Circulating tumor DNA for monitoring classic Hodgkin lymphoma patients: Correlation with FDG-PET/CT.

The value of circulating tumor DNA (ctDNA) as a biomarker of disease activity in classic Hodgkin lymphoma (cHL) patients has not yet been well established. By profiling primary tumors and ctDNA, we identified common variants between primary tumors and longitudinal plasma samples in most of the cases, confirming high spatial and temporal heterogeneity. Although ctDNA analyses mirrored HRS cell genetics overall, the prevalence of variants shows that none of them can be used as a single biomarker. Conversely, the estimation of hGE/mL, based on measures of total ctDNA, reflects disease activity and is almost perfectly correlated with standard parameters such as PET/CT that are associated with refractoriness.

Immune and stromal transcriptional patterns that influence the outcome of classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) is characterized by a rich immune microenvironment as the main tumor component. It involves a broad range of cell populations, which are largely unexplored, even though they are known to be essential for growth and survival of Hodgkin and Reed-Sternberg cells. We profiled the gene expression of 25 FFPE cHL samples using NanoString technology and resolved their microenvironment compositions using cell-deconvolution tools, thereby generating patient-specific signatures. The results confirm individual immune fingerprints and recognize multiple clusters enriched in refractory patients, highlighting the relevance of: (1) the composition of immune cells and their functional status, including myeloid cell populations (M1-like, M2-like, plasmacytoid dendritic cells, myeloid-derived suppressor cells, etc.), CD4-positive T cells (exhausted, regulatory, Th17, etc.), cytotoxic CD8 T and natural killer cells; (2) the balance between inflammatory signatures (such as IL6, TNF, IFN-γ/TGF-ß) and MHC-I/MHC-II molecules; and (3) several cells, pathways and genes related to the stroma and extracellular matrix remodeling. A validation model combining relevant immune and stromal signatures identifies patients with unfavorable outcomes, producing the same results in an independent cHL series. Our results reveal the heterogeneity of immune responses among patients, confirm previous findings, and identify new functional phenotypes of prognostic and predictive utility.

Interactions between the principal risk factors for reduction of the eGFR in unvaccinated COVID­19 survivors: Normal pre-COVID­19 eGFR, not having diabetes and being hospitalized.

There are contradictory results regarding changes in estimated glomerular filtration rate (eGFR) in coronavirus disease 2019 (COVID-19) survivors. An analysis of eGFR changes and clinical characteristics associated with those changes was conducted among COVID-19 survivors. eGFR values were compared at different time points (before and 4-, 8- and 12-months after COVID-19 infection). A multivariate generalized linear mixed model (GENLINMIXED procedure) with a binary logistic regression link was used to determine factors associated with eGFR reduction of ≥10 ml/min/1.73 m2. Being hospitalized (RR=2.90, 95% CI=1.10-7.68, P=0.032), treated with Ivermectin (RR=14.02, 95% CI=4.11-47.80, P<0.001) or anticoagulants (RR=6.51, 95% CI=2.69-15.73, P<0.001) are risk factors for a reduced eGFR. Having a low eGFR (<90 ml/min/1.73 m2) before COVID-19 infection, having B-positive blood type, diabetes, taking vitamin C during the acute phase of COVID-19 or suffering from chronic COVID-19 symptoms, were identified as protective factors. Analysis involving a two-way interaction (A x B, where A and B are factors) demonstrated that the combination of patients with a normal eGFR value before COVID-19 infection without diabetes (RR=58.60, 95% CI=11.62-295.38, P<0.001), or a normal eGFR value with being hospitalized for COVID-19 (RR=38.07, 95% CI=8.68-167.00, P<0.001), increased the probability of a reduced eGFR. The changes in eGFR in COVID-19 survivors varied depending on patient characteristics. Furthermore, the principal risk factors for post-COVID-19 eGFR reduction were analyzed in separate models.

A novel [89Zr]-anti-PD-1-PET-CT to assess response to PD-1/PD-L1 blockade in lung cancer.

Background: Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [89Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC. Materials and methods: A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [89Zr]-labeled anti-PD-1 antibody and measured as 89Zr tumor uptake. Results: Conventional [18F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [89Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [89Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found (Cor = 0.8; p = 0.001). Conclusion: Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC.

A new and effective method to induce infection of Phyllachora maydis into corn for tar spot studies in controlled environments.

BACKGROUND: Tar spot of corn is a significant and spreading disease in the continental U.S. and Canada caused by the obligate biotrophic fungus Phyllachora maydis. As of 2023, tar spot had been reported in 18 U.S. states and one Canadian Province. The symptoms of tar spot include chlorotic flecking followed by the formation of black stromata where conidia and ascospores are produced. Advancements in research and management for tar spot have been limited by a need for a reliable method to inoculate plants to enable the study of the disease. The goal of this study was to develop a reliable method to induce tar spot in controlled conditions. RESULTS: We induced infection of corn by P. maydis in 100% of inoculated plants with a new inoculation method. This method includes the use of vacuum-collection tools to extract ascospores from field-infected corn leaves, application of spores to leaves, and induction of the disease in the dark at high humidity and moderate temperatures. Infection and disease development were consistently achieved in four independent experiments on different corn hybrids and under different environmental conditions in a greenhouse and growth chamber. Disease induction was impacted by the source and storage conditions of spores, as tar spot was not induced with ascospores from leaves stored dry at 25 ºC for 5 months but was induced using ascospores from infected leaves stored at -20 ºC for 5 months. The time from inoculation to stromata formation was 10 to 12 days and ascospores were present 19 days after inoculation throughout our experiments. In addition to providing techniques that enable in-vitro experimentation, our research also provides fundamental insights into the conditions that favor tar spot epidemics. CONCLUSIONS: We developed a method to reliably inoculate corn with P. maydis. The method was validated by multiple independent experiments in which infection was induced in 100% of the plants, demonstrating its consistency in controlled conditions. This new method facilitates research on tar spot and provides opportunities to study the biology of P. maydis, the epidemiology of tar spot, and for identifying host resistance.

PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells.

Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% of patients with NSCLC, with higher frequency in lung squamous carcinomas (LUSC). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy. Development of a Pten-null LUSC mouse model revealed that tumors with PTEN loss were refractory to antiprogrammed cell death protein 1 (anti-PD-1), highly metastatic and fibrotic, and secreted TGFß/CXCL10 to promote conversion of CD4+ lymphocytes into regulatory T cells (Treg). Human and mouse PTEN-low tumors were enriched in Tregs and expressed higher levels of immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists and anti-TGFß antibody aimed to alter this immunosuppressive microenvironment and led to tumor rejection and immunologic memory in 100% of mice. These results demonstrate that lack of PTEN causes immunotherapy resistance in LUSCs by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically. SIGNIFICANCE: PTEN loss leads to the development of an immunosuppressive microenvironment in lung cancer that confers resistance to anti-PD-1 therapy, which can be overcome by targeting PTEN loss-mediated immunosuppression.

Assessment of symptom induction via artificial inoculation of the obligate biotrophic fungus Phyllachora maydis (Maubl.) on corn leaves.

OBJECTIVE: Tar spot is a foliar disease of corn caused by Phyllachora maydis, which produces signs in the form of stromata that bear conidia and ascospores. Phyllachora maydis cannot be cultured in media; therefore, the inoculum source for studying tar spot comprises leaves with stromata collected from naturally infected plants. Currently, there is no effective protocol to induce infection under controlled conditions. In this study, an inoculation method was assessed under greenhouse and growth chamber conditions to test whether stromata of P. maydis could be induced on corn leaves. RESULTS: Experiments resulted in incubation periods ranging between 18 and 20 days and stromata development at the beginning of corn growth stage VT-R1 (silk). The induced stromata of P. maydis were confirmed by microscopy, PCR, or both. From thirteen experiments conducted, four (31%) resulted in the successful production of stromata. Statistical analyses indicate that if an experiment is conducted, there are equal chances of obtaining successful or unsuccessful infections. The information from this study will be valuable for developing more reliable P. maydis inoculation methods in the future.

JAK/STAT blockade reverses the malignant phenotype of Hodgkin and Reed-Sternberg cells.

Constitutive activation of the JAK/STAT pathway is a common phenomenon in classic Hodgkin lymphoma (cHL). The clinical potential of anti-JAK/STAT therapy is being explored in early-stage clinical trials. Notwithstanding, very little information is available about the complex biological consequences of this blockade. Here, we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor that induces apoptosis by concentration- and time-dependent mechanisms. An unbiased whole-transcriptome approach identified expression of the anti-GCSF receptor (CSF3R) as a potential surrogate biomarker of JAK/STAT overactivation. In addition, longitudinal gene expression analyses provided further mechanistic information about pertinent biological pathways involved, including 37 gene pathways distributed in 3 main clusters: cluster 1 was characterized by upregulation of the G2/M checkpoint and major histocompatibility complex-related clusters; 2 additional clusters (2 and 3) showed a progressive downregulation of the tumor-promoting inflammation signatures: JAK/STAT and interleukin 1 (IL-1)/IL-4/IL-13/IL-17. Together, our results confirm the therapeutic potential of JAK/STAT inhibitors in cHL, identify CSF3R as a new biomarker, and provide supporting genetic data and mechanistic understanding.

Gender and age-related variations in human immunodeficiency virus infection trends at the Mexican Institute of Social Security: 2003-2017.

INTRODUCTION: Diagnosing and treating human immunodeficiency virus carriers has led to the identification of a higher prevalence of said infection and, therefore, of a higher risk of transmission of the virus. OBJECTIVE: To find out the trend of new cases of human immunodeficiency virus infection carriers at the Instituto Mexicano del Seguro Social (IMSS) in Mexico within the 2003-2017 period. METHODS: Patients affiliated to the IMSS were analyzed. Data from 42,181 newly-diagnosed cases were collected, with variations related to gender and age being observed. Age-standardized rates per 100,000 population were obtained. RESULTS: The highest mean annual percentage change in males was documented in adolescents (13.0, 95% CI = 9.9, 16.1). Heterogeneous trends were recorded for women, with a significant overall decrease (-2.2, 95% CI = -3.4, -1.0), but growing trends were also observed in some groups. CONCLUSIONS: Our results suggest that the human immunodeficiency epidemic in patients cared for at the Instituto Mexicano del Seguro Social is concentrated in males, with a growing trend particularly in adolescents.

INTRODUCCIÓN: Hacer el diagnóstico y tratar a portadores del virus de la inmunodeficiencia humana ha llevado a identificar mayor prevalencia de esa infección y, por lo tanto, de un mayor riesgo de transmisión de este virus. OBJETIVO: Conocer la tendencia en México de los nuevos casos de portadores de infección por el virus de la inmunodeficiencia humana en el Instituto Mexicano del Seguro Social (IMSS) en el periodo 2003-2017. MÉTODOS: Se analizaron pacientes asegurados en el IMSS. Se obtuvieron datos de 42 181 casos recién diagnosticados y se analizaron las variaciones relacionadas con el sexo y la edad. Se obtuvieron las tasas estandarizadas por edad por 100 000 personas. RESULTADOS: El cambio porcentual anual promedio más alto en hombres se documentó en adolescentes varones (13.0, IC 95 % = 9.9, 16.1). Se registraron tendencias heterogéneas en las mujeres, con una disminución total significativa (­2.2, IC 95 % = ­3.4, ­1.0), pero también se observaron tendencias crecientes en algunos grupos. CONCLUSIONES: Los resultados sugieren que en el IMSS, la epidemia de la inmunodeficiencia humana adquirida se concentra en hombres, con tendencia creciente particularmente en adolescentes.

Variaciones por edad y sexo en las tendencias de infección por el virus de la inmunodeficiencia humana en el Instituto Mexicano del Seguro Social: 2003-2017 / Gender and age-related variations in human immunodeficiency virus infection trends at the Mexican Institute of Social Security: 2003-2017

Resumen Introducción: Hacer el diagnóstico y tratar a portadores del virus de la inmunodeficiencia humana ha llevado a identificar mayor prevalencia de esa infección y, por lo tanto, de un mayor riesgo de transmisión de este virus. Objetivo: Conocer la tendencia en México de los nuevos casos de portadores de infección por el virus de la inmunodeficiencia humana en el Instituto Mexicano del Seguro Social (IMSS) en el periodo 2003-2017. Métodos: Se analizaron pacientes asegurados en el IMSS. Se obtuvieron datos de 42 181 casos recién diagnosticados y se analizaron las variaciones relacionadas con el sexo y la edad. Se obtuvieron las tasas estandarizadas por edad por 100 000 personas. Resultados: El cambio porcentual anual promedio más alto en hombres se documentó en adolescentes varones (13.0, IC 95 % = 9.9, 16.1). Se registraron tendencias heterogéneas en las mujeres, con una disminución total significativa (-2.2, IC 95 % = -3.4, -1.0), pero también se observaron tendencias crecientes en algunos grupos. Conclusiones: Los resultados sugieren que en el IMSS, la epidemia de la inmunodeficiencia humana adquirida se concentra en hombres, con tendencia creciente particularmente en adolescentes.

Abstract Introduction: Diagnosing and treating human immunodeficiency virus carriers has led to the identification of a higher prevalence of said infection and, therefore, of a higher risk of transmission of the virus. Objective: To find out the trend of new cases of human immunodeficiency virus infection carriers at the Instituto Mexicano del Seguro Social (IMSS) in Mexico within the 2003-2017 period. Methods: Patients affiliated to the IMSS were analyzed. Data from 42,181 newly-diagnosed cases were collected, with variations related to gender and age being observed. Age-standardized rates per 100,000 population were obtained. Results: The highest mean annual percentage change in males was documented in adolescents (13.0, 95% CI = 9.9, 16.1). Heterogeneous trends were recorded for women, with a significant overall decrease (-2.2, 95% CI = -3.4,-1.0), but growing trends were also observed in some groups. Conclusions: Our results suggest that the human immunodeficiency epidemic in patients cared for at the Instituto Mexicano del Seguro Social is concentrated in males, with a growing trend particularly in adolescents.

[Obesity, CKD and gender on the 30-day in-hospital mortality risk in adults with COVID-19]. / Obesidad, ERC y género en el riesgo de mortalidad hospitalaria a 30 días en adultos con COVID-19.

Background: The coronavirus disease 2019 (COVID-19) pandemic is a serious health problem. The Mexican adult population has a high prevalence of obesity and chronic diseases that increase the risk of dying from this disease. Objective: To identify comorbidities predicting the risk of mortality at 30 days in hospitalized adult subjects with positive laboratory COVID-19 test and to evaluate the interaction between chronic diseases and gender. Material and methods: A retrospective cohort study was conducted in 2020, in a western region of the Mexican Pacific. Data from 51,135 hospitalized patients with positive COVID-19 test were analyzed and were retrieved from a normative system for the epidemiological surveillance of viral respiratory diseases (SINOLAVE, according to its initials in Spanish). Death within the first 30 days from hospital admission was the main outcome and risk ratios (RR) with 95% confidence intervals (95% CI) were calculated. Results: The overall mortality rate was 49.6% and most of the comorbidities analyzed were associated with a higher risk of death. There were significant interactions between gender and obesity (p = 0.003) and chronic kidney disease (p = 0.019). The effect of obesity on the risk of a fatal outcome varied by gender: female, RR = 1.04 (95% CI 1.03-1.07); male, RR = 1.07 (95% CI: 1.06-1.09). Conclusions: A high mortality was observed among the hospitalized patients analyzed and statistically significant factors associated with their risk were identified (gender, obesity, and kidney disease).

Introducción: la pandemia de la enfermedad por coronavirus 2019 (COVID-19) es un problema serio de salud. La población adulta mexicana tiene una alta prevalencia de obesidad y de enfermedades crónicas que incrementan el riesgo de morir por esta enfermedad. Objetivo: identificar comorbilidades predictoras del riesgo de mortalidad a 30 días en sujetos adultos hospitalizados con COVID-19 demostrado por laboratorio y evaluar la interacción entre enfermedades crónicas y el género del paciente. Material y métodos: se hizo un estudio de cohorte retrospectivo en el 2020, en una región del occidente del pacífico mexicano. Se analizaron los datos de 51,135 pacientes hospitalizados con COVID-19, los cuales fueron extraídos de un sistema normativo para la vigilancia epidemiológica de enfermedades respiratorias virales (SINOLAVE). La muerte dentro de los primeros 30 días desde la admisión hospitalaria fue el evento principal y fueron estimadas razones de riesgo (RR) con intervalos de confianza del 95% (IC 95%). Resultados: la mortalidad global fue del 49.6% y la mayoría de las comorbilidades analizadas se asociaron con un mayor riesgo de muerte. Hubo interacciones significativas entre el género y la obesidad (p = 0.003) y la enfermedad renal crónica (p = 0.019). El efecto de la obesidad sobre el riesgo de un desenlace fatal varió en función del género: mujeres, RR = 1.04 (IC 95% 1.03-1.07); hombres, RR = 1.07 (IC 95% 1.06-1.09). Conclusiones: se observó una alta mortalidad entre los pacientes hospitalizados analizados y se identificaron factores asociados a su riesgo (género, obesidad y enfermedad renal).

YES1 Is a Druggable Oncogenic Target in SCLC.

INTRODUCTION: SCLC is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis. METHODS: Association between YES1 levels and prognosis was evaluated in SCLC clinical samples. In vitro functional experiments for proliferation, apoptosis, cell cycle, and cytotoxicity were performed. Genetic and pharmacologic inhibition of YES1 was evaluated in vivo in cell- and patient-derived xenografts and metastasis. YES1 levels were evaluated in mouse and patient plasma-derived exosomes. RESULTS: Overexpression or gain/amplification of YES1 was identified in 31% and 26% of cases, respectively, across molecular subgroups, and was found as an independent predictor of poor prognosis. Genetic depletion of YES1 dramatically reduced cell proliferation, three-dimensional organoid formation, tumor growth, and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacologic blockade with the novel YES1 inhibitor CH6953755 or dasatinib induced marked antitumor activity in organoid models and cell- and patient-derived xenografts. YES1 protein was detected in plasma exosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/monitoring. CONCLUSIONS: Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of patients with SCLC.

How many people is the COVID-19 pandemic pushing into poverty? A long-term forecast to 2050 with alternative scenarios.

The COVID-19 pandemic has changed the course of human development. In this manuscript we analyze the long-term effect of COVID-19 on poverty at the country-level across various income thresholds to 2050. We do this by introducing eight quantitative scenarios that model the future of Sustainable Development Goal 1 (SDG1) achievement using alternative assumptions about COVID-19 effects on both economic growth and inequality in the International Futures model. Relative to a scenario without the pandemic (the No COVID scenario), the COVID Base scenario increases global extreme poverty by 73.9 million in 2020 (the range across all scenarios: 43.5 to 155.0 million), 63.6 million in 2030 (range: 9.8 to 167.2 million) and 57.1 million in 2050 (range: 3.1 to 163.0 million). The COVID Base results in seven more countries not meeting the SDG1 target by 2030 that would have achieved the target in a No COVID scenario. The most pessimistic scenario results in 17 more countries not achieving SDG1 compared with a No COVID scenario. The greatest pandemic driven increases in poverty occur in South Asia and sub-Saharan Africa.

Empirical Antibiotic Prescribing in Adult COVID-19 Inpatients over Two Years in Mexico.

Background and Objectives: Empirical antibiotic prescribing in patients with coronavirus disease 2019 (COVID-19) has been common even though bacterial coinfections are infrequent. The overuse of antibacterial agents may accelerate the antibiotic resistance crisis. We aimed to evaluate factors predicting empirical antibiotic prescribing to adult COVID-19 inpatients over 2 years (March 2020-February 2021) in Mexico. Materials and Methods: A cross-sectional analysis of a nationwide cohort study was conducted. Hospitalized adults due to laboratory-confirmed COVID-19 were included (n = 214,171). Odds ratios (OR) and 95% confidence intervals (CI), computed by using logistic regression models, were used to evaluate factors predicting empirical antibiotic prescribing. Results: The overall frequency of antibiotic usage was 25.3%. In multiple analysis, the highest risk of antibiotic prescription was documented among patients with pneumonia at hospital admission (OR = 2.20, 95% CI 2.16-2.25). Male patients, those with chronic comorbidities (namely obesity and chronic kidney disease) and longer interval days from symptoms onset to healthcare seeking, were also more likely to receive these drugs. We also documented that, per each elapsed week during the study period, the odds of receiving antibiotic therapy decreased by about 2% (OR = 0.98, 95% CI 0.97-0.99). Conclusion: Our study identified COVID-19 populations at increased risk of receiving empirical antibiotic therapy during the first two years of the pandemic.

COVID-19 vaccines provide better protection against related pneumonia than previous symptomatic infection.

OBJECTIVES: To compare, in a real-world scenario, the protective effect of vaccination and previous laboratory-confirmed symptomatic infection on the risk of COVID-19 pneumonia. METHODS: A retrospective study was conducted and 46,998 adults with laboratory-confirmed COVID-19 were enrolled. Risk ratios (RRs) and 95% confidence intervals (CIs) were used to evaluate the effect of the evaluated exposures on the risk of pneumonia. RESULTS: In multiple analysis and after adjusting by reinfection status, vaccinated participants were at reduced risk of developing pneumonia (RR = 0.974, 95% CI 0.965-0.983). The association of having had a previous infection was not significant (RR = 1.001, 95% CI 0.969-1.034). CONCLUSION: Our results suggest, and if later replicated, that COVID-19 vaccines provide better protection against pneumonia than previous symptomatic infections. Therefore, offering vaccination to all eligible subjects despite past COVID-19 infections might be relevant to reducing the pandemic-related burden.

The Hodgkin Lymphoma Immune Microenvironment: Turning Bad News into Good.

The classic Hodgkin lymphoma (cHL) tumor microenvironment (TME) is by far the most abundant component of tumors and is responsible for most of their biological and clinical characteristics. Recent advances in our knowledge of these networks in cellular interactions allow us to understand that the neoplastic Hodgkin and Reed Sternberg (HRS) cells, although they are in the minority, are the main architects of this dysregulated immune milieu. Here, we review the major changes that have happened in recent years: from TME as a helpless bystander, reflecting an ineffective immune response, to a dynamic tumor-promoting and immunosuppressive element. The HRS cells promote survival through interconnected intrinsic and extrinsic alterations, boosting pro-tumoral signaling pathways through genetic aberrations and autocrine growth signals, in parallel with abnormal cytokine secretion for the recruitment and selection of the best cell partners for this immunosuppressive TME. In turn, cHL is already proving to be the perfect model with which to address an immune checkpoint blockade. Preliminary data demonstrate the utility of druggable key signaling pathways in this ensemble, such as JAK-STAT, NF-κB, and others. In addition, myriad biomarkers predicting a response await validation by new in situ multiplex analytical methods, single-cell gene expression, and other techniques. Together, these components will define the functional phenotypes with which we will elucidate the molecular pathogenesis of the disease and improve the survival of patients who are refractory to conventional therapies.

Efficacy of the use of mefenamic acid combined with standard medical care vs. standard medical care alone for the treatment of COVID­19: A randomized double­blind placebo­controlled trial.

Mefenamic acid is a non­steroidal anti­inflammatory drug exhibiting a wide range of anti­inflammatory, antipyretic, analgesic and probable antiviral activities. The present study evaluated the efficacy of treatment with mefenamic acid combined with standard medical care vs. standard medical care plus a placebo in ambulatory patients with coronavirus disease 2019 (COVID­19; nasal/oropharyngeal swabs reverse transcription­PCR test results positive for severe acute respiratory syndrome coronavirus 2). The present study is a phase II prospective, two­arm, parallel­group, randomized, double­blind placebo­controlled clinical trial which analyzed 36 patients. Two aspects were evaluated during the 14­day follow­up period: i) The time for reaching a patient acceptable symptom state (PASS), and ii) the last day of each COVID­19 symptom presentation. Adverse effects were evaluated. The clinical severity for all the patients in the study was mild (88.9%) and moderate (11.1%). The control (placebo) group achieved PASS on day 8.0±1.3, compared with day 4.4±0.8 in the mefenamic acid group (P=0.020, Kaplan­Meier analyses using log­rank tests). Patients that received mefenamic acid plus standard medical care had a ~16­fold higher probability of achieving PASS on day 8 (adjusted RR, 15.57; 95% CI, 1.22­198.71; P=0.035), compared with the placebo plus standard medical care group. All symptoms lasted for fewer days in the mefenamic acid group, compared with the placebo group; however, only the symptoms of headache (P=0.008), retro­orbital eye pain (P=0.049), and sore throat (P=0.029) exhibited statistically significant differences. The experimental treatment produced no severe adverse effects. On the whole, the present study demonstrates that the administration of mefenamic acid markedly reduced the symptomatology and time to reach PASS in ambulatory patients with COVID­19. Due to its probable antiviral effects and potent anti­inflammatory mechanisms, mefenamic acid may prove to be useful in the treatment of COVID­19, in combination with other drugs, including the new antivirals (remdesivir, molnupiravir, or favipiravir). However, future studies are also required to confirm these findings.

Association of acute urinary retention in postoperative patients with a urinary catheter, with and without bladder catheter clamping. / Asociación de retención urinaria aguda en pacientes postoperados con catéter urinario, con y sin pinzamiento de catéter vesical.

INTRODUCTION: The use of a temporaryor permanent catheter is very common in clinical practice. Between 15.0% and 25.0% of hospitalized patients have in-dwelling bladder catheters, the majority of which are short-term. Bladder catheter clamping before catheter removal was generally regarded as useful in the past. Today, its utility is questionable. OBJECTIVE: To determine the association between bladder catheter clamping and spontaneous micturition or acute urinary retention (AUR) in postoperative patients with short-term indwelling bladder catheter. MATERIALS AND METHODS: A descriptive, comparative,longitudinal study was conducted at a secondary care hospital center in a western Mexican state .AUR was the outcome variable. Two study groups wereformed: patients with bladder catheter clamping (n=43) and the control patients with no bladder catheter clamping (n=41). Descriptive statistical analyses were performed, and percentage comparisons were made with the chi-squaretest. Significant predictors were subsequently added to the multivariate model. RESULTS: Fourteen percent (n=12) of all the study patients, with and without bladder catheter clamping, presented with AUR and 86% (n=72) did not. In the association analysis, there was no statistically significant difference between presenting with AUR and having or not having bladder catheter clamping (p=0.59). The associations of AUR with bladder re-catheterization (p=0.001), age (p=0.01), and the presence of lower urinary symptoms (p= 0.005) were statistically significant. CONCLUSION: Postoperative bladder catheter clamping was not associated with the presence of AUR.

INTRODUCCIÓN: El uso de un catéter urinario temporal o permanente es muy común en la práctica clínica. Entre el 15,0% y el 25,0% de los pacientes hospitalizados tienen catéteres vesicales, la mayoría a corto plazo. Durante mucho tiempo se había considerado a los ejercicios vesicales como una práctica útil antes del retiro de los mismos. En la actualidad su utilidad es muy cuestionable.OBJETIVOS: Determinar la asociación que tienen los ejercicios vesicales sobre la micción espontánea o retención aguda de orina en pacientes postoperados portadores de catéter urinario de corta duración.MATERIAL Y MÉTODOS: Se realizó un estudio comparativo, longitudinal y descriptivo en un hospital de 2º nivel de un estado de occidente de México. La variablede desenlace fue la retención aguda de orina. Se formaron dos grupos de estudio; con ejercicios vesicales y un grupo control sin ejercicios vesicales 43 sujetos vs- 41 respectivamente. Se realizaron pruebas estadísticas descriptivas y a comparación de porcentajes se realizó con la prueba Chi2. Posteriormente se agregaron predictores significativos al modelo multivariable.RESULTADOS: De los pacientes incluidos en el estudio con y sin ejercicios vesicales, 14% (12) presentaron retención aguda de orina (RAO) y 72% (86) no la presentaron. Haciendo un análisis de asociación, no hubo significancia estadística, tener RAO y hacer ejercicios vesicales o no hacerlos (p=0,59). Hubo asociación estadísticamente significativa cuando se compararon la recolocación del catéter urinario con RAO p=0,001, la edad con la RAO p=0,01 y la presencia de síntomas irritativos urinarios bajos p=0,005.CONCLUSIÓN: El realizar ejercicios vesicales en los pacientes postoperados no están asociados a la presencia de retención aguda de orina.

Asociación de retención urinaria aguda en pacientes postoperados con catéter urinario, con y sin pinzamiento de catéter vesical / Association of acute urinary retention in postoperative patients with urinary catheter, with and without bladder catheter clamping

Introducción: El uso de un catéterurinario temporal o permanente es muy común en lapráctica clínica. Entre el 15,0% y el 25,0% de los pacientes hospitalizados tienen catéteres vesicales, la mayoría a corto plazo. Durante mucho tiempo se habíaconsiderado a los ejercicios vesicales como una práctica útil antes del retiro de los mismos. En la actualidadsu utilidad es muy cuestionable. Objetivos: Determinar la asociación que tienen losejercicios vesicales sobre la micción espontánea o retención aguda de orina en pacientes postoperados portadores de catéter urinario de corta duración. MATERIAL Y MÉTODOS: Se realizó un estudio comparativo, longitudinal y descriptivo en un hospital de 2ºnivel de un estado de occidente de México. La variablede desenlace fue la retención aguda de orina. Se formaron dos grupos de estudio; con ejercicios vesicalesy un grupo control sin ejercicios vesicales 43 sujetosvs- 41 respectivamente.Se realizaron pruebas estadísticas descriptivas y a comparación de porcentajes se realizó con la prueba Chi 2.Posteriormente se agregaron predictores significativos almodelo multivariable. Resultados: De los pacientes incluidos en el estudiocon y sin ejercicios vesicales, 14% (12) presentaron retención aguda de orina (RAO) y 72% (86) no la presentaron. Haciendo un análisis de asociación, no hubosignificancia estadística, tener RAO y hacer ejerciciosvesicales o no hacerlos (p=0,59). Hubo asociación estadísticamente significativa cuando se compararon larecolocación del catéter urinario con RAO p=0,001, laedad con la RAO p=0,01 y la presencia de síntomasirritativos urinarios bajos p=0,005. Conclusion: El realizar ejercicios vesicales en lospacientes postoperados no están asociados a la presencia de retención aguda de orina.(AU)

Introduction: The use of a temporary or permanent catheter is very common in clinicalpractice. Between 15.0% and 25.0% of hospitalizedpatients have in-dwelling bladder catheters, the majorityof which are short-term. Bladder catheter clamping before catheter removal was generally regarded as usefulin the past. Today, its utility is questionable. Objetive: To determine the association between bladder catheter clamping and spontaneous micturition oracute urinary retention (AUR) in postoperative patientswith short-term indwelling bladder catheter.Materials and methods: A descriptive, comparative, longitudinal study was conducted at a secondary care hospital center in a western Mexican state.AUR was the outcome variable. Two study groups wereformed: patients with bladder catheter clamping (n=43)and the control patients with no bladder catheter clamping (n=41).Descriptive statistical analyses were performed, andpercentage comparisons were made with the chi-squaretest. Significant predictors were subsequently added tothe multivariate model. Results: Fourteen percent (n=12) of all the study patients, with and without bladder catheter clamping,presented with AUR and 86% (n=72) did not. In theassociation analysis, there was no statistically significantdifference between presenting with AUR and having ornot having bladder catheter clamping (p=0.59). Theassociations of AUR with bladder re-catheterization (p=0.001), age (p=0.01), and the presence of lower urinary symptoms (p= 0.005) were statistically significant. Conclusion: Postoperative bladder catheter clamping was not associated with the presence of AUR.(A U)