Bispectral index monitoring for sedation in scheduled adult colonoscopy: A randomized controlled trial.

BACKGROUND: Patients should be closely monitored during procedures under sedation outside the operating room, but it is unclear which type of monitoring is best. We investigated the efficacy and safety of BIS monitoring vs conventional monitoring for sedation during colonoscopy. METHODS: We performed a double-blind clinical trial in 180 patients undergoing elective colonoscopy. Patients were randomized to 1) the BIS group or 2) a control group, in which sedation was monitored with a BIS monitor or the Ramsay Sedation Score, respectively. The primary outcome was the rate of sedation-induced adverse events in both groups. Secondary outcomes were the characteristics of patients who developed adverse events, and time during colonoscopy when these events occurred, propofol and remifentanil dosage, and patient satisfaction. RESULTS: Univariate analysis showed fewer cardiopulmonary complications in the BIS group (41.11% vs 57.78% in controls; p = 0.02). Multivariate analysis found a significantly higher risk of adverse events in older patients (95% CI, 1.013-1.091; p = 0.0087) and in men (95% CI, 1.129-7.668; p = 0.0272). These events were observed at the hepatic flexure. No significant differences between propofol or remifentanil dosage, use of rescue medication, and patient satisfaction were observed between groups. CONCLUSIONS: Our data suggest that BIS monitoring during sedation in scheduled colonoscopies reduces adverse respiratory events. Although its routine use in sedation does not appear to be warranted, clinicians should take steps to identify patients with a higher risk of complications who might benefit from this type of monitoring.

Patología dermatológica facial asociada al uso de la mascarilla durante la pandemia causada por el virus Sars-CoV-2 / Facial dermatological pathology associated with use of the mask during the pandemic caused by the Sars-CoV-2 virus

The use of facemask has become a key element to prevent the infection of Covid-19. Its prolonged use, both, by health personnel and the general population, has caused the appearance of multiple adverse effects at the facial level; highlighting the report of symptoms such as discomfort with the mask, facial itching, redness, erythema, among others. The appearance of dermatological diseases such as acne, allergic and irritative contact dermatitis, and exacerbation of pre-existing pathologies such as acne, rosacea and seborrheic dermatitis are also frequent. Knowledge of these complications is important for their prevention and proper management. (AU)

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.

BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.

Evaluation of oncogenic cysteinyl leukotriene receptor 2 as a therapeutic target for uveal melanoma.

Uveal melanoma is a rare, but deadly, form of eye cancer that arises from melanocytes within the uveal tract. Although advances have emerged in treatment of the primary tumour, patients are still faced with vision loss, eye enucleation and lethal metastatic spread of the disease. Approximately 50% of uveal melanoma patients develop metastases, which occur most frequently in the liver. Metastatic patients encounter an extremely poor prognosis; as few as 8% survive beyond 2 years. Understanding of the genetic underpinnings of this fatal disease evolved in recent years with the identification of new oncogenic mutations that drive uveal melanoma pathogenesis. Despite this progress, the lack of successful therapies or a proven standard-of-care for uveal melanoma highlights the need for new targeted therapies. This review focuses on the recently identified CYSLTR2 oncogenic mutation in uveal melanoma. Here, we evaluate the current status of uveal melanoma and investigate how to better understand the role of this CYSLTR2 mutation in the disease and implications for patients harbouring this mutation.

Results of surgical treatment of acromioclavicular dislocations type III using modified Weaver Dunn technique. / Resultados del tratamiento quirúrgico de las luxaciones acromioclaviculares tipo iii mediante técnica de Weaver-Dunn modificada.

OBJECTIVE: To evaluate the clinical and radiological results of the surgical treatment of type III acromioclavicular dislocations using the Weaver-Dunn technique in the delayed phase. MATERIAL AND METHOD: A non-randomised controlled retrospective observational study of 38 patients operated between January 2006 and December 2014. We excluded 10 patients due to death or non-localisation. We collected demographic data, time to intervention, complications, analysing the Visual Analog Scale, DASH and Oxford Shoulder Score and the updated radiological result. RESULTS: mean age of patients with right-dominant shoulder affected in 71% of cases predominantly by non-level falls was 35. 70% of the cases had subjective perception of both recovery of strength and disappearance of deformity. Full radiological reduction was observed in 95% of the cases with the appearance of mild osteoarthritis in 44% and moderate osteoarthritis in 5.6%. The results of the DASH presented values of 12,939 (±16,851) and the OSS of 42,736 (±7,794), indicating satisfactory articular function. DISCUSSION: The data from this study shows similar results to previous studies regarding subjective recovery of strength, maintenance of anatomical reduction, functional test results and efficacy of the Weaver-Dunn technique. CONCLUSIONS: The modified Weaver-Dunn technique provided good clinical and radiological results with patient reincorporation to their usual activities and maintenance over time.

Prediction of pathological response to neoadjuvant treatment in rectal cancer with a two-protein immunohistochemical score derived from stromal gene-profiling.

BACKGROUND: Preoperative chemoradiotherapy followed by surgical mesorectal resection is the standard of care for locally advanced rectal carcinomas. Yet, predicting that patients will respond to treatment remains an unmet clinical challenge. EXPERIMENTAL DESIGN: Using laser-capture microdissection we isolated RNA from stroma and tumour glands from prospective pre-treatment samples (n = 15). Transcriptomic profiles were obtained hybridising PrimeView Affymetrix arrays. We modelled a carcinoma-associated fibroblast-specific genes filtering data using GSE39396. RESULTS: The analysis of differentially expressed genes of stroma/tumour glands from responder and non-responder patients shows that most changes were associated with the stromal compartment; codifying mainly for extracellular matrix and ribosomal components. We built a carcinoma-associated fibroblast (CAF) specific classifier with genes showing changes in expression according to the tumour regression grade (FN1, COL3A1, COL1A1, MMP2 and IGFBP5). We assessed these five genes at the protein level by means of immunohistochemical staining in a patient's cohort (n = 38). For predictive purposes we used a leave-one-out cross-validated model with a positive predictive value (PPV) of 83.3%. Random Forest identified FN1 and COL3A1 as the best predictors. Rebuilding the leave-one-out cross-validated regression model improved the classification performance with a PPV of 93.3%. An independent cohort was used for classifier validation (n = 36), achieving a PPV of 88.2%. In a multivariate analysis, the two-protein classifier proved to be the only independent predictor of response. CONCLUSION: We developed a two-protein immunohistochemical classifier that performs well at predicting the non-response to neoadjuvant treatment in rectal cancer.

Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. METHODS: For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at -80°C. RESULTS: In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs. CONCLUSION: Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.

A systematic analysis of orphan cyclins reveals CNTD2 as a new oncogenic driver in lung cancer.

As lung cancer has increased to the most common cause of cancer death worldwide, prognostic biomarkers and effective targeted treatments remain lacking despite advances based on patients' stratification. Multiple core cyclins, best known as drivers of cell proliferation, are commonly deregulated in lung cancer where they may serve as oncogenes. The recent expansion of the cyclin family raises the question whether new members might play oncogenic roles as well. Here, we investigated the protein levels of eight atypical cyclins in lung cancer cell lines and formalin-fixed and paraffin-embedded (FFPE) human tumors, as well as their functional role in lung cancer cells. Of the new cyclins evaluated, CNTD2 was significantly overexpressed in lung cancer compared to adjacent normal tissue, and exhibited a predominant nuclear location. CNTD2 overexpression increased lung cancer cell viability, Ki-67 intensity and clonogenicity and promoted lung cancer cell migration. Accordingly, CNTD2 enhanced tumor growth in vivo on A549 xenograft models. Finally, the analysis of gene expression data revealed a high correlation between elevated levels of CNTD2 and decreased overall survival in lung cancer patients. Our results reveal CNTD2 as a new oncogenic driver in lung cancer, suggesting value as a prognostic biomarker and therapeutic target in this disease.

Long-term effectiveness of irreversible electroporation in a murine model of colorectal liver metastasis.

Irreversible electroporation (IRE) has recently gained in popularity as an ablative technique, however little is known about its oncological long-term outcomes. To determine the long-time survival of animals treated with a high dose of IRE and which histological changes it induces in tumoral tissue, IRE ablation was performed in forty-six athymic-nude mice with KM12C tumors implanted in the liver by applying electric current with different voltages (2000 V/cm, 1000 V/cm). The tumors were allowed to continue to grow until the animals reached the end-point criteria. Histology was harvested and the extent of tumor necrosis was semi-quantitatively assessed. IRE treatment with the 2000 V/cm protocol significantly prolonged median mouse survival from 74.3 ± 6.9 days in the sham group to 112.5 ± 15.2 days in the 2000 V/cm group. No differences were observed between the mean survival of the 1000 V/cm and the sham group (83.2 ± 16.4 days, p = 0.62). Histology revealed 63.05% ± 23.12 of tumor necrosis in animals of the 2000 V/cm group as compared to 17.50% ± 2.50 in the 1000 V/cm group and 25.6% ± 22.1 in the Sham group (p = 0.001). IRE prolonged the survival of animals treated with the highest electric field (2000 V/cm). The animals in this group showed significantly higher rate of tumoral necrosis.

Patient-derived xenografts for childhood solid tumors: a valuable tool to test new drugs and personalize treatments.

The use of preclinical models is essential in translational cancer research and especially important in pediatric cancer given the low incidence of each particular type of cancer. Cell line cultures have led to significant advances in cancer biology. However, cell lines have adapted to growth in artificial culture conditions, thereby undergoing genetic and phenotypic changes which may hinder the translational application. Tumor grafts developed in mice from patient tumor tissues, generally known as patient-derived xenografts (PDXs), are interesting alternative approaches to reproducing the biology of the original tumor. This review is focused on highlighting the interest of PDX models in pediatric cancer research and supporting strategies of personalized medicine. This review provides: (1) a description of the background of PDX in cancer, (2) the particular case of PDX in pediatric cancer, (3) how PDX can improve personalized medicine strategies, (4) new methods to increase engraftment, and, finally, (5) concluding remarks.

Hypopigmented mycosis fungoides: a retrospective clinicohistopathologic study.

IMPORTANCE: Hypopigmented mycosis fungoides is a rare variant of mycosis fungoides with limited published clinicohistopathologic data available. OBJECTIVE: To characterize our patient group, to provide additional information and insight into this malignancy. DESIGN: A 16-year retrospective medical records review (from 1992 to 2009) was conducted of patients with a diagnosis of hypopigmented mycosis fungoides. SETTING: All patients were seen in the department of dermatology at Howard University Hospital, an outpatient clinic in an urban academic institution. PARTICIPANTS: The review comprised of 20 patients. Inclusion required presence of hypopigmented skin lesions and a skin biopsy diagnostic for hypopigmented mycosis fungoides. INTERVENTIONS: Treatment modalities, including oral psoralen with UVA, narrow-band UVB and/or topical medications such as nitrogen mustard and topical corticosteroids were employed. RESULTS: Patients ranged from 4 to 57 years old. Fifteen were African American, three African, one Afro-Caribbean and one Hispanic. The interval from disease onset to diagnosis ranged from 7 months to 24 years. Patients presented at Stage 1A or 1B. Treatment included phototherapy and topical medications. In four patients with pre- and post-treatment biopsies, the original histological diagnosis of hypopigmented mycosis fungoides and the subsequent complete resolution were shown. There was no associated mortality in the patients studied. CONCLUSIONS AND RELEVANCE: Hypopigmented mycosis fungoides affected skin of colour patients in this study. This variant differs from classic mycosis fungoides: younger population, slower progression and the majority of patients remaining in Stage I with treatment. We observed that any repigmentation of lesions suggests an effective treatment regimen, complete repigmentation correlates with clinical and histopathologic resolution, and new hypopigmented lesions during remission suggest relapse. A limitation of this study is the small sample size. This is the first study to correlate the histological resolution of hypopigmented mycosis fungoides with clinical repigmentation of lesions.

Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming.

Components of the SWI/SNF chromatin remodeling complex, including BRG1 (also SMARCA4), are inactivated in cancer. Among other functions, SWI/SNF orchestrates the response to retinoid acid (RA) and glucocorticoids (GC) involving downregulation of MYC. The epigenetic drugs SAHA and azacytidine, as well as RA and GC, are currently being used to treat some malignancies but their therapeutic potential in lung cancer is not well established. Here we aimed to determine the possible therapeutic effects of azacytidine and SAHA (A/S) alone or in combination with GC plus RA (GC/RA) in lung cancers with either BRG1 inactivation or MYC amplification. In vitro, responses to GC/RA treatment were more effective in MYC-amplified cells. These effects were mediated by BRG1 and involved a reprogramming towards prodifferentiation gene expression signatures and downregulation of MYC. In MYC-amplified cells, administration of GC/RA enhanced the cell growth inhibitory effects of A/S which, in turn, accentuated the prodifferentiation features promoted by GC/RA. Finally, these treatments improved overall survival of mice orthotopically implanted with MYC-amplified, but not BRG1-mutant, cells and reduced tumor cell viability and proliferation. We propose that the combination of epigenetic treatments with retinoids and corticoids of MYC-driven lung tumors constitute a strategy for therapeutic intervention in this otherwise incurable disease.

[Neurological manifestations in patients with cancer: more than 17,000 reasons for consultation]. / Manifestaciones neurologicas en pacientes con cancer: mas de 17.000 motivos de consulta.

INTRODUCTION: Cancer is one of the leading causes of death in our population; neurologic manifestations are frequent and are associated with higher rates of morbidity and mortality. AIM: To describe the neurological manifestations in patients with cancer. PATIENTS AND METHODS: From January 2010 to December 2014 a database was created from patients with cancer, required a neuro-oncological assessment at a referral cancer center. RESULTS: 17,092 reasons for neuro-oncological consultation are described. Neoplasms most frequently associated with neurological manifestations were: breast cancer, hematologic malignancies, primary central nervous system tumors, lung cancer and gynecological malignancies. The most frequent neurological manifestations were: neuromuscular disease (including neuropathy), central nervous system metastasis, primary headaches, seizures, stroke and primary neurological tumors. CONCLUSION: It is important that neurologists, physicians and those involved in the management of patients with cancer recognize and get to know the neurological complications.

TITLE: Manifestaciones neurologicas en pacientes con cancer: mas de 17.000 motivos de consulta.Introduccion. El cancer es una de las primeras causas de muerte en nuestra poblacion. Las complicaciones neurologicas asociadas son frecuentes e incrementan significativamente la morbilidad y la mortalidad de estos pacientes. Objetivo. Describir las manifestaciones neurologicas en pacientes con cancer. Pacientes y metodos. Desde enero de 2010 hasta diciembre de 2014 se creo una base de datos de pacientes con cancer que merecian una valoracion por neurooncologia en un centro de referencia. Resultados. Se describen 17.092 motivos de consulta de neurooncologia. Las neoplasias que mas se relacionaron con manifestaciones neurologicas fueron: cancer de mama, neoplasias hematologicas, tumores primarios del sistema nervioso central, cancer de pulmon y neoplasias ginecologicas. Las manifestaciones neurologicas mas frecuentes fueron: afeccion neuromuscular, actividad tumoral en el sistema nervioso central, cefalea primaria, crisis convulsivas, enfermedad vascular cerebral y tumores neurologicos primarios. Conclusiones. Es importante que los neurologos, medicos de distintas areas de la medicina y personal paramedico, involucrados en el manejo de estos pacientes, reconozcan las complicaciones neurologicas de manera temprana.

Versatile theranostics agents designed by coating ferrite nanoparticles with biocompatible polymers.

Three biocompatible polymers, polyethylene glycol (PEG), dextran and chitosan, have been used in this work to control the colloidal stability of magnetic nanoparticles (14 ± 5 nm in diameter) and to vary the aggregation state in order to study their effect on relaxometric and heating properties. Two different coating strategies have been deeply developed; one based on the formation of an amide bond between citric acid coated nanoparticles (NPs) and amine groups present on the polymer surface and the other based on the NP encapsulation. Relaxometric properties revealed that proton relaxation rates strongly depend on the coating layer hydrophilicity and the aggregation state of the particles due to the presence of magnetic interactions. Thus, while PEG coating reduces particle aggregation by increasing inter-particle spacing leading to reduction of both T1 and T2 relaxation, dextran and chitosan lead to an increase mainly in T2 values due to the aggregation of particles in bigger clusters where they are in close contact. Dextran and chitosan coated NPs have also shown a remarkable heating effect during the application of an alternating magnetic field. They have proved to be potential candidates as theranostic agents for cancer diagnosis and treatment. Finally, cytotoxicity of PEG conjugated NPs, which seem to be ideal for intravenous administration because of their small hydrodynamic size, was investigated resulting in high cell viability even at 0.2 mg Fe ml(-1) after 24 h of incubation. This suspension can be used as drug/biomolecule carrier for in vivo applications.