cancer patients.

Most patients with lung cancer are diagnosed at advanced stages of the disease, where chemotherapy plays an important role. This prospective study was conducted to determine the impact of palliative chemotherapy on quality of life (QOL) in advanced-stage lung cancer patients. QOL in lung cancer out-patients was assessed at diagnosis and end of treatment using the EORTC QLQ-C30 questionnaire. Changes in mean QOL scores were calculated. The correlation between patients' tumor response and change in QOL scores was also studied. Scoring was done according to the EORTC manual and results were analyzed using SPSS statistical package. Out of 52 patients, 46 (88.46%) were men and six (11.54%) were women. After chemotherapy, patients' overall QOL score improved significantly (P = 0.005). Cognitive functioning significantly worsened (P = 0.01). Physical functioning (PF) and emotional functioning (EF) scores improved, while role functioning (RF) and social functioning (SF) scores worsened. Pain, dyspnea, and sleep significantly improved (P = 0.001, P = 0.001, and P = 0.005 respectively). On the other hand, nausea, vomiting (P = 0.000), diarrhea (P = 0.004), and financial difficulties (P = 0.009) worsened. Overall QOL improved in patients with partial tumor response (PR) and stable disease (SD) (P = 0.044 and P = 0.000, respectively), but worsened in progressive disease group (PD) (P = 0.648). Symptom scores improved markedly in PR and SD groups. Chemotherapy toxicity was maximum in PD group (P = 0.028). Global quality of life and symptom control significantly improved in lung cancer patients after chemotherapy. Deterioration of cognitive functioning, increased financial burden, and chemotherapy-related toxicity were noteworthy. Changes in QOL were coherent with patients' tumor response.

Determination of the factors contributing to depression and anxiety in advanced stage lung cancer patients.

The diagnosis of cancer and initiation of treatment disrupt physical, emotional, and socio-economical stability of the patients by reducing the quality of lives and ultimately leading to depression and anxiety. We aimed to observe the indicators for anxiety and depression among lung cancer (LC) patients by comparing with other cancer (OC) patients. This study has been conducted between 2017 and 2019. Questionnaires were provided for both LC and OC patients. Two hundred and thirty patients with the ages varied between 18 and 86 (median: 64.0) were included in the study. A total of 115 patients (case group) were diagnosed as LC, and the remaining were with OC diagnosis (control). No difference was determined between the groups in means of median anxiety and depression scores. Patients who required assistance in hospital procedures, daily life activities, and self-care had higher depression and anxiety scores (p < 0.05) compared to those did not require assistance. Anxiety and depression scores in OC groups showed a remarkable difference according to performance status (p < 0.001). The depression score of the patients who stated that they did not know their social rights was remarkably higher than those of the patients who stated that they know their social rights. We found no relationship between depression and anxiety scores because of disease caused income loss and expense increase. For LC patients, declaration of requirement for assistance and supportive care in daily life can be an important indication for anxiety and depression. Lung cancer patients, especially those informed by health care professionals and provided psychosocial support following the information, require a patient-specific professional management approach.

The Effect of Body Mass Index on Survival in Lung Cancer

The prognostic significance of body mass index in lung cancer and the direction of this relationship are not yet clear. This study aimed to evaluate the relationship between BMI and overall survival time of advanced-stage lung cancer patients treated in a center in Turkey, a developing country. In this study, the data of 225 patients diagnosed with stage III or stage IV lung cancer between 2016 and 2020 were analyzed. The effects of BMI and other variables on survival were examined by Cox regression analysis for NSCLC and SCLC. For NSCLC and SCLC, being underweight compared to the normal group, being diagnosed at a more advanced stage, and having a worse performance score were associated with a significantly higher risk of death. Other variables significantly associated with survival were gender, type of radiotherapy for NSCLC, age group, and family history for SCLC. This study showed that being underweight relative to the normal group was associated with worse survival for NSCLC and SCLC but did not support the obesity paradox. Studies that are representative of all BMI categories and free of bias are needed to understand the BMI-lung cancer survival relationship clearly.

Assessment of a Large-Scale Unbiased Malignant Pleural Effusion Proteomics Study of a Real-Life Cohort.

Simple SummaryPleural effusion (PE) occurs as a consequence of various pathologies. Malignant effusion due to lung cancer is one of the most frequent causes. A method for accurate differentiation of malignant from benign PE is an unmet clinical need. Proteomics profiling of PE has shown promising results. However, mass spectrometry (MS) analysis typically involves the tedious elimination of abundant proteins before analysis, and clinical annotation of proteomics profiled cohorts is limited. This study compares the proteomes of malignant PE and nonmalignant PE, identifies lung cancer malignant markers in agreement with other studies, and identifies markers strongly associated with patient survival.Background: Pleural effusion (PE) is common in advanced-stage lung cancer patients and is related to poor prognosis. Identification of cancer cells is the standard method for the diagnosis of a malignant PE (MPE). However, it only has moderate sensitivity. Thus, more sensitive diagnostic tools are urgently needed. Methods: The present study aimed to discover potential protein targets to distinguish malignant pleural effusion (MPE) from other non-malignant pathologies. We have collected PE from 97 patients to explore PE proteomes by applying state-of-the-art liquid chromatography-mass spectrometry (LC-MS) to identify potential biomarkers that correlate with immunohistochemistry assessment of tumor biopsy or with survival data. Functional analyses were performed to elucidate functional differences in PE proteins in malignant and benign samples. Results were integrated into a clinical risk prediction model to identify likely malignant cases. Sensitivity, specificity, and negative predictive value were calculated. Results: In total, 1689 individual proteins were identified by MS-based proteomics analysis of the 97 PE samples, of which 35 were diagnosed as malignant. A comparison between MPE and benign PE (BPE) identified 58 differential regulated proteins after correction of the p-values for multiple testing. Furthermore, functional analysis revealed an up-regulation of matrix intermediate filaments and cellular movement-related proteins. Additionally, gene ontology analysis identified the involvement of metabolic pathways such as glycolysis/gluconeogenesis, pyruvate metabolism and cysteine and methionine metabolism. Conclusion: This study demonstrated a partial least squares regression model with an area under the curve of 98 and an accuracy of 0.92 when evaluated on the holdout test data set. Furthermore, highly significant survival markers were identified (e.g., PSME1 with a log-rank of 1.68 × 10−6).

Application of an Ultrasensitive NGS-Based Blood Test for the Diagnosis of Early-Stage Lung Cancer: Sensitivity, a Hurdle Still Difficult to Overcome.

Simple SummaryCurrently, an accurate diagnosis of lung cancer relies on the microscopic examination of tissue biopsies. These samples can, however, only be obtained by invasive procedures. The aim of our study was to evaluate the use of a liquid biopsy for early-stage lung cancer detection in patients with a lung lesion on imaging. This approach would be particularly relevant for suspected lung lesions that are difficult to reach for a tissue-based diagnosis. Despite technical improvements for the use of liquid biopsy-based cell-free DNA analysis, its application for the detection of early-stage lung cancer is currently limited by sensitivity and a biological background of somatic variants.Diagnosis of lung cancer requires histological examination of a tissue sample, which in turn requires an invasive procedure that cannot always be obtained. Circulating tumor DNA can be reliably detected in blood samples of advanced-stage lung cancer patients and might also be a minimally invasive alternative for early-stage lung cancer detection. We wanted to explore the potential of targeted deep sequencing as a test for the diagnosis of early-stage lung cancer in combination with imaging. Mutation detection on cell-free DNA from pretreatment plasma samples of 51 patients with operable non-small cell lung cancer was performed and results were compared with 12 control patients undergoing surgery for a non-malignant lung lesion. By using a variant allele frequency threshold of 1%, somatic variants were detected in 23.5% of patients with a median variant allele fraction of 3.65%. By using this threshold, we could almost perfectly discriminate early-stage lung cancer patients from controls. Our study results are discussed in the light of those from other studies. Notwithstanding the potential of today’s techniques for the use of liquid biopsy-based cell-free DNA analysis, sensitivity of this application for early-stage lung cancer detection is currently limited by a biological background of somatic variants with low variant allele fraction.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.