Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.

BACKGROUND: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). PATIENTS AND METHODS: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. RESULTS: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. CONCLUSIONS: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.

Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer.

Background: Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of ß2 glycoprotein 1 (ß2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and methods: Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS). Results: A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI 0.88-1.29; P = 0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82-1.22; P = 0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum ß2GP1 levels ≥200 µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P = 0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P = 0.006). Conclusions: The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high ß2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation. Clinical trial number: NCT01999673.

Molecular profiling and feasibility using a comprehensive hybrid capture panel on a consecutive series of non-small-cell lung cancer patients from a single centre.

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

Application of infrared thermography in diagnosing peripherally inserted central venous catheter infections in children with cancer.

APPROACH: Children affected by oncological diseases are often fitted with central venous catheters (CVCs). Catheter infection is a frequent complication, sometimes accompanied by thrombosis. A case/control-type pilot study of children with oncological diseases fitted with a CVC is here designed. OBJECTIVE: The objective of this preliminary study is to use infrared thermography to discern whether there is an infection in patients with a CVC and, if so, to undertake a close follow-up of its evolution, after administering a therapy. Thermal asymmetry by mean and maximum temperatures (temperature affected ROI - temperature contralateral ROI) is measured. MAIN RESULTS: In all cases with catheter infection, thermal asymmetry values were higher than in controls without infection, allowing us to assess improvement after starting the treatment. SIGNIFICANCE: These preliminary results are satisfactory because they reflect the advantages of using infrared thermography on oncological child patients, as it is a harmless, non-contact, accessible and quick technique, allowing us to reduce the use of ionizing radiation and quantify the clinical signs of inflammation, which are otherwise only qualitatively detectable in clinical examination. By doing so, it may be possible to anticipate infection and provide early treatment, and, moreover, to observe whether there is any complication after starting a treatment. More studies need to be undertaken with an extensive paediatric population to establish reference values.

Rheumatic immune-related adverse events in patients on anti-PD-1 inhibitors: Fasciitis with myositis syndrome as a new complication of immunotherapy.

OBJECTIVE: To evaluate the prevalence and type of rheumatic immune-related adverse events (IRAEs) in patients receiving programmed cell death protein-1 (PD-1) inhibitors. METHODS: This is a single-center prospective observational study, including all cancer patients receiving PD-1 inhibitors between January 2016 and January 2018. RESULTS: During the period analyzed, we evaluated a total of 11 patients. No patient had pre-existing rheumatic or autoimmune disease. In this period, a total of 220 patients were treated with PD1 inhibitors in our center; therefore, the estimated minimum prevalence of rheumatic IRAEs related to these therapies in our population was 5%. The rheumatic IRAEs evaluated included 5 cases of oligo- or polyarthritis, 1 with a polymialgia rheumatica-type syndrome, 2 cases of immunotherapy-induced sicca syndrome, 2 patients who presented symptomatic inflammatory myositis with fasciitis in lower extremities, and 1 patient with a paraneoplastic acral vascular syndrome. The median time to IRAE after anti-PD1 exposure was 8 weeks (range: 2-24). In 5 patients, immunotherapy was discontinued (due to the adverse effect in three and cancer progression in two). In general terms the symptoms resolved completely with symptomatic treatment. Disease-modifying antirheumatic drugs were needed for 2 patients. CONCLUSION: Rheumatic IRAEs should be kept in mind during the follow-up and evaluation of patients treated with PD-1 inhibitors. The concomitant development of symptomatic inflammatory myositis with fasciitis in lower extremities appears to be a new adverse effect of anti-PD-1 immunotherapy. Additional studies are needed to determine how to adequately control and manage these complications.

Terapia VAC: técnica avanzada en la cicatrización de heridas por cistectomías. A propósito de un caso clínico / No disponible

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Modificaciones en las proyecciones córtico-motoneuronales que van a la mano en pacientes que reciben rehabilitación intensiva / Modifications in the cortico-motoneuronal projections going to the hand in patients who receive intensive rehabilitation

Introducción. La enfermedad cerebrovascular es una de las principales causas de déficit motor. El presente trabajo evalúa el efecto de la rehabilitación intensiva sobre la reorganización de las proyecciones córtico-motoneuronales a la mano en pacientes con infartos cerebrales del territorio de la arteria cerebral media. Material y método. Se realizó un estudio de cohortes, seleccionando un grupo de 20 pacientes hospitalizados (grupo 1: G1) para recibir tratamiento de rehabilitación intensivo, y otro grupo de 10 pacientes ambulatorios (grupo 2: G2) no tratados en rehabilitación. Todos cumplían los siguientes criterios de inclusión: evolución post-infarto >= 6 meses; puntuación en el índice de Barthel >= 75, y >= 2 en el Medical Research Council de la mano afectada. Se excluyeron aquellos con más de un infarto cerebral, o que portaran dispositivos electromagnéticos. Se realizó la evaluación clínica y electrofisiológica, con un mapeo motor con estimulación magnética transcraneal, analizando el área de respuestas y su localización, antes y después de recibir el tratamiento de 28 días de duración. Se realizaron pruebas de hipótesis para muestras independientes (U de Mann-Whitney) y dependientes (Wilcoxon), alfa = 0,05. Resultados. No se identificaron diferencias significativas entre grupos en las variables analizadas inicialmente (Mann-Whitney U; p > 0,05). En todos los pacientes se obtuvieron respuestas contralaterales al estimular el hemisferio afectado. Los resultados de la segunda evaluación evidenciaron diferencias entre grupos (p < 0,05), con incremento en la puntuación de las escalas clínicas en el G1 con respecto a los valores iniciales (Wilcoxon; Barthel, Z = 3,4793, p = 0,000; MRC; Z = 3,8230, p = 0,00) y en el área de respuestas motoras en ambos hemisferios (Z = 3,9199, p = 0,00). Conclusiones. La rehabilitación intensiva indujo modificaciones en las proyecciones córtico-motoneuronales a la mano en pacientes con infartos cerebrales

Introduction. Cerebrovascular disease is one of the main causes of motor deficits. We evaluated the effect of an intensive rehabilitation program over the reorganization of cortico-motoneuronal projections to the affected hand in patients after stroke from the mean cerebral artery territory. Material and methods. We carried out a cohort study, selecting a group of 20 hospitalized patients (group 1:G1) who were admitted to receive intensive rehabilitation treatment and another group of 10 ambulatory patients (group 2: G2) was selected as control group, they were not receiving at this moment any physical rehabilitation treatment. All the patients fulfilled the following criteria: >= 6 months post-stroke, >= 75 points in the Barthel index, and >= 2 in Medical Research Council in the affected hand. We excluded patients with >= 2 strokes, or who were carriers of electromagnetic devices. Both groups were evaluated before and after 28 days of treatment (only G1); applying the same clinical scales and electrophysiologically with motor mapping using transcranial magnetic stimulation, defining map area and location. Test for dependent (Wilcoxon) and for independent samples (Mann-Whitney U) were performed, with alpha = 0.05. Results. Before treatment both groups were clinically and electrophysiologically similar without any significant statistical difference (Mann Whitney U; p < 0,05). Contralateral responses were obtained in all patients after stimulating the affected hemisphere. Significant differences between groups were demonstrated after treatment; higher values in clinical scales were observed in G1 in comparison to initial values (Wilcoxon: Barthel index, Z = 3.4793, p = 0.000; MRC: Z = 3.8230, p = 0.000) and in the motor map area of both hemispheres (Wilcoxon: Z = 3.9199, p = 0.00). Conclusion. Intensive rehabilitation induced changes in cortico-motoneuronal projections to the hand in patients with stroke