Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab.

PURPOSE: Immune gene expression signatures are emerging as potential biomarkers for immunotherapy (IO). VIGex is a 12-gene expression classifier developed in both nCounter (Nanostring) and RNA sequencing (RNA-seq) assays and analytically validated across laboratories. VIGex classifies tumor samples into hot, intermediate-cold (I-Cold), and cold subgroups. VIGex-Hot has been associated with better IO treatment outcomes. Here, we investigated the performance of VIGex and other IO biomarkers in an independent data set of patients treated with pembrolizumab in the INSPIRE phase II clinical trial (ClinicalTrials.gov identifier: NCT02644369). MATERIALS AND METHODS: Patients with advanced solid tumors were treated with pembrolizumab 200 mg IV once every 3 weeks. Tumor RNA-seq data from baseline tumor samples were classified by the VIGex algorithm. Circulating tumor DNA (ctDNA) was measured at baseline and start of cycle 3 using the bespoke Signatera assay. VIGex-Hot was compared with VIGex I-Cold + Cold and four groups were defined on the basis of the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA). RESULTS: Seventy-six patients were enrolled, including 16 ovarian, 12 breast, 12 head and neck cancers, 10 melanoma, and 26 other tumor types. Objective response rate was 24% in VIGex-Hot and 10% in I-Cold/Cold. VIGex-Hot subgroup was associated with higher overall survival (OS) and progression-free survival (PFS) when included in a multivariable model adjusted for tumor type, tumor mutation burden, and PD-L1 immunohistochemistry. The addition of ΔctDNA improved the predictive performance of the baseline VIGex classification for both OS and PFS. CONCLUSION: Our data indicate that the addition of ΔctDNA to baseline VIGex may refine prediction for IO.

Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.

BACKGROUND: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.

A pan-cancer clinical platform to predict immunotherapy outcomes and prioritize immuno-oncology combinations in early-phase trials.

BACKGROUND: Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing. METHODS: We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types. VIGex was developed as a continuous variable, with cutoffs selected to detect three main categories (hot, intermediate-cold and cold) based on the different inflammatory status of the tumor microenvironment. FINDINGS: Hot tumors had the highest VIGex scores and exhibited an increased abundance of tumor-infiltrating lymphocytes as compared with the intermediate-cold and cold. VIGex scores varied depending on tumor origin and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. The predictive power of VIGex-Hot was observed in a cohort of 98 refractory solid tumor from patients treated in early-phase immunotherapy trials and its clinical performance was confirmed through an extensive metanalysis across 13 clinically annotated gene expression datasets from 877 patients treated with immunotherapy agents. Last, we generated a pan-cancer biomarker platform that integrates VIGex categories with the expression levels of immunotherapy targets under development in early-phase clinical trials. CONCLUSIONS: Our results support the clinical utility of VIGex as a tool to aid clinicians for patient selection and personalized immunotherapy interventions. FUNDING: BBVA Foundation; 202-2021 Division of Medical Oncology and Hematology Fellowship award; Princess Margaret Cancer Center.

Safety and efficiency of discharge to home hospitalization directly after emergency department care of patients with acute heart failure. / Análisis de seguridad y eficiencia de la hospitalización a domicilio directamente desde urgencias en pacientes con insuficiencia cardiaca aguda.

OBJECTIVES: To analyze whether discharge to home hospitalization (HHosp) directly from emergency departments (EDs) after care for acute heart failure (AHF) is efficient and if there are short-term differences in outcomes between patients in HHosp vs those admitted to a conventional hospital ward (CHosp). MATERIAL AND METHODS: Secondary analysis of cases from the EAHFE registry (Epidemiology of Acute Heart Failure in Emergency Departments). The EAHFE is a multicenter, multipurpose, analytical, noninterventionist registry of consecutive AHF patients after treatment in EDs. Cases were included retrospectively and registered to facilitate prospective follow-up. Included were all patients diagnosed with AHF and discharged to HHosp from 2 EDs between March 2016 and February 2019 (3 years). Cases from 6 months were analyzed in 3 periods: March-April 2016 (corresponding to EAHFE-5), January-February 2018 (EAHFE-6), and January-February 2019 (EAHFE-7). The findings were adjusted for characteristics at baseline and during the AHF decompensation episode. RESULTS: A total of 370 patients were discharged to HHosp and 646 to CHosp. Patients in the HHosp group were older and had more comorbidities and worse baseline functional status. However, the decompensation episode was less severe, triggered more often by anemia and less often by a hypertensive crisis or acute coronary syndrome. The HHosp patients were in care longer (median [interquartile range], 9 [7-14] days vs 7 [5-11] days for CHosp patients, P .001), but there were no differences in mortality during hospital care (7.0% vs. 8.0%, P = .56), 30-day adverse events after discharge from the ED (30.9% vs. 32.9%, P = .31), or 1-year mortality (41.6% vs. 41.4%, P = .84). Risks associated with HHosp care did not differ from those of CHosp. The odds ratios (ORs) for HHosp care were as follows for mortality while in care, OR 0.90 (95% CI, 0.41-1.97); adverse events within 30 days of ED discharge, OR 0.88 (95% CI, 0.62-1.26); and 1-year mortality, OR 1.03 (95% CI, 0.76-1.39). Direct costs of HHosp and CHosp averaged €1309 and €5433, respectively. CONCLUSION: After ED treatment of AHF, discharge to HHosp requires longer care than CHosp, but short- and longterm outcomes are the same and at a lower cost.

OBJETIVO: Analizar si la hospitalización domiciliaria (HDom) directamente desde los servicios de urgencias (SU) de pacientes con insuficiencia cardiaca aguda (ICA) resulta eficiente y si se asocia con diferencias en evolución a corto y largo plazo comparada con hospitalización convencional (HCon). METODO: Análisis secundario del registro Epidemiology Acute Heart Failure in Emergency departments (EAHFE), que es un registro multicéntrico, multiporpósito, analítico no intervencionista, con seguimiento prospectivo que incluye de forma consecutiva a los pacientes que acuden por episodio de ICA al SU. Se incluyeron, retrospectivamente, todos los pacientes diagnosticados de ICA en dos SU ingresados directamente en HDom entre marzo de 2016 y febrero de 2019 (3 años) y se compararon sus resultados con los pacientes diagnosticados de ICA incluidos en el registro EAHFE por esos 2 SU e ingresados en HCon durante los periodos marzo-abril 2016 (EAHFE-5), enero-febrero 2018 (EAHFE-6), y enero-febrero 2019 (EAHFE-7) (6 meses). Los resultados se ajustaron por las características basales y clínicas del episodio de descompensación. RESULTADOS: Se incluyeron 370 pacientes en HDom y 646 en HCon. El grupo HDom tenía mayor edad, mayor comorbilidad y peor situación funcional basal, pero menor gravedad del episodio de descompensación, más frecuentemente desencadenado por anemia y menos por crisis hipertensiva y síndrome coronario agudo. La duración del ingreso fue mayor [mediana (RIC) 9 (7-14) días frente a 7 (5-11) días, p 0,001], pero no hubo diferencias en mortalidad intrahospitalaria (7,0% frente a 8,0%, p = 0,56), eventos adversos a 30 días posalta (30,9% frente a 32,9%, p = 0,31) ni mortalidad al año (41,6% frente a 41,4%, p = 0,84). En el modelo ajustado, el riesgo asociado a HDom tampoco difirió significativamente en mortalidad intrahospitalaria (OR = 0,90, IC 95% = 0,41-1,97), eventos adversos posalta a 30m días (HR = 0,88, IC95% = 0,62-1,26) ni mortalidad al año (HR = 1,03, IC 95% = 0,76-1,39). El coste directo promedio del episodio en HDom y HCon fue 1.309 y 5.433 euros, respectivamente. CONCLUSIONES: En la ICA, la HDom directamente desde el SU es más prolongada que la HCon, pero consigue los mismos resultados a corto y largo plazo, y su coste es inferior.

Nutritional status associates with immunotherapy clinical outcomes in recurrent or metastatic head and neck squamous cell carcinoma patients.

BACKGROUND: Beyond programmed death-ligand 1 (PD-L1) assessed by the combined positive score (CPS) and tumor mutational burden (TMB), no other biomarkers are approved for immunotherapy interventions. Here, we investigated whether additional clinical and pathological variables may impact on immunotherapy outcomes in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients. METHODS: R/M HNSCC patients treated with immunotherapy were reviewed. Analyzed variables at baseline included: clinicopathological, laboratory, and variables reflecting the host nutritional status such as the prognostic nutritional index (PNI) and albumin. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS) and objective response rate (ORR). Univariable and multivariable Cox models were fitted and random forest algorithm was used to estimate the importance of each prognostic variable. RESULTS: A total of 100 patients were treated with immunotherapy; 50% with single agent and 50% with experimental immunotherapy combinations. In the multivariable analysis, both ECOG performance status (HR: 1.73; 95%CI 1.07-2.82; p = 0.03) and PNI levels (10-point increments, HR: 0.66; 0.46-0.95; p = 0.03) were significantly associated with PFS. However, the derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were not significantly associated with PFS (p-values > 0.15). In the OS analysis, albumin and PNI were the only statistically significant factors in the multivariable model (p < 0.001). CONCLUSIONS: In our cohort, PNI and ECOG performance status were most strongly associated with PFS in R/M HNSCC patients treated with immunotherapy. These results suggest that parameters informative of nutritional status should be considered before immunotherapy.

The Drying Kinetics and CFD Multidomain Model of Cocoa Bean Variety CCN51.

The CCN51 cocoa bean variety is known for being highly resistant to diseases and temperature variation and for having a relatively low cultivation risk for the producers. In this work, a computational and experimental study is performed to analyze the mass and heat transfer within the bean when dried by forced convection. A proximal composition analysis is conducted on the bean testa and cotyledon, and the distinct thermophysical properties are determined as a function of temperature for an interval between 40 and 70 °C. A multidomain CFD simulation, coupling a conjugate heat transfer with a semiconjugate mass transfer model, is proposed and compared to the experimental results based on the bean temperature and moisture transport. The numerical simulation predicts the drying behavior well and yields average relative errors of 3.5 and 5.2% for the bean core temperature and the moisture content versus the drying time, respectively. The moisture diffusion is found to be the dominant mechanism in the drying process. Moreover, a diffusion approximation model and given kinetic constants present a good prediction of the bean's drying behavior for constant temperature drying conditions between 40 and 70 °C.

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.

Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials.

PURPOSE: Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline. METHODS: Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application. RESULTS: We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3-12.7) for ICIs cohort and 7.7 m (95% CI, 6.6-8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS - ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64-0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%-90%). CONCLUSIONS: PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/.

Quadratic Non-Linear Optical Properties of the poly(2,5-bis(but-2-ynyloxy) Benzoate Containing the 2-(ethyl(4-((4-nitrophenyl)buta-1,3-diynyl)phenyl)amino)ethanol) Chromophore.

Excellent quadratic non-linear optical (ONL-2) properties of the poly(2,5-bis(but-2-ynyloxy) benzoate, containing a polar diacetylene as a chromophore, were found. According with the Maker fringes method, oriented polymer films showing an order parameter of ∼0.23 can display outstanding and stable Second Harmonic Generation (SHG) effects under off-resonant conditions (SHG-532 nm). Also, the macroscopic non-linear optical (NLO)-coefficients were evaluated under the rod-like molecular approximation, obtaining: χzzz(2) and χzxx(2) in the order of 280 ± 10 and 100 ± 10 pm V-1, respectively. The mechanical and chemical properties, in addition to the large ONL-2 coefficients exhibited by this polymer, make it a promising organic material in the development of optoelectronic/photonic devices.

Synthesis of porphyrin-dendrimers with a pyrene in the periphery and their cubic nonlinear optical properties.

Dendrons of pyrene derivatives were attached to a porphyrin core. A marked effect in solution for the dendrimers was observed in the absorption spectra. All the compounds obtained were characterized by (1)H-, (13)C-NMR, FTIR, UV-vis, MALDI-TOF or FAB+ mass spectrometry and elemental analysis. The cubic nonlinear optical behavior of some the synthesized compounds was tested via Z-Scan measurements in spin-coated film samples.

Optical absorption photoacoustic measurements for determination of molecular symmetries in a dichroic organic-film.

A novel approach to specify symmetries and main optical axes in anisotropic polymeric films is proposed. This method is based on the analysis of the optical absorption via the pulsed laser photoacoustic (PLPA)- technique in a common polarizer film, while rotating the polarizer axis at normal incidence. Since the PLPA-signals are directly proportional to the optical absorption, it is shown that a symmetric and complementary Malus's law can be obtained over full root mean square (RMS)- and correlation (CA)-analysis of the PLPA-signals. Such data processing reveals the main material directions of the constituting film molecules defining the symmetry structure of the sample. PLPA-results were compared to the pure optical transmission experiments and show unambiguous information, allowing this technique to be used in nonstandard and opaque polymeric films, where the analysis of the optical measurements represents a difficult task, and in general, in anisotropic media.

Preparation of fullerene (C60) based SiO2 sonogel hybrid composites: UV laser induced photo-polymerization, morphological, and optical properties.

Fullerene (C60) spheres were successfully embedded by diffusion into a catalyst-free SiO2 sonogel network. By this method, homogeneous and stable solid state hybrid samples suitable for optical characterization were produced. Due to the high porosity exhibited by the sonogel matrix on the nanometric length-scale, the preparation of several C60 doped composites with variable dopant concentrations was achieved. The obtained bulk hybrids were irradiated with a pulsed Kr-F laser system in order to induce photo-polymerization of the implanted C60 guest molecules at optimal experimental conditions established according to the pulsed laser photoacoustic technique (LPAT). The adequate purity level displayed by the sonogel route allowed us to perform optimal optical characterizations of these composites (reference hybrids and photo-polymerized samples) in order to evaluate their photo-physical properties for potential photonic applications. In this work the sonolysis process used to prepare amorphous catalyst-free SiO2:C60 sonogel hybrids and their linear and nonlinear optical (NLO) properties are extensively discussed. UV-VIS absorption-, Photo Luminescent (PL)-, and Raman-spectroscopies in conjunction with nonlinear optical limiting (OL) measurements, gave experimental evidence of the inclusion of C60 molecules within the sonogel environment, the laser induced photo-polymerization process and the induced changes of the optical and NLO-properties. Results are discussed in combination with atomic force microscopy (AFM) studies in order to explore the surface morphology of these samples.

Estudo da anomalia de Pelger-Huët em núcleo familiar: [carta ao editor] / Pelger-Huët anomaly study in a family: [letter to the editor]

The Pelger-Huët anomaly is a dominant autosomal disease, characterized by the incomplete segmentation of the granulocytes nucleus without lost of the cellular function. The heterozygotes form of this anomaly is assintomatic and it did not possess physic meant, while the homozygote form is rare and can be lethal, being therefore, important differentiates of other infectious alterations. The pseudo-anomaly can occasionally be observed in cases of granulocitic leukemia, mieloproliferatives Diseases, some infections and after exposition the determined drugs. We evaluate eleven members of a familiar nucleus and, after the blood cells analysis, six of then had presented neutrophils and eosinophils with nuclei characteristic of the heterozygotes form of the Pelger-Huët anomaly. The recognition of this leukocyte anomaly, mainly in patients without infection and presenting great number of not segmented neutrophils, can prevent wrong interpretations of the blood cells count and unnecessary clinical and therapeutically behaviors.

Aneurisma de aorta abdominal roto y contenido a cavidad peritoneal / Rupture abdominal aortic aneurysm restrained in peritoneal cavity

El aneurisma de aorta abdominal roto se asocia con un alto índice de mortalidad reportándose entre 15 por ciento hasta 80 por ciento de los casos. Presentamos el caso de una paciente de 80 años de edad con un aneurisma de aorta abdominal roto y contenido a la cavidad peritoneal presentando tres síntomas relevantes a su ingreso a urgencias: tumoración abdominal pulsátil, dolor abdominal súbito e hipotensión, caracterizada por lipotimia y diaforesis profusa, se documenta con radiografía y tomografía computarizada de abdomen, ya que permaneció hemodinámicamente estable en urgencias. El curso postoperatorio fue satisfactorio. Conclusiones: El síndrome de abdomen agudo tiene como diagnóstico diferencial el aneurisma de aorta abdominal roto y por lo tanto, el cirujano general en las unidades de urgencias debe tener el suficiente criterio para poder diferenciar las modalidades clínicas de cómo se presenta esta patología en especial.

Abordaje retroperitoneal en aneurismas de aorta abdominal / REtroperitoneal approach in abdominal aortic aneurysm

El abordaje retroperitoneal izquierdo para el manejo de aneurismas de aorta abdominal ofrece ventajas técnicas, menor morbimortalidad, y menores costos de hospitalización.Objetivo: Reportar la experiencia del Centro Médico Nacional "20 de Noviembre", ISSSTE, en el manejo de aneurismas de aorta abdominal con abordaje retroperitoneal. Pacientes y métodos: Estudio prospectivo, observacional, comparativo, del 1º de marzo de 1995, al 1º de junio de 2000, se operaron 45 pacientes con diagnóstico de aneurisma de aorta abdominal, 10 pacientes se abordaron por vía retroperitoneal, por tener indicaciones para el mismo y 10 por vía transperitoneal elegidos en forma aleatoria, se aplicó prueba estadística de Mann-Whitney (Wilcoxon), y de Moses. Resultados: No se observaron diferencias en sangrado transoperatorio y número de paquetes globulares transfundidos, tiempo de pinzamiento mayor en el grupo retroperitoneal, no existió diferencia en el tiempo quirúrgico total para los dos grupos (p 0.089), el tiempo de intubación en el grupo retroperitoneal fue de 30 horas, y los del grupo transperitoneal de 53.4 horas (p 0.043); el inicio de vía oral en los pacientes del grupo transperitoneal fue de 4.5 días y para el retroperitoneal de 1.8 días (p 0.002). Las complicaciones en ambos grupos no fueron significativas, el tiempo de estancia en UCI fue menor (p 0.03).Conclusiones: El abordaje RP es el procedimiento de elección en pacientes con indicaciones establecidas ofreciendo menor tiempo de apoyo ventilatorio, inicio temprano de la vía oral y menor tiempo de estancia en la Unidad de Cuidados Intensivos.