Marcela Lagos

Screening trial of human papillomavirus for early detection of cervical cancer in Santiago, Chile

Cervical cancer mortality in Chile is four times higher than in developed countries. We compared the accuracy of human papillomavirus (HPV) DNA testing and conventional Papanicolaou (Pap) testing to detect prevalent precancerous and cancerous lesions in the routine clinical practice of the public health system. Women aged 25 years and older residing in the area covered by three primary care centers of Santiago, Chile, were invited to participate. Eligible women received both HPV DNA (Hybrid Capture 2) and Pap testing. Women positive by either test (Pap: ASCUS+, HC2: RLU/CO ≥1.0) underwent colposcopy and biopsy, as did a sample of double‐negative women with an abnormal cervix at visual inspection or with risk factors for cervical lesions. Crude and verification bias‐corrected sensitivities and specificities were estimated. In total, 8,265 women (98.8% of eligible) had complete screening results. Of these, 10.7% were HPV positive, 1.7% were Pap positive and 1.1% were positive by both tests. In all, 931 (11.3%) women were screen‐positive, of whom 94.3% attended colposcopy. Additionally, 295 control women were invited for colposcopy, of whom 78% attended. In all, 42 CIN2, 45 CIN3 and 9 cancers were identified. Verification bias‐corrected sensitivity for CIN2+ (95% confidence interval) was 92.7% (84.4–96.8) for HPV and 22.1% (16.4–29.2) for Pap; corresponding specificities were 92.0% (91.4–92.6) and 98.9% (98.7–99.0). In conclusion, in routine clinical practice in a developing country, HPV testing was four times more sensitive for CIN2+ than Pap testing, identifying three times more CIN2+ lesions; HPV testing was easily implemented in our established cervical cancer prevention program.

HPV vaginal self-sampling among women non-adherent to Papanicolaou screening in Chile

OBJECTIVE To evaluate acceptance, preference and compliance with referral of vaginal self-sampling for the detection of Human papillomavirus (HPV) among women non-adherent to Papanicolaou (Pap) screening in Santiago, Chile. MATERIALS AND METHODS Using multistage sampling we identified women aged 30-64 years who reported not receiving a Pap test in the previous three years and offered them Pap testing at the health center or vaginal self-sampling for HPV testing at home. Self-collected samples were analyzed with hybrid capture. All HPV+ women were referred for colposcopy, biopsy and treatment when needed. RESULTS 1 254 eligible women were contacted; 86.5% performed self-sampling and 8.1% refused; 124 women were HPV+ (11.4%: 95%CI 9.6-13.5) of whom 85.5% attended colposcopy; 12 had CIN2+ (1.1%: 95 %CI 0.5-1.7). CONCLUSION HPV vaginal self-sampling can be easily implemented in Chile and could improve coverage, successfully reaching women who drop out of the screening program.

Presencia de metalo-ß-lactamasas en Pseudomonas aeruginosa resistente a imipenem

Background: Metallo-s-lactamases (MBL) confer high resistance to carbapenems in Pseudomonas aeruginosa (Psae). They are encoded in mobile elements of different genes (VIM, IMP, SMP, GIM), along with other resistance genes. Aim: To detect the presence of MBL in imipenem resistant Psae strains. Material and methods: Fifty-nine imipenem resistant Psae strains isolated from January 2004 to August 2005 in a University Clinical Hospital, were included. The presence of MBL was studied by Etest (phenotypic) and genotypic polymerase chain reaction (PCR) methods. To rule out a nosocomial outbreak, MBL positive strains, were studied by pulse field gel electrophoresis. Results: The presente of MBL was detected in eleven strains. AH were type VIM and were not clonally related. There was no concordance between phenotypic and genotypic MBL detecting methods. AH the strains were also multiresistant. Conclusions: The presence of MBL was detected in 19% of imipenem resistant Psae strains

Detección precoz del cáncer cervicouterino en Chile: tiempo para el cambio

Mortality rates for cervical cancer (CC) in Chile are higher than those of developed countries and it has an unequal socioeconomic distribution. The recognition of human papilloma virus (HPV) as the causal agent of cervical cancer in the early 80s changed the prevention paradigms. Current goals are to prevent HPV infection by vaccination before the onset of sexual activity and to detect HPV infection in women older than 30 years. This article reviews CC prevention and early detection methods, discusses relevant evidence to support a change in Chile and presents an innovation proposal. A strategy of primary screening based on HPV detection followed by triage of HPV-positive women by colposcopy in primary care or by cytological or molecular reflex testing is proposed. Due to the existence in Chile of a well-organized nationwide CC prevention program, the replacement of a low-sensitivity screening test such as the Papanicolau test with a highly sensitive one such as HPV detection, could quickly improve the effectiveness of the program. The program also has a network of personnel qualified to conduct naked-eye inspections of the cervix, who could easily be trained to perform triage colposcopy. The incorporation of new prevention strategies could reduce the deaths of Chilean women and correct inequities.

Características clínicas, diagnósticas y pronosticas de pacientes con neumonía por Pneumocystis jiroveci en individuos infectados por virus de inmunodeficiencia humana e individuos inmunocomprometidos por otra etiología: comparative study of cases in HIV-infected patients and immunocompromised non-HIV-infected patients

Introduccion: Pneumocystis jiroveci puede causar neumonia en pacientes inmunocomprometidos de cualquier etiologia, pero las diferencias clinicas y pronosticas entre inmunocomprometidos por VIH y por otras causas han sido poco exploradas. Objetivo: Comparar las caracteristicas clinicas, de laboratorio y pronostico de neumonia por P. jiroveci en pacientes inmunocomprometidos por infeccion VIH versus no infectados por VIH. Metodos: Analisis retrospectivo de casos confirmados de neumonia por P. jiroveci en adultos con infeccion por VIH y no infectados, entre los anos 2005 y 2007. Resultados: Se incluyeron 28 pacientes infectados por VIH y 45 no infectados, con neumonia por P. jiroveci confirmada. La poblacion no infectada por VIH presentaba mayor edad (65 vs 36,2 anos, p < 0,01), menor duracion de sintomas previos a la consulta (7 [121] vs 14 [2-45] dias, p < 0,01), mayor requerimiento de tecnica invasora (60 vs 21%, p < 0,01) y estudio molecular (93 vs 68%, p < 0,01) para confirmacion diagnostica, mayor requerimiento de camas criticas (58 vs 25%, p < 0,01), y ventilacion mecanica (56 vs 11%, p < 0,01), con mayor mortalidad atribuible (33 vs 0%, p < 0,01). Conclusiones: La neumonia por P. jiroveci en pacientes inmunocomprometidos no infectados por VIH ofrece mas dificultades diagnosticas y presenta mayor gravedad y mortalidad que en pacientes con infeccion por VIH; por esto, es mandatario optimizar los procesos diagnostico y terapeutico en esta poblacion.BACKGROUND Although P. jiroveci pneumonia affects immunocompromised (IC) patients of any etiology, clinical features and prognostic outcomes are different depending if they are patients with HIV infection or other causes of IC. OBJECTIVES To compare clinical and laboratory features as well as outcomes of P. jiroveci pneumonia in HIV versus non-HIV patients. METHODS Retrospective review of clinical records of HIV and non-HIV patients with P. jiroveci pneumonia managed at the Hospital Clínico Universidad Católica in Santiago, Chile, between 2005 and 2007. RESULTS We included 28 HIV and 45 non-HIV patients with confirmed P. jiroveci pneumonia. The non-HIV population was older (65 vs 36,2 years, p < 0,01), had shorter duration of symptoms (7 [1-21] vs 14 [2-45] days, p < 0,01), required more invasive techniques (60 vs 21%, p < 0,01) and RT-PCR to confirm the diagnosis (93 vs 68%, p < 0,01), were more frequently treated at intensive care units (58 vs. 25%, p < 0,01) requiring artificial ventilation (56 vs 11%, p < 0,01), and had a higher attributable mortality (33% vs 0%, p < 0,01). CONCLUSIONS Our study confirmed that P. jiroveci pneumonia in non-HIV IC patients is more severe, more difficult to diagnose and has higher mortality that in HIV patients. Therefore, it is mandatory to optimize diagnostic and therapeutic strategies for this patients group.

Human papillomavirus testing in cervical cancer screening at a public health service of Santiago Chile

BACKGROUND Molecular techniques for human papillomavirus (HPV) detection have a good performance as screening tests and could be included in cervical cancer early detection programs. We conducted a population-based trial comparing HPV detection and Papanicolaou as primary screening tests, in a public health service in Santiago, Chile. AIM To describe the experience of implementing this new molecular test and present the main results of the study. MATERIAL AND METHODS Women aged 25 to 64 enrolled in three public health centers were invited to participate. In all women, samples were collected for Papanicolaou and HPV DNA testing, and naked-eye visual inspection of the cervix with acetic acid was performed. Women with any positive screening test were referred to the local area hospital for diagnostic confirmation with colposcopy and biopsy of suspicious lesions. RESULTS Screening results were obtained for 8265 women, of whom 931 (11.3%) were positive to any test. The prevalence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was 1.1%; nine women had invasive cervical cancer. Sensitivities for the detection of CIN2+ were 22.1% (95% confidence interval (CI) 16.4-29.2) for Papanicolaou and 92.7% (95% CI 84.4-96.8) for HPV testing; specificities were 98.9% (95% CI 98.7-99.0) and 92.0% (95% CI 91.4-92.6) respectively. CONCLUSION This experience showed that the implementation of a molecular test for cervical cancer screening is not a major challenge in Chile: it was well accepted by both the health team and the participants, and it may improve the effectiveness of the screening program.

Genetic testing for indeterminate thyroid cytology: review and meta-analysis

Thyroid cancer is the most frequent endocrine malignancy, and its incidence is increasing. A current limitation of cytological evaluation of thyroid nodules is that 20–25% are reported as indeterminate. Therefore, an important challenge for clinicians is to determine whether an indeterminate nodule is malignant, and should undergo surgery, or benign, and should be recommended to follow-up. The emergence of precision medicine has offered a valuable solution for this problem, with four tests currently available for the molecular diagnosis of indeterminate cytologies. However, efforts to critically analyze the quality of the accumulated evidence are scarce. This systematic review and meta-analysis is aimed to contribute to a better knowledge about the four available molecular tests, their technical characteristics, clinical performance, and ultimately to help clinicians to make better decisions to provide the best care options possible. For this purpose, we address three critical topics: (i) the proper theoretical accuracy, considering the intended clinical use of the test (rule-in vs rule-out) and the impact on clinical decisions; (ii) the quality of the evidence reported for each test (iii) and how accurate and effective have the tests proved to be after their clinical use. Together with the upcoming evidence, this work provides significant and useful information for healthcare system decision-makers to consider the use of molecular testing as a public health need, avoiding unnecessary surgical risks and costs.

[Pneumocystis jiroveci pneumonia: comparative study of cases in HIV-infected patients and immunocompromised non-HIV-infected patients].

Introduccion: Pneumocystis jiroveci puede causar neumonia en pacientes inmunocomprometidos de cualquier etiologia, pero las diferencias clinicas y pronosticas entre inmunocomprometidos por VIH y por otras causas han sido poco exploradas. Objetivo: Comparar las caracteristicas clinicas, de laboratorio y pronostico de neumonia por P. jiroveci en pacientes inmunocomprometidos por infeccion VIH versus no infectados por VIH. Metodos: Analisis retrospectivo de casos confirmados de neumonia por P. jiroveci en adultos con infeccion por VIH y no infectados, entre los anos 2005 y 2007. Resultados: Se incluyeron 28 pacientes infectados por VIH y 45 no infectados, con neumonia por P. jiroveci confirmada. La poblacion no infectada por VIH presentaba mayor edad (65 vs 36,2 anos, p < 0,01), menor duracion de sintomas previos a la consulta (7 [121] vs 14 [2-45] dias, p < 0,01), mayor requerimiento de tecnica invasora (60 vs 21%, p < 0,01) y estudio molecular (93 vs 68%, p < 0,01) para confirmacion diagnostica, mayor requerimiento de camas criticas (58 vs 25%, p < 0,01), y ventilacion mecanica (56 vs 11%, p < 0,01), con mayor mortalidad atribuible (33 vs 0%, p < 0,01). Conclusiones: La neumonia por P. jiroveci en pacientes inmunocomprometidos no infectados por VIH ofrece mas dificultades diagnosticas y presenta mayor gravedad y mortalidad que en pacientes con infeccion por VIH; por esto, es mandatario optimizar los procesos diagnostico y terapeutico en esta poblacion.BACKGROUND Although P. jiroveci pneumonia affects immunocompromised (IC) patients of any etiology, clinical features and prognostic outcomes are different depending if they are patients with HIV infection or other causes of IC. OBJECTIVES To compare clinical and laboratory features as well as outcomes of P. jiroveci pneumonia in HIV versus non-HIV patients. METHODS Retrospective review of clinical records of HIV and non-HIV patients with P. jiroveci pneumonia managed at the Hospital Clínico Universidad Católica in Santiago, Chile, between 2005 and 2007. RESULTS We included 28 HIV and 45 non-HIV patients with confirmed P. jiroveci pneumonia. The non-HIV population was older (65 vs 36,2 years, p < 0,01), had shorter duration of symptoms (7 [1-21] vs 14 [2-45] days, p < 0,01), required more invasive techniques (60 vs 21%, p < 0,01) and RT-PCR to confirm the diagnosis (93 vs 68%, p < 0,01), were more frequently treated at intensive care units (58 vs. 25%, p < 0,01) requiring artificial ventilation (56 vs 11%, p < 0,01), and had a higher attributable mortality (33% vs 0%, p < 0,01). CONCLUSIONS Our study confirmed that P. jiroveci pneumonia in non-HIV IC patients is more severe, more difficult to diagnose and has higher mortality that in HIV patients. Therefore, it is mandatory to optimize diagnostic and therapeutic strategies for this patients group.

A novel insertion in the FOXL2 gene in a Chilean patient with blepharophimosis ptosis epicanthus inversus syndrome type I

Abstract Objective: A novel insertion in the forkhead transcription factor 2 (FOXL2) was identified in a Chilean patient with blepharophimosis, ptosis, and epicanthus inversus syndrome associated with premature ovarian failure (BPES type I). A clinical and molecular characterization of a patient with BPES type I was performed. Method: We present a 16-year-old adolescent girl with surgically treated blepharophimosis, ptosis, and epicanthus inversus that was associated with delayed puberty and secondary amenorrhea at the age of 15, indicators that suggested that the patient had BPES type I. The FOXL2 gene was analyzed by sequencing its coding region. Results: The sequence analysis of the FOXL2 gene revealed a novel heterozygous mutation: an 11 bp duplication (c.901_911dup11) that was predicted to encode a truncated protein (p.Pro305Argfs*54). Conclusions: A novel out-of-frame duplication following the polyalanine domain in the FOXL2 gene was identified in a Chilean patient with BPES type I. This study characterized the molecular alterations in FOXL2 and confirmed the diagnosis, thereby providing information to allow for improved genetic counseling for the patient and her family.

Análisis de las inversiones del intrón 1 y 22 y secuenciación del gen F8 para el diagnóstico genético-molecular de hemofilia A en Chile

Background: Hemophilia A is an inherited disorder caused by alterations in factor VIII gene (F8) located on the X-chromosome, the intron 22 inversion being the most common mutation. The rest are predominantly point mutations distributed along this large gene of 26 exons. Aim: To implement a molecular diagnostic test to detect mutations in the F8 gene in Chilean patients with Hemophilia A. Material and Methods: To validate the testing methods, we analyzed samples with intron 22 and intron 1 inversion, and with point mutations previously studied, as well as one subject without Hemophilia. We also studied unrelated Chilean patients with Hemophilia A and their female relatives for carrier testing. Intron 22 and intron 1 inversions were studied by long distance polymerase chain reaction (PCR) and point mutations by sequencing the coding and promoter regions of the F8 gene. Results: The results obtained in all samples used for validation were concordant with those obtained previously. In the Chilean patients, the intron 22 inversion and point mutations previously described were observed. In 6 out of 9 patients with mild Hemophilia A we found the same mutation (Arg2159Cys) in exon 23, which has been described as prevalent in mild Hemophilia A. Conclusions: The analysis of intron 22 and intron 1 inversions, as well as of point mutations in the F8 gene will help us to confirm the diagnosis in patients with severe, moderate and mild Hemophilia A, and also it will allow us to perform carrier testing and to provide better genetic counseling.