Recombinant CD5 and CD6 Ectodomains Induce Antiparasitic and Immunomodulatory Effects in Secondary Cystic Echinococcosis.

Scavenger receptors participate in a wide range of biological functions after binding to multiple non-self or altered self-ligands. Among them, CD5 and CD6 are lymphocyte scavenger receptors known to interact with different microbial-associated molecular patterns, and the administration of the recombinant soluble ectodomains of human CD5 (rshCD5) and/or CD6 (rshCD6) has shown therapeutic/prophylactic potential in experimental models of fungal, bacterial and echinococcal infections. The latter is a zoonosis caused by the larval stage of the cestode parasite Echinococcus granulosus sensu lato, which in humans can induce secondary cystic echinococcosis (CE) after the spillage of protoscoleces contained within fertile cysts, either spontaneously or during surgical removal of primary hydatid cysts. Herein, we have analysed the mechanisms behind the significant protection observed in the mouse model of secondary CE following prophylactic administration of rshCD5 or rshCD6. Our results show that both molecules exhibit intrinsic antiparasitic activities in vitro, as well as immunomodulatory functions during early secondary CE, mainly through Th1/Th17 cytokine bias and promotion of peritoneal polyreactive antibodies. These data support the relevance of the parasite components bound by rshCD5 and rshCD6, as well as the potential of their prophylactic administration as a useful strategy to reduce secondary CE in patients.

Case Report: Mycosis fungoides as an exclusive manifestation of common variable immunodeficiency in a family with a NFKB2 gene mutation.

Background: Common variable immunodeficiency disorders (CVIDs), which are primary immunodeficiencies characterized by the failure of primary antibody production, typically present with recurrent bacterial infections, decreased antibody levels, autoimmune features, and rare atypical manifestations that can complicate diagnosis and management. Although most cases are sporadic, approximately 10% of the patients may have a family history of immunodeficiency. Genetic causes involving genes related to B-cell development and survival have been identified in only a small percentage of cases. Case presentation: We present the case of a family with two brothers who presented with mycosis fungoides as an exclusive symptom of a common variable immunodeficiency disorder (CVID). Whole-exome sequencing of the index patient revealed a pathogenic variant of the NFKB2 gene. Based on this diagnosis and re-evaluation of other family members, the father and brother were diagnosed with this rare immune and preneoplastic syndrome. All CVID-affected family members presented with mycosis fungoides as their only symptom, which is, to the best of our knowledge, the first case to be reported. Conclusion: This case highlights the importance of high-throughput sequencing techniques for the proper diagnosis and treatment of hereditary hematological disorders.

Efectividad de la crioterapia suministrada por enfermeras para lesiones preneoplásicas del cuello uterino

Introducción. El cáncer de cuello uterino es un problema de salud pública relevante en países de ingresos medios y bajos. El seguimiento de mujeres con tamización positiva y el acceso a tratamiento para neoplasia intraepitelial cervical (NIC) son retos mayores en estos países. Objetivo. Evaluar la efectividad de la crioterapia suministrada por enfermeras en casos de neoplasia intraepitelial de cérvix. Materiales y métodos. Se hizo la inspección visual directa con ácido acético y solución yodada (VIA-VILI), y se practicó colposcopia con biopsia, a mujeres entre los 25 y los 59 años, residentes en zonas de bajos ingresos de Bogotá. Profesionales de enfermería entrenados ofrecieron tratamiento inmediato con crioterapia a mujeres positivas en la inspección visual. Se les practicó colposcopia con biopsia antes del tratamiento y en un control a los 12 meses. Se evaluó la efectividad mediante tasas de curación (resultado: sin lesión) y regresión de NIC2/3 (resultado: ≤NIC1), por verificación colposcópica e histológica. Resultados. Se tamizaron 4.957 mujeres. En total, 499 fueron positivas y 472 aceptaron el tratamiento inmediato. Recibieron crioterapia por enfermería 365 mujeres (11 NIC2/3). La tasa de curación fue del 72 % (IC95%: 39-94 %) por verificación colposcópica, y del 40 % (IC95%: 22-85 %) por histología. Las tasas de regresión fueron del 100 y el 60 %, respectivamente. Se reportaron dos eventos adversos no graves relacionados. Conclusiones. Las tasas de curación y regresión por verificación colposcópica son similares a las reportadas con crioterapia administrada por médicos. El tamaño de la muestra con NIC2/3 dificulta la comparación por tipo de verificación. Los hallazgos apoyan la implementación de estrategias de "ver y tratar" por parte de enfermería en poblaciones con acceso limitado a servicios de salud.

Introduction. Cervical cancer is a relevant public health problem for low- and middleincome countries. Follow-up of positive-screened women and compliance with treatment of precancerous lesions are major challenges for these settings. Objective. To evaluate the efficacy of cryotherapy delivered by nurses for cervical intraepithelial neoplasia (CIN). Materials and methods. Direct visual inspection with acetic acid and lugol iodine (VIA- VILI), and colposcopy/biopsy were performed on women 25 to 59 years old, residents of low-income areas in Bogotá, Colombia. Trained nurses offered immediate cryotherapy to every woman with positive visual inspection. Colposcopy/biopsy was performed before treatment and at a 12-month follow-up. The effectiveness was measured as cure (outcome: no-lesion) and regression (outcome: CIN1) rates of CIN2/3 using colposcopic and histological verification. Results. A group of 4.957 women with VIA/VILI was valuated. In total, 499 were screen positive and 472 accepted immediate treatment. A total of 365 women (11 CIN2/3) received cryotherapy by nurses. Cure rate was 72% (95%CI: 39%-94%) and 40% (95%CI: 22%- 85%) by colposcopic and histological verification, respectively. Regression rates were 100% and 60%. There were two related non-serious adverse events. Conclusions. Cure and regression rates by colposcopic verification are like those reported for cryotherapy delivered by doctors. The sample size (CIN2/3) hinders comparisons by type of verification. Our findings support the implementation of screen-and-treat algorithms by nurses among populations with limited access to health services.

Effectiveness of cryotherapy delivered by nurses for treatment of cervical preneoplasic lesions / Efectividad de la crioterapia suministrada por enfermeras para lesiones preneoplásicas del cuello uterino.

Introduction. Cervical cancer is a relevant public health problem for low- and middleincome countries. Follow-up of positive-screened women and compliance with treatment of precancerous lesions are major challenges for these settings. Objective. To evaluate the efficacy of cryotherapy delivered by nurses for cervical intraepithelial neoplasia (CIN). Materials and methods. Direct visual inspection with acetic acid and lugol iodine (VIAVILI), and colposcopy/biopsy were performed on women 25 to 59 years old, residents of low-income areas in Bogotá, Colombia. Trained nurses offered immediate cryotherapy to every woman with positive visual inspection. Colposcopy/biopsy was performed before treatment and at a 12-month follow-up. The effectiveness was measured as cure (outcome: no-lesion) and regression (outcome: CIN1) rates of CIN2/3 using colposcopic and histological verification. Results. A group of 4.957 women with VIA/VILI was valuated. In total, 499 were screen positive and 472 accepted immediate treatment. A total of 365 women (11 CIN2/3) received cryotherapy by nurses. Cure rate was 72% (95%CI: 39%-94%) and 40% (95%CI: 22%-85%) by colposcopic and histological verification, respectively. Regression rates were 100% and 60%. There were two related non-serious adverse events. Conclusions. Cure and regression rates by colposcopic verification are like those reported for cryotherapy delivered by doctors. The sample size (CIN2/3) hinders comparisons by type of verification. Our findings support the implementation of screen-and-treat algorithms by nurses among populations with limited access to health services.

Introducción. El cáncer de cuello uterino es un problema de salud pública relevante en países de ingresos medios y bajos. El seguimiento de mujeres con tamización positiva y el acceso a tratamiento para neoplasia intraepitelial cervical (NIC) son retos mayores en estos países. Objetivo. Evaluar la efectividad de la crioterapia suministrada por enfermeras en casos de neoplasia intraepitelial de cérvix. Materiales y métodos. Se hizo la inspección visual directa con ácido acético y solución yodada (VIA-VILI), y se practicó colposcopia con biopsia, a mujeres entre los 25 y los 59 años, residentes en zonas de bajos ingresos de Bogotá. Profesionales de enfermería entrenados ofrecieron tratamiento inmediato con crioterapia a mujeres positivas en la inspección visual. Se les practicó colposcopia con biopsia antes del tratamiento y en un control a los 12 meses. Se evaluó la efectividad mediante tasas de curación (resultado: sin lesión) y regresión de NIC2/3 (resultado: ≤NIC1), por verificación colposcópica e histológica. Resultados. Se tamizaron 4.957 mujeres. En total, 499 fueron positivas y 472 aceptaron el tratamiento inmediato. Recibieron crioterapia por enfermería 365 mujeres (11 NIC2/3). La tasa de curación fue del 72 % (IC95%: 39-94 %) por verificación colposcópica, y del 40 % (IC95%: 22-85 %) por histología. Las tasas de regresión fueron del 100 y el 60 %, respectivamente. Se reportaron dos eventos adversos no graves relacionados.Conclusiones. Las tasas de curación y regresión por verificación colposcópica son similares a las reportadas con crioterapia administrada por médicos. El tamaño de la muestra con NIC2/3 dificulta la comparación por tipo de verificación. Los hallazgos apoyan la implementación de estrategias de "ver y tratar" por parte de enfermería en poblaciones con acceso limitado a servicios de salud.

Tumor de músculo liso uterino de potencial maligno incierto (STUMP): reporte de caso y revisión de la literatura / Uterine smooth muscle tumor of uncertain malignant potential (STUMP): case report and literature review

Myometrial smooth muscle neoplasms are the most common gynecologic tumors with a prevalence of 70-80% at age 50. Among women undergoing hysterectomy or myomectomy for a suspected diagnosis of leiomyoma, 0.01% receive a diagnosis of STUMP. Clinically, the average age of presentation is between 41-48 years. Tumors ranging from 3 to 30 cm have been described. Signs and symptoms are similar to leiomyomas, such as abnormal uterine bleeding, anemia, dysmenorrhea, pelvic pain, pelvic mass, infertility or other types of pain secondary to compression of adjacent organs. Due to the limited literature available, there is no definite management consensus, and treatment and follow-up options are limited to observational studies. The standard treatment is total hysterectomy with or without bilateral salpingo-oophorectomy; if fertility has already been completed, there is no role for adjuvant hormonal therapy or chemotherapy. The overall 5-year survival is 92-100%. A case of a 31-year-old woman with STUMP is presented.

Unraveling post-translational modifications in Echinococcus granulosus sensu lato.

Echinococcus granulosus sensu lato (s.l.) is the helminth parasite responsible for cystic echinococcosis, a neglected tropical disease currently affecting millions of people worldwide. Incomplete knowledge on the parasite biochemistry contributes, at least partially, to the limited development of useful biotechnological advances for the infection control. In this sense, little information is available regarding post-translational modifications (PTMs) occurring in E. granulosus s.l. proteins, which ultimately may affect the performance of biotechnological products to be developed. Therefore, we report here a proteomic analysis of the parasite PTMs identified through FindMod software applied to a set of tegumental proteins previously characterized by mass spectrometry (MALDI-TOF/TOF) analysis of protein spots from a 2D electrophoresis gel. Manual searches for already annotated proteins exhibiting such PTMs were also performed within proteome databases of E. granulosus s.l. and other platyhelminthes. In addition, key enzymes involved in PTMs modifications were searched for within E. granulosus s.l. proteome. Finally, the presence of selected PTMs was further confirmed by a high-resolution proteomic approach (nanoLC-MS/MS). A set of 22 different PTMs most likely to be present in the parasite was suggested, 9 of them with high confidence as they were identified in the same m/z fragment by both proteomic techniques (acetylation, deamidation, deamidation followed by methylation, mono- and di-hydroxylation, mono- and di-methylation, S-nitrosylation and phosphorylation). Interestingly, 5 PTMs were herein identified for the first time in E. granulosus s.l. proteins. Our results expand the scarcely studied topic of PTMs in platyhelminthes.

Melatonin Levels in Children with Obesity Are Associated with Metabolic Risk and Inflammatory Parameters.

Melatonin, the hormone of circadian rhythm regulation, is involved in the modulation of mitochondrial activity through its antioxidant and anti-inflammatory properties. Alteration of circadian rhythms such as sleep is related to obesity and metabolic pathogenesis in adulthood, but studies during childhood are scarce. The present study investigated the association of melatonin with metabolic and inflammatory markers in children with (n = 113) and without obesity (n = 117). Melatonin was measured in saliva four and two hours before bedtime, and after one hour of sleep. Cardiometabolic factors, high sensitivity C-reactive protein, immune markers (monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, tumor necrosis α and interferon-γ), leptin and ghrelin were determined. Sleep duration was recorded by a questionnaire. The melatonin level at 1 h after sleep was found to be increased more than twofold in children with obesity (90.16 (57.16-129.16) pg/mL) compared to controls (29.82 (19.05-61.54) pg/mL, p < 0.001) and was related to fat mass (rho = 0.294, p < 0.001); melatonin levels at 1 h after sleep were inversely correlated with high-density lipoprotein cholesterol. Positive correlation was found with apolipoprotein B, adipokines, high sensitivity C-reactive protein, plasminogen activator inhibitor-1 and tumor necrosis factor-α. Shorter sleep duration and earlier waking times were recorded in children with obesity. In conclusion, melatonin in children with obesity appears to be involved in the global metabolic and inflammatory alteration of this condition.

Ultrastructural characterization of the tegument in protoscoleces of Echinococcus ortleppi.

Cystic echinococcosis is a globally distributed zoonosis caused by cestodes of the Echinococcus granulosus sensu lato (s.l.) complex, with Echinococcus ortleppi mainly involved in cattle infection. Protoscoleces show high developmental plasticity, being able to differentiate into either adult worms or metacestodes within definitive or intermediate hosts, respectively. Their outermost cellular layer is called the tegument, which is important in determining the infection outcome through its immunomodulating activities. Herein, we report an in-depth characterization of the tegument of E. ortleppi protoscoleces performed through a combination of scanning and transmission electron microscopy techniques. Using electron tomography, a three-dimensional reconstruction of the tegumental cellular territories was obtained, revealing a novel structure termed the 'tegumental vesicular body' (TVB). Vesicle-like structures, possibly involved in endocytic/exocytic routes, were found within the TVB as well as in the parasite glycocalyx, distal cytoplasm and close inner structures. Furthermore, parasite antigens (GST-1 and AgB) were unevenly localised within tegumental structures, with both being detected in vesicles found within the TBV. Finally, the presence of host (bovine) IgG was also assessed, suggesting a possible endocytic route in protoscoleces. Our data forms the basis for a better understanding of E. ortleppi and E. granulosus s.l. structural biology.

Vitamin D receptor gene ApaI and FokI polymorphisms and its association with inflammation and oxidative stress in vitamin D sufficient Caucasian Spanish children.

BACKGROUND: Vitamin D has gone from being just one vitamin to being an important prohormone with multiple effects on different tissue types. The mechanism of action of the active form or calcitriol is mediated by the intracellular vitamin D receptor (VDR). The interaction of the VDR with calcitriol modulates the expression of target genes involved in cell proliferation and cytokine production. Several studies have explored the effects of vitamin D deficiency in inflammatory disorders. Furthermore, some mutations in the VDR can affect its functionality. The focus of this study was to explore associations between VDR single nucleotide polymorphisms (SNPs) and markers of inflammation and oxidative stress in vitamin D sufficient children. METHODS: This is a cross-sectional study of a Caucasian Spanish population including 155 healthy children (87 males, 68 females) aged 10 to 14 years. FokI, ApaI and TaqI SNPs of the VDR gene were genotyped. Routine biochemistry, serum levels of interleukin-6, tumor necrosis factor-α, interferon-γ, 8-isoprostaglandin F2α and nitrates were determined. RESULTS: The homozygous major allele AA in the FokI SNP was associated with increased levels of high-density lipoprotein cholesterol in a recessive inheritance mode (P=0.025). The minor allele A of ApaI was significantly associated with decreased serum tumor necrosis factor-α and 8-isoprostaglandin F2α in an additive mode (P=0.016 and P=0.020 respectively). No significant associations were observed between the TaqI SNP and any of the parameters evaluated. Haplotype analysis confirmed the significance of the relationships between ApaI and FokI SNPs and parameters associated with inflammation and oxidative stress. CONCLUSIONS: Genetic variations of VDR are associated with subtle changes in metabolic, inflammatory and oxidative stress markers. These results may provide a better understanding of the relationships between vitamin D and these clinical parameters.

Polyreactive antibodies as potential humoral biomarkers of host resistance to cystic echinococcosis.

Polyreactive antibodies (pAb) bind to a broad range of unrelated structures, providing hosts with functional components able to rapidly recognize and protect against different pathogens. However, their roles against helminth parasites are still unexplored. Here, pAb profiles were analysed in cystic echinococcosis (CE), a zoonosis caused by the cestode Echinococcus granulosus sensu lato. Levels of anti-DNP (2,4-dinitrophenyl-hapten) antibodies were measured as a surrogate parameter of pAb in different biological settings. Firstly, levels of serum and peritoneal pAb were measured during early experimental secondary CE, using both high (Balb/c) and low (C57Bl/6) susceptible mouse strains. Serum pAb mostly differed in normal mice, being pAb levels of IgG subclasses with poor anti-parasite activities predominant in Balb/c animals. Conversely, peritoneal pAb isotypes/subclasses with efficient anti-parasite activities predominated in normal and infected C57Bl/6 mice. Secondly, sera from potentially resistant patients, susceptible individuals and healthy donors were analysed, showing higher pAb levels of the IgA and IgG-particularly IgG1-isotypes in potentially resistant individuals compared to control groups. Finally, since remarkable differences were observed in pAb profiles according to the intrinsic host susceptibility to the infection, we proposed here that pAb might be considered as potential humoral biomarkers for host resistance to CE.

The Lymphocytic Scavenger Receptor CD5 Shows Therapeutic Potential in Mouse Models of Fungal Infection.

Invasive fungal diseases represent an unmet clinical need that could benefit from novel immunotherapeutic approaches. Host pattern recognition receptors (e.g., Toll-like receptors, C-type lectins, or scavenger receptors) that sense conserved fungal cell wall constituents may provide suitable immunotherapeutic antifungal agents. Thus, we explored the therapeutic potential of the lymphocyte class I scavenger receptor CD5, a nonredundant component of the antifungal host immune response that binds to fungal ß-glucans. Antifungal properties of the soluble ectodomain of human CD5 (shCD5) were assessed in vivo in experimental models of systemic fungal infection induced by pathogenic species (Candida albicans and Cryptococcus neoformans). In vitro mechanistic studies were performed by means of fungus-spleen cell cocultures. shCD5-induced survival of lethally infected mice was dose and time dependent and concomitant with reduced fungal load and increased leukocyte infiltration in the primary target organ. Additive effects were observed in vivo after shCD5 was combined with suboptimal doses of fluconazole. Ex vivo addition of shCD5 to fungus-spleen cell cocultures increased the release of proinflammatory cytokines involved in antifungal defense (tumor necrosis factor alpha and gamma interferon) and reduced the number of viable C. albicans organisms. The results prompt further exploration of the adjunctive therapeutic potential of shCD5 in severe invasive fungal diseases.

Visual techniques for cervical cancer screening in Colombia / Técnicas visuales en la tamización del cáncer de cuello uterino

INTRODUCTION: Direct visual inspection for cervical cancer screening remains controversial, whereas colposcopy-biopsy is considered the gold standard for diagnosis of preneoplastic cervical lesions. OBJECTIVES: To determine the rates of cervical intraepithelial neoplasia grade 2 or more and of false positives for colposcopy and direct visual inspection. MATERIALS AND METHODS: Women aged 25-59 underwent direct visual inspection with acetic acid (VIA), Lugol's iodine (VIA-VILI), and colposcopy. Punch biopsies were obtained for all positive tests. Using histology as the gold standard, detection and false positive rates were compared for VIA, VIA-VILI, and colposcopy (two thresholds). Sensitivity and false positive ratios with the corresponding 95% confidence intervals were estimated. RESULTS: We included 5,011 women in the analysis and we obtained 602 biopsies. Positivity rates for colposcopy high-grade and low-grade diagnosis were 1.6% and 10.8%. Positivity rates for VIA and VIA-VILI were 7.4% and 9.9%. VIA showed a significantly lower detection rate than colposcopy with low-grade diagnosis as the threshold (SR=0.72; 95% CI 0.57-0.91), and significantly lower false positive rate (FPR=0.70; 95% CI 0.65-0.76). No differences between VIA-VILI and colposcopy low-grade threshold were observed. VIA and VIA-VILI showed significantly higher detection and false positive rates than colposcopy high-grade threshold. Sensitivity rates for visual inspection decreased with age and false positive rates increased. For all age groups, false positive rates for VIA and VIA-VILI were significantly higher than colposcopy. CONCLUSIONS: Detection rates for VIA-VILI similar to colposcopy low-grade threshold represent a chance to reduce cervical cancer mortality through see-and-treat approaches among women with limited access to health care. Lower detection rates suggest reviewing high-grade colposcopy findings as the threshold for biopsy in certain settings.

Introducción. La inspección visual directa para la tamización del cáncer cervical sigue siendo controversial, mientras que la colposcopia y la biopsia siguen considerándose como métodos de referencia para diagnosticar lesiones cervicales precancerosas. Objetivo. Determinar las tasas de detección de neoplasia intraepitelial cervical de grado 2 y de los falsos positivos en la colposcopia y la inspección visual directa. Materiales y métodos. Se seleccionaron mujeres de 25 a 59 años sometidas a citología convencional, inspección visual directa con ácido acético y disolución de Lugol y colposcopia. Se practicó biopsia en todas las pruebas positivas. Utilizando la histología como el medio de verificación de referencia, se compararon las tasas de detección y de falsos positivos de cada prueba. Se estimaron las razones de sensibilidad y de falsos positivos con los correspondientes intervalos de confianza. Resultados. Se incluyeron 5.011 mujeres. Las colposcopias positivas de alto y bajo grado correspondieron a 1,6 y 10,8 %, respectivamente. La inspección visual directa con ácido acético y solución yodada de Lugol fue positiva en 7,4 y 9,9 %, respectivamente. La inspección visual directa con ácido acético tuvo tasas de detección y falsos positivos significativamente menores que la coloscopia con umbral de bajo grado (razón de sensibilidad: 0,72; IC95% 0,57-0,91; razón de falsos positivos: 0,70; CI95% 0,65-0,76); no hubo diferencias entre la inspección visual directa con solución yodada de Lugol y la colposcopia con dicho umbral. Las tasas de detección y de falsos positivos de los dos tipos de inspección visual fueron significativamente más altas que las de la colposcopia con el umbral de alto grado. Las tasas de detección de la inspección visual disminuyeron con la edad y las de falsos positivos aumentaron. Conclusiones: Las tasas de detección similares para la inspección visual directa con ácido acético o con solución yodada de Lugol y la colposcopia con umbral de bajo grado representan una oportunidad para reducir la mortalidad por cáncer de cuello uterino cuando el acceso a los servicios de salud es limitado. Las tasas de detección más bajas para la colposcopia con umbral de alto grado sugieren la necesidad de revisar dicho umbral en ciertos entornos.

Visual techniques for cervical cancer screening in Colombia / Técnicas visuales en la tamización del cáncer de cuello uterino

Abstract Introduction: Direct visual inspection for cervical cancer screening remains controversial, whereas colposcopy-biopsy is considered the gold standard for diagnosis of preneoplastic cervical lesions. Objectives: To determine the rates of cervical intraepithelial neoplasia grade 2 or more and of false positives for colposcopy and direct visual inspection. Materials and methods: Women aged 25-59 underwent direct visual inspection with acetic acid (VIA), Lugol's iodine (VIA-VILI), and colposcopy. Punch biopsies were obtained for all positive tests. Using histology as the gold standard, detection and false positive rates were compared for VIA, VIA-VILI, and colposcopy (two thresholds). Sensitivity and false positive ratios with the corresponding 95% confidence intervals were estimated. Results: We included 5,011 women in the analysis and we obtained 602 biopsies. Positivity rates for colposcopy high-grade and low-grade diagnosis were 1.6% and 10.8%. Positivity rates for VIA and VIA-VILI were 7.4% and 9.9%. VIA showed a significantly lower detection rate than colposcopy with low-grade diagnosis as the threshold(SR=0.72; 95% CI0.57-0.91), and significantly lower false positive rate (FPR=0.70; 95% CI 0.65-0.76). No differences between VIA-VILI and colposcopy low-grade threshold were observed. VIA and VIA-VILI showed significantly higher detection and false positive rates than colposcopy high-grade threshold. Sensitivity rates for visual inspection decreased with age and false positive rates increased. For all age groups, false positive rates for VIA and VIA-VILI were significantly higher than colposcopy. Conclusions: Detection rates for VIA-VILI similar to colposcopy low-grade threshold representa chance to reduce cervical cancer mortality through see-and-treat approaches among women with limited access to health care. Lower detection rates suggest reviewing high-grade colposcopy findings as the threshold for biopsy incertain settings.

Resumen Introducción. La inspección visual directa para la tamización del cáncer cervical sigue siendo controversial, mientras que la colposcopia y la biopsia siguen considerándose como métodos de referencia para diagnosticar lesiones cervicales precancerosas. Objetivo. Determinar las tasas de detección de neoplasia intraepitelial cervical de grado 2 y de los falsos positivos en la colposcopia y la inspección visual directa. Materiales y métodos. Se seleccionaron mujeres de 25 a 59 años sometidas a citología convencional, inspección visual directa con ácido acético y disolución de Lugol y colposcopia. Se practicó biopsia en todas las pruebas positivas. Utilizando la histología como el medio de verificación de referencia, se compararon las tasas de detección y de falsos positivos de cada prueba. Se estimaron las razones de sensibilidad y de falsos positivos con los correspondientes intervalos de confianza. Resultados. Se incluyeron 5.011 mujeres. Las colposcopias positivas de alto y bajo grado correspondieron a 1,6 y 10,8 %, respectivamente. La inspección visual directa con ácido acético y solución yodada de Lugol fue positiva en 7,4 y 9,9 %, respectivamente. La inspección visual directa con ácido acético tuvo tasas de detección y falsos positivos significativamente menores que la coloscopia con umbral de bajo grado (razón de sensibilidad: 0,72; IC95% 0,57-0,91; razón de falsos positivos: 0,70; CI95% 0,65-0,76); no hubo diferencias entre la inspección visual directa con solución yodada de Lugol y la colposcopia con dicho umbral. Las tasas de detección y de falsos positivos de los dos tipos de inspección visual fueron significativamente más altas que las de la colposcopia con el umbral de alto grado. Las tasas de detección de la inspección visual disminuyeron con la edad y las de falsos positivos aumentaron. Conclusiones: Las tasas de detección similares para la inspección visual directa con ácido acético o con solución yodada de Lugol y la colposcopia con umbral de bajo grado representan una oportunidad para reducir la mortalidad por cáncer de cuello uterino cuando el acceso a los servicios de salud es limitado. Las tasas de detección más bajas para la colposcopia con umbral de alto grado sugieren la necesidad de revisar dicho umbral en ciertos entornos.

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age.

OBJECTIVE: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). METHODS: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods. RESULTS: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs. CONCLUSION: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs. CLINICAL TRIAL REGISTRATION: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.

Efficacy, immunogenicity, and safety of a 9-valent human papillomavirus vaccine in Latin American girls, boys, and young women.

BACKGROUND: A 9-valent human papillomavirus (HPV6/11/16/18/31/33/45/52/58; 9vHPV) vaccine was developed to expand coverage of the previously developed quadrivalent (HPV6/11/16/18; qHPV) vaccine. METHODS: Efficacy, immunogenicity, and safety outcomes were assessed in Latin American participants enrolled in 2 international studies of the 9vHPV vaccine, including a randomized, double-blinded, controlled with qHPV vaccine, efficacy, immunogenicity, and safety study in young women aged 16-26 years, and an immunogenicity and safety study in girls and boys aged 9-15 years. Participants (N=5312) received vaccination at Day 1, Month 2, and Month 6. Gynecological swabs were collected regularly in young women for cytological and HPV DNA testing. Serum was analyzed for HPV antibodies in all participants. Adverse events (AEs) were also monitored in all participants. RESULTS: The 9vHPV vaccine prevented HPV 31-, 33-, 45-, 52-, and 58-related high-grade cervical, vulvar, and vaginal dysplasia with 92.3% efficacy (95% confidence interval 54.4, 99.6). Anti-HPV6, 11, 16, and 18 geometric mean titers at Month 7 were similar in the 9vHPV and qHPV vaccination groups. Anti-HPV antibody responses following vaccination were higher among girls and boys than in young women. Most (>99%) 9vHPV vaccine recipients seroconverted for all 9 HPV types at Month 7. Antibody responses to the 9 HPV types persisted over 5 years. The most common AEs were injection-site related, mostly of mild to moderate intensity. CONCLUSIONS: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Latin American young women, girls, and boys. These data support 9vHPV vaccination programs in Latin America, a region with substantial cervical cancer burden.

Human papillomavirus detection in cervical neoplasia attributed to 12 high-risk human papillomavirus genotypes by region.

BACKGROUND: We estimated the proportion of cervical intraepithelial neoplasia (CIN) cases attributed to 14 HPV types, including quadrivalent (qHPV) (6/11/16/18) and 9-valent (9vHPV) (6/11/16/18/31/33/45/52/58) vaccine types, by region METHODS: Women ages 15-26 and 24-45 years from 5 regions were enrolled in qHPV vaccine clinical trials. Among 10,706 women (placebo arms), 1539 CIN1, 945 CIN2/3, and 24 adenocarcinoma in situ (AIS) cases were diagnosed by pathology panel consensus. RESULTS: Predominant HPV types were 16/51/52/56 (anogenital infection), 16/39/51/52/56 (CIN1), and 16/31/52/58 (CIN2/3). In regions with largest sample sizes, minimal regional variation was observed in 9vHPV type prevalence in CIN1 (~50%) and CIN2/3 (81-85%). Types 31/33/45/52/58 accounted for 25-30% of CIN1 in Latin America and Europe, but 14-18% in North America and Asia. Types 31/33/45/52/58 accounted for 33-38% of CIN2/3 in Latin America (younger women), Europe, and Asia, but 17-18% of CIN2/3 in Latin America (older women) and North America. Non-vaccine HPV types 35/39/51/56/59 had similar or higher prevalence than qHPV types in CIN1 and were attributed to 2-11% of CIN2/3. CONCLUSIONS: The 9vHPV vaccine could potentially prevent the majority of CIN1-3, irrespective of geographic region. Notwithstanding, non-vaccine types 35/39/51/56/59 may still be responsible for some CIN1, and to a lesser extent CIN2/3.

Attribution of 12 high-risk human papillomavirus genotypes to infection and cervical disease.

BACKGROUND: We estimated the prevalence and incidence of 14 human papillomavirus (HPV) types (6/11/16/18/31/33/35/39/45/51/52/56/58/59) in cervicovaginal swabs, and the attribution of these HPV types in cervical intraepithelial neoplasia (CIN), and adenocarcinoma in situ (AIS), using predefined algorithms that adjusted for multiple-type infected lesions. METHODS: A total of 10,656 women ages 15 to 26 years and 1,858 women ages 24 to 45 years were enrolled in the placebo arms of one of three clinical trials of a quadrivalent HPV vaccine. We estimated the cumulative incidence of persistent infection and the proportion of CIN/AIS attributable to individual carcinogenic HPV genotypes, as well as the proportion of CIN/AIS lesions potentially preventable by a prophylactic 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine. RESULTS: The cumulative incidence of persistent infection with ≥1 of the seven high-risk types included in the 9-valent vaccine was 29%, 12%, and 6% for women ages 15 to 26, 24 to 34, and 35 to 45 years, respectively. A total of 2,507 lesions were diagnosed as CIN or AIS by an expert pathology panel. After adjusting for multiple-type infected lesions, among women ages 15 to 45 years, these seven high-risk types were attributed to 43% to 55% of CIN1, 70% to 78% of CIN2, 85% to 91% of CIN3, and 95% to 100% of AIS lesions, respectively. The other tested types (HPV35/39/51/56/59) were attributed to 23% to 30% of CIN1, 7% to 14% of CIN2, 3% to 4% of CIN3, and 0% of AIS lesions, respectively. CONCLUSIONS: Approximately 85% or more of CIN3/AIS, >70% CIN2, and approximately 50% of CIN1 lesions worldwide are attributed to HPV6/11/16/18/31/33/45/52/58. IMPACT: If 9-valent HPV vaccination programs are effectively implemented, the majority of CIN2 and CIN3 lesions worldwide could be prevented, in addition to approximately one-half of CIN1.

Evaluation of the immune response to human papillomavirus types 16, 18, 31, 45 and 58 in a group of Colombian women vaccinated with the quadrivalent vaccine / Evaluación de la respuesta inmune hacia el virus del papiloma humano tipos 16, 18, 31, 45 y 58 en un grupo de mujeres colombianas que recibieron la vacuna tetravalente

Objective: To analyze whether the immune response to HPV-16, -18, -31, -45 and -58 capsids in women vaccinated with the quadrivalent vaccine induces cross-reactivity against other HPV virus-like particles (VLPs). Methods: A total of 88 women aged between 18 and 27 years attending the HPV clinic at the Instituto Nacional de Cancerología were enrolled and vaccinated against HPV. Follow-up visits were scheduled at months 7, 12, and 24. Samples were collected for cytology, HPV-DNA typing, and detection of HPV antibodies. IgG antibodies were measured by ELISA using HPV-16, -18, -31, -45, and -58 VLPs. HPV-DNA detection was done by GP5+/GP6+PCR-ELISA and HPV typing was performed by Reverse Line-Blot assay. Results: Pre-vaccination, the seroprevalence of HPV-16, -18, -31, -45, and -58 was 39%, 31.7%, 15.9%, 31.7%, and 23.2%, respectively. One month post-vaccination, the seroprevalence increased close to 100% for all types. At month 24, this response was maintained only for HPV-16 and -18. For HPV-31, -45 and -58, the seroprevalence decreased to below 50%. The prevalence of HPV DNA types 16, 18 and 58 before vaccination was little changed 1 month after vaccination. No new infections were observed at 24 months. For HPV-16 and -18 related types, no differences were observed before vaccination and at month 24. For other high-risk HPV types, the prevalence increased 18 months post-vaccination (15.5%) compared with pre-vaccination (9.8%). Conclusion: Immune response to all HPV types increased after vaccination, but this increase was maintained only for HPV-16 and -18. These results suggest a possible cross-reactivity against HPV types 31, 45 and 58, but this cross-reactivity wanes with time. © 2012 Instituto Nacional de Cancerología. Publicado por Elsevier España, S.L. Todos los derechos reservados.

Objetivo: Analizar si la respuesta inmune hacia las cápsides del VPH tipos 16, 18, 31, 45 y 58 en mujeres que recibieron la vacuna tetravalente induce reactividad cruzada hacia otros tipos virales. Métodos: Ochenta y ocho mujeres entre 18 y 27 años, asistentes al Grupo VPH del Instituto Nacional de Cancerología, recibieron la vacuna de VPH. Visitas de seguimiento en los meses 7, 12 y 24. Se tomaron muestras para prueba de Papanicolaou, tipificación de VPH y detección de anticuerpos. Los anticuerpos se detectaron por ELISA, usando VLP-VPH. La detección del ADN-VPH se realizó por Reverse Line Blot. Resultados: Prevacunación, la seroprevalencia de VPH tipos 16, 18, 31, 45 y 58 fue de 39, 31,7, 15,9, 31,7 y 23,2%, respectivamente. Al mes 7 aumentó cerca del 100% para todos los tipos. Al mes 24 esta respuesta se mantuvo para VPH tipos 16 y 18. Para VPH tipos 31, 45 y 58 disminuyó por debajo del 50%. La prevalencia de ADN-VPH tipos 16, 18 y 58 tuvo poca variación antes y un mes después de la vacunación. Al mes 24, no se observaron nuevas infecciones. Para VPH tipos 16 y 18, no se observaron diferencias antes ni al mes 24. En otros tipos de HR-VPH aumentó la prevalencia al mes 24 (15,5%), comparada con la prevacunación (9,8%). Conclusión: Se observó un aumento de la respuesta inmune a todos los tipos de VPH después de la vacunación, pero esta se mantuvo solamente para los VPH tipos 16 y 18. Los resultados sugieren una posible reactividad cruzada contra VPH tipos 31, 45 y 58. Sin embargo, esta reactividad cruzada disminuye con el tiempo.

Long-term follow-up observation of the safety, immunogenicity, and effectiveness of Gardasil™ in adult women.

BACKGROUND: Previous analyses from a randomized trial in women aged 24-45 have shown the quadrivalent HPV vaccine to be efficacious in the prevention of infection, cervical intraepithelial neoplasia (CIN) and external genital lesions (EGL) related to HPV 6/11/16/18 through 4 years. In this report we present long term follow-up data on the efficacy, safety and immunogenicity of the quadrivalent HPV vaccine in adult women. METHODS: Follow-up data are from a study being conducted in 5 sites in Colombia designed to evaluate the long-term immunogenicity, effectiveness, and safety of the qHPV vaccine in women who were vaccinated at 24 to 45 years of age (in the original vaccine group during the base study [n = 684]) or 29 to 50 years of age (in the original placebo group during the base study [n = 651]). This analysis summarizes data collected as of the year 6 post-vaccination visit relative to day 1 of the base study (median follow-up of 6.26 years) from both the original base study and the Colombian follow-up. RESULTS: There were no cases of HPV 6/11/16/18-related CIN or EGL during the extended follow-up phase in the per-protocol population. Immunogenicity persists against vaccine-related HPV types, and no evidence of HPV type replacement has been observed. No new serious adverse experiences have been reported. CONCLUSIONS: Vaccination with qHPV vaccine provides generally safe and effective protection from HPV 6-, 11-, 16-, and 18-related genital warts and cervical dysplasia through 6 years following administration to 24-45 year-old women. TRIAL REGISTRATION: Clinicaltrials.govNCT00090220.

Presencia y persistencia de variantes moleculares del ORF E6 y ORF E7 del VPH 58 en mujeres con citología normal que pertenecen a la cohorte de Bogotá, Colombia / Presence and persistence of HPV 58 molecular variations ORF E6 and ORF E7 among women with normal cytology in the Bogotá, Colombia cohort

Objetivo: Analizar la presencia y persistencia de variantes en E6/E7/VPH 58 en muestras de mujeres con infecciones prevalentes por VPH 58, con citología normal, que pertenecen a la cohorte de Bogotá, Colombia. Métodos: Se utilizaron cepillados cervicales de 34 mujeres VPH 58, con citología normal, pertenecientes a la línea de base de la cohorte, con su respectivo seguimiento. Se amplificó la región E6/E7 del VPH 58 usando los iniciadores E6F1-E7R1 y los iniciadores E7P1-E7P2. Para el análisis de las variantes se utilizó la técnica de secuencia automática directa. La secuencia referencia del VPH 58 se utilizó para comparar las secuencias obtenidas. Resultados: En 27/34 muestras se lograron detectar variantes de E6/E7 de VPH 58. En total, se detectaron cinco variantes diferentes, dos de ellas nunca antes reportadas (A169/T307/A694/G744/A761 y T307/A694/G744/A761/G763). Los análisis de eliminación mostraron que el 75% de las variantes se habían eliminado antes de los dos años de seguimiento, y todas las variantes ya se habían eliminado a los seis años de seguimiento. Conclusiones: Dos nuevas variantes se reportaron a escala mundial de gran relevancia en los ámbitos filogenético y epidemiológico.

Objective: To analyze the presence and persistence of E6/E7 HPV58 variations in women with prevalent HPV 58 infection, with normal cytology, who belong to the Bogotá, Colombia cohort. Methods: Cervical cytobrush was used on 34 HPV58 women, with normal cytology, who are part of the cohort base line; respective follow was performed. The HPV58 E67/E7 region was broadened by using E6F1-E7R1 and E7P1-E7P2 indicators. Variation analysis was carried out with automatic direct sequencing. HPV58 sequence reference was used to compare the sequences that had been obtained. Results: In 27/34 samples, E6/E7 variations of HPV58 were successfully detected. A total of five different variations were detected, two of which had never been reported before (A169/T307/A694/G744/A761 and T307/A694/G744/A761/G763). Elimination analysis revealed that 75% of variations had been eliminated within two years of follow up, and that all variation had been eliminated at the end of six years of follow up. Conclusions: Two new variations of universal phylogenetic and epidemiologic noteworthiness were reported.