Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping.

BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.

Sectoral multipole focused beams.

We discuss the properties of pure multipole beams with well-defined handedness or helicity, with the beam field a simultaneous eigenvector of the squared total angular momentum and its projection along the propagation axis. Under the condition of hemispherical illumination, we show that the only possible propagating multipole beams are "sectoral" multipoles. The sectoral dipole beam is shown to be equivalent to the non-singular time-reversed field of an electric and a magnetic point dipole Huygens' source located at the beam focus. Higher order multipolar beams are vortex beams vanishing on the propagation axis. The simple analytical expressions of the electric field of sectoral multipole beams, exact solutions of Maxwell's equations, and the peculiar behaviour of the Poynting vector and spin and orbital angular momenta in the focal volume could help to understand and model light-matter interactions under strongly focused beams.

Causes of death in patients with locally advanced head and neck cancer treated with radiotherapy and systemic therapy.

BACKGROUND: To investigate the incidence of non-cancer mortalities and prognostic factors associated with competitive causes of death in a homogeneous cohort of patients with locally advanced head and neck cancer treated with radiotherapy and systemic treatment. METHODS: This study included 284 patients with locally advanced head and neck cancer treated with radiotherapy and systemic treatment between 2005 and 2017. The cumulative incidence of death associated with tumour, second tumours, treatment, side effects and comorbidity was calculated. A Fine and Gray regression model was used to investigate factors associated with cancer and competitive mortality. RESULTS: The cumulative incidence of tumoral death at 5 and 10 years were 35 and 47% respectively, whereas the cumulative incidence of competitive mortality were 10 and 12% respectively. In the multivariate analysis, age and comorbidity were independent factors for non-cancer mortality. Patients with a high risk of non-cancer mortality presented a cumulative incidence of 17.3% at 5 years and 18.4% at 10 years. CONCLUSIONS: This study demonstrated a high incidence of competing mortality in older patients with comorbidities. Non-cancer deaths should be considered when selecting patients for combination therapies and in the study design ofclinical trials.

Subcellular localisation of pMEK has a different prognosis in locally advanced head and neck cancer treated with concomitant radiochemotherapy.

BACKGROUND: MEK1 (MAP2K1) and MEK2 (MAP2K2) are closely related dual-specificity protein kinases which function by phosphorylating both serine/threonine and tyrosine residues of their substrates ERK1 and ERK2, controlling fundamental cellular processes that include cell growth and proliferation. To investigate the prognostic significance of pMEK expression in the nucleus and cytoplasm among patients with locally advanced head and neck cancer treated with concurrent radiochemotherapy. METHODS: Immunohistochemistry was performed on the retrieved archival tissue of 96 patients to detect pMEK, p53 and Ki-67. RESULTS: Sixty-six percent of patients were positive for pMEK expression in the nucleus and 41 % in cytoplasm. On univariate analysis, high nuclear pMEK was predictive of worse 5y-DFS and 5y-OS, with a trend to significance (26 % vs. 41 %, p = 0.09; 36 % vs. 47 %, p = 0.07). High cytoplasmic pMEK was predictive of better 5-y OS and 5-y DFS outcomes (61 % vs. 27 %, p = 0.01; 46 % vs. 22 %, p = 0.02). On multivariate analysis, low cytoplasmic pMEK and high nuclear pMEK predicted worse DFS and OS (p = 0.01; p = 0.04 and p = 0.02; p = 0.02 respectively). CONCLUSIONS: Subcellular localisation of pMEK has different prognosis in locally advanced head and neck cancer treated with radiochemotherapy.

Development and validation of a smart system for medullation and diameter assessment of alpaca, llama and mohair fibres.

Medullated fibres, due to their higher resistance to bending and pressure, constitute a problem for the textile industry. Thus, having practical instruments to identify them is essential. Therefore, the aim of this research was to develop and validate a novel, swift, automatic system (referred to as S-FiberMed) for medullation and diameter assessment of animal fibres based on artificial intelligence. The medullation of 88 samples of alpaca, llama and mohair fibres (41, 43 and 4, respectively) was evaluated. Additionally, 269 samples of alpacas were considered for average fibre diameter (AFD) and the results were compared with the Portable Fiber Tester (PFT) and Optical Fibre Diameter Analyser (OFDA) methods (72 and 197 samples, respectively). The preparation of each sample to be analysed followed the procedure described in IWTO-8-2011. Version 5 of "You Only Look Once" and DenseNet models were used to recognise the type of medullation and diameter of the fibres, respectively. Within each image (n = 661 for alpaca), all fibres were labelled (as Non-Medullated, Fragmented Medulla, Uncontinuous Medulla, Continuous Medulla and Strongly Medullated) using the LabelImg tool. Data augmentation technique was applied to obtain 3 966 images. Such data set was divided into 3 576 and 390 images for training and test data, respectively. For mohair samples (n = 321), a similar process was carried out. The data to train the model used to infer the diameter contained 16 446 fibres labelled with his respective AFD. A complementary hardware composed of three subsystems (mechanical, electronic, and optical) was developed for evaluation purposes. T-test, Pearson and Concordance correlation, Bland-Altman plot and linear regression analyses were used to validate and compare the S-Fiber Med with other methods. Results indicate that there was no significant difference between medullation percentage obtained with the projection microscope and the S-Fiber Med. The Pearson and Concordance correlation analysis shows a strong, high and significant relationship (P-value < 0.001). The AFDs of alpaca and llama fibre samples obtained with the two methods are very similar, because no significant difference was found at the t-test (P-value > 0.172), and they have a strong, high and significant relationship between them, given the high Pearson correlation value (r ≥ 0.96 with P-value < 0.001), high Concordance coefficient and bias correction factor. Similar results were found when PFT and OFDA100 were compared with S-Fiber Med. As a conclusion, this new system provides precise, accurate measurements of medullation and AFD in an expeditious fashion (40 seconds/sample).

Lurbinectedin, a selective inhibitor of oncogenic transcription, in patients with pretreated germline BRCA1/2 metastatic breast cancer: results from a phase II basket study.

BACKGROUND: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer. PATIENTS AND METHODS: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia). CONCLUSIONS: This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted.

Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part.

BACKGROUND: Novel therapies are needed to improve the poor prognosis of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN). METHODS: ADVANTAGE is a phase I/II, multicentre study evaluating the integrin inhibitor cilengitide combined with cetuximab and platinum-based chemotherapy in patients with recurrent and/or metastatic SCCHN. The phase I part tested cilengitide (500, 1000 and 2000 mg) twice weekly with standard doses of cetuximab, cisplatin and 5-fluorouracil. RESULTS: Ten patients (9 male, 1 female; median 56 years old) were included in the phase I part. No dose-limiting toxicities (DLTs: grade 3/4 toxicities in the first 3 weeks as defined per protocol) or deaths occurred. The most common adverse events (AEs) were constipation, rash, nausea, anorexia and fatigue. Cilengitide-related grade 3/4 AEs, all of which occurred after the DLT observation period, were anaemia, angioedema, asthenia, mucosal inflammation, nausea and vomiting (one event per category). Best overall tumour response was partial response (PR) for 4 out of 10 patients and stable disease (SD) for 6 out of 10 patients across all cohorts. Disease control rate (complete response, PR and SD) was 100%. CONCLUSION: Cilengitide combined with cetuximab and platinum-based chemotherapy was well tolerated. No DLTs or unexpected AEs were observed. Cilengitide 2000 mg was considered safe and was selected for the subsequent randomised phase II part assessing progression-free survival.

Nutritional status in a multicenter study among institutionalized patients in Spain.

INTRODUCTION: The aim of our study was to investigate and evaluate, in a multicenter study, the prevalence of malnutrition as well as the relationship between different anthropometric and biochemical markers with Mininutritional assessment (MNA) scores. SUBJECTS AND METHODS: A representative sample of the institutionalized Spanish population aged 65 and older (stricly speaking, born in 1942 or earlier), is covered in this cross-sectional survey. Anthropometric variables, MNA test and biochemical evaluation were performed by Geriatrics Units specialists. RESULTS: The percentage of patients classified as well nourished (27.8%) was larger in the 85-94 (39.4%) range than in the 65-74 (26.2%), 75-84 (24%) and > 95 (14.8%) age ranges. A population of 254 patients (49.6%) were at risk of undernutrition, a number which was larger in 75-84 (52%), 65-74 (53.8%) and > 95 (53.7%) than in the 85-94 (44.1%) ones. On the other hand, undernourishment (22.5%) was larger in those of 95 and older (31.5%) than in 85-94 (16.5%), 75-84 (24%) and 65-74 (20%) patients. According to our investigation females are worse nourished (Odd's Ratio 0.51 CI 95%: 0.33-0.79) and, consequently, more undernourished (Odd's Ratio 2.36 CI 95%: 1.48-3.74) than males. No significant differences in the "at risk of undernutrition category" (Odd's Ratio 0.76 CI 95%: 0.52-1.10) were observed but, in transferrin, iron, haemoglobin and total cholesterol, statistical differences among MNA classification were detected. MNA scores were correlated with iron, total cholesterol, albumin, transferrin, age and haemoglobin. CONCLUSION: In this multicenter study, institutionalized patients have a high prevalence of undernutrition or are at-risk, as well as females are more undernourished than males.

SEOM clinical guidelines for the treatment of head and neck cancer (2020).

Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m2 in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease.

Treatment options beyond immunotherapy in patients with wild-type lung adenocarcinoma: a Delphi consensus.

PURPOSE: Immunotherapy-based approaches are standard first-line treatments for advanced/metastatic lung cancer or for chemoradiotherapy consolidation in locally advanced disease. Uncertainty on how to treat patients at disease progression prompted us to develop a consensus document on post-immunotherapy options in Spain for patients with advanced wild-type lung adenocarcinoma. METHODS: After extensive literature review, a 5-member scientific committee generated 33 statements in 4 domains: general aspects (n = 4); post-durvalumab in locally advanced disease (n = 6); post-first-line immunotherapy ± chemotherapy in advanced/metastatic disease (n = 11); and post-first-line platinum-based chemotherapy in advanced/metastatic disease (n = 12). A panel of 26 lung cancer experts completed 2 Delphi iterations through an online platform rating their degree of agreement/disagreement (first-round scale 1-5 and second-round scale 1-4, 1 = strongly disagree, 4/5 = strongly agree) for each statement. Second-round consensus: ≥ 70% of responses were in categories 1/2 (disagreement) or 3/4 (agreement). RESULTS: Consensus was reached for 2/33 statements in the first Delphi round and in 29/31 statements in the second round. Important variables informing treatment at disease progression with an immunotherapy-based treatment include: disease aggressiveness, previous treatment, accumulated toxicity, progression-free interval, PD-L1 expression, and tumour mutational burden. A platinum-based chemotherapy should follow a first-line immunotherapy treatment without chemotherapy. Treatment with docetaxel + nintedanib may be appropriate post-durvalumab in refractory patients or following progression to first-line chemotherapy + immunotherapy, or second-line chemotherapy after first-line immunotherapy, or first-line chemotherapy in some patients with low/negative PD-L1 expression, or second-line immunotherapy after first-line chemotherapy. CONCLUSIONS: To support decision making following progression to immunotherapy-based treatment in patients with advanced wild-type lung adenocarcinoma, a consensus document has been developed.

SEOM clinical guideline thyroid cancer (2019).

Thyroid carcinoma is the most frequent endocrine malignancy and accounts for around 3% of global cancer incidence. Different histologies and clinical scenarios make necessary a multidisciplinary approach that includes new diagnostic methods and surgical, radiopharmaceutical and systemic therapies. This guideline updates several aspects of management of thyroid cancer.

SEOM guidelines for the management of non-small-cell lung cancer (NSCLC).

Lung cancer is currently the most common malignancy and also the leading cause of mortality related to cancer in the world [1]. The crude incidence of lung cancer in the EU is 52.5/100,000/year, while the mortality 48.7/100,000/year. Among men the rates are 82.5 and 77.0/100,000/year, and among women 23.9 and 22.3/100,000/year, respectively. Non-small-cell lung cancer (NSCLC) accounts for 80% of all cases. In Spain, there were 16,879 deaths in men, with a mean age of 68 years, and 2634 deaths in women, with a mean age of 66 years. The incidence of lung cancer in Spain was 68.3/100,000 among men and 13.8/100,000 among women, according to the latest data published in the year 2006 by the Instituto Nacional de Estadística. About 90% of lung cancer mortality among men (and 80% among women) is attributable to smoking.

[Prevalence of dementia in institutionalized patients. The RESYDEM study]. / Prevalencia de demencia en pacientes institucionalizados: estudio RESYDEM.

INTRODUCTION: To determine the prevalence of dementia in nursing homes in Spain and to analyze the associated factors in an elderly population in the institutional setting. MATERIAL AND METHODS: We performed a multicenter, cross-sectional, observational study of 852 residents of public, private and state-assisted nursing homes throughout Spain. Dementia was diagnosed according to the DSM-IV-TR clinical criteria. The Hughes Clinical Dementia Rating scale was used to measure global impairment or the global severity of dementia. Sociodemographic, clinical and neuropsychological variables, together with the pharmacological treatments prescribed to the participants, were recorded. RESULTS: The overall prevalence of dementia was 61.7% (95% CI 58.4-65.1) and that of Alzheimer's disease was 16.9% (95% CI 14.3-19.5). Vascular dementia was found in 7.3% (95% CI 5.5-9.1). Female sex was independently associated with a greater frequency of dementia. The prevalence of dementia increased with age. Only 18.8% (95% CI 15.4-22.3) of the patients diagnosed with dementia received specific treatment for the disorder. CONCLUSIONS: Two-thirds of the elderly persons living in nursing homes in Spain have dementia. Undertreatment of this disease is common. Increased awareness among health care professionals is important for the early diagnosis and appropriate management of dementia, which would represent a radical change in the approach to this disease.

SEOM clinical guidelines for the treatment of non-small cell lung cancer (2018).

Non-small cell lung cancer (NSCLC) accounts for up to 85% of all lung cancers. The last few years have seen the development of a new staging system, diagnostic procedures such as liquid biopsy, treatments like immunotherapy, as well as deeper molecular knowledge; so, more options can be offered to patients with driver mutations. Groups with specific treatments account for around 25% and demonstrate significant increases in overall survival, and in some subgroups, it is important to evaluate each treatment alternative in accordance with scientific evidence, and even more so with immunotherapy. New treatments similarly mean that we must reconsider what should be done in oligometastatic disease where local treatment attains greater value.

18FDG PET/CT & arterial inflammation: predicting cardiovascular events in lung cancer.

BACKGROUND: 18F-FDG PET/CT predicts cardiovascular disease. To analyze the predictive value of cardiovascular events from inflammation and arterial calcification in patients who underwent an 18F-FDG PET/CT for lung cancer. METHODS: A retrospective study of 274 patients with primary lung neoplasia. We determined: (i) TBR (target-to-background ratio), and (ii) the calcium score, at eight common arterial segments. We took as arteriosclerosis, a TBR ≥1.6 and ≥15 Calcium Score sum. We registered cardiovascular risk factors, comorbidities, histology, stage, treatment, status at the last clinical review, cause of death and cardiovascular event during the follow-up. RESULTS: The territory presenting the greatest uptake of 18F-FDG, was the thoracic aorta with an average of 1.77 (± 0.27 TBR) in the aortic arch, while the greatest degree of calcification was obtained in the abdominal aorta (52% with a Calcium Score ≥ 3). 24% of the patients presented a sum Calcium Score ≥15, and 17% a TBR ≥1.6. Patients with high TBR, (17%), had not a higher frequency of cardiovascular comorbidities beforehand, nor did they in the follow-up. However, those with a sum Calcium Score ≥15 (24%), were older, had more cardiovascular risk factors and ischemic events during follow-up. The calcium score, but not the TBR, predicted the emergence of a cardiovascular event (HR 4.9 IC95% 2.1-9.1, P < 0.05). CONCLUSION: In our cohort, a high Calcium Score was an independent predictor for developing cardiovascular events.

Colony membership is reflected by variations in cuticular hydrocarbon profile in a Neotropical paper wasp, Polistes satan (Hymenoptera, Vespidae).

Nestmate recognition is one the most important features in social insect colonies. Although epicuticular lipids or cuticular hydrocarbons have both structural and defensive functions in insects, they also seem to be involved in several aspects of communication in wasps, bees and ants. We analyzed and described for the first time the cuticular hydrocarbons of a Neotropical paper wasp, Polistes satan, and found that variation in hydrocarbon profile was sufficiently strong to discriminate individuals according to their colony membership. Therefore, it seems that small differences in the proportion of these compounds can be detected and used as a chemical-based cue by nestmates to detect invaders and avoid usurpation.

[Zonisamide and neuropathic pain]. / Zonisamida y dolor neuropático.

INTRODUCTION: In neuropathic pain, as occurs in epilepsy, researchers are striving to find a drug capable of inhibiting the pain-generating ectopic discharges that are produced as a result of neuronal hyperexcitability. This is mediated by ionic exchanges across the channels of the synaptic membrane. This is why the drugs that act on the different types of channels involved in this transmission can regulate neuronal hyperexcitability and therefore have an effect on the pain. DEVELOPMENT: In recent years researchers have gained a deeper understanding of the mechanisms of action of antiepileptic drugs and, since the discovery of their action on one or several synaptic channels, the use of these agents to treat neuropathic pain has become increasingly common. Patients suffering from central pain are also beginning to benefit from the administration of these drugs, especially agents that have proved to be capable of acting with several mechanisms of action and on several channels at the same time. In addition, fewer and less severe side effects are produced, something that is fundamental if we bear in mind the characteristics of patients with central pain, most of whom are adults and elderly. This, together with the fact that there are fewer interactions with other drugs, has led to the new antiepileptic drugs' becoming the preferred medication for this pathology today. CONCLUSIONS: Zonisamide acts on several types of channels and it is known to have four different mechanisms of action, which means it can be effective in treating these patients, although further studies are required (above all randomised double-blind trials) in order to really evaluate the usefulness of these drugs in the treatment of neuropathic pain.

Long-term survival in advanced non-squamous NSCLC patients treated with first-line bevacizumab-based therapy.

BACKGROUND/AIM: First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. PATIENTS AND METHODS: This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9 months. RESULTS: Median overall survival and PFS were 30.7 and 15.1 months, respectively. The overall response rate was 83 %. Weight loss ≤5 %, ECOG PS = 0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. CONCLUSION: Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.

A consensus statement on the gender perspective in lung cancer.

Lung cancer is the most common cancer globally and has the highest mortality. Although this disease is not associated with a particular gender, its incidence is rising among women, who are diagnosed at an increasingly younger age compared with men. One of the main reasons for this rise is women taking up smoking. However, many non-smoking women also develop this disease. Other risk factors implicated in the differential development of lung cancer in women are genetic predisposition, tumour histology and molecular profile. Proportionally more women than men with lung cancer have a mutation in the EGFR gene. This consensus statement reviews the available evidence about the epidemiological, biological, diagnostic, therapeutic, social and psychological aspects of lung cancer in women.