8040 Background: Cancer-associated cachexia is underdiagnosed and not routinely captured in cancer registries, despite its negative impact on quality of life and survival. We aim to determine the prevalence of cachexia in patients with locally advanced NSCLC and to perform a multidisciplinary characterization of cachexia to inform the development of future therapeutic interventions. Methods: In this prospective study, 51 patients diagnosed with locally advanced unresectable NSCLC candidates to concurrent chemoradiotherapy followed by immunotherapy at the HUB-ICO Comprehensive Cancer Centre (2022-2024) were included. The primary objectives were to (1) determine the frequency of cachexia according to Fearon’s criteria and (2) characterize patients before and after completing chemoradiotherapy in terms of nutritional status, metabolic parameters, body composition and circulating cytokine levels. Baseline assessment results are reported here. Results: Most patients were male (80%) and ever smokers (98%), with a median age of 68 years. All patients completed the planned concurrent chemoradiotherapy regimen, whereas only 43% initiated durvalumab consolidation therapy. At baseline, 27 patients met the diagnostic criteria for cachexia (53%, 95% CI 39-66) and women were more likely to have cachexia than men (80% vs 46%, respectively), although this difference was not statistically significant. Cachexia was significantly associated with more advanced tumor stage (p < 0.001), worse performance status (p = 0.027), lower skeletal muscle index (p = 9e-4) and reduced total adipose tissue index (p = 0.004), elevated C-Reactive Protein blood levels (p = 0.004), moderate to severe malnutrition (p < 0.001), reduced caloric intake (p = 0.007) and decreased physical strength (p = 0.001). Cachectic patients had lower fat intake compared with non-cachectic individuals (p = 0.006), while protein intake was similar in both subgroups. Proteomic profiling using the O-link platform identified significant differences in circulating cytokine levels between cachectic and non-cachectic patients. Cachexia was associated with significantly increased levels of CCL23, IL-6, C1QA, CSF1, motilin and agouti-related protein (AGRP), among others, which showed varying degrees of correlation with caloric intake. By contrast, GDF-15 was significantly associated with weight loss (p = 0.00014) but showed no association with caloric intake or body composition parameters. Conclusions: This prospective study reveals that cancer-associated cachexia is highly prevalent in patients with unresectable locally advanced NSCLC before treatment initiation. Beyond previously described inflammatory mediators, we identified several understudied cytokines, which may contribute to the progression of the cachexia phenotype and represent potential targets for future therapeutic interventions.

Pleural mesothelioma (PM) is a rare and lethal cancer with limited treatment options. Intratumor heterogeneity (ITH) has been postulated as one of the reasons for the poor treatment response observed in most PM patients. In this regard, we aimed to characterize ITH in a multi-site tumor specimen using single-cell RNA-sequencing (scRNA-seq). METHODS:Tumor cells from three distant biopsies (costal, diaphragmatic, and mediastinal) of an epithelioid PM were analyzed with scRNA-seq. RESULTS:Three main cell states were identified in all regions: C1, stem-like; C2, epithelial-like; and C3, mesenchymal-like. C1 state was the most prominent globally, although it was less abundant in the mediastinal biopsy, compared to the other two studied regions. Trajectory analysis was suggestive of an epithelial-mesenchymal plasticity dynamic, including a stem-like intermediate state. Signatures of upregulated genes in each state (SigC1, SigC2, SigC3) were obtained and assessed in a large cohort of PM samples. Patients with tumors enriched in SigC3 were associated with worse survival and with reduced sensitivity to standard of care PM regimens. Additionally, SigC1 appeared to be potentially more sensitive to anti-angiogenic therapies. CONCLUSIONS:This study highlights that scRNA-seq is useful to capture PM cellular and molecular heterogeneity and identifies gene-expression signatures with potential clinical relevance for future treatment tailoring.

Background: Cancer-associated cachexia, a frequent complication of solid tumours, is not recorded in cancer registries. Cachexia affects patients diagnosed with non-small cell lung cancer (NSCLC); however, a detailed characterization of nutritional and body composition parameters matched with blood-based, non-invasive markers is lacking. We hypothesized that a systematic characterization of cachectic patients may facilitate the development of interventions aimed to improve clinical outcomes. Methods: We conducted a prospective study of 51 patients diagnosed with locally advanced unresectable NSCLC who underwent concurrent chemoradiotherapy followed by immunotherapy at the HUB-ICO Comprehensive Cancer Centre from 2022 to 2024. The primary objectives were (1) to determine the prevalence of cachexia according to Fearon criteria and (2) to comprehensively characterize patients before and after completing chemoradiotherapy in terms of nutritional status, metabolic parameters, body composition and circulating cytokine levels. Here, we report the baseline assessment results. Results: Most patients were male (80%), ever smokers (98%) with a median age of 68 years. All patients completed the planned concurrent chemoradiotherapy regimen, while only 43% initiated durvalumab consolidation therapy. At baseline, 53% of patients met the diagnostic criteria for cachexia. Women were more likely to have cachexia at baseline compared to men, although these differences were not statistically significant. Cachexia was significantly associated with tumor stage (p < 0.001), performance status (p = 0.027), lower skeletal muscle index (p = 9e-4) and total adipose tissue index (p = 0.004), elevated C-Reactive Protein blood levels (p = 0.004), moderate to severe malnutrition (p < 0.001), reduced caloric intake (p = 0.007) and diminished physical strength (p=0.001). Proteomic profiling using the O-link platform revealed significant differences in circulating cytokine levels between cachectic and non-cachectic patients. Cachexia was significantly associated with elevated levels of CCL23, IL-6, IL-11, Oncostatin M (OSM), pentraxin-related protein 3 (PTX3), and agouti-related protein (AGRP), among others, demonstrating varying degrees of correlation with caloric intake. GDF15 was associated with weight loss (p = 0.00014), but not with calorie intake or body composition. Conclusions: This prospective study reveals that cancer cachexia is highly prevalent in patients with unresectable locally advanced NSCLC. In addition to previously known cytokines, we identified several understudied cytokines, which may contribute to a more comprehensive characterization of the cachexia phenotype and help uncover potential targets for therapeutic interventions. ### Competing Interest Statement Ernest Nadal. Research funding: Roche, Pfizer, Merck-Serono, Bristol Myers Squibb. Advisory board and consulting: Amgen, Apollomics, AstraZeneca, BeiGene, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, Genmab, Johnson & Johnson, Lilly, Merck Sharp & Dohme (MSD), Merck-Serono, Pfizer, Pierre Fabre, Qiagen, Regeneron, Roche, Sanofi and Takeda. Honoraria for lectures: Amgen, AstraZeneca, BeiGene, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, Illumina, Johnson & Johnson, Lilly, Merck Sharp & Dohme (MSD), Merck-Serono, Pfizer, Pierre Fabre, Qiagen, Regeneron, Roche, Sanofi and Takeda. Travel support: Roche, Takeda, Johnson and Johnson, and MSD. Lorena Arribas research funding: Nestle Healthcare. Honoraria for lectures: Fresenius Kabi, Nutricia, Merck. Advisory board and consulting: Pfizer, Fresenius Kabi, Merck Travel support: Vegenat Heatlhscience. Inmaculada Peiro: Honoraria for lectures: Fresenius Kabi, Vegenat Heatlhscience, EISAI. Advisory board and consulting: Nestle Healtcare, Fresenius Kabi. Travel support: Novartis, Fresenius Kabi. Eduard Montanya, advisory boards, consulting fees or speaker honoraria from Medcom, Merck Sharp & Dohme, Novo Nordisk, Roche and Sanofi. Miguel Mosteiro. Honoraria for lectures: Takeda, AstraZeneca, BMS, Pfizer. Travel support: Roche, Takeda, Pfizer, Lilly, AstraZeneca and BMS. Cristina Munoz-Pinedo. Honorarium for lecture: BMS. Felipe Jimenez, Aina Llenas, Joaquim Moreno, Miriam Nunez, Sara Hijazo-Pechero declare that they have no conflict of interest. ### Funding Statement We thank CERCA Programme / Generalitat de Catalunya for institutional support. This study has been funded by La Marato de TV3, 201929-30 project, the Ministerio de Ciencia e Innovacion y Universidades of Spain (MICINN/MCIU), which is part of Agencia Estatal de Investigacion (AEI), through the Generacion de Conocimiento grant number PID2022-140457OB-I00. Funding by Instituto de Salud Carlos III: grants PI21/00789 and PI24/00702 to E.N. (co-funded by the European Regional Development Fund/FEDER) and CD20/00191 to F.L-M. (co-funded by European Social Fund. ESF investing in your future). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Human studies have been approved by the Bellvitge ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

OBJECTIVES:The aim of this study was to identify biomarkers of cancer-related cognitive impairment (CRCI) in patients with small-cell lung cancer (SCLC). METHODS:Patients with SCLC were prospectively recruited between 2019 and 2023 and evaluated using neuropsychological (NPS) battery; structural MRI; and serologic analysis of neuronal antibodies, cytokines, brain-derived neurotrophic factor (BDNF), and cognitive-related single nucleotide variants (SNVs). Voxel-based morphometry and tract-based analysis assessed gray and white matter integrity. One month after completing chemotherapy, patients were re-evaluated. RESULTS:Fifty-two patients were initially evaluated: 16 (31%) exhibited cognitive impairment (CI), primarily affecting executive functioning. MRI disclosed gray matter damage in precuneus and fusiform-parahippocampal regions, linked to visuospatial abilities and memory, and white matter damage in cingulum and corpus callosum. After chemotherapy, 31 patients were re-evaluated: 10 (32%) exhibited CI, of whom 7 (23%) had persistent CI and 3 (10%) developed de novo CI (chemobrain). The chemobrain group had higher smoking exposure (60 vs 44 pack-years, p = 0.05) while the persistent CI group had more advanced disease at diagnosis (80% vs 20%, p = 0.004), compared to the never CI group (15/31, 48%). DISCUSSION:CRCI affected one-third of our patients with SCLC at diagnosis while chemobrain was uncommon and primarily associated with tobacco use. These findings underscore the role of early biomarkers in predicting CRCI and its persistence in patients with SCLC.

Background: Neoadjuvant therapy, particularly the combination of chemotherapy and immunotherapy, has become standard in treating locally advanced non-small cell lung cancer (NSCLC). While this approach improves pathologic responses, its effect on postoperative outcomes following robotic-assisted thoracic surgery (RATS) is not fully characterized. Objective: This study aimed to evaluate the impact of neoadjuvant therapy on postoperative outcomes in patients undergoing RATS for NSCLC, focusing on operative time, conversion rates to open surgery, and postoperative complications. Methods: A retrospective cohort analysis was performed on patients who underwent RATS for NSCLC between February 2019 and August 2024. Propensity score matching was utilized to balance preoperative characteristics between the groups. The primary outcomes compared were operative time, conversion rates to open surgery, and postoperative complications, with statistical significance defined as p < 0.05. Results: A total of 253 patients were included in the analysis, of whom 23 received neoadjuvant therapy (either chemotherapy or chemoimmunotherapy) and 230 did not. The neoadjuvant group had significantly longer operative times (250 min vs. 221 min, p = 0.001) but there were no significant differences in conversion rates to open surgery (8.7% vs. 3.9%, p = 0.5). However, the neoadjuvant group showed a higher incidence of prolonged air leaks (>5 days) (39.13% vs. 35.21%, p < 0.001). Other parameters, such as hospital stay and chest drainage duration, showed no statistically significant differences between the groups (p = 0.860 and p = 0.760, respectively). Conclusions: These findings support the feasibility of robotic-assisted thoracic surgery following neoadjuvant therapy in NSCLC, suggesting that this approach may be safely integrated into clinical practice for selected patients. Further studies are needed to define patient selection criteria and optimize postoperative management, potentially guiding personalized treatment strategies in complex cases.

Malignant mesothelioma (MM) is associated with asbestos exposure and about 10–15% of patients are carriers of germline pathogenic or likely pathogenic variants (GPV/GLPV) in genes associated with cancer predisposition. The prevalence of GPV/GLPV in patients diagnosed with MM in our country is unknown.

Abstract BACKGROUND Small cell lung cancer patients (SCLC) are treated with platinum-based chemotherapy, thoracic radiation, and some of them will also receive prophylactic cranial irradiation (PCI). Following therapy, nearly 45% of SCLC will exhibit moderate to severe cognitive impairment (CI). The aim of our study was to identify early biomarkers including clinical, serological and changes in brain structure associated with an increased risk of CI in SCLC population. MATERIAL AND METHODS Fifty-two SCLC were prospectively recruited from January 2019-December 2022 at our institution and evaluated at diagnosis using a neuropsychological battery (NPS), a structural MRI (T1-weighted), and serological markers including: a) cytokines (interleukin 1, 2, 6, 8, 10 and TNF alpha) and b) single nucleotide polymorphisms (SNP) of apolipoprotein E (APOE), multidrug resistance protein (MDR1) and brain-derived neurotrophic factor (BDNF). They were also clinically and NPS evaluated at 1-month following chemotherapy-before PCI, at 3-6 months, at one-year and at 2-3 years post-PCI. Voxel-based morphometry (T1-VBM) was used to analyze gray matter (GM) integrity. RESULTS Of the 52 patients included, 70% were male, median age was 65 years (46-82). Most (94%) had an ECOG PS ≤1. Half had hypertension (52%) and dyslipidemia (46%); one third (36%) moderate alcoholism and 25% were diabetic. Nearly half (54%) had limited stage and received cisplatin-based chemotherapy (52%). One third (29%, n=15) exhibited brain metastasis (BM): 4 at baseline (8%) and the other during follow-up (21%). Regarding smoking, median packs per year was 45 (12-100). Twenty-nine (56%) received cranial radiation, most of them (n=22, 42%) PCI (25Gy). Median overall survival was 18 months (2.5, 71); twenty-one (40%) were alive at the end of the study.Nearly half of our cohort (48%, n=25) exhibited CI: 31% (n=16) at baseline and another 17% (n= 9) during follow-up. CI group performed significantly worse in all the domains explored, especially in verbal memory (p < 0.001) and executive functioning (p < 0.001). Only smoking habit resulted significantly different between groups: CI patients were heavier smokers (p=0.04). VBM analysis showed that CI group exhibited significant GM damage in anterior and mid cingulate, superior, and inferior temporal gyrus, precuneus and fusiform gyrus. GM volume positively correlated with measures of cognitive functioning at baseline (all correlations, p <0.04). We found no differences regarding cytokines levels or SNPs of APOE, MDR1 and BDNF between groups. CONCLUSION This study confirms that nearly half of the SCLC population exhibit CI. Of greater interest, however, is the fact that most of them already exhibit CI before therapy that seem to correlate with GM alterations previously described in this population. In addition, smoking seems to be the most important clinical risk factor.

Background: Surgery and stereotactic body radiotherapy (SBRT) are two of the options available as local treatments for pulmonary oligometastases from colorectal cancer (CRC). We hypothesized that SBRT would have, at least, a similar local control rate to surgery. Methods: We identified an initial cohort of 100 patients with CRC who received SBRT or surgery for lung metastases. This was then narrowed down to 75 patients: those who underwent surgery (n = 50) or SBRT (n = 25) as their first local thoracic treatment between 1 January 2004 and 29 December 2017. The Kaplan–Meier method was used to calculate lung-progression-free survival (L-PFS) and overall survival (OS). Results: The 1 and 2-year L-PFS was 85% and 70% in the surgical group and 87% and 71% in the SBRT group, respectively (p = 0.809). No significant differences were found between the two groups in terms of OS. The biologically effective dose (BED), age and initial CRC stage did not have a significant effect on local control or survival. No grade 3 or above acute- or late-toxicity events were reported. Conclusions: These results add retrospective evidence that SBRT and surgery have similar results in terms of OS and local control in patients with lung oligometastases from CRC.

Background: Targeted next-generation sequencing (NGS) is recommended to screen actionable genomic alterations (GAs) in patients with non-small-cell lung cancer (NSCLC). We determined the feasibility to detect actionable GAs using TruSightTM Oncology 500 (TSO500) in 200 consecutive patients with NSCLC. Materials and methods: DNA and RNA were sequenced on an Illumina (R) NextSeq 550 instrument and processed using the TSO500 Docker pipeline. Clinical actionability was defined within the molecular tumour board following European Society for Medical Oncology (ESMO) guidelines for oncogene-addicted NSCLC. Overall survival (OS) was estimated as per the presence of druggable GAs and treatment with targeted therapy.Results: Most patients were males (69.5%) and former or current smokers (86.5%). Median age was 64 years. The most common histological type and tumour stage were lung adenocarcinoma (81%) and stage IV (64%), respectively. Sequencing was feasible in most patients (93.5%) and actionable GAs were found in 26.5% of patients. A high concordance was observed between single-gene testing and TSO500 NGS panel. Patients harbouring druggable GAs and receiving targeted therapy achieved longer OS compared to patients without druggable GAs. Conversely, patients with druggable GAs not receiving targeted therapy had a trend toward shorter OS compared with driver negative patients.Conclusions: Hybrid capture sequencing using TSO500 panel is feasible to analyse clinical samples from patients with NSCLC and is an efficient tool for screening actionable GAs.

Background There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. Methods We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. Results Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models evaluated. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest, thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice. Conclusions Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM.

Background and objective Radiation pneumonitis (RP) could be a lethal complication of lung cancer treatment. No reliable predictors of RP severity have been recognized. This prospective pilot study was performed to identify early predictors of high grade lung toxicity and to evaluate clinical, biological or dosimetric features associated with different grades of toxicity. Method Sixteen patients with non-small cell lung cancer with indication of concurrent chemoradiotherapy using 60 Gy/2 Gy/fraction starting at cycle one of platinum based chemotherapy were included. Bronchoalveolar lavage (BAL), pulmonary function testing (PFT), and 18 F-2-fluoro-2-deoxy-D-glucose positron-emission tomography was performed before radiotherapy (RT), after three weeks of treatment, and two months post-RT. For analysis, patients were grouped by grade (low [G1-G2] vs. high [G3-G5]). The two groups were compared to identify predictors of RP. Protein expression BAL and lung tissue metabolism was evaluated in two patients (RP-G1 vs. RP-G3). Categorical variables such as comorbidities, stages and locations were summarized as percentages. Radiation doses, pulmonary function values and time to RP were summarized by medians with ranges or as means with standard deviation. Longitudinal analysis PFT was performed by a T-test. Results All 16 patients developed RP, as follows: G1 (5 pts; 31.3%); G2 (5 pts; 31.3%); G3 (5 pts; 31.3%); and G5 (1 pts; 6.1%). Patients with high grade RP presented significant decrease ( p = 0.02) in diffusing lung capacity for carbon monoxide (DLCO) after three weeks of RT. No correlation between dosimetric values and RP grades was observed. BAL analysis of the selected patients showed that CXCL-1, CD154, IL-1ra, IL-23, MIF, PAI-1 and IFN-γ were overexpressed in the lungs of the RP-G3 patient, even before treatment. The pre-RT SUVmax value in the RP-G3 patient was non-significantly higher than in the patient with RP-G1. Conclusions RT induces some degree of RP. Our data suggest that decrease in DLCO% is the most sensitive parameter for the early detection of RP. Moreover, we detect biological differences between the two grades of pneumonitis, highlighting the potential value of some cytokines as a prognostic marker for developing high grade lung toxicity. Further multicenter studies with larger sample size are essential to validate these findings.

Germline mutations in BAP1 and in other genes, such as BRCA2, CHEK2, CDKN2A or ATM, have been associated to hereditary predisposition to malignant pleural mesothelioma (MPM). We aim to characterize the genomic landscape in MPM patients at germline and somatic level. We analyzed 22 consecutive patients with MPM by germline and somatic next generation sequencing (NGS). Blood DNA was sequenced using an ad hoc gene panel of 164 genes associated to hereditary cancer risk. Tumoral DNA and RNA were analyzed using the TSO500+ gene panel (Illumina®) with the aim of identifying somatic small variants, copy number alterations, microsatellite instability (MSI) and tumoral mutational burden (TMB). The mean age of subjects was 68 years and histology consisted of 20 epithelioid, 1 sarcomatoid and 1 atypical mesothelial hyperplasia. Seventeen patients had family history of cancer and 15 were exposed to asbestos. Three out of 22 MPM patients (13.6%) harbored germline likely-pathogenic (P) variants: 2 patients carried BAP1 [c.592dup p.(Glu198Glyfs*45) and c.3_6del p.(?)] and 1 carried BARD1 [c.998_999del p.(Ser333*)]. All three had family history of cancer (3 out of 17, 17.6%) and epithelioid histology. Tumor analysis confirmed germline mutations, and the most frequent somatic mutations were: BAP1, 22.7%; NF2, 22.7%; TP53, 13.6%; SETD2, 13.6% and LATS2, 4.5%. BAP1 and NF2 mutations were mutually exclusive, while SETD2 and LATS2 cooccurred with BAP1 and NF2 respectively. All but one sample had low TMB, and no evidence of MSI was detected. This is the first study assessing both germline and somatic genetic alterations by NGS in MPM patients in our country. As 17.6% of MPM patients with family history of cancer were carriers of P germline mutations, we propose the implementation of mutational analysis of cancer susceptibility genes in all MPM cases with family history of cancer. Further validation in a larger cohort is ongoing.

BACKGROUND:Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lung mesothelium. Immune checkpoint inhibitors (ICI) in MPM have not been extremely successful, likely due to poor identification of suitable candidate patients for the therapy. We aimed to identify cellular immune fractions associated with clinical outcome and classify patients with MPM based on their immune contexture. For each defined group, we sought for molecular specificities that could help further define our MPM classification at the genomic and transcriptomic level, as well as identify differential therapeutic strategies based on transcriptional signatures predictive of drug response.METHODS:The abundance of 20 immune cell fractions in 516 MPM samples from 7 gene expression datasets was inferred using gene set variation analysis. Identification of clinically relevant fractions was performed with Cox proportional-hazards models adjusted for age, stage, sex, and tumor histology. Immune-based groups were defined based on the identified fractions.RESULTS:T-helper 2 (TH2) and cytotoxic T (TC) cells were found to be consistently associated with overall survival. Three immune clusters (IG) were subsequently defined based on TH2 and TC immune infiltration levels: IG1 (54.5%) was characterized by high TH2 and low TC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high TC levels. IG1 and IG3 groups were associated with worse and better overall survival, respectively. While no differential genomic alterations were identified among immune groups, at the transcriptional level, IG1 samples showed upregulation of proliferation signatures, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, the integration of gene expression with functional signatures of drug response showed that IG3 patients might be more likely to respond to ICI.CONCLUSIONS:This study identifies a novel immune-based signature with potential clinical relevance based on TH2 and TC levels, unveiling a fraction of patients with MPM with better prognosis and who might benefit from immune-based therapies. Molecular specificities of the different groups might be used to tailor specific potential therapies in the future.

Diabetes is related with increased cancer mortality across multiple cancer types. Its role in lung cancer mortality is still unclear. We aim to determine the prognostic value of fasting plasma glucose (FPG) and diabetes mellitus in patients with locally advanced non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy. One-hundred seventy patients with stage III NSCLC received definitive concurrent chemoradiotherapy from 2010 to 2014. Clinico-pathological data and clinical outcome was retrospectively registered. Fifty-six patients (33%), met criteria for type 2 diabetes mellitus (T2DM) at baseline. The prognostic value of FPG and other clinical variables was assessed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method and Cox proportional models and log-rank test were used. With a median follow-up of 36 months, median PFS was 8.0 months and median OS was 15.0 months in patients with FPG ≥7 mmol/L compared to 20 months (HR 1.13; 95% CI 1.07–1.19, p < 0.001) and 31 months (HR 1.09; 95% CI 1.04–1.15; p < 0.001) respectively, for patients with FPG < 7 mmol/L. In the multivariate analysis of the entire cohort adjusted by platinum compound and comorbidities, high levels of FPG as a continuous variable (HR 1.14; 95% CI 1.07–1.21; p < 0.001), the presence of comorbidity (HR 1.72; 95% CI 1.12–2.63; p = 0.012), and treatment with carboplatin (HR 1.95; 95% CI 1.26–2.99; p = 0.002) were independent predictors for shorter OS. In additional multivariate models considering non-diabetic patients as a reference group, diabetic patients with poor metabolic control (HbA1c > 8.5%) (HR 4.53; 95% CI 2.21–9.30; p < 0.001) and those receiving insulin (HR 3.22; 95% CI 1.90–5.46 p < 0.001) had significantly independent worse OS. Baseline FPG level is an independent predictor of survival in our cohort of patients with locally advanced NSCLC treated with concurrent chemoradiotherapy. Studies in larger cohorts of patients are warranted to confirm this relevant association.

8557 Background: There is no consensus on the treatment of elderly patients with unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). We aimed to determine whether the comprehensive geriatric assessment (CGA) as well as other screening tools were able to predict toxicity in this clinical setting. Methods: Elderly patients (≥ 75y) with LA-NSCLC underwent CGA, the Vulnerable Elders Survey (VES-13) screening tool and the Cancer and Aging Research Group (CARG) toxicity predictive tool. Based on CGA, fit and medium-fit patients were deemed candidates for platinum-based chemotherapy concurrent with thoracic radiation therapy (cCRT) and unfit patients received best supportive care. The ability of CGA, CARG and VES-13 to predict grade 3–4 (G3-4) toxicity was assessed by logistic regression. Results: 85 elderly patients with LA-NSCLC were assessed by CGA and classified into fit 37%, medium fit 48% and unfit 15%. Based on VES-13, 56% were considered vulnerable. Fifty-four fit and medium-fit patients received cCRT and 42 (78%) patients completed the scheduled treatment. No differences in treatment completion were seen among both CGA groups. Reasons for not completing cCRT were toxicity (10%), cancer recurrence (4%), patient decision (4%) or aggravation of comorbidities (4%). The median OS (mOS) in fit and medium-fit patients receiving cCRT was 21.1 months (95% CI 16.2 – 26.0). Most common G3-4 adverse events were neutropenia (20%), febrile neutropenia (7.5%), asthenia/fatigue (11%), respiratory infection (13%) and radiation pneumonitis (13%). CARG toxicity tool classified fit and medium-fit patients into high 10%, medium 52% and low risk 38%. GGA groups were not predictive of G3-4 toxicity. Medium and high risk patients based on CARG were more likely to have G3-4 toxicity (p = 0.086).Vulnerable patients defined by VES-13 had significantly higher risk of grade 3-4 toxicity (OR = 3.99, 95% CI 1.28-12.37, p = 0.017). Conclusions: CGA is helpful in selecting elderly patients with unresectable LA-NSCLC that may benefit from cCRT. VES-13 was significantly associated with higher risk of G3-4 toxicity in this clinical setting.

Background: Although concurrent chemoradiotherapy (cCRT) increases survival in patients with inoperable, locally advanced non-small-cell lung cancer (NSCLC), there is no consensus on the treatment of elderly patients. The aim of this study was to determine the prognostic value of the comprehensive geriatric assessment (CGA) and its ability to predict toxicity in this setting. Methods: We enrolled 85 consecutive elderly (⩾75 years) participants, who underwent CGA and the Vulnerable Elders Survey (VES-13). Those classified as fit and medium-fit by CGA were deemed candidates for cCRT (platinum-based chemotherapy concurrent with thoracic radiation therapy), while unfit patients received best supportive care. Results: Fit (37%) and medium-fit (48%) patients had significantly longer median overall survival (mOS) (23.9 and 16.9 months, respectively) than unfit patients (15%) (9.3 months, log-rank P =0.01). In multivariate analysis, CGA groups and VES-13 were independent prognostic factors. Fit and medium-fit patients receiving cCRT ( n =54) had mOS of 21.1 months (95% confidence interval: 16.2, 26.0). In those patients, higher VES-13 (⩾3) was associated with shorter mOS (16.33 vs 24.3 months, P =0.027) and higher risk of G3-4 toxicity (65 vs 32%, P =0.028). Conclusions: Comprehensive geriatric assessment and VES-13 showed independent prognostic value. Comprehensive geriatric assessment may help to identify elderly patients fit enough to be treated with cCRT.

BACKGROUND:Bronchoscopy is a safe technique for diagnosing peripheral pulmonary lesions (PPLs), and virtual bronchoscopic navigation (VBN) helps guide the bronchoscope to PPLs.OBJECTIVES:We aimed to compare the diagnostic yield of VBN-guided and unguided ultrathin bronchoscopy (UTB) and explore clinical and technical factors associated with better results. We developed a diagnostic algorithm for deciding whether to use VBN to reach PPLs or choose an alternative diagnostic approach.METHODS:We compared diagnostic yield between VBN-UTB (prospective cases) and unguided UTB (historical controls) and analyzed the VBN-UTB subgroup to identify clinical and technical variables that could predict the success of VBN-UTB.RESULTS:Fifty-five cases and 110 controls were included. The overall diagnostic yield did not differ between the VBN-guided and unguided arms (47 and 40%, respectively; p = 0.354). Although the yield was slightly higher for PPLs ≤20 mm in the VBN-UTB arm, the difference was not significant (p = 0.069). No other clinical characteristics were associated with a higher yield in a subgroup analysis, but an 85% diagnostic yield was observed when segmentation was optimal and the PPL was endobronchial (vs. 30% when segmentation was suboptimal and 20% when segmentation was optimal but the PPL was extrabronchial).CONCLUSIONS:VBN-guided UTB is not superior to unguided UTB. A greater impact of VBN-guided over unguided UTB is highly dependent on both segmentation quality and an endobronchial location of the PPL. Segmentation quality should be considered before starting a procedure, when an alternative technique that may improve yield can be chosen, saving time and resources.