HBV continuum of care using community- and hospital-based screening interventions in Senegal: Results from the PROLIFICA programme.

Background & Aims: Strategies to implement HBV screening and treatment are critical to achieve HBV elimination but have been inadequately evaluated in sub-Saharan Africa (sSA). Methods: We assessed the feasibility of screen-and-treat interventions in 3 real-world settings (community, workplace, and hospital) in Senegal. Adult participants were screened using a rapid HBsAg point-of-care test. The proportion linked to care, the proportion who had complete clinical staging (alanine transaminase [ALT], viral load, and FibroScan®), and the proportion eligible for treatment were compared among the 3 intervention groups. Results: In 2013-2016, a total of 3,665 individuals were screened for HBsAg in the community (n = 2,153) and in workplaces (n = 1,512); 199/2,153 (9.2%) and 167/1,512 (11%) were HBsAg-positive in the community and workplaces, respectively. In the hospital setting (outpatient clinics), 638 HBsAg-positive participants were enrolled in the study. All infected participants were treatment naïve. Linkage to care was similar among community-based (69.9%), workplace-based (69.5%), and hospital-based interventions (72.6%, p = 0.617). Of HBV-infected participants successfully linked to care, full clinical staging was obtained in 47.5% (66/139), 59.5% (69/116), and 71.1% (329/463) from the community, workplaces, and hospitals, respectively (p <0.001). The proportion eligible for treatment (EASL criteria) differed among community- (9.1%), workplace- (30.4%), and hospital-based settings (17.6%, p = 0.007). Acceptability of antiviral therapy, adherence, and safety at 1 year were very good. Conclusions: HBV screen-and-treat interventions are feasible in non-hospital and hospital settings in Senegal. However, the continuum of care is suboptimal owing to limited access to full clinical staging. Improvement in access to diagnostic services is urgently needed in sSA. Lay summary: Hepatitis B infection is highly endemic in Senegal. Screening for infection can be done outside hospitals, in communities or workplaces. However, the hepatitis B continuum of care is suboptimal in Senegal and needs to be simplified to scale-up diagnosis and treatment coverage.

Female genital mutilation and noninvasive cervical abnormalities and invasive cervical cancer in Senegal, West Africa: A retrospective study.

Female genital mutilation or cutting (FGM/C) is a traditional practice that affects a significant portion of women in sub-Saharan Africa, Egypt, areas of the Middle East and some countries in Asia. While clinical and epidemiological studies have established a close association between inflammation and carcinogenesis, particularly in epithelial cancers, the relationship between FGM/C and cervical cancer is not well known. We performed a secondary analysis using combined data from six research studies conducted in and around Dakar, Senegal from 1994 to 2012. Study subjects included both asymptomatic women who presented to outpatient clinics but were screened for cervical cancer, and women with cancer symptoms who were referred for cervical cancer treatment. We used unconditional logistic regression to estimate adjusted pooled odds ratios (ORs) and 95% confidence intervals (CI) for associations between FGM/C and (1) Invasive cervical cancer (ICC) and (2) noninvasive cervical abnormalities. After adjusting for confounding, women with ICC were 2.50 times more likely to have undergone FGM/C than women without cervical abnormalities (95% CI, 1.28-4.91). Restricting to HPV-positive women increased the strength of the association (OR = 4.23; 95% CI 1.73-10.32). No significant associations between FGM/C and noninvasive cervical abnormalities were observed, except in commercial sex workers with FGM/C (OR = 2.01; 95% CI 1.19-3.40). The potential increased risk for ICC suggested by our study warrants further examination. Study results may impact cancer prevention efforts in populations where FGM/C is practiced and draw awareness to the additional health risks associated with FGM/C.

[Sesame Health Programme at Senegal: Limitations of this free healthcare model]. / Plan Sésame au Sénégal : limites de ce modèle de gratuité.

INTRODUCTION: Up until now, elderly people have experienced medical management difficulties despite the free care provided by the Sesame Health Programme. The objective of this study was to determine the costs borne by beneficiaries and/or their families and to evaluate these costs in relation to overall management. This comprehensive, cross-sectional, quantitative study was conducted from 21 February to 21 March 2011 in the Ouakam gerontology centre. METHODS: Epi Info Version 6 software was used for data analysis. The study population was composed of 203 patients with a mean age of 68 years, with 59% of women and 63% of retired subjects. The most common diseases were hypertension (52%), cataract (16%), and osteoarthritis (12%). RESULTS: The beneficiaries healthcare costs were covered by the Sesame Health Programme, apart from most of the drugs used to treat chronic diseases, which remained at the charge of patients and/or their families. The overall mean cost of monthly management of the diseases detected in elderly people was estimated to be CFA 37,700, a large share of which (65%) was supported by the patient and/or the family corresponding to the purchase of these drugs. Other dysfunctions were also observed, particularly the difficulty of targeting beneficiaries, generic stock shortages, absence of generics for the treatment of chronic diseases. CONCLUSION: Recommendations are formulated to improve implementation of the Sesame Health Programme.

A pilot study of Auron Misheil Therapy in patients with advanced cervical cancer: tumor response and its correlation with clinical benefit response, and preliminary quality of life data.

This pilot study of Auron Misheil Therapy (AMT) in women with advanced cervical cancer was an open-label, single arm study to collect initial safety, efficacy, and quality of life data. Fifteen women with stage IIIb or IVa cervical cancer were given twice daily intramuscular injections of AMT (insulin, chlorpheniramine and camomile extract) for 3 months. Objective tumor response was evaluated using CT scans and analyzing the data according to the WHO RECIST criteria. Clinical Benefit Response (CBR) was assessed using a composite score comprising Karnovsky performance status, pain intensity and body weight. Safety and tolerability parameters were monitored. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC C-30). Eight out of 15 patients were rated as clinical responders (CBR) at 12 weeks. One patient had a partial response and 11 stable disease (WHO RECIST criteria). AMT was well tolerated. An initial analysis showed improvement in quality of life (EORTC C-30). Promising response rates, early indications of improved quality of life, and no significant safety issues mean that the second, randomized phase of the trial can be initiated with a longer treatment duration. Patients with advanced cervical cancer showed positive clinical responses to Auron Misheil Therapy. The treatment was well tolerated, with indications of improved quality of life.

HIV infection as a risk factor for cervical cancer and cervical intraepithelial neoplasia in Senegal.

Cervical cancer is the second leading cause of cancer mortality in women worldwide, and the leading cause in Africa. There is uncertainty in the role of HIV infection as a risk factor for invasive and preinvasive cervical lesions, particularly in African populations. In a case-control study in Dakar, Senegal, we studied 150 women with invasive cervical cancer (ICC), 92 with cervical intraepithelial neoplasia (CIN) 2 or 3, 70 with CIN 1, and 515 control women. We used logistic regression analysis to estimate associations between HIV-1 and HIV-2 infection and the risk of cervical neoplasia. We found large increases in the risk of ICC and CIN 2-3, but not of CIN 1, associated with the presence of either HIV-1 or HIV-2 infection (odds ratios of 6.5 and 10.4 for ICC and CIN 2-3). Our analysis thus shows increases in the risk of both advanced and early cervical pathology associated with HIV infection in an African population.

The impact of HIV status and type on the clearance of human papillomavirus infection among Senegalese women.

BACKGROUND: Persistent infection with human papillomavirus (HPV) is associated with the development and progression of HPV-related disease, including cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. METHODS: We examined the impact of human immunodeficiency virus (HIV) status and type on the clearance of HPV infection among 614 Senegalese women enrolled in a longitudinal study of HPV and CIN. Women were examined every 4 months for HPV DNA. Clearance was defined as 2 consecutive negative HPV DNA test results. RESULTS: Cox proportional hazard regression with time-dependent covariates indicated that HIV-positive women were less likely to clear HPV infection (adjusted hazard ratio [HR], 0.31 [95% confidence interval {CI}, 0.21-0.45]) than HIV-negative women. Among HIV-positive women, those with CD4 cell counts <200 or from 200 to 500 cells/microL showed a 71% (adjusted HR, 0.29 [95% CI, 0.11-0.76]) and 32% (adjusted HR, 0.68 [95% CI, 0.31-1.48]) reduction in the likelihood of HPV clearance, respectively, compared with those with CD4 cell counts >500 cells/microL. HIV-2 infection was associated with an increased likelihood of HPV clearance (adjusted HR, 2.46 [95% CI, 1.17-5.16]), compared with that for HIV-1 infection. CONCLUSIONS: HIV infection reduces the likelihood of HPV clearance. Among HIV-positive women, immunosuppression, as measured by CD4 cell count, reduces the likelihood of HPV clearance, and HIV type appears to be associated with HPV clearance.

Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses.

Accumulating data indicate that tumor-infiltrating regulatory T cells (Treg) are present in human tumors and locally suppress antitumor immune cells. In this study, we found an increased Treg/CD8 ratio in human breast and cervical cancers. A similar intratumoral lymphocyte pattern was observed in a mouse model for cervical cancer (TC-1 cells). In this model, systemic Treg depletion was inefficient in controlling tumor growth. Furthermore, systemic CTL-associated antigen-4 (CTLA-4) blockade, an approach that can induce tumor immunity in other tumor models, did not result in TC-1 tumor regression but led to spontaneous development of autoimmune hepatitis. We hypothesized that continuous expression of an anti-CTLA-4 antibody localized to the tumor site could overcome Treg-mediated immunosuppression and locally activate tumor-reactive CD8+ cells, without induction of autoimmunity. To test this hypothesis, we created TC-1 cells that secrete a functional anti-CTLA-4 antibody (TC-1/alphaCTLA-4-gamma1 cells). When injected into immunocompetent mice, the growth of TC-1/alphaCTLA-4-gamma1 tumors was delayed compared with control TC-1 cells and accompanied by a reversion of the intratumoral Treg/CD8 ratio due to an increase in tumor-infiltrating IFNgamma-producing CD8+ cells. When local anti-CTLA-4 antibody production was combined with Treg inhibition, permanent TC-1 tumor regression and immunity was induced. Importantly, no signs of autoimmunity were detected in mice that received local CTLA-4 blockade alone or in combination with Treg depletion.

Promoter hypermethylation of tumor suppressor genes in urine from patients with cervical neoplasia.

We examined the feasibility of using detection of high-risk human papillomavirus (HPV) DNA in combination with the presence of aberrantly methylated genes (DAPK1, RARB, TWIST1, and CDH13) for urine-based cervical cancer screening. Urine samples from 129 Senegalese women, aged 35 years or older, 110 with (same day) biopsy-proven cervical neoplasia [cervical intraepithelial neoplasia grade 1 (CIN-1): n = 9; CIN-2-3/carcinoma in situ (CIS): n = 29; invasive cervical cancer (ICC): n = 72], and 19 without cervical neoplasia on biopsy were examined. Hypermethylation of at least one of the four genes identified 62% of ICC and 28% of CIN-2-3/CIS and was present in only 4% of CIN-1 or normal urines. High-risk HPV DNA was detected in urine in 70% of those with biopsy-proven ICC, 59% of those with CIN-2-3/CIS on biopsy, 44% of those with CIN-1 on biopsy, and only 11% of women negative for cervical neoplasia on biopsy. Urine-based detection of either high-risk HPV or hypermethylation of any of the four genes identified 84% of ICC, 64% of CIN-2-3/CIS, 44% of CIN-1, but only 19% of women negative for cervical neoplasia. The sensitivity for detection of CIN-2-3/CIS/ICC by high-risk HPV DNA or aberrant DNA methylation of four genes seems to be comparable to that of an exfoliated cervical cytology. This study shows the potential feasibility of using molecular markers detected in urine for cervical cancer screening.

Detection of aberrant methylation of four genes in plasma DNA for the detection of breast cancer.

PURPOSE: Novel approaches to breast cancer screening are necessary, especially in the developing world where mammography is not feasible. In this study, we explored the hypothesis that blood-based biomarkers have potential for biomarkers for breast cancer. PATIENTS AND METHODS: We first determined the frequency of aberrant methylation of four candidate genes (APC, GSTP1, Rassf1A, and RARbeta2) in primary breast cancer tissues from West African women with predominantly advanced cancers. We used a high-throughput DNA methylation assay (quantitative methylation-specific polymerase chain reaction) to examine plasma from 93 women with breast cancer and 76 controls for the presence of four methylated genes. Samples were randomly divided evenly into training and validation data sets. Cutoff values for gene positivity of the plasma-based assay and the gene panel were determined by receiver operating characteristic curves in the training data set and subsequently evaluated as a screening tool in the validation data set. RESULTS: Methylation of at least one gene resulted in a sensitivity of 62% and a specificity of 87%. Moreover, the assay successfully detected 33% (eight of 24) of early-stage tumors. CONCLUSION: These data suggest that epigenetic markers in plasma may be of interest for detection of breast cancer. Identification of additional breast cancer specific methylated genes with higher prevalence in early stage cancers would improve this approach.

Evaluation of adenovirus vectors containing serotype 35 fibers for vaccination.

In contrast to commonly used serotype 5-based adenovirus (Ad) vectors, Ad's containing fibers derived from B-group serotype 35 (Ad5/35) efficiently transduce human DCs ex vivo and appear to target antigen-presenting cells after intravenous injection into baboons. Based on this, Ad5/35 vectors could be valuable tools for immunotherapy and vaccination. On the other hand, a number of studies indicate that signaling through the B-group Ad receptor, CD46, can cause tolerance or immunosuppression. Since mice do not express CD46 in a human-like pattern, we studied the in vivo properties of Ad5/35 in transgenic mice that express CD46 in a pattern and at a level similar to those of humans. Hypersensitivity assays and analyses of frequencies of regulatory T cells and T cell responses did not indicate that Ad5/35 injection exerts detrimental effects on the host's immune system. An Ad5/35 vector expressing a model antigen was able to trigger a strong T cell response against the test antigen after intramuscular injection. Overall, compared to Ad5 vectors, Ad5/35 vectors had a better safety profile, reflected by lower serum levels of proinflammatory cytokines.

Incident high-grade squamous intraepithelial lesions in Senegalese women with and without human immunodeficiency virus type 1 (HIV-1) and HIV-2.

BACKGROUND: Women infected with human immunodeficiency virus type 1 (HIV-1) and -2 may be at higher risk of developing cervical cancer than uninfected women. We assessed the relationships among human papillomavirus (HPV) types and persistence, HIV-1 and/or HIV-2 infection, and the development of high-grade cervical squamous intraepithelial lesions (HSILs) in a prospective study. METHODS: We studied 627 women with and without HIV-1 and/or HIV-2 infection and high-risk HPV infection in Senegal, West Africa, who were assessed every 4 months for HSIL and HPV DNA over a mean follow-up of 2.2 years. Cox regression modeling was used to assess risks associated with development of HSIL. RESULTS: During follow-up, 71 (11%) of 627 women developed HSIL as detected by cytology. HIV-infected women with high-risk HPV types were at greatest risk for development of HSIL. In multivariable modeling, infection with oncogenic HPV types--both persistent (hazard ratio [HR] = 47.1, 95% confidence interval [CI] = 16.3 to 136) and transient (HR = 14.0, 95% CI = 3.7 to 54)--was strongly associated with HSIL risk. In univariate analyses, HIV-positive women infected with HIV-2 were less likely to develop HSIL (HR = 0.3, 95% CI = 0.1 to 0.9) than HIV-positive women infected with HIV-1. HIV-positive women with CD4+ cell counts between 200 and 500 cells per microliter (HR = 2.2, 95% CI = 0.8 to 6.3) or fewer than 200 cells per milliliter (HR = 5.5, 95% CI = 2.0 to 15.2) were at greater risk of HSIL than HIV-positive women with CD4 counts of more than 500 cells per milliliter. High plasma HIV RNA levels were associated with increased HSIL risk (HR for each order of magnitude increase in the level of plasma HIV RNA = 1.4, 95% CI = 1.1 to 1.7; P = .005). After adjustment for HPV types and persistence, however, HIV type, plasma HIV RNA level, and CD4 count were no longer statistically significantly associated with increased risk of HSIL. CONCLUSIONS: HIV-1 and HIV-2 are associated with increased risk for development of HSIL. This risk appears to be associated primarily with increased HPV persistence that may result from immunosuppression related to HIV-1 and/or HIV-2 infection.

Detection of hypermethylated genes in women with and without cervical neoplasia.

BACKGROUND: DNA methylation changes are an early event in carcinogenesis and are often present in the precursor lesions of various cancers. We examined whether DNA methylation changes might be used as markers of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC). METHODS: We used methylation-specific polymerase chain reaction (PCR) to analyze promoter hypermethylation of 20 genes, selected on the basis of their role in cervical cancer, in 319 exfoliated cell samples and matched tissue biopsy specimens collected during two studies of Senegalese women with increasingly severe CIN and ICC (histology negative/atypical squamous cells of undetermined significance [ASCUS] = 142, CIN-1 = 39, CIN-2 = 23, CIN-3/carcinoma in situ [CIS] = 23, ICC = 92). Logic regression was used to determine the best set of candidate genes to use as disease markers. All statistical tests were two-sided. RESULTS: Similar promoter methylation patterns were seen in genes from exfoliated cell samples and corresponding biopsy specimens. For four genes (CDH13, DAPK1, RARB, and TWIST1), the frequency of hypermethylation increased statistically significantly with increasing severity of neoplasia present in the cervical biopsy (P<.001 for each). By using logic regression, we determined that the best panel of hypermethylated genes included DAPK1, RARB, or TWIST1. At least one of the three genes was hypermethylated in 57% of samples with CIN-3/CIS and in 74% of samples with ICC but in only 5% of samples with CIN-1 or less. The estimated specificity of the three-gene panel was 95%, and its sensitivity was 74% (95% confidence interval [CI] = 73% to 75%) for ICC and 52% (95% CI = 49% to 55%) for CIN-3/CIS. By extrapolation, we estimated that, among Senegalese women presenting to community-based clinics, detection of the DAPK1, RARB, or TWIST1 hypermethylated gene would reveal histologically confirmed CIN-3 or worse with a sensitivity of 60% (95% CI = 57% to 63%) and a specificity of 95% (95% CI = 94% to 95%). CONCLUSIONS: Aberrant promoter methylation analysis on exfoliated cell samples is a potential diagnostic tool for cervical cancer screening that potentially may be used alone or in conjunction with cytology and/or human papillomavirus testing.

Mammaglobin as a novel breast cancer biomarker: multigene reverse transcription-PCR assay and sandwich ELISA.

BACKGROUND: The aim of this study was to examine the potential usefulness of a mammaglobin multigene reverse transcription-PCR (RT-PCR) assay and a mammaglobin sandwich ELISA as diagnostic tools in breast cancer. METHODS: We studied peripheral blood samples from 147 untreated Senegalese women with biopsy-confirmed breast cancer and gathered patient information regarding demographic, and clinical staging of disease. The samples were tested for mammaglobin and three breast cancer-associated gene transcripts by a multigene real-time RT-PCR assay and for serum mammaglobin protein by a sandwich ELISA assay. RESULTS: In 77% of the breast cancer blood samples, a positive signal was obtained in the multigene RT-PCR assay detecting mammaglobin and three complementary transcribed genes. Fifty samples from healthy female donors tested negative. Significant correlations were found between mammaglobin protein in serum, presence of mammaglobin mRNA-expressing cells in blood, stage of disease, and tumor size. Circulating mammaglobin protein was detected in 68% of the breast cancer sera, and was increased in 38% in comparison with a mixed control population. The RT-PCR assay and the ELISA for mammaglobin produced a combined sensitivity of 84% and specificity of 97%. CONCLUSION: The ELISA and RT-PCR for mammaglobin and mammaglobin-producing cells could be valuable tools for diagnosis and prognosis of breast cancer.

[Secretory breast carcinoma in a man. A case report with rapid evolution unfavorable]. / Carcinome sécrétoire du sein chez l'homme. A propos d'un cas d'évolution rapide.

Secretory carcinoma or juvenile carcinoma of the breast is a very rare tumor of male adults. Generally, it has a good prognosis after locoregional treatment. The authors report an observation of a secretory carcinoma occurring in a 20 year old man. The lesion presented as a voluminous tumor 12 cm in diameter with 3 positive lymph nodes; it was treated by mastectomy and axillary dissection. Tumor developed in a few months, with visceral metastasis and fatal issue. The cytological, histological and immuno-histochemical features necessary to the diagnosis are described. The rapid development of this case of secretory carcinoma is unusual. This leads the authors to propose the use of an additional treatment for adult secretory breast carcinoma with more than 3 positive lymph nodes.

Increased risk of high-grade cervical squamous intraepithelial lesions and invasive cervical cancer among African women with human immunodeficiency virus type 1 and 2 infections.

To assess the risk of prevalent high-grade cervical squamous intraepithelial lesions (HSILs) or invasive cervical cancer (ICC) associated with human immunodeficiency virus (HIV) type 1, HIV-2, and human papillomavirus (HPV) infections, HIV load, and CD4 cell count, we studied 4119 women attending an outpatient clinic in Senegal. HIV infection was associated with increased rates of cervical infection with high-risk HPVs. Among women infected with high-risk HPVs, those with HIV-1 (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.0-4.8), HIV-2 (OR, 6.0; 95% CI, 2.1-17.1), or dual HIV infection (OR, 8.0; 95% CI, 2.0-31.5) were more likely to have HSILs or ICC diagnosed than were HIV-negative women; this association was not observed among women not infected with high-risk HPVs. Among women with HIV, higher HIV plasma RNA loads and lower CD4 cell counts were associated with high-risk HPV infection and degree of cervical abnormality. Furthermore, HIV-2-positive women were more likely to have HSILs (OR, 3.3; 95% CI, 0.9-12.4) or ICC (OR, 7.9; 95% CI, 1.1-57) than were HIV-1-positive women.