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Purpose:Characterization of the T-cell receptor (TCR) repertoire may be a promising source for predictive biomarkers of pathologic response to immunotherapy in locally advanced non–small cell lung cancer (NSCLC).Experimental Design:In this study, next-generation TCR sequencing was performed in peripheral blood and tissue samples of 40 patients with NSCLC, before and after neoadjuvant chemoimmunotherapy (NADIM clinical trial, NCT03081689), considering their complete pathologic response (CPR) or non-CPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined.Results:We have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequently ranked clones (top 1%) present in diagnostic biopsies occupied greater frequency in the total clonal space of CPR patients, achieving an AUC ROC to identify CPR patients of 0.967 (95% confidence interval, 0.897–1.000; P = 0.001), and improving the results of PD-L1 tumor proportion score (TPS; AUC = 0.767; P = 0.026) or tumor mutational burden (TMB; AUC = 0.550; P = 0.687). Furthermore, tumors with high pretreatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selective expansion of pretreatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveillance, which could explain the high survival rate of these patients.Conclusions:We have identified two parameters derived from TCR repertoire analysis that could outperform PD-L1 TPS and TMB as predictive biomarkers of CPR after neoadjuvant chemoimmunotherapy, and unraveled possible mechanisms of CPR involving enhanced tumor immunogenicity and peripheral immunosurveillance.

Lung cancer is the leading cause of cancer-related death in worldwide. The most important treatment for patients with stage I and II non-small cell lung cancer (NSCLC) is surgery. Resected stage II and III NSCLC patients should be offered adjuvant chemotherapy and in patients with resected stage IB disease and with a primary tumor >4 cm this treatment could be considered. The treatment of resectable locally advanced NSCLC should be evaluated within an experienced multidisciplinary team. Neoadjuvant chemotherapy can be considered in patients with resectable disease and clear candidates for complementary chemotherapy. Neoadjuvant chemotherapy has similar impact on overall survival (OS) than adjuvant chemotherapy, however postoperative chemotherapy has more evidence-based support. Immunotherapy is being studied in early and locally advanced NSCLC as a neoadjuvant or adjuvant treatment. Different prognostic factors have been described in patients with stage III who have received neoadjuvant treatment, which we intend to review in this article.

Prognosis of early stage non-small cell lung cancer (eNSCLC) is poor even when treated radically with surgery and (neo)adjuvant chemotherapy (Cht). The discovery of tyrosine kinase inhibitors (TKIs) for oncogene addicted NSCLC and immune checkpoint inhibitors (ICIs) have revolutionised the therapeutic paradigm and improved survival of advanced NSCLC. The unprecedented impact of these drugs has shifted the focus of investigation to early stage disease aiming at improving cure. In this context, several single arm phase II studies evaluating neoadjuvant ICI alone or in combination with platinum-based Cht have shown encouraging rates of pathological response which have spurred several ongoing randomized trials with (neo)adjuvant ICI. More recently, ADAURA study evaluating adjuvant osimertinib demonstrated a profound reduction of the risk of recurrence in patients with stage I (>4 cm)-IIIA eNSCLC harbouring EGFR sensitizing mutations. ICIs and TKIs represent a true revolution in the treatment of eNSCLC call to challenge the current standard of care. However, questions regarding drug resistance, recurrence patterns, biomarker identification, optimal treatment duration and sequencing need be answered to effectively integrate new drugs in the rapidly evolving therapeutic landscape of NSCLC. In this review we critically review new developments and future perspectives of TKIs and ICI as (neo)adjuvant strategies for eNSCLC.

The new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) coronavirus has generated a pandemic, in which there are population groups at higher risk and who are potentially fatal victims of the disease. Cancer patients have been considered a group with special susceptibility, particularly patients with lung tumour involvement and haematological neoplasms. The Spanish Lymphoma Oncology Group (GOTEL) carried out a multicenter study of SARS-CoV-2 seroprevalence in patients with lymphoma. Results: A total of 150 patients were included between 22 May and 11 June 2020. The mean age was 65 years (range 17–89), 70 women (46.5%) and 80 men (53, 5%). At the time of diagnosis of lymphoma, 13 cases were stage I (9%), 27 (18%) stage II, 37 (24.5%) stage III, and 73 (48.5%) stage IV, while 6.6% had a primary extranodal origin. A total of 10 cases with positive serology for SARS-CoV-2 were identified, which is a prevalence of 6% in this population. None of the patients required intensive care unit management and all fully recovered from the infection. Conclusion: IgG antibody seroprevalence in lymphoma patients appears similar to that of the general population and does not show greater aggressiveness., This study was supported by the European Union Horizon 2020 research and innovation programme under grant agreement number 875160

Objective This study aimed to provide an extensive overview of clinical and pathological findings along with various therapeutic options analyzing in addiction, retrospectively, the surgical outcomes of a single center cohort. Background Thymic neoplasms are rare thoracic tumors which commonly are located in the anterior mediastinum and are associated with a wide spectrum of clinical presentations. They may run an indolent course or could present a very aggressive biologic progression with infiltration of mediastinal structures and presence of distant metastases. The pathogenesis of these tumors is so far not completely clear. Several treatment modalities in a multidisciplinary setting have to be considered in order to provide the best treatment for patients affected by thymic tumors. Methods We conducted a retrospective cohort analysis of all patients who underwent surgery due to thymic tumor in a university hospital located in Switzerland (Bern University Hospital) and then we performed a narrative review of the English literature using PubMed, Embase, Cochrane Database of Systematic Reviews and Scopus. Conclusions Minimally invasive techniques play an important role in the treatment of thymic tumors. A careful patients selection in a multidisciplinary setting is mandatory in order to offer the best treatment for patients affected by thymic tumors.

Introduction: Madrid has been the epicenter of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in Spain. We analyzed our experience with SARS-CoV-2 infected and cancer patients. Patients and Methods: We included patients from March 1 to April 30 2020 at Hospital Universitario Puerta de Hierro, Majadahonda, Madrid (Spain). The inclusion criteria were diagnosis of SARS-CoV-2 infection made by reverse transcription polymerase chain reaction (RT-PCR) of nasopharyngeal specimens in cancer patients who were admitted to the hospital due to the need for respiratory support. The exclusion criteria were suspected cases not confirmed. The primary objective was to analyze the mortality rates of patients with cancer, especially those with lung cancer and COVID-19. Results: Overall in-hospital mortality of cancer patients with coronavirus disease 2019 (COVID-19) was 15.2% similar to 12.7% of the global COVID-19 hospitalized population (p=0.615) and greater than that of patients admitted without SARS-CoV-2 infection during the same period 4.3% (p, This paper is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 875160.

e18734 Background: In the last five years, different immunotherapy (IO) clinical trials have improved overall survival (OS) for stage IV non-small cell lung cancer (NSCLC) without driver mutation. However, it is necessary to check whether outcomes of clinical trials are reproduced in the general population, the true objective of any scientific advance. Methods: We conducted a retrospective observational study selecting all patients with stage IV NSCLC without driver mutation treated in the Medical Oncology Department at Puerta de Hierro University Hospital between 2016 and 2019. Data cut off was June 30, 2021. Our goal was to evaluate treatment changes for NSCLC in clinical practice in our institution with OS in the real-world as the main outcome, in addition to assessing quality of care. Results: Between 2016 and 2019, 317 patients with stage IV NSCLC were diagnosed, 260 without driver mutation and 189 of them received systemic treatment. We observed a higher proportion of stage IVB patients in 2018 and 2019 compared to 2016 and 2017. A progressive greater use of IO was observed, except for a small decrease in 2019 compared to 2018. At the date of analysis, 77.8% of patients had died. With a median follow-up of 40.8 months, we observed a gradual increase in OS, with medians of 12.3, 13.6, and 18.9 months for patients diagnosed in 2016, 2017, and 2018, respectively, with a decrease to 10.4 months for patients diagnosed in 2019. Survival rates over time show the same trend. IO (any line) was significantly associated with a reduced risk of death: HR 0.35 (95% CI: 0.23 - 0.58) in multivariate analysis. The deterioration of the results of the patients diagnosed in 2019 is manifested in the median survival and in the survival rates at different points from 6 months onwards, which should correspond to the excess mortality in the year 2020 in our studied population. Conclusions: Our study shows that IO reduced risk of death: HR 0.35 (95% CI: 0.23 - 0.58) in stage IV NSCLC, observing an increase in overall survival from a median of 12.3 to 18.9 months for patients diagnosed in 2016 and 2018, suggesting that the progressive use of IO for NSCLC in the years 2016, 2017 and 2018 has transferred the benefit observed in clinical trials to the general population. The deterioration of outcomes for patients diagnosed in 2019, with a median OS of 10.4 months and decreased survival at 6, 12 and 18 months, could suggest the negative impact and excess mortality in the pandemic year 2020.[Table: see text]

7569 Background: Follicular lymphoma (FL) is the most frequently occurring indolent non-Hodgkin lymphoma, with generally favorable outcomes but a variable clinical course. Around 20% of patients suffer progression of disease within 24 months (POD24) of chemoimmunotherapy. In this prospective study, we examined the prognostic value of circulating tumor DNA (ctDNA), before and during treatment, to predict response and POD24 in FL patients. Methods: We collected 110 plasma samples from 39 patients diagnosed with FL, prospectively enrolled in 8 Spanish hospitals and treated with Chemotherapy-Rituximab regimen from April 2017 to November 2020 with a median follow-up of 41 months (m). Samples were collected before treatment (basal), mid-treatment (3m), at the end of treatment (EOT) (6m) and relapse or follow-up. We performed targeted deep sequencing in cell-free DNA and paired genomic DNA from 30 formalin-fixed paraffin-embedded tumoral (FFPET) samples with the same gene panel. Results: Before treatment, ctDNA levels, measured as haploid genome equivalents per milliliter of plasma (hGE/mL), were detected in 17/30 patients. Basal ctDNA levels were higher in patients without complete response (CR) than in CR patients [18 vs 14 log2(hGE/mL); Mann-Whitney P = 0.007] and in patients with POD24 compared to those not-POD24 [18 vs 13 log2(hGE/mL); P = 0.005]. None of the 13 patients with zero basal ctDNA levels, experienced POD24. Patients with at least one mutation detected in basal ctDNA had an inferior 24-months PFS than patients without alterations (64 vs 100%, log-rank test P = 0.027). In addition, basal ctDNA levels were detected in one patient with low FLIPI, but partial response and POD24, and by contrast, no ctDNA was detected in another patient with CR and no progression event but high FLIPI. From the alterations detected in FFPET samples, 66% were also identified in basal ctDNA. No alterations were detected in basal ctDNA from 7 patients with CR and 3 patients with watch-and-wait strategy. Dynamic analysis showed that ctDNA levels decreased after treatment for every patient (3 mo), but the reduction at EOT was higher in patients achieving CR than in non-CR patients (12 vs 3 log-reduction) and in not-POD24 patients compared to those with POD24 (10 vs 8). Furthermore, patients with at least one mutation detected in ctDNA at EOT had a shorter 24-months PFS than those without alterations (50 vs 90%). The sensitivity to detect alterations in ctDNA at EOT was 94% in patients not achieving a CR and no mutation was detected in patients with CR. Conclusions: In a real-life, prospective-based population, we showed that pre-treatment and dynamic molecular response measured by ctDNA, could be useful to stratify patients and predict response to treatment and early relapse in FL patients.

8501 Background: Non-small cell lung cancer (NSCLC) is incurable in most patients with locally advanced stage IIIA disease. Previous results indicate that the use of neoadjuvant chemoimmunotherapy could increase the percentage of cured patients being a promising therapeutic option that has to be tested in randomized clinical trials. Methods: NADIM II (NCT03838159) is an open-label, randomized, two-arm, phase II, multi-center clinical trial. Patients with resectable clinical stage IIIA (per AJCC 7th ed) NSCLC, ECOG PS 0-1, and no known EGFR/ALK alterations were randomized to receive Nivolumab (NIVO) 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days (+/- 3 days) as neoadjuvant treatment followed by surgery, or Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days (+/- 3 days) followed by surgery. Patients with R0 resection confirmed by pathological evaluation initiated adjuvant administration of NIVO within the 3rd to 8th week (+7 days) from surgery and for 6 months. The primary endpoint was pathological complete response (pCR) by blinded independent pathological review (BIPR) in the intent-to-treat population (ITT). pCR was defined as 0% viable tumor cells in resected lung and lymph nodes; patients who did not undergo surgery were classified as non-responders. Major pathological response (MPR; ≤ 10% viable tumor) per BIPR, overall response rate (ORR), toxicity profile, and potential predictive biomarkers are secondary endpoints. Results: Between February 8, 2019, and November 11, 2021, 90 patients were enrolled, of whom 87 patients were valid. Neoadjuvant NIVO + chemo significantly increased the pCR rate compared to chemo in the ITT (36.2% vs 6.8%; Relative Risk (RR) 5.25 [99% CI 1.32-20.87]; P = 0.0071). NIVO + chemo also improved MPR rates vs chemo in the ITT (52 % vs 14 %), as well as ORR (74 % vs 48%). Definitive surgery occurred for 91% of pts treated with NIVO + chemo and 69% with chemo; surgery was cancelled rarely due to AEs (1 pts/experimental arm) and due to disease progression in 1 and 4 pts in the experimental and control arm respectively. Grade 3-4-related AEs were reported in 24 % vs 10% in the NIVO + chemo vs chemo arms, respectively. In the ITT experimental arm, patients with pCR had higher PD-L1 TPS (median 70%, IQR 5-90%) compared to non-responders (median 0%, IQR 0-37.5%, P = 0.0035). AUC to predict pCR was 0.734 (95% CI 0.59-0.88; P = 0.005). The pCR rate rises across increasing categories of PD-L1 TPS ( < 1% 14.3%; 1-49% 41.7%; ≥50% 61.1%; P = 0.008). Conclusions: This study confirms the superiority of the chemo-immuno combination in patients with resectable stage IIIA NSCLC in terms of pCR, as well as the feasibility of surgery, with a moderate increase in grade 3-4 toxicity. Thus, this treatment should become the standard of care in these patients. Clinical trial information: NCT03838159.

e18736 Background: Immunotherapy (IO) is increasingly widespread in current clinical practice; however, little is known about its cardiovascular safety profile. The aim of this study is to identify clinical factors that are associated with increased risk of having a cardiac event (CE). Methods: we conducted a retrospective study in a single institution including patients treated with IO from 2014 to 2020. We analyzed their clinical characteristics and the CE developed during IO treatment and compared those who had a registered CE with those who had not. Results: 378 patients were analyzed. After a mean-follow up 15.9 months, we registered the following CE: ECG abnormalities 12.2%, congestive heart failure 3.4%, pulmonary embolism 1.9%, coronary syndrome 0.8%, myocarditis 0.5% and pericarditis 0.5%. The specific cardiac mortality was 0.8%. Results are shown in Table. Conclusions: In our study, elder age, history of ischemic heart disease or arrythmia, and reporting other immune-related adverse events (irAE), appear to be risk factors for developing a CE during IO treatment. Although most are well-known cardiovascular risk factors, the relationship between other irAEs and CE should be highlighted, and prospective studies are needed to delve into this hypothesis.[Table: see text]

Background Lung cancer is currently the leading cause of cancer death. Despite its high incidence and mortality, there are few studies describing its symptoms at diagnosis broken down by tumour stage and tobacco use. Accordingly, this study was proposed to describe the frequency of the most common symptoms of non-small cell lung cancer and small cell lung cancer (SCLC) at diagnosis, with a breakdown by stage and tobacco use. Patients and methods Cases were collected from the Spanish Thoracic Tumour Registry, a nationwide registry sponsored by the Spanish Lung Cancer Group. More than 50 hospitals recruited histologically confirmed lung cancer cases and information was gathered through personal interview plus data contained in the electronic clinical record. There were no data available on the lag between the appearance of the first symptoms and diagnosis of lung cancer. Results A total of 9876 patients (74% male, median age 64 years) were recruited from 2016 to 2019. Of these, 12.5% presented with SCLC. Stage IV was the most frequent stage at diagnosis (46.6%), and the most frequent symptom was cough (33.9%), followed by dyspnoea (26.7%). No symptom was present in 59% of patients diagnosed in stage I; 40% of stage I patients presented with at least one symptom, while 27.7% of patients in stage IV had no symptoms at diagnosis. Cough was the most frequent symptom in SCLC (40.6%), followed by dyspnoea (34.3%). The number of symptoms was similar across the respective smoking categories in SCLC, and differences between the symptoms analysed did not exceed 7% in any case. Conclusion The absence of the most frequent symptoms (ie, cough, pain, dyspnoea) should not lead to a decision to rule out the presence of lung cancer. A relevant percentage of stage IV patients displayed no symptoms at diagnosis.

Nodular lymphocytic predominance Hodgkin lymphoma (NLPHL) is a very uncommon subtype of Hodgkin lymphoma (HL), representing approximately 5% of all HL cases, with an incidence of 0.3/100,000 cases per year and with unique characteristics which distinguish it from classic Hodgkin lymphoma. Given its low frequency, there is a lack of prospective randomized studies to inform practice, the accumulated experience of academic groups being the main source of relevant information for the management of these patients. Eighty-five patients recruited by the Spanish Lymphoma Group (GOTEL) from 12 different hospitals were retrospectively analyzed to describe their sociodemographic and clinical characteristics. The median follow-up was 16 years, with a 10-year overall survive of 92.9% and 81.2% at 20 years. Five patients developed a second malignancy. No transformation to a more aggressive lymphoma was detected. A total of 31% tumor relapses was found: 77% in a single location; most of them at a supra-diaphragmatic level. Patients received different first-line treatments, and progression was observed in 3/4 (75%) of the patients who did not receive any type of treatment, 6/23 (26%) who received both chemotherapy (CH) and radiotherapy (RT), 12/43 (27%) who received RT and 7/15 (47%) that received only CH treatment. The mean time to relapse was 3 years and 47% presented relapses beyond 5 years (higher probability in stage IV p < 0.001). This is one of the longest follow-up series of NLPHL published, confirming its excellent prognosis, and that treatments may be adapted to reduce toxicity. Causes of death in these patients are varied, and the minority due to a primary malignancy relapses.

Background: Despite impressive and durable responses, patients treated with ALK inhibitors (ALK-Is) ultimately progress. We investigated potential resistance mechanisms in a series of ALK-positive non-small cell lung cancer (NSCLC) patients progressing on different types of ALK-Is.Methods: 26 plasma and 2 cerebrospinal fluid samples collected upon disease progression to an ALK-I, from 24 advanced ALK-positive NSCLC patients, were analyzed by next-generation sequencing (NGS). A tool to retrieve variants at the ALK locus was developed. Results: 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1) FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3 and CCND1. Overall, We identified at least one mutation in ALK locus in 10 (38.5%) plasma samples, being the G1269A and G1202R mutations the most prevalent among patients progressing to first- and second-generation ALK-I treatment, respectively. An exon 19 deletion in EGFR was identified in a patient showing primary resistance to ALK-I. Likewise, the G466V mutation in BRAF and the F129L mutation in MAP2K1 (MEK1) were identified as the underlying mechanism of resistance in three patients who gained no or little benefit from second-line treatment with an ALK-I. Putative ALK-I resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and a FGFR3, were detected in a patient progressing on a first-line treatment with crizotinib. Conclusions: NGS analysis of liquid biopsies upon disease progression identified putative ALK-I resistance mutations in most cases, being a valuable approach to devise therapeutic strategies upon ALK-I failure.

Background: AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain.Methods: Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. 155 patients were enrolled (August 2016-December 2018) from 30 sites. Primary objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources.Results: 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. 155 patients were evaluable for response, 1.3% complete response, 40.7% partial response, 31% stable disease and 11.6% progressive disease. Objective response rate was 42%. Median progression-free survival was 9.4 months. 49% reported an adverse event, the majority of which (78%) were grade 1 or 2. The resource cost study indicates early use is warranted. Conclusion: This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events.Clinical trial registration number: NCT03790397

Introduction: Based on the high incidence of thromboembolic events (TEs) observed in lung adenocarcinomas with ALK translocations and taking into account the biological proximity of ROS1 and ALK, we conducted a retrospective analysis of patients with advanced lung carcinoma carrying rearrangements in ROS1 from 23 centres in Spain and one centre in Portugal. Methods: The main objective of the study was to analyse the incidence of TE in this population, looking for predictive risk factors, and its impact on overall survival. Results: A total of 58 patients were included. The incidence of TEs throughout the disease was 46.6% (n = 27) with a median follow-up of 19 months (range: 1-78 months) and a median overall survival of 52 months in the total population and 50 months for the patients presenting TEs, with a hazards ratio of 1.12 (95% confidence interval: 0.47-2.65) p = 0.78. The majority of the events were venous (n = 24; 89%) and occurred in the ambulatory setting (n = 18; 67%). Almost half of the patients (n = 13; 48%) presented the TE in the peri-diagnostic period. Conclusions: The high incidence of thrombosis, especially during the cancer diagnosis process, requires special attention from a clinician. Despite the limitations of such a small descriptive study, its results are in accordance with previously reported data. It would be important to design prospective studies of antithrombotic prophylaxis in this population because of their possible impact in reducing the risk of TEs. (C) 2020 Elsevier Ltd. All rights reserved.

Aim: Immune checkpoint inhibitors (ICIs) are a cornerstone in cancer treatment but they can induce immune-related adverse events (irAEs). Furthermore, patients with pre-existing autoimmune and/or inflammatory disease (AID) have been excluded from clinical trials. The objective of this study is to evaluate the efficacy and safety of ICIs in patients with cancer and AID. Materials & methods: This is an observational, retrospective study carried out at the Medical Oncology Department of Hospital Universitario Puerta de Hierro, Majadahonda, Madrid between January 2016 and December 2018. Results: A total of 202 cancer patients treated with ICIs were included, 15 (7, 4%) of them had pre-existing autoimmune diseases. The most frequent pre-existing AID were thyroid diseases (33.3%): autoimmune hypothyroidism, Graves–Basedow disease and Hashimoto’s thyroiditis. Three patients had psoriasis, two antinuclear antiboides + polyarthritis, one rheumatoid arthritis, another latent autoimmune diabetes in adults, another systemic lupus erythematosus and the last one, a polymyalgia rheumatica. In this series, the majority of patients (73.33%) did not experience any flare up of their autoimmune disease. In patients who had AID flare up, this was treated with corticosteroids. The most frequent cause of immunotherapy discontinuation was tumor progression (40%). A total of 20% of patients had to discontinue immunotherapy due to toxicity. Conclusion: In our series, AID flare ups or irAEs in patients with pre-existing AID who receive immunotherapy are not very common and can often be controlled without interrupting treatment. Prospective studies are needed to establish the incidence of irAEs in patients with pre-existing autoimmune conditions, evaluate risk–benefit and elaborate management clinical guidelines in this population.

Summary Background Non-small-cell lung cancer (NSCLC) is terminal in most patients with locally advanced stage disease. We aimed to assess the antitumour activity and safety of neoadjuvant chemoimmunotherapy for resectable stage IIIA NSCLC. Methods This was an open-label, multicentre, single-arm phase 2 trial done at 18 hospitals in Spain. Eligible patients were aged 18 years or older with histologically or cytologically documented treatment-naive American Joint Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be surgically resectable by a multidisciplinary clinical team, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received neoadjuvant treatment with intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was progression-free survival at 24 months, assessed in the modified intention-to-treat population, which included all patients who received neoadjuvant treatment, and in the per-protocol population, which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Safety was assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov , NCT03081689 , and is ongoing but no longer recruiting patients. Findings Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for eligibility, of whom 46 patients were enrolled and received neoadjuvant treatment. At the time of data cutoff (Jan 31, 2020), the median duration of follow-up was 24·0 months (IQR 21·4–28·1) and 35 of 41 patients who had tumour resection were progression free. At 24 months, progression-free survival was 77·1% (95% CI 59·9–87·7). 43 (93%) of 46 patients had treatment-related adverse events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse events of grade 3 or worse; however, none of the adverse events were associated with surgery delays or deaths. The most common grade 3 or worse treatment-related adverse events were increased lipase (three [7%]) and febrile neutropenia (three [7%]). Interpretation Our results support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC. Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable. Funding Bristol-Myers Squibb, Instituto de Salud Carlos III, European Union's Horizon 2020 research and innovation programme.

Tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase gene (ALK) have significantly improved the quality of life and survival of non-small cell lung cancer (NSCLC) patients whose tumors harbor an ALK translocation. However, most of these patients relapse within 2 to 3 years as the tumor acquires resistance mutations. Unlike beaming and digital PCR (dPCR), which only allow a few mutations to be analyzed, next-generation sequencing (NGS) approaches enable the simultaneous screening of multiple genetic alterations even when the frequencies of the variants are very low. We present the case of a 52-year-old man who was diagnosed with an ALK-positive NSCLC and was treated with crizotinib and, subsequently, ceritinib. The analysis of serial liquid biopsies by NGS detected two asynchronous mutations arising in the ALK locus during disease progression, namely p.Gly1269Ala (c.3806G>C) and p.Gly1202Arg (c.3604G>A), that conferred resistance to crizotinib and ceritinib, respectively. The resistance mutations were detected independently at different times, and could be imputed to different metastatic lesions, thereby highlighting the importance of heterogeneity in advance disease. Plasma levels of ALK resistance mutations correlated well with tumor responses assessed by CT scans and bone scintigraphy, demonstrating that non-invasive tumor molecular profiling by NGS allows the efficient dynamic monitoring of ALK-positive NSCLC patients, and outperforms dPCR and beaming because more somatic mutations can be tracked over the course of the treatment. In conclusion, this case report illustrates the usefulness NGS to guide therapeutic decisions in ALK-positive NSCLC patients based tumor molecular profile upon disease progression.

Background: Several clinical trials have demonstrated the efficacy and safety of osimertinib in advanced nonsmall-cell lung cancer (NSCLC). However, there is significant unexplained variability in treatment outcome. Methods: Observational prospective cohort of 22 pre-treated patients with stage IV NSCLC harboring the epidermal growth factor receptor (EGFR) p.T790M resistance mutation and who were treated with osimertinib. Three hundred and twenty-six serial plasma samples were collected and analyzed by digital PCR (dPCR) and next-generation sequencing (NGS). Results: The median progression-free survival (PFS), since the start of osimertinib, was 8.9 [interquartile range (IQR): 4.6–18.0] months. The median treatment durations of sequential gefitinib + osimertinib, afatinib + osimertinib and erlotinib + osimertinib treatments were 30.1, 24.6 and 21.1 months, respectively. The p.T790M mutation was detected in 19 (86%) pre-treatment blood samples. Undetectable levels of the original EGFR-sensitizing mutation after 3 months of treatment were associated with superior PFS (HR: 0.2, 95% CI: 0.05–0.7). Likewise, re-emergence of the original EGFR mutation, alone or together with the p.T790M mutation was significantly associated with shorter PFS (HR: 8.8, 95% CI: 1.1–70.7 and HR: 5.9, 95% CI: 1.2–27.9, respectively). Blood-based monitoring revealed three molecular patterns upon progression to osimertinib: sensitizing+/T790M+/C797S+, sensitizing+/T790M+/C797S–, and sensitizing+/T790M–/ C797S–. Median time to progression in patients showing the triplet pattern (sensitizing+/T790M+/C797S+) was 12.27 months compared with 4.87 months in patients in whom only the original EGFR sensitizing was detected, and 2.17 months in patients showing the duplet pattern (sensitizing+/T790M+). Finally, we found that mutations in exon 545 of the PIK3CA gene were the most frequent alteration detected upon disease progression in patients without acquired EGFR-resistance mutations. Conclusions: Different molecular patterns identified by plasma genotyping may be of prognostic significance, suggesting that the use of liquid biopsy is a valuable approach for tumor monitoring. post-print 468 KB

Bendamustine is a drug widely used in the treatment of follicular lymphoma. Although it was initially approved as monotherapy in patients refractory to rituximab [1], better results were obtained w...

Introduction: Neoadjuvant chemoimmunotherapy been shown to be highly effective in resectable stage IIIA NSCLC. Now we provide long term survival data Methods: This was an open-label, multicentre, single-arm phase 2 trial in which patients with histologically or cytologically documented stage IIIA NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 and who were deemed locally to be surgically resectable by a multidisciplinary clinical team were treated with neoadjuvant intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6;6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). Here we report progression-free survival (PFS) and Overall survival (OS) at 36 and 42 months, assessed in the modified intention-to-treat population (ITT), which included all patients who received neoadjuvant treatment, and in the per-protocol population (PP), which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Results: Median follow-up time was 37.9 months (95%CI: 36.7-40.7), with a 94% maturity at 36 months. Among the ITT population (N=46), 37 patients, constituting the PP population, received subsequent adjuvant therapy. Of them, 27 (58.7%) patients completed the adjuvant treatment (16 cycles), 10 (21.7%) patients received between 3 and 15 cycles of adjuvant therapy, and 9 (19.6%) patients did not receive adjuvant therapy. At the time of data cutoff (March 2021), progression disease was diagnosed in 14 patients and 9 deaths were recorded in the ITT population. Of these, three deaths corresponded to patients who did not undergo surgery and had disease progression, four deaths corresponded to patients who underwent surgery and had disease progression, and the two remaining deaths corresponded to patients who were diagnosed as being disease free but died from COVID19 infection. Notably, among patients who could not undergo surgery (N=5), one of them is still alive and with no evidence of disease. PFS at 36 and 42 months in the ITT population were 69.6% (95%CI: 54.1-80.7), in both cases. Similarly, PFS at 36 and 42 in the PP population were 81.1% (95%CI: 64.4-90.5) in both cases. The percentage of patients who were alive at 36 and 42 months in the modified ITT population were 81.86% (95% CI: 66.8-90.6) and 78.94% (95%CI: 63.1-88.6), respectively. Likewise, OS at 36 and 42 months in the PP population was 91.0% (95%CI: 74.2-97.0) and 87.3% (95%CI: 69.3-95.1), respectively. Conclusion: The efficacy of nivolumab in combination with platinum-based chemotherapy in patients with resectable stage IIIA NSCLC is clearly supported by long term survival data. Keywords: NADIM trial, neoadjuvant chemo-therapy, long term survival

There is growing evidence supporting that long-term survival of neoadjuvant chemo-immunotherapy for locally advanced NSCLC patients can be achieved. However, some patients invariably progress within the short-term. Identification of patients at high risk of progression is needed to achieve a better control of the disease. Concentrations of baseline ctDNA have been shown to be of prognostic significance. Patients and methods 42 pre-treatment plasma samples from the NADIM clinical trial (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab, were analyzed by NGS, using the Oncomine Pan-Cancer Cell-Free Assay™ (Thermo Fisher Scientific®). Variant calling, annotation and filtering were performed on the Ion Reporter (v5.14) platform using the OncomineTagSeq Pan-Cancer Liquid Biopsy workflow (v2.3). The final variant matrix was obtained from vcf files as generated from Ion Reporter (v5.14) platform and applying an internal pipeline (R-code is available upon request). Progression disease was evaluated by RECIST criteria V1.1. Results A total of 116 variants were detected in 88.10% (N=37) of the plasma samples collected before neoadjuvant treatment. The average number of variants detected per sample was 3.13. The most frequently mutated genes were TP53, which accounts for 59.52% of the detected variants, followed by PIK3CA (30.95%), MAP2K1 (30.95%), APC (23.81%), MTOR (9.52%) and KIT (9.52%). Patients in whom a GNA11 mutation was detected in the plasma sample by NGS showed worsen progression free survival (PFS) (HR: 14. 95%; CI: 2.6-71, P-value with Fold Discovery Rate correction: 0.019). Finally, ctDNA levels at Mutant Allele Frequency (MAF) below 1% at baseline were associated with improved PFS (P=0.025). At 30 months, PFS was 80.30% for these patients compared with 58.33% in patients with ctDNA levels ≥ 1%. Conclusions Molecular profiling of liquid biopsies collected before neoadjuvant chemo-immunotherapy using NGS can identify patients at high risk of progression who might require more aggressive adjuvant treatment in order to achieve a better control of the disease. Citation Format: Mariano Provencio, Roberto Serna-Blasco, Ernest Nadal, Amelia Insa, M. Rosario Garcia-Campelo, Diego Pereiro Corbacho, Manuel Domine, Margarita Majem, Delvys Rodriguez-Abreu, Alex Martinez-Marti, Javier de Castro, Manuel Cobo, Guillermo Lopez-Vivanco, Edel del Barco, Reyes Bernabe, Nuria Viñolas, Isidoro Barneto, Santiago Viteri, Eva Pereira, Ana Royuela, Marta Casarrubios, Clara Salas, Edwin R Parra, Ignacio Wistuba, Virginia Calvo, Raquel Laza-Briviesca, Bartomeu Massuti, Alberto Cruz-Vermudez, Atocha Romero. High levels of baseline ctDNA constitute a poor prognostic factor in progression-free survival in patients receiving neo-adjuvant chemo-immunotherapy: Results from NADIM clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 560.

BACKGROUND Relatively few studies have analyzed the mortality of follicular lymphoma (FL) patients in comparison with a sex- and age-matched general population. This study analyzed the overall survival (OS) of patients with FL and compared their survival with the expected survival of a general population. METHODS Patients diagnosed with FL were prospectively enrolled from 1980 to 2013. Standardized mortality ratios (SMRs) were obtained from yearly sex- and age-specific mortality rates in Spain, and OS was compared with age- and sex-matched general population data. RESULTS A total of 1074 patients with newly diagnosed FL were enrolled. The median OS was 231 months (95% confidence interval [CI], 195-267 months). Event-free survival at 12 months (EFS12) and event-free survival at 24 months (EFS24) were associated with an increased probability of early death, with an SMR of 10.27 (95% CI, 8.26-12.77) for EFS12. The overall SMR, including all causes of death, was 2.55 (95% CI, 2.23-2.92), and it was higher for women (SMR, 3.02; 95% CI, 2.48-3.67) and young adults (SMR, 6.01; 95% CI, 3.13-11.55). More than 10 years after the diagnosis, mortality rates for FL patients were lower than those for the general population (SMR, 0.47; 95% CI, 0.28-0.78). When FL was excluded as a cause of death, the overall SMR was 1.35 (95% CI, 1.11-1.65) without a statistically significant mortality increase in the >60-year-old group in comparison with age- and sex-matched general population data. More than 15% of the patients included in the study (n = 158) had more than 10 years of follow-up. CONCLUSIONS EFS12 and EFS24 predict an early increase in mortality. The long-term SMR, over the course of 10 years of follow-up, shows that patients with FL have a risk of dying similar to that of a sex- and age-matched general population. Cancer 2017. © 2017 American Cancer Society.

Survival rates in patients with stage IIIA non-small cell lung cancer (NSCLC) remain low despite curative treatment. This is due to tumor recurrence at distant sites. The aim of neoadjuvant chemotherapy (NA-CT) is to eradicate occult micrometastatic disease and improve survival in patients that are not candidates for surgery following induction therapy. A total of 21 patients with ipsilateral mediastinal node involvement (N2) with potentially resectable disease, who had been diagnosed with stage IIIA (T1-3 N1-2 and T4N0) NSCLC and who had received cisplatin and vinorelbine as induction treatment were included in this retrospective study. Patients who responded to the treatment underwent surgery, and those who were unresponsive received radical radiotherapy. Follow-up was conducted between March 2008 and April 2014. The median age of patients was 61 years, and all patients exhibited a good Eastern Cooperative Oncology Group performance status. The majority of patients were histologically diagnosed with adenocarcinoma (48%) or squamous cell carcinoma (38%), which was a poor prognostic factor for overall survival (OS). A total of 7 patients underwent surgery (of which 6 were down-staged), with a 3-year survival rate of 42.8%. The most significant factor associated with response to induction treatment was multistation nodal involvement. The complete resection rate for surgical patients was 85.7%. Unresectable patients had a 3-year survival rate of 25.8%. OS time for the whole cohort was 28.5 months, and the 3- and 5-year OS rates were 28.5% and 4.7%, respectively. CT-induced toxicity did not affect any treatment regime or surgical procedures. In conclusion, the use of cisplatin plus vinorelbine is feasible in a neoadjuvant setting, with good response rates and acceptable toxicity. Multistation N2 involvement is the main prognostic factor for a poor response to induction treatment.

Background Non-small cell lung cancer (NSCLC) patients benefit from targeted therapies both in first- and second-line treatment. Nevertheless, molecular profiling of lung cancer tumors after first disease progression is seldom performed. The analysis of circulating tumor DNA (ctDNA) enables not only non-invasive biomarker testing but also monitoring tumor response to treatment. Digital PCR (dPCR), although a robust approach, only enables the analysis of a limited number of mutations. Next-generation sequencing (NGS), on the other hand, enables the analysis of significantly greater numbers of mutations. Methods A total of 54 circulating free DNA (cfDNA) samples from 52 NSCLC patients and two healthy donors were analyzed by NGS using the Oncomine™ Lung cfDNA Assay kit and dPCR. Results Lin’s concordance correlation coefficient and Pearson’s correlation coefficient between mutant allele frequencies (MAFs) assessed by NGS and dPCR revealed a positive and linear relationship between the two data sets (ρc = 0.986; 95% confidence interval [CI] = 0.975–0.991; r = 0.987; p Conclusions MAFs assessed by NGS were highly correlated with MAFs assessed by dPCR, demonstrating that NGS is a robust technique for ctDNA quantification using clinical samples, thereby allowing for dynamic genomic surveillance in the era of precision medicine.

The widespread adoption of Electronic Health Records (EHRs) is generating an ever-increasing amount of unstructured clinical texts. Processing time expressions from these domain-specific-texts is crucial for the discovery of patterns that can help in the detection of medical events and building the patient’s natural history. In medical domain, the recognition of time information from texts is challenging due to their lack of structure; usage of various formats, styles and abbreviations; their domain specific nature; writing quality; and the presence of ambiguous expressions. Furthermore, despite of Spanish occupying the second position in the world ranking of number of speakers, to the best of our knowledge, no Natural Language Processing (NLP) tools have been introduced for the recognition of time expressions from clinical texts, written in this particular language. Therefore, in this paper we propose a Temporal Tagger for identifying and normalizing time expressions appeared in Spanish clinical texts. We further compare our Temporal Tagger with the Spanish version of SUTime. By using a large dataset comprising EHRs of people suffering from lung cancer, we show that our developed Temporal Tagger, with an F1 score of 0.93, outperforms SUTime, with an F1 score of 0.797.

The immunotherapy (IO) agents in the renal cell carcinoma represent the best option in the second line of treatment. However, these drugs can be associated with different types of toxicities. The vascular toxicity related with IO is very uncommon. We report a case of a 46-year-old man diagnosed with stage IV renal cell carcinoma. He received a second-line treatment with nivolumab. After the fourth cycle, he presented a small-vessel serious vasculitis associated with IO toxicity. He required treatment with corticosteroids and immunosuppressors for toxicity control. We speculate that the anti-PD-1 agents can generate a disproportionate vascular inflammatory process mediated by T cells. The data suggest that there is an intimate relationship between alterations in the PD-1/PD-L1 pathway and vasculitis.

e18709 Background: Patients with cancer may be more susceptible to infection and at increased risk of more severe COVID-19 disease; however, prognostic factors are not yet clearly identified. The LunG canceR pAtients coVid19 Disease (GRAVID) study aimed to describe clinical characteristics, outcomes, and predictors of poor outcome in patients with lung cancer and COVID-19. Methods: In this large nationwide study, we reviewed medical records of patients with lung cancer and confirmed COVID-19 diagnosis from 65 Spanish hospitals. Clinical features, treatments and disease outcomes were collected. The primary endpoint was to determine all-cause mortality; secondary endpoints were hospitalization and admission to intensive care units (ICU). Risk factors for poor prognosis were identified by univariate and multivariate logistic regression models. Results: Overall, 447 patients were included for analysis. Mean age was 67·1 ± 9·8 years; 332 (74·3%) were men, and 383 (85·7%) current/former smokers. NSCLC was the most frequent type of cancer (377, 84·5%), consisting mainly of adenocarcinoma (228, 51·0%), and stage III metastatic or unresectable disease (354, 79·2%). Two-hundred and sixty-six (59·5%) patients were receiving anticancer treatment, mostly first-line chemotherapy. In total, 350 (78·3%) patients were hospitalized for a mean of 13·4 ± 11·4 days, nine (2·0%) patients were admitted to the ICU, and 146 (32·7%) died. Advanced disease and the use of corticosteroids to treat COVID-19 during hospitalization were predictors of mortality. Hospitalized, non-end-of-life stage patients with lymphocytopenia and high LDH had an increased risk of death. Severity of COVID-19 correlated to higher mortality, ICU admission, and mechanical ventilation rates. Conclusions: Due to their underlying comorbidities and immunocompromised status, patients with lung cancer and COVID-19 show high hospitalization and mortality rates. These outcomes, alongside the identification of prognostic factors, may inform physicians on the risks and benefits in this population, in order to provide individualized oncological care.

e18751 Background: In the last years, Immunotherapy (IT) has emerged as a standard treatment in an increasing number of tumors. This type of treatment has a specific toxicity profile which is clearly different from chemotherapy, known as an Immuno-related Adverse Event (AEir). We know the data from clinical trials, but little about the incidence and impact of this EAir in our clinical practice. Methods: A retrospective observational study was carried out including all patients from our institution (HUPHM in Madrid) who had received IT, either in monotherapy or in combination between January 2014 and December 2019. A total of 279 patients were included and data were collected between January and July 2020, guaranteeing a minimum 6-month follow-up after receiving the first dose of immunotherapy. The toxicities found were classified into four categories: pulmonary, digestive, endocrine and others, and have been graded according to CTCEA v.5 (Common Terminology Criteria for Adverse Event) published in November 2017 and analyzed according to drug and tumor. Results: The most frequent diagnoses in our patients were: 60% lung carcinoma, 15% melanoma, 8% kidney carcinoma, and 6% bladder carcinoma. 76% of the patients received IT as first or second line in a metastatic context, 6% in the initial stage (clinical trials) and the rest in more advanced lines of treatment (3 or more). 67% received anti-PD1 drug, 6% anti-PDL1, 4% anti-CTL4 monotherapy, 10% a combination of several IT drugs, and 14% an IT combination and chemotherapy. 45% of the total presented EAir (16% grade I, 14% grade II, 11% grade III and 4% grade IV). 1/5 of the patients had manifestations in more than one organ. The incidence of the different toxicities in our population was listed in the table below. These patients reported 8% dermatological toxicities, 6% had renal toxicity (most of them grade III or IV), only 2% had arthralgia or myalgia, and 3% asthenia. Combined IT treatment had significantly higher rates of pneumonitis, colitis, and endocrine toxicities. These differences were not observed between the monotherapy treatment and the combination of immunotherapy plus chemotherapy. Conclusions: Immunotherapy has represented an important advance in oncology, achieving long survivals in a growing group of tumors. Immunotherapy has a unique toxicity profile that is very different from chemotherapy and with which we must become familiar. Most of the adverse events are mild and if they are diagnosed early and with the appropriate treatment, maintenance of IT is possible. Severe toxicity (III-IV) means in most cases the suspension of treatment, compromising its efficacy. Therefore, we must learn to recognize these toxicities early and apply the recommended treatments as soon as possible.[Table: see text]

TPS8581 Background: The results of current studies are considered acceptable evidence to support the hypothesis of efficacy of the proposed combination of immunotherapy with chemotherapy (CT-IO) in patients with NSCLC stages Ib-IIIA candidates for adjuvant treatment. Methods: This is an open-label, randomised, two-arm, phase III, multi-centre clinical trial. Primary objective and endpoint: The primary objective is disease free survival (DFS) defined time from randomization to the earliest event defined as disease recurrence, any new lung cancer (even in the opposite lung), or death from any cause at any known point in time Sample size: 210 patients NSCLC stages Ib-IIIA (Experimental Arm (Adjuvant Chemotherapy-Inmunotherapy + maintenance adjuvant Inmunotherapy): 105 patients, Control Arm (Adjuvant Chemotherapy): 105 patients Treatment Patients randomised to the experimental arm will receive Nivolumab 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 4 cycles every 21 days (+/- 3 days) as adjuvant treatment followed by maintenance adjuvant treatment for 6 cycles with Nivolumab 480 mg Q4W (+/- 3 days). Patients randomized to the control arm will receive Paclitaxel 200mg/m2 + Carboplatin AUC5 for 4 cycles every 21 days (+/- 3 days) followed by 2 observation visits. Total trial duration: 6.5 years, 3.5 years of recruitment, 1 year of adjuvant treatment or observation and 2 years of follow up. The start date was January 2021. The estimated primary completion date is June 2027. Clinical trial information: NCT04564157.

The book-trailer is a marketing resource created by publishing houses in order to spread and promote books in the digital environment. This article presents the findings of a research study focused on book-trailers as a paratext (Gray 2010) which may be used to develop the literary competence in the context of Pre-School classrooms. The results obtained show the importance of the book-trailer as a tool to develop the literary competence.

El concepto de literatura infantil se ha ido definiendo a lo largo del tiempo a traves de propuestas de autores que han marcado una forma de entender el discurso literario dirigido a la infancia. Maurice Sendak es, sin duda, uno de esos autores, de tal modo que se le atribuye una suerte de «reinvencion» de la literatura infantil. Tras establecer las bases sobre las que se asienta esta afirmacion, se analizan desde esta perspectiva varias obras del autor, insistiendo particularmente en la metafora como estrategia discursiva. La presencia de metaforas relacionadas con el ambito de la comida constituye un elemento recurrente en la obra de Sendak, a manera de «intertexto restringido», en un sentido muy amplio. ______________________________________________________________________________________________________________________ Abstract: The concept of Children’s Literature has been defined over time through proposals from authors who have made a way of understanding the literary discourse to children. Certainly, Maurice Sendak is one of those authors so he is attributed to a sort of «reinvention» of Children´s Literature. After establishing the basis on which this statement is based, we analyze –from this perspective– various works by the author, with particular emphasis on the metaphor as a discursive strategy. Thus the presence of related metaphors in the fields of food constitutes a recurring element in the work of Sendak, seen in a way as a «restricted intertextuality» in a very wide sense.

Simple Summary In recent years there has been a trend towards an increase in the proportion of non-small cell lung cancer patients diagnosed with localized stage instead of advanced. However, 5-year survival rates continue to be low, even among patients diagnosed at early stages. In recent years major advances have been made in the treatment of advanced NSCLC, in large part due to the irruption of immunotherapy. PD-1 axis blocking-based immunotherapy is already a well-established standard of care treatment for patients with advances NSCLC, in frontline setting and in pretreated patients. Our greatest challenge now is to move the benefit of immunotherapy to patients with early-stage NSCLC so as to increase 5-year survival rate. The aim of this manuscript is to make a comprehensive review of available evidence, make a critical review of the results of published and ongoing studies, and analyze the role of biomarkers, main areas of controversy and future challenges. Abstract Despite numerous advances in targeted therapy and immunotherapy in the last decade, lung cancer continues to present the highest mortality rate of all cancers. Targeted therapy based on specific genomic alterations, together with PD-1 and CTLA-4 axis blocking-based immunotherapy, have significantly improved survival in advanced non-small cell lung cancer (NSCLC) and both therapies are now well-established in this clinical setting. However, it is time for immunotherapy to be applied in patients with early-stage disease, which would be an important qualitative leap in the treatment of lung cancer patients with curative intent. Preliminary data from a multitude of studies are highly promising, but therapeutic decision-making should be guided by an understanding of the molecular features of the tumour and host. In the present review, we discuss the most recently published studies and ongoing clinical trials, controversies, future challenges and the role of biomarkers in the selection of best therapeutic options.

BACKGROUND: Biological differences between the sexes have a major impact on disease and treatment outcome. In this paper, we evaluate the prognostic value of sex in stage IV non-small-cell lung cancer (NSCLC) in the context of routine clinical data, and compare this information with other external datasets. METHODS: Clinical data from stage IV NSCLC patients from Hospital Puerta de Hierro (HPH) were retrieved from electronic health records using big data analytics (N = 397). In addition, data from the Spanish Lung Cancer Group (GECP) Tumor Registry (N = 1382) and from a published study available from the cBioPortal (MSK) (N = 601) were analyzed. Survival curves were estimated using the Kaplan-Meier method. A Cox proportional hazards regression model was used to assess the prognostic value of sex. A meta-analysis to compare the outcome for males and females in terms of overall survival (OS) and progression free survival (PFS) was performed. RESULTS: The median OS time was 12 months for males and 19 months for females (overall HR = 0.77; 95% CI: 0.68-0.87; P < 0.001). Similarly, females with stage IV NSCLC harboring an EGFR-sensitizing mutation lived significantly longer than males (median OS: males, 19 months; females, 32 months) with a lower risk of death compared with males (overall HR = 0.75; 95% CI: 0.67-0.84). In addition, female patients benefited more from EGFR inhibitors in terms of PFS and OS (overall HR = 0.45; 95% CI: 0.32-0.64, and HR = 0.62; 95% CI: 0.48-0.80, respectively). Median PFS was 21 months in females and 12 months in males (P < 0.001). CONCLUSIONS: Using routine clinical data we confirmed the previous finding that among stage IV NSCLC patients, females had a significantly better prognosis than males. The effect size of the sex was notable, highlighting the fact that survival rates are usually estimated and patients are generally managed without considering the sexes separately, which may lead to suboptimal results.

9041 Background: Characterization of the peripheral blood T-cell receptor (TCR) repertoire has become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, there is lack of knowledge about the clinical relevance of TCR repertoire in terms of pathological response and clinical outcomes (PFS and OS) in chemo-immunotherapy. To answer this question we have analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab. Methods: Using ION Torrent-based next-generation sequencing we have analysed TCR repertoire of peripheral blood from 30 patients receiving chemo-immunotherapy. Using 25ng of total RNA from PBMCs, clonal convergence, evenness and diversity were calculated at diagnosis (pre-treatment) and after 3 cycles of Nivolumab plus carboplatin (post-treatment). Regarding pathological responses, patients were classified in 3 groups: complete response (pCR) (0% viable tumour at the resection specimen), mayor response (pMR) ( < 10% viable tumour) and incomplete response (pIR) ( > 10% of viable tumour). At data analysis, PFS and OS median follow-up times were longer than 20 months. Results: No statistically significant differences in TCR repertoire in terms of evenness (p = 0,373), diversity (p = 0,691) or convergence (p = 0,054) between pre- and post-neoadjuvant treatment were observed. Similarly, no significant differences were observed in these metrics between pathological response groups. However, a detailed analysis of the clones showed that the percentage of frequent clones (greater than 0.1%) that increase after neoadjuvant therapy does show differences between the different pathological response groups (pIR vs pMR), being elevated in patients who presented responses greater than 90% (p = 0.0385). Regarding the clinical benefit, having this parameter higher than the median (43,90% in this cohort) is associated with a higher PFS (p = 0.0490) and OS (p = 0.078) using KM Log-rank test. Conclusions: Evenness, Diversity and Convergence derived from immune repertoire analysis do not appear to be clinically useful in the context of neoadjuvant chemo-immunotherapy in lung cancer. However, the detailed analysis of the clones seems promising. The increase of the most frequent clones after treatment seems to be associated to different clinical variables such as pathological response and PFS in these patients. Clinical trial information: NCT03081689.

[Background]: Platinum-based chemotherapy remains the standard of care for most lung cancer cases. However chemoresistance is often developed during the treatment, limiting clinical utility of this drug. Recently, the ability of tumor cells to adapt their metabolism has been associated to resistance to therapies. In this study, we first described the metabolic reprogramming of Non-Small Cell Lung Cancer (NSCLC) in response to cisplatin treatment., [Methods]: Cisplatin-resistant versions of the A549, H1299, and H460 cell lines were generated by continuous drug exposure. The long-term metabolic changes, as well as, the early response to cisplatin treatment were analyzed in both, parental and cisplatin-resistant cell lines. In addition, four Patient-derived xenograft models treated with cisplatin along with paired pre- and post-treatment biopsies from patients were studied. Furthermore, metabolic targeting of these changes in cell lines was performed downregulating PGC-1α expression through siRNA or using OXPHOS inhibitors (metformin and rotenone)., [Results]: Two out of three cisplatin-resistant cell lines showed a stable increase in mitochondrial function, PGC1-α and mitochondrial mass with reduced glycolisis, that did not affect the cell cycle. This phenomenon was confirmed in vivo. Post-treatment NSCLC tumors showed an increase in mitochondrial mass, PGC-1α, and a decrease in the GAPDH/MT-CO1 ratio. In addition, we demonstrated how a ROS-mediated metabolism reprogramming, involving PGC-1α and increased mitochondrial mass, is induced during short-time cisplatin exposure. Moreover, we tested how cells with increased PGC-1a induced by ZLN005 treatment, showed reduced cisplatin-driven apoptosis. Remarkably, the long-term metabolic changes, as well as the metabolic reprogramming during short-time cisplatin exposure can be exploited as an Achilles' heel of NSCLC cells, as demonstrated by the increased sensitivity to PGC-1α interference or OXPHOS inhibition using metformin or rotenone., [Conclusion]: These results describe a new cisplatin resistance mechanism in NSCLC based on a metabolic reprogramming that is therapeutically exploitable through PGC-1α downregulation or OXPHOS inhibitors., Work in the authors’ laboratories is supported by ‘‘Instituto de Salud Carlos III’’ PI13/01806 and PIE14/0064 to M.P. A.C-B, received a Spanish Lung Cancer Group fellowship. R.L-B, is supported by Comunidad Autónoma de Madrid “Garantía juvenil” contract.

High incidence and prognostic relevance of thromboembolic disease in patients with ALK-rearranged NSCLCs

This paper explores the work of Kitty Crowther, one of the authors who has managed over the last few years to create her own world in which the topics traditionally considered as difficult for the child reader, such as: solitude, death, absence, mourning, identity and sexism, arise in a natural way, emerging from her own conception of the reader. In this sense, Astrid Lindgren and Beatrix Potter have constituted inexcusable references in her work. This study is based on Nodelman (2008), Salisbury and Styles (2012), Nikolajeva (2014), Kümmerling-Meibauer (2015), Antoine-Andersen (2016) in order to analyze Kitty Crowther's work. Through analysis of her books we discover an innovative way of dealing with the more difficult topics of children's literature. The empathy with which the author presents topics such as death, loneliness, sexism or filial relationships emphasizes the idea of the illustrated literature's conception as a meeting space, where the creator expresses their stories through their own emotions and talks with the reader with honesty. This implies the need to deal with life with its lights and shadows in a conception of children's literary discourse very similar to that of Maurice Sendak.