BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas.

Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months' duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8-33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0-8.6) and a CBR of 31.7% (95% CI, 18.1-48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.

Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study.

BACKGROUND: Avadomide (CC-122) is a novel oral cereblon-modulating agent with promising activity in non-Hodgkin lymphoma. We aimed to examine the safety and preliminary activity of avadomide plus obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma. METHODS: CC-122-NHL-001 was a phase 1b dose escalation and expansion study at eight sites in France, Italy, and the Netherlands. Eligible patients (aged ≥18 years) had histologically confirmed CD20-positive relapsed or refractory non-Hodgkin lymphoma, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received previous treatment. In the dose expansion phase, only patients with previously treated relapsed or refractory follicular lymphoma (grade 1, 2, or 3a) were included. Avadomide was administered in escalating doses and two formulations: active pharmaceutical ingredient in capsule in 1·0 mg, 2·0 mg, 3·0 mg, and 4·0 mg doses and as formulated capsules in 3·0 mg and 4·0 mg doses orally once daily on days 1-5 followed by 2 days off (5-7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was administered intravenously on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability, the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). All patients who received treatment were included in the safety analyses. Efficacy-evaluable patients completed at least one cycle of treatment and had baseline and at least one post-baseline assessment. The study is registered with ClinicalTrials.gov, NCT02417285 and EudraCT 2014-003333-26, and is ongoing. FINDINGS: Between June 24, 2015, and Dec 5, 2018, 73 patients were enrolled and treated; 19 had diffuse large B-cell lymphoma, 53 follicular lymphoma, and one marginal zone lymphoma. Median follow-up was 253 days (IQR 127-448). The median number of previous anticancer regimens was three (IQR 2-4). The maximum tolerated dose and non-tolerated dose were not reached in the dose escalation phase. On the basis of safety and pharmacokinetic-pharmacodynamic data, the avadomide RP2D was established as 3·0 mg as formulated capsules on a 5-7-day schedule in combination with 1000 mg of obinutuzumab. Patients enrolled in the expansion cohort received the established RP2D of avadomide. Across all doses, three patients had dose-limiting toxicities; one patient treated at the RP2D had dose-limiting toxicity (grade 3 sepsis). The most common adverse events of grade 3 and above were neutropenia (41 [56%] of 73) and thrombocytopenia (17 [23%] of 73). 34 (47%) patients had serious adverse events, which were considered to be avadomide-related in 23 (32%) of 73 patients and obinutuzumab-related in 20 (27%) of 73 patients. Two treatment-related deaths occurred, one owing to tumour flare and one from acute myeloid leukaemia after study discontinuation. INTERPRETATION: Avadomide plus obinutuzumab has a manageable toxicity, being a tolerable treatment option for most patients. Although the prespecified threshold for activity was not met in the trial, we believe that the preliminary antitumour activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated relapsed or refractory non-Hodgkin lymphoma warrants further investigation as a chemotherapy-free option in this setting. FUNDING: Celgene Corporation.

Epidemiología de la dislipidemia aterogénica en un área urbana de la ciudad de Barcelona / Epidemiology of atherogenic dyslipidemia in an urban area of the city of Barcelona

Se ha realizado un estudio epidemiológico descriptivo y transversal sobre los datos del perfil lipídico y la glucemia de 2.021 pacientes recogidos por muestreo consecutivo y anónimo. Se han calculado las prevalencias de dislipidemia aterogénica según el sexo, según los diferentes puntos de corte de colesterol HDL en mujeres, y en la totalidad de la muestra, así como su asociación con la diabetes. Existen en el estudio sesgos de selección, ya que está realizado en los pacientes que acuden a un laboratorio de atención primaria y no a una muestra de la población general. Los datos epidemiológicos de prevalencias son por tanto aproximativos y provisionales

We performed a descriptive cross-sectional epidemiological study data on lipid profile and blood glucose of sample collected in 2021 consecutive and anonymous patients. We calculated the prevalence of atherogenic dyslipidemia by sex, according to several cutoff HDL cholesterol in women, and in the whole sample, and its association with diabetes. There is in the study selection bias, as it is performed in patients attending in a Primary Care Laboratory and not in a sample of the general population. Prevalence epidemiological data are therefore approximate and provisional

[Epidemiology of atherogenic dyslipidemia in an urban area of the city of Barcelona]. / Epidemiología de la dislipidemia aterogénica en un área urbana de la ciudad de Barcelona.

We performed a descriptive cross-sectional epidemiological study data on lipid profile and blood glucose of sample collected in 2021 consecutive and anonymous patients. We calculated the prevalence of atherogenic dyslipidemia by sex, according to several cutoff HDL cholesterol in women, and in the whole sample, and its association with diabetes. There is in the study selection bias, as it is performed in patients attending in a Primary Care Laboratory and not in a sample of the general population. Prevalence epidemiological data are therefore approximate and provisional.

Un método de detección de gammapatías monoclonales de IgM en un analizador / A method for detect Ig M monoclonal gammopathies in an autoanalyzer

Introducción. Frecuentemente el mieloma múltiple es precedido de una gammapatía monoclonal de significado incierto. Este estudio analiza la utilidad de una lipidemia falsamente positiva como un método rutinario y barato de detección de gammapatías monoclonales de IgM. Material y métodos. Se examinaron los sueros de 244 pacientes consecutivos con un índice lipidémico falso positivo (n=34) o negativo (n=210) y triglicéridos < 1,7mmol/L. Las concentraciones de inmunoglobulinas se estudiaron mediante un autoanalizador AU-5430. Los test de lipidemia fueron realizados con una concentración salina de 0,038M y los proteinogramas mediante una electroforesis capilar de la zona. Resultados. Con el diagnóstico de banda monoclonal la lipidemia falsa positiva tuvo una sensibilidad del 97% (95% CI: 91-100) y especificidad del 94% (95% CI: 91-97). El valor predictivo positivo y negativo fue de 72% (95% CI: 59-85) y 99% (95% CI: 99-100), respectivamente. Para el diagnóstico de IgM elevada la sensibilidad fue del 71% (95% CI: 55-86), la especificidad del 99% (95% CI: 98-100) y el valor predictivo positivo y negativo del 92% (95% CI: 82-103) y 95% (95% CI: 93-98), respectivamente. El OR ajustado por edad y sexo de la lipidemia falso positivo fue de 768,0 (95% CI: 75,8-7.799,3) para la IgM elevada y de 219,4 (95% CI: 42,9-1.120,5) para la banda monoclonal. Conclusiones. La lipidemia falsamente positiva se asoció a la IgM elevada y particularmente a la gammapatía monoclonal. Es una herramienta barata, sensible y específica para detectar una gammapatía monoclonal de IgM en los índices de interferencia rutinarios en analizadores (AU)

Introduction. Most patients with multiple myeloma have a previous monoclonal gammopathy of undetermined significance. This study analyzes the possible clinical usefulness of a false positive lipemia as a routine, inexpensive screening tool for IgM monoclonal gammopathies. Material and methods. Serum samples from 244 consecutive patients with a false positive (n=34) or negative lipemia test (n=210), with triglycerides <1.7mmol/L were studied. Immunoglobulin levels were quantified in an AU-5430 autoanalyzer. Lipemia tests were performed in a final saline concentration of 0,038M, and proteins by capillary-zone electrophoresis. Results. Sensitivity for monoclonal band detection was 97% (95% CI 91-100) for false lipemia, with 94% (95% CI: 91-97) specificity. The positive and negative predictive values were 72% (95% CI: 59-85) and 99% (95% CI: 99-100), respectively. Its sensitivity for elevated IgM detection was 71% (95% CI: 55-86) and 99% (95% CI: 98-100) specificity, positive and negative predictive values of 92% (95% CI: 82-100) and 95% (95% CI: 93-98), respectively. Age and sex-adjusted odds ratio of elevated IgM for false lipemic serum patients was 768.0 (95% CI: 75.8-7799.3), and 219.4 (95% CI: 42.9-1120.5) for the monoclonal band. Conclusions. A false positive lipemic test was associated with elevated IgM, and particularly with monoclonal gammopathy. This finding offers an inexpensive, sensitive and specific screening tool to detect IgM monoclonal gammopathy processes in routine autoanalyzer interference tests (AU)

Recomendaciones para la sedación y la analgesia por médicos no anestesiólogos y odontólogos de pacientes mayores de 12 años / Sedation and analgesia recommendations for non-anesthesiologist physicians and dentists in patients over 12 years old

Las complicaciones relacionadas con la sedación son, en su enorme mayoría, prevenibles. El presente documento establece unas recomendaciones para que los no anestesiólogos puedan realizar sedaciones nivel I y II con un buen nivel de seguridad. Sus aspectos másimportantes son: administración de la sedación por una persona diferente del operador; recomendaciones en cuanto a la capacitación, la monitorización, el uso de un solo medicamento para la sedación y la disponibilidad de medicamentos y equipos de respaldo;la necesidad de realizar una evaluación previa a la sedación, así como el consentimiento informado y el registro durante el procedimiento; y recomendaciones para considerar un bajo umbral con el fin de solicitar el apoyo de un anestesiólogo.

Most of the complications related to sedation are preventable. This document defines some recommendations for non-anesthesiologists so that they can provide sedation level I and II with adequate safety. The most important recommendations are: that the sedation be provided by someone different from the person who performs the surgical procedure; designation of the training and monitoring of thje person who sedates; the use of only one medication for sedation, and the availability of medications and equipment to manage complications; the mandatory need of an assessment prior to the sedation, as well as informed consent and record of events during the procedure; and the recommendation of having a low threshold to request the support of an anesthesiologist.

Lipoatrofia semicircular: una revisión sistemática de la literatura / Semicircular lipoatrophy: a sistematic review of the literature

Introducción: La lipoatrofia semicircular (LS) es un trastorno benigno del tejido subcutáneo, de causa desconocida. Se caracteriza por depresiones semicirculares en la cara anterolateral de los muslos, unilaterales o bilaterales. Se relaciona con condiciones ambientales laborales, microtraumas repetidos y factores personales. Se plateó esta revisión sistemática de la literatura científica para caracterizar el conocimiento existente.Métodos: Revisión sistemática. Bases de datos: IBECS, IBSST, LILACS, IME, OSH-UPDATE, ISI-WOK, PubMed, CIS-DOC y Cochrane. Se incluyeron los artículos sobre lipoatrofia semicircular relacionada con condiciones de trabajo y medioambientales. Se utilizaron los niveles de evidencia científica del Scottish Intercollegiate Guidelines Network.Resultados: Se recuperaron 66 artículos. Solo 22 cumplieron los criterios de inclusión: Quince con nivel de evidencia 3 y 7 con nivel 4. Siete estudios de series de casos y ocho de casos únicos, sumaron 838 casos, informados entre 1982-2010. Los principales factores de riesgo para LS son: Microtraumas repetidos, humedad relativa baja y electricidad en los edificios modernos de oficinas. Las depresiones semicirculares ocurren en la cara anterolateral de muslos, sin alteración de la piel, en mujeres (85%), sin signos inflamatorios con histopatología inespecífica. La resonancia magnética, radiología y los anticuerpos antinucleares son negativos. El diagnóstico es clínico, apoyado con ecografía. El tratamiento psicológico y fisioterapia pueden ser útiles. Las medidas preventivas de mayor impacto son controlar los factores mencionados.Conclusiones: Existe insuficiente evidencia científica sobre las causas de LS. Es un trastorno prevalente, que genera alarma, relacionado con las condiciones de trabajo. Es necesario continuar la investigación sobre agentes causales (AU)

Introduction: The semicircular lipoatrophy (LS) is a benign disorder of the subcutaneous tissue with unkvown cause. It is characterized by unilateral o bilateral semicircular depressions in the anterolateral side of the thighs. It is related to environmental labor conditions, repeated microtraumas and personal factors. We conducted this systematic review of the scientific literature to characterize the existing knowledge.Methods: Systematic Review. Databases: IBECS, IBSST, LILACS, IME, OSH-UPDATE, ISI-WOK, PubMed, CIS-DOC and Cochrane. We included articles about semicircular lipoatrophy related to working and environmental conditions. We used the levels of scientific evidence of the Scottish Intercollegiate Guidelines Network.Results: 66 articles were recovered. Only 22 fulfilled the inclusion criteria: Fifteen with evidence level 3 and 7 with evidence level 4. Seven studies were series of cases and 8 were unique case reports. All of them added 838 cases, informed between 1982-2010. The principal risk factors for LS are repetitive microtrauma, low relative humidity and electricity in modern office buildings. The semicircular depressions occur in the anterolateral side of thighs, without alteration of the skin and muscles, mostly in women (85%), without inflammatory signs and with unspecific histopathology. The magnetic resonance, x rays and the antinuclear antibodies are negative. The diagnosis is clinical, supported by ultrasonography. Psychological treatment and physical therapy can be useful. The preventive measures of greater impact are controlling risk factors.Conclusions: Insufficient scientific evidence exists about the causes of LS. It is a prevalent disorder that generates alarm, related to workplace conditions. It is necessary to continue investigating about causative agents (AU)

¿Elevación de albuminuria o posible contaminación con albúmina seminal? / Increased urine albumin or possible contamination with seminal albumin?

La cuantificación de la albúmina en orina se utiliza para la detección precoz de la insuficiencia renal crónica. En este estudio se recomienda interpretar esta magnitud con precaución en los sujetos varones, ya que en determinadas circunstancias se puede encontrar albúmina en la orina posteyaculación por contaminación de la albúmina del semen. Por ello, en las albuminurias discordantes con la clínica, aconsejamos en los varones, la abstinencia sexual en las 24h previas a la recogida de orina (AU)

The quantification of albumin in urine is commonly used in detection of early chronic kidney disease. This study shows experimentally that this parameter must be interpreted with caution in the male subjects, as in certain circumstances contamination by post-ejaculation albumin can be found in urine. Thus in the presence of albuminuria discordant with the clinical picture, men should be advised to practice sexual abstinence in the 24 hours prior to the urine collection (AU)

Detección de un error sistemático constante en un procedimiento directo de medida del colesterol de las lipoproteínas de baja densidad / Constant sistematic error detected in adirect assay for measurement of LDL-cholesterol

En el trabajo habitual de nuestro laboratorio de asistencia primaria, se determina el colesterol de las lipoproteínas de baja densidad (cLDL) directamente, con equipo suministrado por Olympus España y creado por WAKO, en pacientes cuyos triglicéridos son > 400 mg/dl. Movidos por una revisión de la bibliografía sobre este método y no disponiendo de medios (ultracentrífuga) para estudiar la posible inespecificidad que se cita en la bibliografía, hemos recurrido a medir con dicho método el cLDL de pacientes con triglicéridos ¾ 200 mg/dl, a los que, al aplicar la fórmula de Friedewald, su resultado de LDL sería más transferible con la ultracentrifugación. Hemos detectado un error sistemático constante del LDL directo frente al calculado y, por métodos estadísticos, hemos llegado a la conclusión de que ese error sistemático constante se debe a que el reactivo Olympus mide, inespecíficamente, el colesterol de las lipoproteínas de muy baja densidad. Creemos que estos datos son importantes para los usuarios de este reactivo, tanto como la pronta respuesta a las dos preguntas que se plantean al final del estudio (AU)

In our primary care laboratory, we routinely perform the direct low density lipoprotein (LDL) cholesterol test, supplied by Olympus España and created by WAKO, in patients with triglyceride levels of > 400 mg/dl. Studies in the literature have reported systematic error when this method is used. Because an ultracentrifuge was not available to study the possible lack of specificity reported in the literature, we used this test to measure LDL cholesterol in patients with triglyceride levels of ¾ 200 mg/dl in whom, on applying the Friedewald formula, the results for LDL cholesterol would be more concordant with those obtained by ultracentrifugation. We detected a constant systematic error in the direct LDL cholesterol test versus Freidewald calculation and, using statistical methods, we concluded that this constant systematic error is due to the fact that the Olympus reagent measures, nonspecifically, VLDL cholesterol. We believe that users of this reagent should be aware of these data and that a rapid response should be given to the two questions posed at the end of the study (AU)