Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer.

BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients. METHODS: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety. RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%). CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).

Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.

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.

Germline c.1A>C heterozygous pathogenic variant in SDHA reported for the first time in a young adult with a gastric gastrointestinal stromal tumour (GIST): a case report.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) represent the most frequent mesenchymal tumor of the gastrointestinal tract. Less than 5% of them seem to be hereditary, being succinate dehydrogenase complex (SDHx) deficient disorders and neurofibromatosis type 1 the more related inherited conditions. Wild type (WT) KIT and PDGFRα GISTs constitute a clue for a hypothetical underlying germline condition. CASE PRESENTATION: We present a case of a 20 years old female diagnosed of a gastric WT GIST who developed hepatic metastases during her clinical course. No significant or typical phenotypic features suggestive of a specific syndrome were detected by physical examination. Also, her family history seemed to be irrelevant, since no other cases of GISTs, paragangliomas or pheochromocytomas were reported. Her paternal grandfather died as a consequence of a pituitary adenoma. In light of the age of tumor presentation and somatic features of gastric GIST, we performed genetic testing of SDHx genes. Analysis obtained from peripheral blood sample revealed the presence, in heterozygous state, of the c.1A > C; p.(Met1?) pathogenic variant in the SDHA. CONCLUSIONS: To the best of our knowledge, this is the first published report in which the c.1A > C; p.(Met1?) pathogenic variant in the SDHA is associated with a GIST. SDHA pathogenic variants increase the risk of paraganglioma, pheochromocytoma, GIST, pituitary adenoma and renal cancer in an autosomal dominant inherited condition named paraganglioma syndrome type 5. The absence of family history of tumors in SDHA pathogenic variants carriers could be related to its low penetrance. All patients diagnosed with WT GISTs should be referred to a hereditary cancer genetic counseling unit regardless of the age at presentation or the absence of a suspicious family history.

Hereditary pancreatic cancer: related syndromes and clinical perspective.

Pancreatic cancer is a very aggressive disease with a poor prognosis. The majority of them are attributed to sporadic causes, especially to many modifiable risk factors such as tobacco or alcohol abuse. The principal histologic subtype of pancreatic cancer is ductal adenocarcinoma. Pancreatic neuroendocrine tumors, which constitute a more indolent entity, represent second type of pancreatic cancer in terms of incidence. Individuals with a family history of pancreatic cancer carry an increased risk of developing the disease, which may be related to an underlying hereditary component. Unfortunately, in the majority of these families the suspected germline genetic cause responsible of the disease will not be identified, but approximately in a 20% of the cases a hereditary cancer predisposition syndrome with increased risk of pancreatic cancer development can be recognized. This review will be focused on the leading hereditary cancer syndromes related to pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors. Additionally, we will try to explain clinical aspects related to the identification of germline mutations in pancreatic cancer patients and their potential implications in oncologic treatment decisions.

Supervised physical exercise to improve the quality of life of cancer patients: the EFICANCER randomised controlled trial.

BACKGROUND: The optimal form of exercise for individuals with cancer has yet to be identified, but there is evidence that exercise improves their quality of life. The aim of this study is to assess the efficacy and efficiency of an innovative physical exercise programme, for individuals undergoing chemotherapy for breast, gastrointestinal or non-small cell lung tumours, for improving quality of life, reducing level of fatigue, and enhancing functional capacity over time. DESIGN/METHODS: We will conduct a clinical trial in 66 patients with stage IV breast, gastrointestinal or non-small cell lung cancer, recruited by the Department of Oncology of the referral hospital from 4 primary care health centres of the Basque Health Service (Osakidetza). These patients will be randomised to one of two groups. The treatment common to both groups will be the usual care for cancer: optimized usual drug therapies and strengthening of self-care; in addition, patients in the intervention group will participate in a 2-month exercise programme, including both aerobic and strength exercises, supervised by nurses in their health centre. The principal outcome variable is health-related quality of life, measured blindly with the 30-item European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire and Short Form-36 four times: at baseline, and 2, 6 and 12 months later. The secondary outcome variables are fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire), functional capacity (6-Minute Walk Test and cardiorespiratory test), muscle strength (hand-held dynamometry and sit-to-stand test), radiological response to treatment (Response Evaluation Criteria In Solid Tumors) and progression-free and overall survival. Age, sex, diagnosis, chemotherapy regimen, Eastern Cooperative Oncology Group performance status and smoking status will be considered as predictive variables. Data will be analysed on an intention-to-treat basis, comparing changes at each time point between groups, adjusting for baseline values by analysis of covariance. DISCUSSION: As well as achieving the objectives set, this study will provide us with information on patient perception of the care received and an opportunity to develop a project based on collaborative action between the primary care and oncology professionals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01786122 Registration date: 02/05/2013.

Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study.

BACKGROUND: Subcutaneous trastuzumab has shown non-inferior efficacy and a similar pharmacokinetic and safety profile when compared with intravenous trastuzumab in patients with HER2-positive early breast cancer. We assessed patient preference for either subcutaneous or intravenous trastuzumab in the international, randomised PrefHer study. METHODS: Eligible patients were women aged 18 years or older with HER2-positive, histologically confirmed primary invasive breast adenocarcinoma, no evidence of residual, locally recurrent, or metastatic disease after completion of surgery and chemotherapy (neoadjuvant or adjuvant), an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left-ventricular ejection fraction of 55% or more before the first dose of trastuzumab. Radiotherapy or hormone therapy was allowed. Patients were randomised (randomly permuted blocks of four) to receive four cycles of 600 mg fixed-dose subcutaneous adjuvant trastuzumab via a single-use injection device or hand-held syringe followed by four cycles of standard intravenous trastuzumab, or the reverse sequence. Randomisation was stratified by de-novo versus non-de-novo use of intravenous trastuzumab. The primary endpoint was the proportion of patients indicating an overall preference for subcutaneous or intravenous trastuzumab, assessed by patient interview in the evaluable intention-to-treat (ITT) population (patients who completed both interviews and had at least one administration of both subcutaneous and intravenous trastuzumab). Data collection for PrefHer is ongoing. This study is registered with ClinicalTrials.gov, number NCT01401166. FINDINGS: 124 patients were randomly allocated to receive subcutaneous followed by intravenous trastuzumab, and 124 to receive the reverse sequence. 117 patients in the subcutaneous first group and 119 in the intravenous first group were included in the evaluable ITT population. Subcutaneous trastuzumab via the single-use injection device was preferred by 216 patients (91·5%, 95% CI 87·2-94·7; p<0·0001). Only 16 patients preferred intravenous trastuzumab (6·8%, 3·9-10·8), and four had no preference (1·7%, 0·5-4·3). Clinician-reported adverse events occurred in 141 of 242 (58%) patients during the pooled subcutaneous periods and 105 of 241 (44%) patients during the pooled intravenous periods; seven (3%) and five (2%) were grade 3, no patients had a grade 4 or 5 event. The most common grade 3 adverse event was influenza (two [0·8%] patients). INTERPRETATION: Patient preference and safety results from PrefHer, combined with the known non-inferior efficacy and pharmacokinetic and safety profile data, suggest that a fixed dose of 600 mg trastuzumab administered subcutaneously every 3 weeks is a validated, well tolerated treatment option for HER2-positive breast cancer, and is the preferred treatment of patients.

Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. METHODS: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. FINDINGS: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. INTERPRETATION: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. FUNDING: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

Differences in Quality of Life and Emotional Well-being in Breast, Colon, and Lung Cancer Patients During Outpatient Adjuvant Chemotherapy: A Longitudinal Study.

BACKGROUND: Adjuvant chemotherapy used at each cancer site may affect quality of life (QoL) and emotional well-being (affect) of cancer patients differently; however, these differences between groups have not been studied. OBJECTIVES: The aim of this study was to assess differences in QoL and affect by cancer site at the start of outpatient adjuvant chemotherapy, whether QoL and affect change during this treatment, and whether adverse effects influence these variables. METHODS: A multicenter longitudinal descriptive study was conducted with 247 participants with breast, colon, or lung cancer at the beginning (T1) and end of treatment (T2). We used the SF-12 Health Survey, Positive and Negative Affect Scale, and an "ad hoc" adverse effects questionnaire. RESULTS: At the start of chemotherapy, the lung group had poorer Physical Component Summary and poorer positive and negative affect ( P < .05) scores. In the end-of-treatment comparisons, breast and colon cancer patients' status had worsened, whereas lung cancer patients had tended to stabilize, although they remained the most vulnerable. Adverse effect severity was significant for Physical Component Summary ( r = -0.13, P = .035), with decreases in positive affect ( r = -0.17, ß = -.16) and increases in negative affect ( r = 0.15, ß = .14). CONCLUSIONS: Changes in QoL and emotional state differ between groups, implying a need for varying levels of follow-up and emotional support. Patients with lung cancer seem particularly vulnerable. IMPLICATIONS FOR PRACTICE: Cancer nurses could strengthen the assessment of patients undergoing chemotherapy using more sensitive instruments such as the Positive and Negative Affect Scale and considering differences by cancer site, to provide care tailored to individual patient needs and preferences.

Nurse-Supervised Exercise for People with Stage IV Cancer: The EFICANCER Randomized Clinical Trial.

OBJECTIVES: To assess the effectiveness of the EFICANCER individualized and supervised exercise program for people with gastrointestinal, breast, or non-small cell lung stage IV cancer, in terms of quality of life and functional capacity. DATA SOURCES: Randomized controlled clinical trial with two parallel groups: EFICANCER (n = 47) and control (n = 43). Both groups received standard oncological care. In addition, the EFICANCER group participated in a nurse-supervised exercise program. Primary outcome was cancer-specific (EORTC QLQ-C30 questionnaire) and general quality of life (SF-36) at baseline and after 2, 6, and 12 months. Secondary outcomes were functional capacity (6-minute walking test), strength, and fatigue. The evolution in both groups was compared over 12 months using mixed-effect longitudinal models; 74.47% of patients completed at least one session of the program. At 12 months, EFICANCER group had better scores in cancer-related quality of life, with a difference between groups of 15.7 points (95% confidence interval 4.4 to 25.9) and in functional capacity, with a difference of 4.5 points (95% confidence interval -0.5 to 9.5). No significant differences in any other secondary variables were observed. CONCLUSION: The EFICANCER primary care nurse supervised exercise program is safe and feasible and improves cancer patient's outcomes. IMPLICATIONS FOR NURSING PRACTICE: Providing the best care and trying to improve the quality of life of cancer patients are essential parts of nursing practice. Eficancer adds a new dimension to nursing practice by providing greater attention and care to patients during treatment through the supervision of physical exercise, thereby contributing to improve the quality of life of this population.

Immunogenicity of COVID-19 vaccines in lung cancer patients.

OBJECTIVE: Patients with lung cancer are at increased risk of SARS-CoV-2 infection and severe complications from COVID-19, but information on the efficacy of anti-SARS-CoV-2 vaccine in these patients is scarce. We aimed at evaluating the safety and immunogenicity of COVID-19 vaccines in this population. PATIENTS AND METHODS: The prospective, nationwide SOLID substudy, enrolled adults with lung cancer who were fully vaccinated against COVID-19. Serum anti-SARS-CoV-2 IgG antibody levels were quantitatively assessed two weeks and six months after receipt of the last dose using a chemiluminescent microparticle immunoassay. Multivariate odds ratios for the association between demographic and clinical factors and seronegativity after vaccination were estimated. RESULTS: 1973 lung cancer patients were enrolled. Most patients had stage IV disease (66%) and were receiving active cancer treatment (82.7%). No significant differences were found in the probability of being seronegative for anti-SARS-CoV-2 IgG antibodies after full vaccination between patients who were receiving active cancer treatment and those who were not (p = 0.396). The administration of immunotherapy or oral targeted therapy and immunization with mRNA-1273 COVID-19 vaccine were factors independently associated with increased odds of being seropositive after vaccination. From all patients, 1405 received the second dose of vaccine and high levels of antibody titers were observed in 93.6% of patients two weeks after second dose. At six months, multivariate logistic regression analysis showed that performance status ≥ 2 was independently associated with a higher probability of being seronegative after full vaccination with an OR 4.15. On the other hand, received chemotherapy or oral target therapy and vaccination with mRNA-1273 were a factor independently associated with lower odds of being seronegative after full vaccination with an OR 0.52, 0.37 and 0.34, respectively. CONCLUSIONS: Lung cancer patients can safely achieve a strong immune response against SARS-CoV-2 after full vaccination, regardless of the cancer treatment received. TRIAL REGISTRATION: NCT04407143.

Molecular mechanism implicated in Pemetrexed-induced apoptosis in human melanoma cells.

BACKGROUND: Metastatic melanoma is a lethal skin cancer and its incidence is rising every year. It represents a challenge for oncologist, as the current treatment options are non-curative in the majority of cases; therefore, the effort to find and/or develop novel compounds is mandatory. Pemetrexed (Alimta®, MTA) is a multitarget antifolate that inhibits folate-dependent enzymes: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, required for de novo synthesis of nucleotides for DNA replication. It is currently used in the treatment of mesothelioma and non-small cell lung cancer (NSCLC), and has shown clinical activity in other tumors such as breast, colorectal, bladder, cervical, gastric and pancreatic cancer. However, its effect in human melanoma has not been studied yet. RESULTS: In the current work we studied the effect of MTA on four human melanoma cell lines A375, Hs294T, HT144 and MeWo and in two NSCLC cell lines H1299 and Calu-3. We have found that MTA induces DNA damage, S-phase cell cycle arrest, and caspase- dependent and -independent apoptosis. We show that an increment of the intracellular reactive oxygen species (ROS) and p53 is required for MTA-induced cytotoxicity by utilizing N-Acetyl-L-Cysteine (NAC) to blockage of ROS and p53-defective H1299 NSCLC cell line. Pretreatment of melanoma cells with NAC significantly decreased the DNA damage, p53 up-regulation and cytotoxic effect of MTA. MTA was able to induce p53 expression leading to up-regulation of p53-dependent genes Mcl-1 and PIDD, followed by a postranscriptional regulation of Mcl-1 improving apoptosis. CONCLUSIONS: We found that MTA induced DNA damage and mitochondrial-mediated apoptosis in human melanoma cells in vitro and that the associated apoptosis was both caspase-dependent and -independent and p53-mediated. Our data suggest that MTA may be of therapeutic relevance for the future treatment of human malignant melanoma.

Screening for epidermal growth factor receptor mutations in lung cancer.

BACKGROUND: Activating mutations in the epidermal growth factor receptor gene (EGFR) confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small-cell lung cancer. We evaluated the feasibility of large-scale screening for EGFR mutations in such patients and analyzed the association between the mutations and the outcome of erlotinib treatment. METHODS: From April 2005 through November 2008, lung cancers from 2105 patients in 129 institutions in Spain were screened for EGFR mutations. The analysis was performed in a central laboratory. Patients with tumors carrying EGFR mutations were eligible for erlotinib treatment. RESULTS: EGFR mutations were found in 350 of 2105 patients (16.6%). Mutations were more frequent in women (69.7%), in patients who had never smoked (66.6%), and in those with adenocarcinomas (80.9%) (P<0.001 for all comparisons). The mutations were deletions in exon 19 (62.2%) and L858R (37.8%). Median progression-free survival and overall survival for 217 patients who received erlotinib were 14 months and 27 months, respectively. The adjusted hazard ratios for the duration of progression-free survival were 2.94 for men (P<0.001); 1.92 for the presence of the L858R mutation, as compared with a deletion in exon 19 (P=0.02); and 1.68 for the presence of the L858R mutation in paired serum DNA, as compared with the absence of the mutation (P=0.02). The most common adverse events were mild rashes and diarrhea; grade 3 cutaneous toxic effects were recorded in 16 patients (7.4%) and grade 3 diarrhea in 8 patients (3.7%). CONCLUSIONS: Large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in decisions about treatment.

Identification of a biomarker panel for colorectal cancer diagnosis.

BACKGROUND: Malignancies arising in the large bowel cause the second largest number of deaths from cancer in the Western World. Despite progresses made during the last decades, colorectal cancer remains one of the most frequent and deadly neoplasias in the western countries. METHODS: A genomic study of human colorectal cancer has been carried out on a total of 31 tumoral samples, corresponding to different stages of the disease, and 33 non-tumoral samples. The study was carried out by hybridisation of the tumour samples against a reference pool of non-tumoral samples using Agilent Human 1A 60-mer oligo microarrays. The results obtained were validated by qRT-PCR. In the subsequent bioinformatics analysis, gene networks by means of Bayesian classifiers, variable selection and bootstrap resampling were built. The consensus among all the induced models produced a hierarchy of dependences and, thus, of variables. RESULTS: After an exhaustive process of pre-processing to ensure data quality--lost values imputation, probes quality, data smoothing and intraclass variability filtering--the final dataset comprised a total of 8, 104 probes. Next, a supervised classification approach and data analysis was carried out to obtain the most relevant genes. Two of them are directly involved in cancer progression and in particular in colorectal cancer. Finally, a supervised classifier was induced to classify new unseen samples. CONCLUSIONS: We have developed a tentative model for the diagnosis of colorectal cancer based on a biomarker panel. Our results indicate that the gene profile described herein can discriminate between non-cancerous and cancerous samples with 94.45% accuracy using different supervised classifiers (AUC values in the range of 0.997 and 0.955).

Just an Acute Pulmonary Edema? Paraneoplastic Thyroid Storm Due to Invasive Mole.

Hydatidiform mole is a malignant entity included in the gestational trophoblastic diseases. It usually produces pregnancy hormones such as beta-human chorionic gonadotropin (ß-hCG), which in turn stimulates endogenous thyroid hormone production. We report the case of a high-risk complete invasive hydatidiform mole with pulmonary metastasis and associated paraneoplastic syndrome. The patient is a 30-year-old woman who presented symptoms of pregnancy and metrorrhagia. A uterine mass was detected. Urine ß-hCG was found negative. In serum, 2,662,000 mIU/mL (normal range: <5) was found, together with parameters of severe hyperthyroidism. The patient underwent uterine curettage with diagnostic and therapeutic means. At that precise moment, her pregnancy-like symptoms worsened and she developed restlessness, tachycardia, diaphoresis, dyspnea at rest, and peripheral edema. A scan showed bilateral pulmonary nodules suggestive of metastasis, acute pulmonary edema, and bilateral pleural effusion without signs of pulmonary thromboembolism. At that time, she presented a free T4 of 2.34 ng/dL (normal range: 0.8-1.8 ng/dL), causing a thyroid storm with secondary cardiac dysfunction. The patient was treated with corticosteroid therapy to decrease peripheral conversion of thyroid hormone T4 to active T3. Her symptoms remitted within 8 h. After 48 h, T4 level was 1.2 ng/dL while serum ß-hCG was 80,000 mIU/mL, with a positive urine result. The change in the urine analysis is due to the "hook effect" of the reactive test. An effective chemotherapy treatment was started according to the EMA-CO scheme, remaining free of disease at present. Knowing paraneoplastic syndromes is necessary to achieve the best clinical management and to start treatment early.

Identification of ALK-positive patients with advanced NSCLC and real-world clinical experience with crizotinib in Spain (IDEALK study).

OBJECTIVES: To determine the incidence of ALK translocations in patients with advanced/metastatic NSCLC in Spain, to describe the clinical characteristics of these patients, and to evaluate the effectiveness and safety of treatment with crizotinib in a real-world setting. METHODS: This is an observational prospective and retrospective cohort study to determine the incidence of ALK translocations and to analyze the effectiveness and safety of crizotinib in a real-world setting. Patient characteristics, treatment patterns, time to best overall response, duration of treatment, objective response rates (ORR), rates of adverse events (AE), progression free survival (PFS) and overall survival (OS) were evaluated in the ALK study cohort of patients treated with crizotinib (prospective and retrospective). ALK incidence and quality of life (QoL) questionnaires were measured from patients included in the prospective cohort. RESULTS: The incidence of ALK translocations was 5.5 % (31 of 559 patients). Compared with ALK-negative patients, ALK-positive patients were significantly younger, predominantly female, and non-smokers. In the crizotinib effectiveness and safety study, 91 patients (42 prospective, 49 retrospective) with ALK-positive NSCLC (43.9 % in first-line, 56.1 % in second or more lines) were included. The ORR was 59.3 % and the median duration of response was 13.5 months (IQR, 5.3-26.2). The median PFS was 15.8 months (95 % CI, 11.8-22.3) and the median OS was 46.5 months, with 53 patients (58.2 %) still alive at data cut-off date. Frequently reported AEs included elevated transaminases, gastrointestinal disorders, and asthenia. Most patients (76.5 %) reported improved or stable scores for global QoL during treatment. CONCLUSIONS: The observed incidence of ALK translocations in NSCLC patients is aligned with published reports. This analysis of the real-world clinical experience in Spain confirms the therapeutic benefit and safety of crizotinib in advanced/metastatic ALK-positive NSCLC. CLINICALTRIALS: gov: NCT02679170.

Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial).

PURPOSE: Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non-small-cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported. METHODS: This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial. RESULTS: OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72). CONCLUSION: The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3-year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival.

Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy.

BACKGROUND: Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. METHODS: Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. RESULTS: CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFNγ signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. CONCLUSIONS: Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC.

Seroprevalence and immunological memory against SARS-CoV-2 in lung cancer patients: the SOLID study.

BACKGROUND: At present, we did not find any articles that studied seroprevalence and its persistence several months later in lung cancer patients in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Most patients with coronavirus disease 2019 (COVID-19) go on to develop antibodies (Abs) against viral proteins. However, it is not known how long these Abs last nor whether cancer treatments could affect the duration of immune response. METHODS: This prospective, longitudinal, multicenter serological study in the setting of SARS-CoV-2 infection was carried out in 50 Spanish hospitals. Eligibility criterion was the diagnosis of any lung cancer. The determination of anti-SARS-CoV-2 IgG Abs was performed by qualitative immuno-enzymatic assay using enzyme-linked immunosorbent assay (ELISA) kit from NovaLisa whose Abs target the recombinant antigen N of the nucleocapsid of SARS-CoV-2. The first Ab determination was performed between April 21 and June 3, 2020. The second Ab determination was performed in all previously seropositive patients, between September 10 and November 20, 2020. Study objectives were to prospectively determine seroprevalence in unselected lung cancer patients during the first wave of the pandemic; the persistence of immunity; protection or lack thereof against reinfection; and the influence of treatments on maintenance or loss of immunity. RESULTS: Of 1,500 patients, 128 were seropositive, overall prevalence of 8.5% seropositivity [95% confidence interval (CI): 7.2-10.1%]. Seventy-five percent were in active cancer treatment. Forty-seven point seven percent of IgG positive participants had experienced a symptomatic illness suspected of being infected with SARS-CoV-2 (95% CI: 38.8-56.6%). A second determination was performed on average 4.5 months later [interquartile range (IQR), 4.0-5.0 months] and obtained for 104 of the initially seropositive patients (81%), it could not be obtained in 24 patients, the majority due to death caused by disease progression (73%). In the second determination, IgG was not detected in 30.8% of patients. The severity of the infection, the need for hospitalization (P=0.032) and the presence of symptoms at diagnosis (P=0.02) were associated with persistence of immunity in the second determination. No variables or treatments received were associated with Abs loss. CONCLUSIONS: Immunity against SARS-CoV-2 does not appear to be compromised by treatment and persists beyond 4 months. Neither do mortality rates appear to be particularly high in this unselected population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04407143.

First-line osimertinib in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer and with a coexisting low allelic fraction of Thr790Met.

AIM OF THE STUDY: The AZENT (NCT02841579) study aimed to assess the efficacy and safety of first-line osimertinib in patients with epidermal growth factor receptor(EGFR)mutation-positive advanced non-small-cell lung cancer (NSCLC) and with a coexisting low allelic fraction of Thr790Met. METHODS: In this multicentre, single-arm, open-label, phase IIa study, patients with locally advanced or metastatic NSCLC harbouring centrally confirmedEGFR Thr790Met mutation received 80 mg osimertinib daily. The primary end-point was objective response rate (ORR). The secondary end-points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Efficacy was assessed as per Response Evaluation Criteria in Solid Tumours, version 1.1. Blood samples collected at baseline, end of week 2 and disease progression were analysed using next-generation sequencing. As osimertinib was approved as a first-line therapy during the trial, this led to early termination of phase II; thus, analysis is considered exploratory. RESULTS: Twenty-two patients were enrolled and received osimertinib. All 22 patients were included in the efficacy and safety analysis. At the data cutoff, 10 (50%) patients remained on treatment. The median duration of follow-up was 24.4 months (interquartile range 12.9 to 26.0). The ORR was 77.3% (17/22 [95% confidence interval {CI} 54.6 to 89.3]). The DCR was 86.4% (19/22, [95% CI 65.1 to 97.1]). The median PFS was 23.1 months (95% CI 14.1 to NE). The median OS was 28·4 months (95% CI 25.6 to NE). CONCLUSION: Despite early study termination, osimertinib first-line therapy yields an overall PFS of 23.1 months in EGFR-mutant patients harbouring a coexisting low allelic fraction of EGFR Thr790Met mutation.

Phase II clinical trial of nab-paclitaxel plus gemcitabine in elderly patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma: the BIBABRAX study.

PURPOSE: To evaluate the health-related quality of life (HRQoL), global health status (GHS), and deterioration-free survival of an elderly population (> 70 years) with unresectable locally advanced (LAPC) or metastatic pancreatic cancer (mPC) treated with nab-paclitaxel in combination with gemcitabine. METHODS: In this open-label, single-arm, multicenter, phase II trial, patients received 4-week cycles of intravenous (i.v.) nab-paclitaxel at a dose of 125 mg/m2, followed by i.v. injections of gemcitabine at a dose of 1000 mg/m2 on days 1, 8 and 15 until disease progression or unacceptable toxicity was observed. The primary outcome was the HRQoL (deterioration-free rate at 3 months as evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. RESULTS: Eighty patients (median age: 74.6 years) were enrolled (56 with mPC, 24 with LAPC). The percentage of patients who had not experienced deterioration at 3 months was 54.3% (95% CI 41.6-67.0%). The median (interquartile range) time until definite deterioration was 1.6 (1.1-3.7) months. The objective response rate and clinical benefit rate were achieved by 11 (13.8%, 95% CI 6.2-21.3%) and 54 patients (67.5%, 95% CI 57.2-77.8%), respectively. The median overall survival was 9.2 months (95% CI 6.9-11.5), and the median progression-free survival was 7.2 months (95% CI 5.8-8.5). Only fatigue and neutropenia demonstrated a grade 3-4 toxicity incidence > 20%. CONCLUSIONS: Our study confirms the clinical benefit of the combination of nab-paclitaxel and gemcitabine in an elderly population with pancreatic cancer in terms of improved survival and clinical response. However, we were unable to confirm a benefit in terms of quality-of-life.