Mucus-penetrating and permeation enhancer albumin-based nanoparticles for oral delivery of macromolecules: Application to bevacizumab.

The oral administration of therapeutic proteins copes with important challenges (mainly degradation and poor absorption) making their potential therapeutic application extremely difficult. The aim of this study was to design and evaluate the potential of the combination between mucus-permeating nanoparticles and permeation enhancers as a carrier for the oral delivery of the monoclonal antibody bevacizumab, used as a model of therapeutic protein. For this purpose, bevacizumab was encapsulated in PEG-coated albumin nanoparticles as a hydrophobic ion-pairing complex with either sodium deoxycholate (DS) or sodium docusate (DOCU). In both cases, complex formation efficiencies close to 90% were found. The incorporation of either DS or DOCU in PEG-coated nanoparticles significantly increased their mean size, particularly when DOCU was used. Moreover, the diffusion in mucus of DOCU-loaded nanoparticles was significantly reduced, compared with DS ones. In a C. elegans model, DS or DOCU (free or nanoencapsulated) disrupted the intestinal epithelial integrity, but the overall survival of the worms was not affected. In rats, the relative oral bioavailability of bevacizumab incorporated in PEG-coated nanoparticles as a complex with DS (B-DS-NP-P) was 3.7%, a 1000-fold increase compared to free bevacizumab encapsulated in nanoparticles (B-NP-P). This important effect of DS may be explained not only by its capability to transiently disrupt tight junctions but also to their ability to increase the fluidity of membranes and to inhibit cytosolic and brush border enzymes. In summary, the current strategy may be useful to allow the therapeutic use of orally administered proteins, including monoclonal antibodies.

Gliadin nanoparticles for oral administration of bioactives: Ex vivo and in vivo investigations.

This study aims to provide a thorough characterization of Brij O2-stabilized gliadin nanoparticles to be used for the potential oral administration of various compounds. Different techniques were used in order to evaluate their physico-chemical features and then in vivo studies in rats were performed for the investigation of their biodistribution and gastrointestinal transit profiles. The results showed that the gliadin nanoparticles accumulated in the mucus layer of the bowel mucosa and evidenced their ability to move along the digestive systems of the animals. The incubation of the nanosystems with Caenorhabditis elegans, used as an additional in vivo model, confirmed the intake of the particles and evidenced their presence along the entire gastrointestinal tract of these nematodes. The gliadin nanoparticles influenced neither the egg-laying activity of the worms nor their metabolism of lipids up to 10 µg/mL of nanoformulation. The systems decreased the content of the age-related lipofuscin pigment in the nematodes in a dose-dependent manner, demonstrating a certain antioxidant activity. Lastly, dihydroethidium staining showed the absence of oxidative stress upon incubation of the worms together with the formulations, confirming their safe profile. This data paves the way for the future application of the proposed nanosystems regarding the oral delivery of various bioactives.

Prevalence of thrombosis in patients with cancer and SARS-CoV-2 infection.

Background: Covid-19 infection and cancer are associated with an increased risk of thrombotic events. The aim of our study is to analyze the cumulative incidence of thrombosis in oncological patients with Covid-19 and detect differences with the non-cancer Covid-19 population. Methods: We retrospectively reviewed 1127 medical records of all admitted patients to ward of the Hospital Universitario Infanta Leonor (Madrid, Spain), including 86 patients with active cancer between March 5th, 2020 to May 3rd, 2020. We analyzed cumulative incidence of thrombosis and risk factors associated to the cancer patient's cohort. Results: We diagnosed 10 thrombotic events in 8 oncological patients with a cumulative incidence of 9.3%. A statistically significant association was found regarding thrombosis and history of obesity (p = 0.009). No differences related to cumulative incidence of thrombosis between both groups were detected (9.8% vs 5.80%) in our hospital (p = 0.25). Conclusion: No significant differences were observed in the cumulative incidence of thrombosis in the two study groups. The thrombotic effect of Covid-19 is not as evident in cancer patients and does not seem to be added to its prothrombotic activity.

Antecedentes: La infección por COVID-19 y el cáncer se asocian a mayor riesgo de eventos trombóticos. El objetivo de nuestro estudio es analizar la incidencia acumulada de trombosis en pacientes oncológicos con COVID-19 y detectar diferencias con la población sin cáncer y COVID-19. Métodos: Revisamos retrospectivamente 1.127 historias clínicas de los pacientes ingresados en del Hospital Infanta Leonor (Madrid, España), incluyendo 86 pacientes con cáncer activo entre el 5 de marzo y el 3 de mayo de 2020. Se analizó la incidencia acumulada de trombosis y los factores de riesgo asociados a la cohorte de pacientes con cáncer. Resultados: Diagnosticamos 10 eventos trombóticos en 8 pacientes oncológicos, con una incidencia acumulada del 9,3%. Se encontró una asociación estadísticamente significativa entre trombosis y obesidad (p = 0,009). No se detectaron diferencias relacionadas con la incidencia acumulada de trombosis entre ambos grupos (9,8%vs. 5,80%, p = 0,25). Conclusión: No se observaron diferencias significativas en la incidencia acumulada de trombosis en los 2 grupos de estudio. El efecto trombótico de la COVID-19 no es tan evidente en los pacientes con cáncer y no parece sumarse a su actividad protrombótica.

Prevalence of thrombosis in patients with cancer and SARS-CoV-2 infection

Background: Covid-19 infection and cancer are associated with an increased risk of thrombotic events. The aim of our study is to analyze the cumulative incidence of thrombosis in oncological patients with Covid-19 and detect differences with the non-cancer Covid-19 population.MethodsWe retrospectively reviewed 1127 medical records of all admitted patients to ward of the Hospital Universitario Infanta Leonor (Madrid, Spain), including 86 patients with active cancer between March 5th, 2020 to May 3rd, 2020. We analyzed cumulative incidence of thrombosis and risk factors associated to the cancer patient's cohort.ResultsWe diagnosed 10 thrombotic events in 8 oncological patients with a cumulative incidence of 9.3%. A statistically significant association was found regarding thrombosis and history of obesity (p=0.009). No differences related to cumulative incidence of thrombosis between both groups were detected (9.8% vs 5.80%) in our hospital (p=0.25).ConclusionNo significant differences were observed in the cumulative incidence of thrombosis in the two study groups. The thrombotic effect of Covid-19 is not as evident in cancer patients and does not seem to be added to its prothrombotic activity. (AU)

Antecedentes: La infección por COVID-19 y el cáncer se asocian a mayor riesgo de eventos trombóticos. El objetivo de nuestro estudio es analizar la incidencia acumulada de trombosis en pacientes oncológicos con COVID-19 y detectar diferencias con la población sin cáncer y COVID-19.MétodosRevisamos retrospectivamente 1.127 historias clínicas de los pacientes ingresados en del Hospital Infanta Leonor (Madrid, España), incluyendo 86 pacientes con cáncer activo entre el 5 de marzo y el 3 de mayo de 2020. Se analizó la incidencia acumulada de trombosis y los factores de riesgo asociados a la cohorte de pacientes con cáncer.ResultadosDiagnosticamos 10 eventos trombóticos en 8 pacientes oncológicos, con una incidencia acumulada del 9,3%. Se encontró una asociación estadísticamente significativa entre trombosis y obesidad (p=0,009). No se detectaron diferencias relacionadas con la incidencia acumulada de trombosis entre ambos grupos (9,8%vs. 5,80%, p=0,25).ConclusiónNo se observaron diferencias significativas en la incidencia acumulada de trombosis en los 2 grupos de estudio. El efecto trombótico de la COVID-19 no es tan evidente en los pacientes con cáncer y no parece sumarse a su actividad protrombótica. (AU)

New perspectives in the management of small cell lung cancer.

The treatment of small cell lung cancer (SCLC) is a challenge for all specialists involved. New treatments have been added to the therapeutic armamentarium in recent months, but efforts must continue to improve both survival and quality of life. Advances in surgery and radiotherapy have resulted in prolonged survival times and fewer complications, while more careful patient selection has led to increased staging accuracy. Developments in the field of systemic therapy have resulted in changes to clinical guidelines and the management of patients with advanced disease, mainly with the introduction of immunotherapy. In this article, we describe recent improvements in the management of patients with SCLC, review current treatments, and discuss future lines of research.

Prevalence of thrombosis in patients with cancer and SARS-CoV-2 infection.

BACKGROUND: Covid-19 infection and cancer are associated with an increased risk of thrombotic events. The aim of our study is to analyze the cumulative incidence of thrombosis in oncological patients with Covid-19 and detect differences with the non-cancer Covid-19 population. METHODS: We retrospectively reviewed 1127 medical records of all admitted patients to ward of the Hospital Universitario Infanta Leonor (Madrid, Spain), including 86 patients with active cancer between March 5th, 2020 to May 3rd, 2020. We analyzed cumulative incidence of thrombosis and risk factors associated to the cancer patient's cohort. RESULTS: We diagnosed 10 thrombotic events in 8 oncological patients with a cumulative incidence of 9.3%. A statistically significant association was found regarding thrombosis and history of obesity (p=0.009). No differences related to cumulative incidence of thrombosis between both groups were detected (9.8% vs 5.80%) in our hospital (p=0.25). CONCLUSION: No significant differences were observed in the cumulative incidence of thrombosis in the two study groups. The thrombotic effect of Covid-19 is not as evident in cancer patients and does not seem to be added to its prothrombotic activity.

Lung cancer patients with COVID-19 in Spain: GRAVID study.

INTRODUCTION: Patients with cancer may be at increased risk of more severe COVID-19 disease; however, prognostic factors are not yet clearly identified. The GRAVID study aimed to describe clinical characteristics, outcomes, and predictors of poor outcome in patients with lung cancer and COVID-19. METHODS: Prospective observational study that included medical records of patients with lung cancer and PCR-confirmed COVID-19 diagnosis across 65 Spanish hospitals. The primary endpoint was all-cause mortality; secondary endpoints were hospitalization and admission to intensive care units (ICU). RESULTS: A total of 447 patients with a mean age of 67.1 ± 9.8 years were analysed. The majority were men (74.3 %) and current/former smokers (85.7 %). NSCLC was the most frequent type of cancer (84.5 %), mainly as adenocarcinoma (51.0 %), and stage III metastatic or unresectable disease (79.2 %). Nearly 60 % of patients were receiving anticancer treatment, mostly first-line chemotherapy. Overall, 350 (78.3 %) patients were hospitalized for a mean of 13.4 ± 11.4 days, 9 (2.0 %) were admitted to 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: Mortality rate was higher among patients treated with corticosteroids during hospitalization, while anticancer therapy was not associated with an increased risk of hospitalization or death. Tailored approaches are warranted to ensure effective cancer management while minimizing the risk of exposure to SARS-CoV-2.

Características y evolución de los pacientes con cáncer de pulmón e infección Covid-19 en un hospital de segundo nivel durante los 3 primeros meses de pandemia / Characteristics and outcome of lung cancer patients and Covid-19 infection in a second-level hospital during the first 3 months of the pandemic

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Covid-19 and lung cancer: A greater fatality rate?

BACKGROUND: Currently there are no reported series determining the Covid-19 infected lung cancer patient´s characteristics and outcome that allow us to clarify strategies to protect our patients. In our study we determine whether exists differences in cumulative incidence and severity of Covid-19 infection between lung cancer patients visiting our Medical Oncology department and the reference population of our center (320,000 people), in the current epicenter of the pandemic in Europe (Madrid, Spain). We also describe clinical and demographic factors associated with poor prognosis and Covid-19 treatment outcomes. PATIENTS AND METHODS: We retrospectively reviewed 1878 medical records of all Covid-19 patients who were admitted at Hospital Universitario Infanta Leonor of Madrid between March 5, 2020 and April 7, 2020, in order to detect cumulative incidence of Covid-19 in lung cancer patients. We also described Covid-19 treatment outcome, mortality and associated risk factors using univariate and multivariate logistic regression analysis. RESULTS: 17/1878 total diagnosis in our center had lung cancer (0.9 %) versus 1878/320,000 of the total reference population (p = 0.09). 9/17 lung cancer patients with Covid-19 diagnosis died (52.3 %) versus 192/1878 Covid-19 patients in our center (p < 0.0001). Dead lung cancer patients were elderly compared to survivors: 72 versus 64.5 years old (p = 0.12). Combined treatment with hydroxychloroquine and azithromycin improves the outcome of Covid-19 in lung cancer patients, detecting only 1/6 deaths between patients under this treatment versus others treatment, with statistical significance in the univariate and multivariate logistic regression (OR 0.04, p = 0.018). CONCLUSIONS: Lung cancer patients have a higher mortality rate than general population. Combined hydroxychloroquine and azithromycin treatment seems like a good treatment option. It is important to try to minimize visits to hospitals (without removing their active treatments) in order to decrease nosocomial transmission.

Protein-based nanoparticles for drug delivery purposes.

Proteins represent a group of biopolymers with interesting properties to be employed as raw materials in the preparation of nanoparticles for drug delivery purposes. Due to the inherent properties of proteins (i.e., biodegradability, amphiphilic properties, etc.) the resulting nanoparticles can be considered as versatility platforms for a variety of applications. Moreover, some proteins possess a GRAS (Generally Recognized as Safe) status or are considered as excipients by different Regulatory Agencies. As result of this, the resulting nanoparticles and potential translation to clinic would be facilitated, compared to other materials (i.e., polymers). This review is focused on the main proteins employed in the preparation of nanoparticles as well as the procedures permitting their transformation into nanoparticles able of accommodating a high variety of bioactive compounds and drugs. Moreover, the review also provides examples of application of nanoparticles prepared from albumins, globulins, prolamins or macromolecules derived from proteins.

Endovascular stenting as the first step in the overall management of malignant superior vena cava syndrome.

OBJECTIVE: Self-expandable metal stents were inserted in cancer patients with superior vena cava (SVC) syndrome to assess their effectiveness as a primary treatment for symptom relief. SUBJECTS AND METHODS: Between January 1993 and June 2008, Wallstent prostheses (n = 208) were inserted in 149 cancer patients (137 men, 12 women; median age, 65 years; age range, 44-84 years) diagnosed as having SVC syndrome. A single stent was sufficient to restore vessel patency in 102 patients, two stents in 36, three stents in 10, and four stents in one. Survival data were calculated using Kaplan-Meier curves and multivariate analysis using the Cox regression method. RESULTS: Complete resolution of symptoms was achieved in 123 patients within 72 hours, partial resolution in 22 patients, and no response in only four patients. At follow-up, 30 complications were noted: 16 obstructions, four cases of thrombosis, one partial stent migration to the right atrium, two cases of incorrect stent placement, six stent "shortenings," and one case in which stent expansion was insufficient. All complications except two were successfully resolved by repeat stenting or by angioplasty. The median symptom-free survival was 6 months (range, 2 days-43 months). As of June 2008, eight patients were alive with patent stents. CONCLUSION: The Wallstent vascular endoprosthesis is an effective initial treatment in patients with SVC syndrome of neoplastic origin: Morbidity and complications are minimal, and clinical relief of symptoms is very rapid. Because the clinical decision for subsequent elective chemotherapy or radiation therapy is not prejudiced, stenting is a very effective initial step in the overall palliative treatment of patients with SVC syndrome.