Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation.

Adhesion G-protein-coupled receptors (aGPCRs) bear notable similarity to Notch proteins1, a class of surface receptors poised for mechano-proteolytic activation2-4, including an evolutionarily conserved mechanism of cleavage5-8. However, so far there is no unifying explanation for why aGPCRs are autoproteolytically processed. Here we introduce a genetically encoded sensor system to detect the dissociation events of aGPCR heterodimers into their constituent N-terminal and C-terminal fragments (NTFs and CTFs, respectively). An NTF release sensor (NRS) of the neural latrophilin-type aGPCR Cirl (ADGRL)9-11, from Drosophila melanogaster, is stimulated by mechanical force. Cirl-NRS activation indicates that receptor dissociation occurs in neurons and cortex glial cells. The release of NTFs from cortex glial cells requires trans-interaction between Cirl and its ligand, the Toll-like receptor Tollo (Toll-8)12, on neural progenitor cells, whereas expressing Cirl and Tollo in cis suppresses dissociation of the aGPCR. This interaction is necessary to control the size of the neuroblast pool in the central nervous system. We conclude that receptor autoproteolysis enables non-cell-autonomous activities of aGPCRs, and that the dissociation of aGPCRs is controlled by their ligand expression profile and by mechanical force. The NRS system will be helpful in elucidating the physiological roles and signal modulators of aGPCRs, which constitute a large untapped reservoir of drug targets for cardiovascular, immune, neuropsychiatric and neoplastic diseases13.

Liver injury after SARS-CoV-2 vaccination: Features of immune-mediated hepatitis, role of corticosteroid therapy and outcome.

BACKGROUND AND AIMS: A few case reports of autoimmune hepatitis-like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series. APPROACH AND RESULTS: We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range: 18-79) years at presentation. Liver injury was diagnosed a median 15 (range: 3-65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3-4 liver injury than for grade 1-2 liver injury (88.9% vs. 43.5%, p = 0.001) and more often for patients with than without immune-mediated hepatitis (71.1% vs. 38.2%, p = 0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up. CONCLUSIONS: SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine-associated liver injury led to fulminant liver failure in one patient.

Impact of COVID-19 Infection on Patients with Cancer: Experience in a Latin American Country: The ACHOCC-19 Study.

INTRODUCTION: The ACHOCC-19 study was performed to characterize COVID-19 infection in a Colombian oncological population. METHODOLOGY: Analytical cohort study of patients with cancer and COVID-19 infection in Colombia. From April 1 to October 31, 2020. Demographic and clinical variables related to cancer and COVID-19 infection were collected. The primary outcome was 30-day mortality from all causes. The association between the outcome and the prognostic variables was analyzed using logistic regression models and survival analysis with Cox regression. RESULTS: The study included 742 patients; 72% were >51 years. The most prevalent neoplasms were breast (132, 17.77%), colorectal (92, 12.34%), and prostate (81, 10.9%). Two hundred twenty (29.6%) patients were asymptomatic and 96 (26.3%) died. In the bivariate descriptive analysis, higher mortality occurred in patients who were >70 years, patients with lung cancer, ≥2 comorbidities, former smokers, receiving antibiotics, corticosteroids, and anticoagulants, residents of rural areas, low socioeconomic status, and increased acute-phase reactants. In the logistic regression analysis, higher mortality was associated with Eastern Cooperative Oncology Group performance status (ECOG PS) 3 (odds ratio [OR] 28.67; 95% confidence interval [CI], 8.2-99.6); ECOG PS 4 (OR 20.89; 95% CI, 3.36-129.7); two complications from COVID-19 (OR 5.3; 95% CI, 1.50-18.1); and cancer in progression (OR 2.08; 95% CI, 1.01-4.27). In the Cox regression analysis, the statistically significant hazard ratios (HR) were metastatic disease (HR 1.58; 95% CI, 1.16-2.16), cancer in progression (HR 1.08; 95% CI, 1.24-2.61) cancer in partial response (HR 0.31; 95% CI, 0.11-0.88), use of steroids (HR 1.44; 95% CI, 1.01-2.06), and use of antibiotics (HR 2.11; 95% CI, 1.47-2.95). CONCLUSION: In our study, patients with cancer have higher mortality due to COVID-19 infection if they have active cancer, metastatic or progressive cancer, ECOG PS >2, and low socioeconomic status. IMPLICATIONS FOR PRACTICE: This study's findings raise the need to carefully evaluate patients with metastatic cancer, in progression, and with impaired Eastern Cooperative Oncology Group status to define the relevance of cancer treatment during the pandemic, consider the risk/benefit of the interventions, and establish clear and complete communication with the patients and their families about the risk of complications. There is also the importance of offering additional support to patients with low income and residence in rural areas so that they can have more support during cancer treatment.

Drug-induced liver injury: A management position paper from the Latin American Association for Study of the liver.

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) is an uncommon cause of liver disease presenting with a wide range of phenotypes and disease severity, acute hepatitis mimicking viral hepatitis to autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes. Disease severity ranges from asymptomatic liver test abnormalities to acute liver failure. DILI has been traditionally classified in predictable or intrinsic (dose-related) or unpredictable (not dose-related) mechanisms. Few prospective studies are assessing the real prevalence and incidence of hepatotoxicity in the general population. DILI registries represent useful networks used for the study of liver toxicity, aimed at improving the understanding of causes, phenotypes, natural history, and standardized definitions of hepatotoxicity. Although most of the registries do not carry out population-based studies, they may provide important data related to the prevalence of DILI, and also may be useful to compare features from different countries. With the support of the Spanish Registry of Hepatotoxicity, our Latin American Registry (LATINDILI) was created in 2011, and more than 350 DILI patients have been recruited to date. This position paper describes the more frequent drugs and herbs-induced DILI in Latin America, mainly focusing on several features of responsible medicaments. Also, we highlighted the most critical points on the management of hepatotoxicity in general and those based on findings from our Latin American experience in particular.

Comparison of different prognostic scores for patients with cirrhosis hospitalized with SARS-CoV-2 infection.

INTRODUCTION AND OBJECTIVES: Viral infections have been described to increase the risk of decompensation in patients with cirrhosis. We aimed to determine the effect of SARS-CoV-2 infection on outcome of hospitalized patients with cirrhosis and to compare the performance of different prognostic models for predicting mortality. PATIENTS: We performed a prospective cohort study including 2211 hospitalized patients with confirmed SARS-CoV-2 infection from April 15, 2020 through October 1, 2020 in 38 Hospitals from 11 Latin American countries. We registered clinical and laboratory parameters of patients with and without cirrhosis. All patients were followed until discharge or death. We evaluated the prognostic performance of different scoring systems to predict mortality in patients with cirrhosis using ROC curves. RESULTS: Overall, 4.6% (CI 3.7-5.6) subjects had cirrhosis (n = 96). Baseline Child-Turcotte-Pugh (CTP) class was assessed: CTP-A (23%), CTP-B (45%) and CTP-C (32%); median MELD-Na score was 19 (IQR 14-25). Mortality was 47% in patients with cirrhosis and 16% in patients without cirrhosis (P < .0001). Cirrhosis was independently associated with death [OR 3.1 (CI 1.9-4.8); P < .0001], adjusted by age, gender, and body mass index >30. The areas under the ROC curves for performance evaluation in predicting 28-days mortality for Chronic Liver Failure Consortium (CLIF-C), North American Consortium for the Study of End-Stage Liver Disease (NACSELD), CTP score and MELD-Na were 0.85, 0.75, 0.69, 0.67; respectively (P < .0001). CONCLUSIONS: SARS-CoV-2 infection is associated with elevated mortality in patients with cirrhosis. CLIF-C had better performance in predicting mortality than NACSELD, CTP and MELD-Na in patients with cirrhosis and SARS-CoV-2 infection. Clinicaltrials.gov:NCT04358380.

Prospective Latin American cohort evaluating outcomes of patients with COVID-19 and abnormal liver tests on admission.

INTRODUCTION & OBJECTIVES: The independent effect of liver biochemistries as a prognostic factor in patients with COVID-19 has not been completely addressed. We aimed to evaluate the prognostic value of abnormal liver tests on admission of hospitalized patients with COVID-19. MATERIALS & METHODS: We performed a prospective cohort study including 1611 hospitalized patients with confirmed SARS-CoV-2 infection from April 15, 2020 through July 31, 2020 in 38 different Hospitals from 11 Latin American countries. We registered clinical and laboratory parameters, including liver function tests, on admission and during hospitalization. All patients were followed until discharge or death. We fit multivariable logistic regression models, further post-estimation effect through margins and inverse probability weighting. RESULTS: Overall, 57.8% of the patients were male with a mean age of 52.3 years, 8.5% had chronic liver disease and 3.4% had cirrhosis. Abnormal liver tests on admission were present on 45.2% (CI 42.7-47.7) of the cohort (n = 726). Overall, 15.1% (CI 13.4-16.9) of patients died (n = 244). Patients with abnormal liver tests on admission presented higher mortality 18.7% (CI 15.9-21.7), compared to those with normal liver biochemistries 12.2% (CI 10.1-14.6); P < .0001). After excluding patients with history of chronic liver disease, abnormal liver tests on admission were independently associated with death [OR 1.5 (CI 1.1-2.0); P = 0.01], and severe COVID-19 (2.6 [2.0-3.3], P < .0001), both adjusted by age, gender, diabetes, pneumonia and body mass index >30. CONCLUSIONS: The presence of abnormal liver tests on admission is independently associated with mortality and severe COVID-19 in hospitalized patients with COVID-19 infection and may be used as surrogate marker of inflammation. CLINICALTRIALS.GOV: NCT04358380.

A Latin American survey on demographic aspects of hospitalized, decompensated cirrhotic patients and the resources for their management.

INTRODUCTION & OBJECTIVES: Liver cirrhosis is a major cause of mortality worldwide. Adequate diagnosis and treatment of decompensating events requires of both medical skills and updated technical resources. The objectives of this study were to search the demographic profile of hospitalized cirrhotic patients in a group of Latin American hospitals and the availability of expertise/facilities for the diagnosis and therapy of decompensation episodes. METHODS: A cross sectional, multicenter survey of hospitalized cirrhotic patients. RESULTS: 377 patients, (62% males; 58±11 years) (BMI>25, 57%; diabetes 32%) were hospitalized at 65 centers (63 urbans; 57 academically affiliated) in 13 countries on the survey date. Main admission causes were ascites, gastrointestinal bleeding, hepatic encephalopathy and spontaneous bacterial peritonitis/other infections. Most prevalent etiologies were alcohol-related (AR) (40%); non-alcoholic-steatohepatitis (NASH) (23%), hepatitis C virus infection (HCV) (7%) and autoimmune hepatitis (AIH) (6%). The most frequent concurrent etiologies were AR+NASH. Expertise and resources in every analyzed issue were highly available among participating centers, mostly accomplishing valid guidelines. However, availability of these facilities was significantly higher at institutions located in areas with population>500,000 (n=45) and in those having a higher complexity level (Gastrointestinal, Liver and Internal Medicine Departments at the same hospital (n=22). CONCLUSIONS: The epidemiological etiologic profile in hospitalized, decompensated cirrhotic patients in Latin America is similar to main contemporary emergent agents worldwide. Medical and technical resources are highly available, mostly at great population urban areas and high complexity medical centers. Main diagnostic and therapeutic approaches accomplish current guidelines recommendations.

Alcohol-related liver disease: Clinical practice guidelines by the Latin American Association for the Study of the Liver (ALEH).

Alcohol-related liver disease (ALD) is a major cause of advanced chronic liver disease in Latin-America, although data on prevalence is limited. Public health policies aimed at reducing the alarming prevalence of alcohol use disorder in Latin-America should be implemented. ALD comprises a clinical-pathological spectrum that ranges from steatosis, steatohepatitis to advanced forms such as alcoholic hepatitis (AH), cirrhosis and hepatocellular carcinoma. Besides genetic factors, the amount of alcohol consumption is the most important risk factor for the development of ALD. Continuous consumption of more than 3 standard drinks per day in men and more than 2 drinks per day in women increases the risk of developing liver disease. The pathogenesis of ALD is only partially understood and recent translational studies have identified novel therapeutic targets. Early forms of ALD are often missed and most clinical attention is focused on AH, which is defined as an abrupt onset of jaundice and liver-related complications. In patients with potential confounding factors, a transjugular biopsy is recommended. The standard therapy for AH (i.e. prednisolone) has not evolved in the last decades yet promising new therapies (i.e. G-CSF, N-acetylcysteine) have been recently proposed. In both patients with early and severe ALD, prolonged abstinence is the most efficient therapeutic measure to decrease long-term morbidity and mortality. A multidisciplinary team including alcohol addiction specialists is recommended to manage patients with ALD. Liver transplantation should be considered in the management of patients with end-stage ALD that do not recover despite abstinence. In selected cases, increasing number of centers are proposing early transplantation for patients with severe AH not responding to medical therapy.

Is cognitive impairment associated with antipsychotic dose and anticholinergic equivalent loads in first-episode psychosis?

BACKGROUND: Cognitive deficits are a core feature of early stages in schizophrenia. However, the extent to which antipsychotic (AP) have a deleterious effect on cognitive performance remains under debate. We aim to investigate whether anticholinergic loadings and dose of AP drugs in first episode of psychosis (FEP) in advanced phase of remission are associated with cognitive impairment and the differences between premorbid intellectual quotient (IQ) subgroups. METHODS: Two hundred and sixty-six patients participated. The primary outcomes were cognitive dimensions, dopaminergic/anticholinergic load of AP [in chlorpromazine equivalents (Eq-CPZ) and the Anticholinergic Risk Scale (ARS), respectively]. RESULTS: Impairments in processing speed, verbal memory and global cognition were significantly associated with high Eq-CPZ and verbal impairment with high ARS score. Moreover, this effect was higher in the low IQ subgroup. CONCLUSIONS: Clinicians should be aware of the potential cognitive impairment associated with AP in advanced remission FEP, particularly in lower premorbid IQ patients.

Catheter Ablation of Atypical Atrioventricular Nodal Reentrant Tachycardia.

BACKGROUND: Because of its low prevalence, data on atypical atrioventricular nodal reentrant tachycardia (AVNRT) are scarce, and the optimal ablation method has not been established. Our study aimed at assessing the efficacy and safety of conventional slow pathway ablation, as applied for typical cases, in atypical AVNRT. METHODS: We studied 2079 patients with AVNRT subjected to slow pathway ablation. In 113 patients, mean age 48.5±18.1 years, 68 female, atypical AVNRT or coexistent atypical and typical AVNRT without other concomitant arrhythmia was diagnosed. Ablation data and outcomes were compared with a group of age- and sex-matched control patients with typical AVNRT. RESULTS: Fluoroscopy and radiofrequency current delivery times were not different in the atypical and typical groups, 20.3±12.2 versus 20.8±12.9 minutes (P=0.730) and 5.9±5.0 versus 5.5±4.5 minutes (P=0.650), respectively. Slow pathway ablation was accomplished from the right septum in 110 patients, and from the left septum in 3 patients, in the atypical group. There was no need for additional ablation lesions at other anatomic sites, and no cases of atrioventricular block were encountered. Recurrence rates of the arrhythmia were 5.6% in the atypical (6/108 patients) and 1.8% in the typical (2/111 patients) groups in the next 3 months following ablation (P=0.167). CONCLUSIONS: Conventional ablation at the anatomic area of the slow pathway is the therapy of choice for symptomatic AVNRT, regardless of whether the typical or atypical form is present.

Expert consensus: Profiling and management of advanced or metastatic epithelial ovarian cancer / Consenso de expertos basado en la evidencia: perfilamiento y manejo del carcinoma epitelial de ovario de alto grado avanzado.

Introduction and objective: The approach to patients with advanced or metastatic high-grade epithelial ovarian cancer (EOC) has evolved over time with the advent of new therapies and multimodal strategies. The objective of this consensus of experts is to generate national recommendations for the profiling and management of advanced or metastatic high-grade OEC, defined as stages III and IV of the "The International Federation of Gynecology and Obstetrics (FIGO) classification at the time of diagnosis to base on the literature review that included international evidence-based clinical practice guidelines (CPG). Material and methods: Eleven panelists (oncologists and gynecological oncologists) answered 8 questions about the profiling and management of advanced or metastatic ovarian epithelial carcinoma. The panelists were chosen for their academic profile and influence in national health institutions. Guidelines from the "ESMO Standardized Operating Procedures Consensus Conference" were used to develop the consensus. It was agreed that the level of agreement to accept a recommendation should be ≥ 80%. The document was peer reviewed. Results: Eight general recommendations are made, which are presented into five domains. Some of these recommendations are subdivided into specific recommendations. Initial treatment Recommendation 1.1 Complete primary cytoreduction (PCS) surgery is suggested as the initial therapy of choice for patients with high-grade or metastatic EOC, which should ideally be carried out in centers with experience, followed by adjuvant therapy. 1.2 Neoadjuvant chemotherapy followed by interval cytoreduction surgery (ICS) is suggested in those who are unlikely to achieve a complete cytoreduction in PCS either due to unresectable metastatic disease or who present unresectability criteria (imaging, laparoscopic and/or by laparotomy) and that have been defined by a gynecological oncologist and patients with poor functional status and comorbidities according to the criteria of the multidisciplinary team (clinical oncology, gynecological oncology, radiology, etc.). Recommendation 2. In patients with high-grade epithelial ovarian cancer (EOC), in stage III locally advanced or metastatic, who received neoadjuvant chemotherapy and achieved a complete or partial response (cytoreduction with tumor residue < 2.5 mm), the use of Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) could be considered as an alternative to standard platinum-based adjuvant intravenous chemotherapy during interval cytoreductive surgery, after discussion in a multidisciplinary tumor board, at a center experienced in treating this type of patients. Use of genetic testing. Recommendation 3. It is suggested at the time of diagnosis to offer molecular genetic testing to all patients with high-grade advanced or metastatic EOC regardless of family history. Recommendation 4. It is suggested to offer genetic counseling, by qualified personnel, to all patients with high-grade advanced or metastatic EOC who are ordered genetic testing. Recommendation 5. It is suggested that all patients with advanced or metastatic high-grade EOC undergo a germ panel that includes the Breast Cancer Susceptibility Genes 1/2 genes (BRCA 1/2) and the other susceptibility genes according to with institutional protocols and the availability of genetic testing panels; If it is negative, then somatic testing should be performed that includes the homologous recombination deficiency (HRD) status, regardless of family history. Adjuvant Therapy Recommendation 6. 6.1. It is suggested that all patients with advanced stage III/IV EOC, with PSC of (0-2), got adjuvant intravenous chemotherapy as standard treatment within six weeks after Prc. It is suggested paclitaxel/carboplatin. Recommendation 6.2. It is suggested to use standard chemotherapy base on platinum plus Bevacizumab as adjuvant chemotherapy to patients with high-risk disease (EOC stage IV or stage III with suboptimal tumor cytoreduction), following by bevacizumab as maintenance. The use of bevacizumab as maintenance therapy is not recommended if bevacizumab was not included in the first line of treatment. We suggested the dose used in GOG-0218 and ICON7 trials. Recommendation 6.3 It is suggested combined intravenous/intraperitoneal chemotherapy only for selected patients, with optimal cytoreduction (residual lesions < 1 cm), especially those without residual disease (R0) and who are evaluated in a multidisciplinary meeting. It is not considered standard treatment. Recommendation 6.4. 6.4.1 It is suggested to use Poly ADP ribose polymerase (PARP) inhibitors such as olaparib or niraparib as maintenance after receiving first-line chemotherapy in patients with stage III/IV BRCA1/2 positive EOC who received platinumbased chemotherapy and obtained complete response/partial response (CR/PR), 6.4.2 It is suggested to use olaparib alone or in combination with bevacizumab or niraparib in patients with stage III/IV BRCA1/2 positive EOC who received platinum-based chemotherapy plus bevacizumab and achieved CR/PR. 6.4.3 It is suggested to use niraparibin patients with stage III/IV BRCA1/2 negative or unknown EOC who received platinum-based chemotherapy and achieved CR/PR. 6.4.4 It is suggested to use bevacizumab or olaparib plus bevacizumab in patients with EOC stage III/IV BRCA1/2 negative or unknown (HRD positive) who received platinum-based chemotherapy plus bevacizumab and obtained CR/PR. Treatment of disease relapse Recommendation 7. Secondary cytoreductive surgery followed by chemotherapy is suggested for selected patients with high-grade advanced EOC in first relapse, platinum-sensitive (platinum-free interval ≥ 6 months), positive "Arbeitsgemeinschaft Gynäkologische Onkologie ­ AGO" score or "I-model" positive (< 4.7) with a potential resection to R0 in centers with access to optimal surgical and postoperative support. Note: Platinum-free interval and AGO score have only been developed as positive predictors of complete resection and not to exclude patients from surgery. Recommendation 8. 8.1 For patients with relapse advanced high-grade EOC platinum-sensitive, the following is suggested: Platinum-based combination chemotherapy: carboplatin/liposomal doxorubicin or carboplatin/paclitaxel or carboplatin/nab-paclitaxel or carboplatin/docetaxel or carboplatin/gemcitabine) for six cycles. If combination therapy is not tolerated, give carboplatin or cisplatin alone. Combination chemotherapy (carboplatin/gemcitabine or carboplatin/paclitaxel or carboplatin/doxorubicin liposomal) plus bevacizumab followed by bevacizumab as maintenance (until progression or toxicity). Recommendation 8.2 For patients with relapsed advanced high-grade EOC platinum-resistant, it is suggested: Sequential treatment with chemotherapy, preferably with a non-platinum single agent (weekly paclitaxel or pegylated liposomal doxorubicin or docetaxel or oral etoposide or gemcitabine or trabectidine or, topotecan). Weekly paclitaxel or pegylated liposomal doxorubicin or topotecan could be administrate with or without bevacizumab. Other agents are considered potentially active (capecitabine, cyclophosphamide, ifosfamide, irinotecan, oxaliplatin, pemetrexed, vinorelbine, cyclophosphamide) could be recommended for later lines. Hormone receptor-positive patients who do not tolerate or have no response to cytotoxic regimens may receive hormone therapy with tamoxifen or other agents, including aromatase inhibitors (anastrozole and letrozole) or leuprolide acetate, or megestrol acetate. Patients with a performance score ≥ 3 should be considered only for best supportive care. Recommendation 8.3 Maintenance therapy with PARP inhibitors: It is suggested in patients with relapse advanced high-grade EOC stage III/IV BRCA1/2 (positive, negative or unknown) who have received two or more lines of platinum-based chemotherapy and have achieved CR/PR, use olaparib, niraparib or rucaparib. Niraparib could be useful in BRCA 1/2 +/-/unknown patients, as rucaparib, however, the latter does not yet have approval from the regulatory office in Colombia. Conclusions: It is expected that the recommendations issued in this consensus will contribute to improving clinical care, oncological impact, and quality of life of these women.

Introducción y objetivo: el abordaje de pacientes con cáncer epitelial de ovario (CEO) de alto grado avanzado o metastásico ha ido evolucionando a través del tiempo con el advenimiento de nuevas terapias y estrategias multimodales. El objetivo de este consenso de expertos es generar recomendaciones nacionales para el perfilamiento y manejo del CEO de alto grado avanzado o metastásico, definido como estadios III y IV de la clasificación de la Federación Internacional de Ginecología y Obstetricia (FIGO) al momento del diagnóstico, a partir de la revisión de la literatura que incluyó guías de práctica clínica (GPC) internacionales basadas en la evidencia. Materiales y métodos: once panelistas (oncólogos y ginecólogos oncólogos) respondieron ocho preguntas sobre el perfilamiento y manejo del carcinoma epitelial de ovario avanzado o metastásico. Los panelistas fueron escogidos por su perfil académico e influencia en instituciones de salud nacionales. Para el desarrollo del consenso se utilizaron los lineamientos de la "Conferencia de consenso de procedimientos operativos estandarizados de ESMO". Se definió que el nivel de acuerdo para aceptar una recomendación debía ser ≥ 80%. El documento fue revisado por pares. Resultados: Se hacen 8 recomendaciones generales, presentadas en cinco dominios; algunas de ellas se subdividen en recomendaciones específicas. Tratamiento inicial Recomendación 1 1.1. Como terapia inicial de elección para pacientes con CEO de alto grado o metastásico se sugiere la cirugía de citorreducción primaria (Cpr) completa que, idealmente, debe realizarse en centros con experiencia, seguida de terapia adyuvante. 1.2. Se sugiere quimioterapia neoadyuvante seguida de cirugía de citorreducción de intervalo (Cint) en quienes sea improbable alcanzar una citorreducción completa en la Cpr, bien sea por enfermedad metastásica no resecable o que presenten criterios de irresecabilidad (imagenológicos, laparoscópicos o por laparotomía) que hayan sido definidos por un ginecólogo oncólogo. También en pacientes con un pobre estado funcional y comorbilidades de acuerdo con el criterio del equipo multidisciplinario (oncología clínica, ginecología oncológica, radiología, etc.). Recomendación 2. En pacientes con CEO de alto grado, en estadio III localmente avanzado o metastásico, que recibieron quimioterapia neoadyuvante y alcanzaron respuesta completa o parcial (citorreducción con residuo tumoral < 2,5 mm), se podría evaluar el uso de la quimioterapia intraperitoneal hipertérmica (Hyperthermic IntraPeritoneal Chemotherapy - HIPEC) como alternativa a la quimioterapia IV adyuvante estándar basada en platinos durante la Cint, previa discusión en junta multidisciplinaria, en un centro de experiencia en este tipo de pacientes. Uso de pruebas genéticas Recomendación 3. Al momento del diagnóstico, se sugiere ofrecer testeo molecular genético a toda paciente con CEO de alto grado avanzado o metastásico, independientemente de la historia familiar. Recomendación 4. Se sugiere ofrecer asesoramiento genético, por parte de personal calificado, a toda paciente con CEO de alto grado avanzado o metastásico a quien se le ordene un testeo genético. Recomendación 5. Se sugiere que a toda paciente con CEO de alto grado avanzado o metastásico se le realice panel germinal que incluya los genes de susceptibilidad al cáncer de mama 1/2 (BRCA 1/2) y los otros genes de susceptibilidad de acuerdo con los protocolos institucionales y la disponibilidad de paneles de testeo genético; si es negativo entonces se debería realizar testeo somático que incluya el estatus de deficiencia de la recombinación homóloga (homologous recombination deficiency - HRD), independientemente de la historia familiar. Terapia adyuvante Recomendación 6 6.1. Se sugiere que a toda paciente con CEO estadios III/IV avanzado o metastásico, con estatus de desempeño (performance score care - PSC) de 0-2 se le administre como tratamiento estándar quimioterapia intravenosa (IV) adyuvante dentro de las seis semanas posteriores a la Cpr. Se sugiere administrar paclitaxel/carboplatino. 6.2. Se sugiere utilizar quimioterapia estándar basada en platino más bevacizumab como adyuvancia en pacientes con enfermedad de alto riesgo (CEO estadios IV o III con citorreducción tumoral subóptima), continuando con bevacizumab como mantenimiento. No se recomienda el uso de bevacizumab como terapia de mantenimiento si no se incluyó en la primera línea de tratamiento. Se sugiere seguir los esquemas de los estudios Gynecologic Oncology Group Study (GOG-0218) e International Collaborative Ovarian Neoplasm (ICON7). 6.3. Se sugiere la quimioterapia combinada IV/intraperitoneal (IP) solo para pacientes seleccionadas, con una citorreducción óptima (lesiones residuales < 1 cm), en especial aquellas sin enfermedad residual (R0) y que sean evaluadas en junta multidisciplinaria. La quimioterapia combinada IV/IP no se considera como tratamiento estándar. 6.4. 6.4.1. Se sugiere utilizar inhibidores de poli(ADP-ribosa) polimerasa (PARP) tales como olaparib o niraparib como mantenimiento después de recibir una primera línea de quimioterapia en pacientes con CEO estadios III/IV BRCA1/2 positivo que recibieron quimioterapia basada en platino y obtuvieron respuesta completa/respuesta parcial (RC/RP). 6.4.2. Se sugiere utilizar olaparib solo o en combinación con bevacizumab o niraparib en pacientes con CEO estadios III/IV BRCA1/2 positivo que recibieron quimioterapia basada en platino más bevacizumab y obtuvieron RC/RP. 6.4.3. Se sugiere utilizar niraparib en pacientes con CEO estadio III/IV BRCA1/2 negativo o desconocido que recibieron quimioterapia basada en platino y obtuvieron RC/RP. 6.4.4. Se sugiere utilizar bevacizumab u olaparib más bevacizumab en pacientes con CEO estadios III/IV BRCA1/2 negativo o desconocido (HRD positivo) que recibieron quimioterapia basada en platino más bevacizumab y obtuvieron RC/RP. Tratamiento de la recaída de la enfermedad Recomendación 7. Se sugiere la realización de la cirugía de citorreducción secundaria (Csec), seguida de quimioterapia, a pacientes seleccionadas con CEO de alto grado avanzado o metastásico en primera recaída, platino-sensibles (intervalo libre de platinos ≥ 6 meses), puntuación Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) positiva o Integrate model (I-Model) positivo (< 4,7), y con una potencial resección a R0, en centros con acceso a soporte quirúrgico y posoperatorio óptimo. Nota: el intervalo libre de tratamiento con platinos y la puntuación AGO solo se han desarrollado como predictores positivos de resección completa y no para excluir a las pacientes de la cirugía. Recomendación 8 8.1. Para pacientes con CEO de alto grado avanzado o metastásico en recaída platino-sensibles se sugiere: Quimioterapia combinada basada en platino: carboplatino/doxorrubicina liposomal o carboplatino/paclitaxel o carboplatino/ nab-paclitaxel o carboplatino/docetaxel o carboplatino/gemcitabina, por seis ciclos. Si no se tolera la terapia combinada, dar carboplatino o cisplatino solo. Quimioterapia combinada: carboplatino/gemcitabina o carboplatino/paclitaxel o carboplatino/doxorubicina liposomal, más bevacizumab, seguida de bevacizumab como mantenimiento (hasta progresión o toxicidad). 8.2. Para pacientes con CEO de alto grado avanzado o metastásico en recaída, platino-resistentes, se sugiere: Tratamiento secuencial con quimioterapia, preferiblemente con un agente único que no sea un platino (paclitaxel semanal o doxorrubicina liposomal pegilada o docetaxel o etopósido oral o gemcitabina o trabectidina o topotecan). El paclitaxel semanal o la doxorrubicina liposomal pegilada o el topotecan pueden ser administrados con o sin bevacizumab. Existen otros agentes que se consideran potencialmente act ivos (capecitabina, ciclofosfamida, ifosfamida, irinotecán, oxaliplatino, pemetrexed, vinorelbina, ciclofosfamida), que se podrían recomendar para líneas posteriores. Las pacientes con receptores hormonales positivos que no toleran o no tienen respuesta a los regímenes citotóxicos pueden recibir terapia hormonal con tamoxifeno u otros agentes, incluidos los inhibidores de la aromatasa (anastrozol y letrozol) o acetato de leuprolide o acetato de megestrol. Pacientes con PSC ≥ 3 deberían ser consideradas solo para el mejor cuidado de soporte. 8.3. Terapia de mantenimiento con inhibidores PARP. Para pacientes con CEO de alto grado avanzado o metastásico en recaída estadios III/IV BRCA1/2 (positivo, negativo o desconocido), que hayan recibido dos o más líneas de quimioterapia basada en platino y hayan alcanzado RC/RP, se sugiere utilizar olaparib, niraparib o rucaparib. El niraparib podría ser útil en pacientes BRCA 1/2 +/-/desconocido, al igual que el rucaparib, sin embargo, este último no tiene aún aprobación del ente regulador en Colombia. Conclusiones: se espera que las recomendaciones emitidas en este consenso contribuyan a mejorar la atención clínica, el impacto oncológico y la calidad de vida de estas mujeres.

The adhesion G-protein-coupled receptor mayo/CG11318 controls midgut development in Drosophila.

Adhesion G-protein-coupled receptors (aGPCRs) form a large family of cell surface molecules with versatile tasks in organ development. Many aGPCRs still await their functional and pharmacological deorphanization. Here, we characterized the orphan aGPCR CG11318/mayo of Drosophila melanogaster and found it expressed in specific regions of the gastrointestinal canal and anal plates, epithelial specializations that control ion homeostasis. Genetic removal of mayo results in tachycardia, which is caused by hyperkalemia of the larval hemolymph. The hyperkalemic effect can be mimicked by a raise in ambient potassium concentration, while normal potassium levels in mayoKO mutants can be restored by pharmacological inhibition of potassium channels. Intriguingly, hyperkalemia and tachycardia are caused non-cell autonomously through mayo-dependent control of enterocyte proliferation in the larval midgut, which is the primary function of this aGPCR. These findings characterize the ancestral aGPCR Mayo as a homeostatic regulator of gut development.

Inflammatory blood cells and ratios at remission for psychosis relapse prediction: A three-year follow-up of a cohort of first episodes of schizophrenia.

BACKGROUND: The clinical course following a first episode of schizophrenia (FES) is often characterized by recurrent relapses, resulting in unfavorable clinical and functional outcomes. Inflammatory dysregulation has been implicated in relapse risk; however, the predictive value of inflammatory blood cells in clinically remitted patients after a FES has not been previously explored. METHODS: In this study, we closely monitored 111 patients in remission after a FES until relapse or a three-year follow-up endpoint. The participants were recruited from the multicenter 2EPS Project. Data on inflammatory blood cells and ratios were collected at baseline and at the time of relapse or after three years of follow-up. RESULTS: Monocyte counts (OR = 1.91; 95 % CI = 1.07-3.18; p = 0.009) and basophil counts (OR = 1.09; 95 % CI = 1.01-1.12; p = 0.005) at baseline were associated with an increased risk of relapse, while the platelet-lymphocyte ratio (OR = 0.98; 95 % CI = 0.97-0.99; p = 0.019) was identified as a protective factor. However, after adjusting for cannabis and tobacco use during the follow-up, only monocyte counts (OR = 1.73; 95 % CI = 1.03-2.29; p = 0.027) and basophil counts (OR = 1.08; 95 % CI = 1.01-1.14; p = 0.008) remained statistically significant. ROC curve analysis indicated that the optimal cut-off values for discriminating relapsers were 0.52 × 10^9/L (AUC: 0.66) for monocytes and 0.025 × 10^9/L (AUC: 0.75) for basophils. When considering baseline inflammatory levels, no significant differences were observed in the inflammatory biomarkers at the endpoint between relapsers and non-relapsers. CONCLUSION: This study provides evidence that higher monocyte and basophil counts measured at remission after a FES are associated with an increased risk of relapse during a three-year follow-up period.

Clinical Outcomes and Prognostic Factors of Patients With Early Malignant Melanoma in One Latin American Country: Results of the Epidemiological Registry of Malignant Melanoma in Colombia Study.

To describe the population with early malignant melanoma, we performed a cohort study on the basis of the Epidemiological Registry of Malignant Melanoma in Colombia-Asociacion Colombiana de Hematologia y Oncologia. From January 2011 until December 2021, 759 patients were included; the average age was 66 years, 57% were women, acral lentiginous histology was found in 27.8% of patients, and the median follow-up was 36.5 months. The prognostic factors for overall survival in our population are Eastern Cooperative Oncology Group 3-4 (hazard ratio [HR], 13.8), stage III (HR, 5.07), received radiotherapy (HR, 3.38), ulceration on histology (HR, 2.68), chronic sun exposure (HR, 2.3), low income (HR, 2.04), previous local surgery (HR, 0.27), and have received adjuvant treatment (HR, 0.41).

Structural covariance predictors of clinical improvement at 2-year follow-up in first-episode psychosis.

The relationship between structural brain alterations and prediction of clinical improvement in first-episode psychosis (FEP) has been scarcely studied. We investigated whether structural covariance, a well-established approach to identify abnormal patterns of volumetric correlation across distant brain regions, which allows incorporating network-level information to structural assessments, is associated with longitudinal clinical course. We assessed a sample of 74 individuals from a multicenter study. Magnetic resonance imaging scans were acquired at baseline, and clinical assessments at baseline and at a 2-year follow-up. Participants were split in two groups as a function of their clinical improvement after 2 years (i.e., ≥ < 40% reduction in psychotic symptom severity, (n = 29, n = 45)). We performed a seed-based approach and focused our analyses on 3 cortical and 4 subcortical regions of interest to identify alterations in cortical and cortico-subcortical networks. Improvers presented an increased correlation between the volumes of the right posterior cingulate cortex (PCC) and the left precentral gyrus, and between the left PCC and the left middle occipital gyrus. They also showed an increased correlation between right posterior hippocampus and left angular gyrus volumes. Our study provides a novel mean to identify structural correlates of clinical improvement in FEP, describing clinically-relevant anatomical differences in terms of large-scale brain networks, which is better aligned with prevailing neurobiological models of psychosis. The results involve brain regions considered to participate in the multisensory processing of bodily signals and the construction of bodily self-consciousness, which resonates with recent theoretical accounts in psychosis research.

Impact of vaccination against COVID-19 on patients with cancer in ACHOC-C19 study: Real world evidence from one Latin American country.

Introduction: During the pandemic, it has been recommended that vaccination against COVID-19 be a priority for patients with cancer; however, these patients were not included in the initial studies evaluating the available vaccines. Objective: To define the impact of vaccination against COVID-19 in preventing the risk of complications associated with the infection in a cohort of patients with cancer in Colombia. Methods: An analytical observational cohort study, based on national registry of patients with cancer and COVID 19 infection ACHOC-C19, was done. The data was collected from June 2021, until October 2021. Inclusion criteria were: Patients older than 18 years with cancer diagnosis and confirmed COVID-19 infection. Data from the unvaccinated and vaccinated cohorts were compared. Outcomes evaluated included all-cause mortality within 30 days of COVID-19 diagnosis, hospitalization, and need for mechanical ventilation. The estimation of the effect was made through the relative risk (RR), the absolute risk reduction (ARR) and the number needed to treat (NNT). Multivariate analysis was performed using generalized linear models. Results: 896 patients were included, of whom 470 were older than 60 years (52.4%) and 59% were women (n=530). 172 patients were recruited in the vaccinated cohort and 724 in the non-vaccinated cohort (ratio: 1 to 4.2). The cumulative incidence of clinical outcomes among the unvaccinated vs vaccinated patients were: for hospitalization 42% (95% CI: 38.7%-46.1%) vs 29%; (95% CI: 22.4%-36.5%); for invasive mechanical ventilation requirement 8.4% (n=61) vs 4.6% (n=8) and for mortality from all causes 17% (n=123) vs 4.65% (n=8). Conclusion: In our population, unvaccinated patients with cancer have an increased risk of complications for COVID -19 infection, as hospitalization, mechanical ventilation, and mortality. It is highly recommended to actively promote the vaccination among this population.

Relapse, cognitive reserve, and their relationship with cognition in first episode schizophrenia: a 3-year follow-up study.

Schizophrenia is frequently characterized by the presence of multiple relapses. Cognitive impairments are core features of schizophrenia. Cognitive reserve (CR) is the ability of the brain to compensate for damage caused by pathologies such as psychotic illness. As cognition is related to CR, the study of the relationship between relapse, cognition and CR may broaden our understanding of the course of the disease. We aimed to determine whether relapse was associated with cognitive impairment, controlling for the effects of CR. Ninety-nine patients with a remitted first episode of schizophrenia or schizophreniform disorder were administered a set of neuropsychological tests to assess premorbid IQ, attention, processing speed, working memory, verbal and visual memory, executive functions and social cognition. They were followed up for 3 years (n=53) or until they relapsed (n=46). Personal and familial CR was estimated from a principal component analysis of the premorbid information gathered. Linear mixed-effects models were applied to analyse the effect of time and relapse on cognitive function, with CR as covariate. Patients who relapsed and had higher personal CR showed less deterioration in attention, whereas those with higher CR (personal and familial CR) who did not relapse showed better performance in processing speed and visual memory. Taken together, CR seems to ameliorate the negative effects of relapse on attention performance and shows a positive effect on processing speed and visual memory in those patients who did not relapse. Our results add evidence for the protective effect of CR over the course of the illness.

In vitro leishmanicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against Leishmania infantum and Leishmania braziliensis species.

OBJECTIVES: To evaluate the in vitro leishmanicidal activity of imidazole-based (1-4) and pyrazole-based (5-6) benzo[g]phthalazine derivatives against Leishmania infantum and Leishmania braziliensis. METHODS: The in vitro activity of compounds 1-6 was assayed on extracellular promastigote and axenic amastigote forms, and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. The mechanisms of action were analysed by iron superoxide dismutase (Fe-SOD) and copper/zinc superoxide dismutase (CuZn-SOD) inhibition, metabolite excretion and transmission electronic microscopy (TEM). RESULTS: Compounds 1-6 were more active and less toxic than meglumine antimoniate. Data on infection rates and amastigote mean numbers showed that 2, 4 and 6 were more active than 1, 3 and 5 in both L. infantum and L. braziliensis. The inhibitory effect of these compounds on the antioxidant enzyme Fe-SOD of promastigote forms of the parasites was remarkable, whereas inhibition of human CuZn-SOD was negligible. The ultrastructural alterations observed in treated promastigote forms confirmed the greater cell damage caused by the most active compounds 2, 4 and 6. The modifications observed by (1)H-NMR in the nature and amounts of catabolites excreted by the parasites after treatment with 1-6 suggested that the catabolic mechanisms could depend on the structure of the side chains linked to the benzo[g]phthalazine moiety. CONCLUSIONS: All the compounds assayed were active in vitro against the two Leishmania species and were less toxic against mammalian cells than the reference drug, but the monosubstituted compounds were significantly more effective and less toxic than their disubstituted counterparts.

Peripheral Neural Sheath Breast Sarcoma: Case Report and Literature Review.

Primary sarcomas of the breast are heterogeneous neoplasms derived from the non-epithelial elements of the mammary gland. Malignant peripheral nerve sheath tumors comprise 5-10% of all malignant soft tissue sarcomas. Its heterogeneity and low incidence (1 in 100,000) limit the performance of prospective studies. Therefore, most published articles include individual reports and case series with a small number of patients, making it impossible to determine clear treatment standards in this scenario. A 36-year-old young woman with no personal history consulted the National Cancer Institute of Colombia with a 1-year progression of a rapidly growing mass in her left breast until reaching an approximate tumor size of 20 × 20 cm. Histopathological analysis with a tru-cut biopsy taken from the lesion revealed the presence of a breast sarcoma with positive staining for SOX-10 and S-100. A radical mastectomy as her first treatment included the resection of a costal arch and, therefore, the reconstruction of the chest wall with coverage of the defect with an extended latissimus dorsi flap followed by consolidation therapy with adjuvant radiotherapy (RT) and chemotherapy. Evidence regarding malignant peripheral nerve sheath sarcoma of the breast treatment corresponds to retrospective analyses and case reports with high heterogeneity and variability about strategies in surgical procedures and adjunctive therapy such as complementary chemotherapy and RT; therapeutic approach should always include a multidisciplinary team.

Nisin and Nisin Probiotic Disrupt Oral Pathogenic Biofilms and Restore Their Microbiome Composition towards Healthy Control Levels in a Peri-Implantitis Setting.

Peri-implantitis is characterized by chronic inflammation of the peri-implant supporting tissues that progressively and irreversibly leads to bone loss and, consequently, implant loss. Similar to periodontal disease, oral dysbiosis is thought to be a driver of peri-implantitis. However, managing peri-implantitis with traditional treatment methods, such as nonsurgical debridement or surgery, is not always successful. Thus, novel strategies have been proposed to address these shortcomings. One strategy is the use of probiotics as antimicrobial agents since they are considered safe for humans and the environment. Specifically, the probiotic Lactococcus lactis produces nisin, which has been used worldwide for food preservation. The objective of this study was to determine whether nisin and the wild-type (WT) nisin-producing L. lactis probiotic can disrupt oral pathogenic biofilms and promote a healthier oral microbiome within these oral biofilms on titanium discs. Using confocal imaging and 16S rRNA sequencing, this study revealed that nisin and WT L. lactis probiotic disrupt oral pathogenic biofilms in a peri-implantitis setting in vitro. More specifically, nisin decreased the viability of the pathogen-spiked biofilms dose-dependently from 62.53 ± 3.69% to 54.26 ± 3.35% and 44.88 ± 2.98%, respectively. Similarly, 105 CFU/mL of WT L. lactis significantly decreased biofilm viability to 52.45 ± 3.41%. Further, both treatments shift the composition, relative abundance, and diversity levels of these biofilms towards healthy control levels. A total of 1 µg/mL of nisin and 103 CFU/mL of WT L. lactis were able to revert the pathogen-mediated changes in the Proteobacteria (from 80.5 ± 2.9% to 75.6 ± 2.0%, 78.0 ± 2.8%, and 75.1 ± 5.3%, respectively) and Firmicutes (from 11.6 ± 1.6% to 15.4 ± 1.3%, 13.8 ± 1.8%, and 13.7 ± 2.6%, respectively) phyla back towards control levels. Thus, nisin and its nisin-producing L. lactis probiotic may be useful in treating peri-implantitis by promoting healthier oral biofilms, which may be useful for improving patient oral health.