Effectiveness of trichloroacetic acid versus electrocautery for the treatment of anal high-grade squamous intraepithelial lesions in persons with HIV.

PURPOSE: This study aimed to compare trichloroacetic acid (TCA) versus electrocautery (ECA) for the treatment of anal high-grade squamous intraepithelial lesions (HSIL). METHODS: This is an observational, single-center study. All subjects with HIV who had anal HSIL treated with TCA or ECA from 2010 to 2022 were included. Effectiveness was evaluated by on-treatment analysis, defining response as the resolution of HSIL and recurrence as a new diagnosis of HSILs during follow-up. A propensity score analysis was used to adjust for confounding factors. RESULTS: In total, 227 and 260 HSIL episodes were treated with ECA and TCA, respectively. Response was observed in 61.7% (95% CI: 55.3-68) of cases treated with ECA and in 73.1% (95% CI: 67.8-78.5) with TCA (p = .004). The effectiveness of TCA was higher in large and multifocal HSILs. Side effects were common with both treatments, but no serious events were described. Tolerability was good in 77.1% and 80.7% of patients treated with ECA and TCA, respectively. At 24 months, recurrent HSIL were observed in 36.3% (95% CI: 27.3-45) and 28% (95% CI: 20.2-35.8) in the ECA and TCA groups (p = .049). A nadir CD4 cell count ≤200 cells/µl was found to be a risk factor for recurrence (OR: 1.77; 95% CI: 1.12-2.78). CONCLUSIONS: In this study, treatment with TCA showed high effectiveness, low recurrence and good tolerability. Considering the benefits of TCA, it could be considered one of the first-line treatments for anal HSIL.

New insights into the characterization of the mechanism of action of hyoscine butylbromide in the human colon ex vivo.

INTRODUCTION: Hyoscine butylbromide (HBB) is one of the most used antispasmodics in clinical practice. Recent translational consensus has demonstrated a similarity between human colonic motor patterns studied ex vivo and in vivo, suggesting ex vivo can predict in vivo results. It is unclear whether the mechanism of action of antispasmodics can predict different use in clinical practice. The aim of the present study is to bridge this gap dissecting HBB's role in excitatory and inhibitory neural pathways. METHODS: 309 colon samples from 48 patients were studied in muscle bath experiments. HBB was tested on: 1-spontaneous phasic contractions (SPCs); 2-carbachol-induced contractility; electrical field stimulation (EFS)-induced selective stimulation of 3-excitatory and 4-inhibitory pathways and 5- SPCs and EFS-induced contractions enhanced by neostigmine. Atropine, AF-DX116 (M2 blocker) and DAU-5884 (M3 blocker) were used as comparators. RESULTS: In the presence of tetrodotoxin (TTX), HBB and atropine 1 µM reduced SPCs. HBB and atropine concentration-dependently reduced carbachol- and EFS-induced contractions. Inhibitory effects of DAU-5884 on EFS-induced contractions were more potent than of AF-DX116. HBB did not affect the off-response associated to neural inhibitory responses. Neostigmine enhanced both SPCs and EFS-induced contractions. In the presence of TTX and ω-conotoxin (GVIA), neostigmine still enhanced SPCs. Addition of HBB and atropine reduced these responses. CONCLUSIONS: This study demonstrates that HBB inhibits neural cholinergic contractions associated to muscarinic (mainly M3) receptors. HBB has a potential role in reducing colonic spasm induced by the release of acetylcholine from enteric motor neurons and from an atypical source including a potential non-neuronal origin.

Evaluation of the mechanism of action of paracetamol, drotaverine, and peppermint oil and their effects in combination with hyoscine butylbromide on colonic motility: human ex-vivo study.

Introduction: Drotaverine, paracetamol, and peppermint oil are often prescribed for the treatment of gastrointestinal spasm and pain. This study aimed to evaluate the effect of these drugs alone and combined with the well-known antispasmodic hyoscine butylbromide on the human colon. Methods: Colon samples were obtained from macroscopically normal regions of 68 patients undergoing surgery and studied in muscle bath. Drotaverine, paracetamol, and peppermint oil were tested alone and in combination with hyoscine butylbromide on (1) spontaneous contractility induced by isometric stretch (in the presence of 1 µM tetrodotoxin) and (2) contractility induced by 10-5 M carbachol and after (3) electrical field stimulation-induced selective stimulation of excitatory (in the presence of 1 mM Nω-nitro-L-arginine and 10 µM MRS2179) and (4) inhibitory (under non-adrenergic, non-cholinergic conditions) pathways. (5) Drotaverine alone was also tested on cAMP-dependent pathway activated by forskolin. Results: Compared with the vehicle, drotaverine and paracetamol (10-9-10-5 M) did not modify spontaneous contractions, carbachol-induced contractions, and responses attributed to selective activation of excitatory pathways. The addition of hyoscine butylbromide (10-7-10-5 M), concentration-dependently reduced myogenic contractions and carbachol- and electrical field stimulation-induced contractile responses. The association of paracetamol (10-4 M) and hyoscine butylbromide (10-7-10-5 M) was not different from hyoscine butylbromide alone (10-7-10-5 M). At higher concentrations (10-3M-3*10-3 M), paracetamol decreased myogenic and carbachol-induced contractions. The adenylate cyclase activator, forskolin, concentration-dependently reduced contractility, leading to smooth muscle relaxation. The effect of forskolin 10-7 M was concentration-dependently enhanced by drotaverine (10-6M-10-5M). Discussion: Peppermint oil reduced myogenic activity and carbachol- and electrical field stimulation-induced contractions. The association of hyoscine butylbromide and peppermint oil was synergistic since the interaction index measured with the isobologram was lower than 1. No effect was seen on the neural-mediated inhibitory responses with any of the drugs studied although peppermint oil reduced the subsequent off-contraction. Drotaverine and hyoscine butylbromide have a complementary effect on human colon motility as one stimulates the cAMP inhibitory pathway and the other inhibits the excitatory pathway. Peppermint oil is synergic with hyoscine butylbromide suggesting that a combination therapy may be more effective in treating patients. In contrast, at therapeutic concentrations, paracetamol does not modify colonic contractility, suggesting that the association of paracetamol and hyoscine butylbromide has independent analgesic and antispasmodic properties.

Intraepithelial CD15 infiltration identifies high-grade anal dysplasia in people with HIV.

Men who have sex with men (MSM) with HIV are at high risk for squamous intraepithelial lesion (SIL) and anal cancer. Identifying local immunological mechanisms involved in the development of anal dysplasia could aid treatment and diagnostics. Here, we studied 111 anal biopsies obtained from 101 MSM with HIV, who participated in an anal screening program. We first assessed multiple immune subsets by flow cytometry, in addition to histological examination, in a discovery cohort. Selected molecules were further evaluated by immunohistochemistry in a validation cohort. Pathological samples were characterized by the presence of resident memory T cells with low expression of CD103 and by changes in natural killer cell subsets, affecting residency and activation. Furthermore, potentially immunosuppressive subsets, including CD15+CD16+ mature neutrophils, gradually increased as the anal lesion progressed. Immunohistochemistry verified the association between the presence of CD15 in the epithelium and SIL diagnosis for the correlation with high-grade SIL. A complex immunological environment with imbalanced proportions of resident effectors and immune-suppressive subsets characterized pathological samples. Neutrophil infiltration, determined by CD15 staining, may represent a valuable pathological marker associated with the grade of dysplasia.

RhoA downregulation in the murine intestinal epithelium results in chronic Wnt activation and increased tumorigenesis.

Rho GTPases are molecular switches regulating multiple cellular processes. To investigate the role of RhoA in normal intestinal physiology, we used a conditional mouse model overexpressing a dominant negative RhoA mutant (RhoAT19N) in the intestinal epithelium. Although RhoA inhibition did not cause an overt phenotype, increased levels of nuclear ß-catenin were observed in the small intestinal epithelium of RhoAT19N mice, and the overexpression of multiple Wnt target genes revealed a chronic activation of Wnt signaling. Elevated Wnt signaling in RhoAT19N mice and intestinal organoids did not affect the proliferation of intestinal epithelial cells but significantly interfered with their differentiation. Importantly, 17-month-old RhoAT19N mice showed a significant increase in the number of spontaneous intestinal tumors. Altogether, our results indicate that RhoA regulates the differentiation of intestinal epithelial cells and inhibits tumor initiation, likely through the control of Wnt signaling, a key regulator of proliferation and differentiation in the intestine.

Actualización de la recomendación para la determinación de biomarcadores en el carcinoma colorrectal. Consenso Nacional de la Sociedad Española de Oncología Médica y de la Sociedad Española de Anatomía Patológica / Update of the recommendations for the determination of biomarkers in colorectal carcinoma. National Consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology

En esta actualización del consenso de la Sociedad Española de Oncología Médica (SEOM) y la Sociedad Española de Anatomía Patológica (SEAP) se revisan los avances producidos en el análisis de biomarcadores en cáncer colorrectal (CCR) avanzado, así como en los marcadores de susceptibilidad del CCR hereditario y los biomarcadores moleculares del CCR localizado. También se evalúan la información publicada recientemente sobre la determinación imprescindible de las mutaciones de KRAS, NRAS y BRAF y la conveniencia de determinar la amplificación del receptor del factor de crecimiento epidérmico 2 (HER2), la expresión de las proteínas de la vía reparadora de ADN y el estudio de las fusiones de NTRK. Desde el punto de vista anatomopatológico, se revisa la importancia de analizar la presencia de células tumorales aisladas o en pequeños grupos de menos de 5 en el frente invasivo tumoral del CCR y su valor pronóstico en el CCR. También se revisa la incorporación de tecnologías pangenómicas, como la secuenciación de nueva generación (next-generation sequencing [NGS]) y la biopsia líquida, en el manejo clínico del paciente con CCR. Todos estos aspectos se desarrollan en la presente guía que, como la anterior, permanecerá abierta a cualquier revisión necesaria en el futuro

This update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica - SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica - SEAP), reviews the advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the possible benefits of determining the amplification of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From a pathological point of view, the importance of analysing the tumour budding and poorly differentiated clusters and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide which, like the previous one, will be revised when necessary in the future

Actualización de la recomendación para la determinación de biomarcadores en el carcinoma colorrectal. Consenso Nacional de la Sociedad Española de Anatomía Patológica y de la Sociedad Española de Oncología Médica / Updated guidelines for biomarker testing in colorectal carcinoma. A National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

La publicación de este documento de consenso es una iniciativa conjunta de la Sociedad Española de Anatomía Patológica y de la Sociedad Española de Oncología Médica, quienes proponen revisar y actualizar las recomendaciones diagnósticas y terapéuticas publicadas hace 2 años para el manejo del paciente con carcinoma colorrectal y el uso de biomarcadores. Por tanto, supone una oportunidad para mejorar la eficiencia de la actividad asistencial y la utilización de recursos en estos pacientes. Este grupo de expertos recomienda determinar el estado de KRAS y NRAS en todos los pacientes con carcinoma colorrectal metastásico en los que se considere la administración de una terapia antirreceptor del factor de crecimiento epidérmico (anti-EGFR), debido a que este tipo de tratamiento solo debe utilizarse en pacientes que no tengan mutaciones en estos genes. En cambio, la determinación del estado mutacional de BRAF, EGFR, PI3K y PTEN no es necesaria para la toma de decisiones terapéuticas y, por tanto, no es necesario realizarlas de forma rutinaria (AU)

The publication of this consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), which aims to revise and update the diagnostic and treatment recommendations published two years ago on biomarker use and the management of patients with colorectal carcinoma, with the intention of improving healthcare efficiency and use of resources. This group of experts recommends testing for KRAS and NRAS status in all patients with metastatic colorectal carcinoma being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes. In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision-making and therefore does not need to be done routinely (AU)

Recomendaciones para la determinación de mutaciones de K-RAS en cáncer de colon / Guideliness for kras gene mutations testing in colorrectal cancer

Las determinaciones de mutaciones en el gen KRAS en el cáncer colorrectal en España se han venido realizando de manera sistemática en relativamente pocos centros, o bien se han realizado en un contexto de ensayo clínico. No obstante, gracias a la implementación de nuevas herramientas terapéuticas basadas en anticuerpos monoclonales frente al EGFR, el conocimiento del estado mutacional de KRAS es hoy en día un factor clave para la toma de decisiones terapéuticas debido a su valor predictivo negativo de respuesta al uso de dichos tratamientos. Este hecho ha potenciado la necesidad de la implementación de dichas determinaciones en la mayoría de los servicios de Anatomía Patológica de una manera estandarizada dentro de la práctica asistencial. Esta revisión propone una serie de recomendaciones generales con el fin de estandarizar la determinación de las mutaciones de KRAS, exponiendo los diferentes métodos técnicos disponibles, sus características y los aspectos clínicos relacionados, que serán de interés a la hora de incorporar dichas determinaciones en la rutina asistencial(AU)

Various centres in Spain systematically perform mutational status analyses of KRAS in colorectal cancer, some of which are related to various clinical trials. However, in the light of the use of anti-EGFR monoclonal antibodies in the treatment of colorectal cancer, the predictive value of KRAS has become a key factor in therapeutic decision making. Thus there is a growing necessity for the implantation of a standardized method of KRAS mutation analysis in the majority of pathology laboratories. The characteristics and associated clinical aspects of the different techniques available are reviewed and general recommendations for the standardization of KRAS mutation analysis are proposed(AU)

Tumor trofoblástico epitelioide de presentación en la posmenopausia / Epithelioid trophoblastic tumor developing in the postmenopausal period

El tumor trofoblástico epitelioide (TTE) es una neoplasia infrecuente de bajo potencial maligno derivada del trofoblasto intermedio de tipo coriónico. La mayoría de los TTE se originan durante la edad reproductiva tras un parto normal, un aborto o, raramente, una mola hidatidiforme. Presentamos el caso de una paciente de 63 años de edad, menopáusica desde los 45 años, que consulta por sangrado vaginal. Su último antecedente obstétrico fue un embarazo a término a los 33 años. Se observa una lesión bien delimitada, localizada en el endocérvix, con características histológicas de TTE. En el momento del diagnóstico presentaba valores séricos discretamente elevados de gonadotropina coriónica humana (18,7 U/ml), que tras la histerectomía retornaron a sus valores normales. Cuatro años después de la cirugía, la paciente no presenta evidencia de enfermedad. En conclusión, las lesiones trofoblásticas deben ser incluidas en el diagnóstico diferencial de los sangrados uterinos, aún en mujeres posmenopáusicas

Epithelioid trophoblastic tumor (ETT) is an uncommon neoplasm with low malignant potential derived from chorionic-type intermediate trophoblast. Most ETT arise during the reproductive years following normal pregnancy, an abortion or, rarely, a complete hydatidiform mole. We report the case of a 63-year-old woman who complained of uterine bleeding. Menopause had occurred at the age of 45 and the patient's last documented obstetric antecedent was a normal pregnancy with full-term delivery at the age of 33 years. A well-circumscribed lesion located in the endocervix with histological characteristics of ETT was detected. At diagnosis, the patient presented a mild increase of beta-human chorionic gonadotrophin (18.7 U/mL), which returned to normal levels after hysterectomy. Four years after surgery, the patient is alive with no evidence of disease. In conclusion, trophoblastic lesions should be included in the differential diagnosis of uterine bleeding in the late menopause