PD-L1 immunoexpression and molecular characterization of histological subtypes in urothelial carcinoma.

INTRODUCTION: Urothelial carcinoma (UC) has histological subtypes whose phenotype reflects their molecular diversity, behavior and response to conventional therapy. Immune checkpoint inhibitors (ICIs) have improved the management of UC by evaluation of PD-L1. In the case of PD-L1 22C3, the initiation of ICI is considered from a combined positive score (CPS) greater than 10. However, UC subtypes with absent PD-L1 22C3 expression in cases with CPS>10 may not respond to these treatments. This study aims to establish a correlation between the PD-L1 immunoexpression and molecular alterations in divergent differentiation and histological subtypes of UC (UC-s). MATERIAL AND METHODS: Twenty-six samples of UC were detected from a total of 24 patients. Two pathologists performed separately an assessment of UC-s on hematoxylin-eosin as well as PD-L1 expression. Molecular study of each case was performed by next generation sequencing (NGS). A descriptive analysis of the variables included was conducted. RESULTS: Nine cases (34.61%) showed a CPS>10, some with negative PD-L1 immunoexpression in aggressive UC-s. The molecular study revealed alterations in genes belonging to the p53/cell cycle control, RAS, and DNA repair pathways, among others. None of the alterations were exclusive to any histological subtype. DISCUSSION: Special attention should be paid to CPS>10 cases that include histological subtypes of UC with divergent expression for PD-L1 as they may not respond to treatment with ICI. We recommend examining the proportion and PD-L1 status of each subtype, especially if it has aggressive behavior.

PD-L1 immunoexpression and molecular characterization of histological subtypes in urothelial carcinoma / Inmunoexpresión de PD-L1 y caracterización molecular de subtipos histológicos de carcinoma urotelial

Introduction: Urothelial carcinoma (UC) has histological subtypes whose phenotype reflects their molecular diversity, behavior and response to conventional therapy. Immune checkpoint inhibitors (ICIs) have improved the management of UC by evaluation of PD-L1. In the case of PD-L1 22C3, the initiation of ICI is considered from a combined positive score (CPS) greater than 10. However, UC subtypes with absent PD-L1 22C3 expression in cases with CPS>10 may not respond to these treatments. This study aims to establish a correlation between the PD-L1 immunoexpression and molecular alterations in divergent differentiation and histological subtypes of UC (UC-s). Material and methods: Twenty-six samples of UC were detected from a total of 24 patients. Two pathologists performed separately an assessment of UC-s on hematoxylin–eosin as well as PD-L1 expression. Molecular study of each case was performed by next generation sequencing (NGS). A descriptive analysis of the variables included was conducted. Results: Nine cases (34.61%) showed a CPS>10, some with negative PD-L1 immunoexpression in aggressive UC-s. The molecular study revealed alterations in genes belonging to the p53/cell cycle control, RAS, and DNA repair pathways, among others. None of the alterations were exclusive to any histological subtype. Discussion: Special attention should be paid to CPS>10 cases that include histological subtypes of UC with divergent expression for PD-L1 as they may not respond to treatment with ICI. We recommend examining the proportion and PD-L1 status of each subtype, especially if it has aggressive behavior.(AU)

Introducción: El carcinoma urotelial (CU) presenta subtipos histológicos cuyo fenotipo refleja su diversidad molecular, su comportamiento y su respuesta al tratamiento. Los inhibidores de puntos de control inmunitario (ICI) han mejorado el manejo del CU mediante la evaluación de PD-L1. En el caso de PD-L1 22C3, se considera el inicio de ICI a partir de una puntuación positiva combinada (combined positive score [CPS]) mayor de 10. Sin embargo, los subtipos de CU con ausencia de expresión de PD-L1 22C3 en casos con CPS>10 podrían no responder a estos tratamientos. Este estudio pretende establecer una correlación entre la inmunoexpresión de PD-L1 y las alteraciones moleculares en áreas con diferenciación divergente y subtipos histológicos de CU (CU-s). Material y métodos: Se obtuvieron 26 muestras con CU de 24 pacientes. Dos patólogos evaluaron de manera independiente las CU-s en hematoxilina-eosina y la expresión de PD-L1. Se realizó el estudio molecular mediante Next Generation Sequencing (NGS). Se realizó un análisis descriptivo de las variables incluidas. Resultados: Nueve casos (34,61%) mostraron un CPS>10, algunos con PD-L1 negativo en los CU-s de comportamiento agresivo. El estudio molecular reveló alteraciones en genes de las vías de p53/control del ciclo celular, RAS y reparación del ADN, entre otras. Ninguna alteración fue exclusiva de algún CU-s. Discusión: Debe prestarse especial atención a los casos con CPS>10 que incluyan subtipos histológicos con expresión divergente para PD-L1, ya que podrían no responder al tratamiento con ICI. Se recomienda cuantificar la proporción y el estado de PD-L1 de cada subtipo, especialmente si es de comportamiento agresivo.(AU)

Ocular surface characterization after allogeneic stem cell transplantation: A prospective study in a referral center.

Purpose: To characterize anatomical and functional changes in the ocular surface after hematopoietic stem cell transplantation. Methods: Three groups of patients were included in the study. Group 1: patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT) (n = 26). Group 2: patients who developed chronic graft versus host disease (GvHD) after HSCT (n = 14). Group 3: healthy subjects (n = 20). A complete ophthalmological examination was undertaken in all subjects, including Schirmer's test, TBUT (break-up-time) test, Oxford scale, OSDI test, corneal tomography, and conjunctival CD8+ lymphocyte detection. Results: In Branch 1 (comparative analysis before and after HSCT in Group 1), statistically significant differences were found in the following variables: best-corrected visual acuity (BCVA) OD (P = 0.08), OSDI test (P = 0.003), TBUT OU (OD P= 0, OS P= 0.0003), Oxford test OU (OD P= 0.01, OS P= 0.0049), and CD8+ lymphocytes OU (OD P= 0.003, OS P= 0.01). In Branch 2 (comparative analysis between Group 2 and 3), the variables with statistically significant differences (P < 0.001) in OU were: BCVA, OSDI test, Schirmer's test OU, TBUT test, Oxford test, and CD8+ lymphocytes. Finally, in Branch 3 (comparative analysis between Group 1 after HSCT and Group 2), statistically significant differences (P < 0.001) were found OU: in OSDI test, Schirmer's test, and Oxford test OU; and with P < 0.005 in TBUT test OU. Conclusion: In our study, statistically significant changes were observed in the OSDI test, TBUT test, Oxford Scale, and the detection of CD8+ lymphocytes in patients who underwent HSCT. Differences were more significant in those patients who had developed GvHD after HSCT compared to those without GvHD.

Incidencia de cáncer en una cohorte de pacientes con lupus eritematoso sistémico / Rheumatology in the community of Madrid: current availability of rheumatologists and future needs using a predictive model

Objetivo. Determinar la incidencia y prevalencia del cáncer en una cohorte de pacientes con lupus eritematoso sistémico (LES) e identificar los factores de riesgo asociados. Pacientes y métodos. El estudio incluyó una cohorte dinámica de los pacientes con LES (de noviembre de 1989 a diciembre del 2006) en un centro hospitalario de tercer nivel. Se utilizó un control externo ajustado por edad y sexo a través de un registro hospitalario de tumores de la misma área sanitaria. Resultados. El estudio incluyó a 175 pacientes con LES (90% mujeres), con un tiempo en riesgo de 1370,5 pacientes-año. Catorce mujeres (8%) murieron, principalmente por eventos cardiovasculares. Ningún paciente falleció por tumor maligno. Se encontraron 35 tumores en 28 pacientes, 25 de ellos después del diagnóstico de LES, de los cuales 5 fueron malignos. La tasa de tumores benignos fue de 14,6/1000 pacientes-año (IC del 95%, 8,9–22,5) y de los tumores malignos 3,6/1000 pacientes-año (IC del 95%, 1,5 a 8,8), con una razón de momios de incidencia cruda para los tumores malignos de 3,5 (IC del 95%, 01,05 a 07,09). Sin embargo, esta significación se perdió cuando se estandarizaron las tasas. En cuanto a los factores de riesgo asociados, se encontraron diferencias en la velocidad de sedimentación globular media (HR 1,4 [1,1–1,7]), y la presencia de trombosis (HR 6,9 [1,49 a 41,2]), en especial la trombosis arterial. Conclusiones. Encontramos una tasa cruda de incidencia de cáncer casi 4 veces mayor en los pacientes con LES en comparación con la tasa esperada en nuestra área de influencia del hospital (zona oeste de Málaga) (AU)

Objective: To determine the incidence and prevalence of cancer in a cohort of patients with systemic lupus erythematosus (SLE) and identify associated risk factors. Patients and methods: The study comprised a dynamic cohort of SLE patients (November 1989 to December 2006) at a tertiary referral centre. An adjusted external control from the hospital tumour registry was used. Results: The study included 175 SLE patients (90% women), with a mean time at risk of 1370.5 patientyears. Fourteen women (8%) died, mainly from cardiovascular events. No patient died due to malignancy. We found 35 tumours in 28 patients, 25 of them after the diagnosis of SLE, of which 5 were malignant. The rate of benign tumours was 14.6/1000 patient-years (95% CI, 8.9–22.5) and of malignant tumours 3.6/1000 patient-years (95% CI, 1.5–8.8), with a crude incidence odds ratio for malignant tumours of 3.5 (95% CI, 1.5–7.9). However, this significance was lost after standardizing the rates. Concerning associated risk factors, differences were found in the mean erythrocyte sedimentation rate [HR 1.4 (1.1–1.7)], and the presence of thrombosis [HR 6.9 (1.49–41.2)], especially arterial thrombosis. Conclusions: We found a crude incidence rate of cancer that was almost four times greater in our SLE patients as compared with the expected rate in the hospital area of western Malaga (AU)

Incidence of cancer in a cohort of Spanish patients with systemic lupus erythematosus.

OBJECTIVE: To determine the incidence and prevalence of cancer in a cohort of patients with systemic lupus erythematosus (SLE) and identify associated risk factors. PATIENTS AND METHODS: The study comprised a dynamic cohort of SLE patients (November 1989 to December 2006) at a tertiary referral centre. An adjusted external control from the hospital tumour registry was used. RESULTS: The study included 175 SLE patients (90% women), with a mean time at risk of 1370.5 patient-years. Fourteen women (8%) died, mainly from cardiovascular events. No patient died due to malignancy. We found 35 tumours in 28 patients, 25 of them after the diagnosis of SLE, of which 5 were malignant. The rate of benign tumours was 14.6/1000 patient-years (95% CI, 8.9-22.5) and of malignant tumours 3.6/1000 patient-years (95% CI, 1.5-8.8), with a crude incidence odds ratio for malignant tumours of 3.5 (95% CI, 1.5-7.9). However, this significance was lost after standardizing the rates. Concerning associated risk factors, differences were found in the mean erythrocyte sedimentation rate [HR 1.4 (1.1-1.7)], and the presence of thrombosis [HR 6.9 (1.49-41.2)], especially arterial thrombosis. CONCLUSIONS: We found a crude incidence rate of cancer that was almost four times greater in our SLE patients as compared with the expected rate in the hospital area of western Malaga.

HPV Direct Flow CHIP: a new human papillomavirus genotyping method based on direct PCR from crude-cell extracts.

HPV Direct Flow CHIP is a newly developed test for identifying 18 high-risk and 18 low-risk human papillomavirus (HPV) genotypes. It is based on direct PCR from crude-cell extracts, automatic flow-through hybridization, and colorimetric detection. The aim of this study was to evaluate the performance of HPV Direct Flow CHIP in the analysis of 947 samples from routine cervical screening or the follow-up of abnormal Pap smears. The specimens were dry swab samples, liquid-based cytology samples, or formalin-fixed paraffin-embedded tissues. The genotype distribution was in agreement with known epidemiological data for the Spanish population. Three different subgroups of the samples were also tested by Linear Array (LA) HPV Genotyping Test (n=108), CLART HPV2 (n=82), or Digene Hybrid Capture 2 (HC2) HPV DNA Test (n=101). HPV positivity was 73.6% by HPV Direct Flow CHIP versus 67% by LA, 65.9% by HPV Direct Flow CHIP versus 59.8% by CLART, and 62.4% by HPV Direct Flow CHIP versus 42.6% by HC2. HPV Direct Flow CHIP showed a positive agreement of 88.6% with LA (k=0.798), 87.3% with CLART (k=0.818), and 68.2% with HC2 (k=0.618). In conclusion, HPV Direct Flow CHIP results were comparable with those of the other methods tested. Although further investigation is needed to compare the performance of this new test with a gold-standard reference method, these preliminary findings evidence the potential value of HPV Direct Flow CHIP in HPV vaccinology and epidemiology studies.