Xavier Carcopino

Potential impact of a nonavalent HPV vaccine on the occurrence of HPV-related diseases in France

BackgroundHuman Papillomavirus (HPV) infection is known to be associated with a number of conditions including cervical, vaginal, vulvar, penile, anal neoplasias and cancers, oropharynx cancers and genitals warts (GW). Two prophylactic vaccines are currently available: a bivalent vaccine designed to prevent HPV type 16 and 18 infection and a quadrivalent vaccine targeting HPV 6, 11, 16, and 18. In France, HPV vaccination is recommended in 11-14 year-old girls with a catch-up for girls aged 15-19. The objective of this study was to assess the potential impact of an HPV 6/11/16/18/31/33/45/52/58 nonavalent vaccine on anogenital and oropharyngeal HPV-related diseases in France.MethodsHPV genotype distributions from 6 multicentric retrospective studies (EDiTH I to VI) were analyzed including 516 cases of invasive cervical cancers (ICC), 493 high-grade cervical neoplasias (CIN2/3), 397 low-grade squamous intraepithelial lesions (LSIL), 423 GW, 366 anal cancer and 314 oropharyngeal carcinomas. Low and high estimates of HPV vaccine impact were calculated as follows: low estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association but excluding presence of another HPV type; high estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association, possibly in presence of another HPV type.ResultsEstimates of potential impact varied from 85% (low estimate) to 92% (high estimate) for ICC, 77% to 90% for CIN2/3, 26% to 56% for LSIL, 69% to 90% for GW, 81% to 93% for anal cancer, and 41% to 44% for oropharyngeal carcinomas. Compared to the quadrivalent vaccine, the proportion of additional cases potentially prevented by the nonavalent vaccine was 9.9%-15.3% for ICC, 24.7%-33.3% for CIN2/3, 12.3%-22.7% for LSIL, 2.1%-5.4% for GW, 8.5%-10.4% for anal cancer, and 0.0%-1.6% for oropharyngeal carcinoma.ConclusionsThe nonavalent HPV vaccine showed significant increased potential impact compared to the HPV 6/11/16/18 quadrivalent vaccine for ICC, CIN2/3 and LSIL. Considering a 100% vaccine efficacy and high vaccine coverage, about 90% of ICC, CIN2/3, GW or anal cancer cases could be prevented by a nonavalent HPV vaccine in France.

Testing for human papillomavirus and measurement of viral load of HPV 16 and 18 in self-collected vaginal swabs of women who do not undergo cervical cytological screening in Southern France

Self‐sampling using vaginal swabs could be a valuable alternative to screen for cervical cancer for women who do not attend regular cytological screening. The aim of this study was to determine the prevalence of high and low‐risk HPV types and of HPV type 16 and 18 DNA load in self‐collected vaginal swabs from 35‐ to 69‐year‐old Southern French women of low socioeconomic level or migrant populations who do not attend regular cervical screening. A good concordance (93.1%) was found between cervical brush and vaginal swabs in 29 samples. Self‐collected vaginal swabs were examined from 120 women. HPV infection was found in 28 women (23.3%; median age 48 years), 17 (14.1%) of whom harbored high‐risk HPV types. HPV type 16 was the high risk type found most frequently, followed by types 53, 31, 18, 58, and 66. The low‐risk type detected most frequently was HPV type 6, followed by types 61, 70, and 81. The mean HPV 16 and 18 load was 6.3 log10 copies/106 cells and 2.4 log10 copies/106 cells, respectively. These results suggest that vaginal self‐swabs can be a reliable tool for cervical cancer screening in non‐attending and inadequately screened elderly women. J. Med. Virol. 82:1431–1437, 2010.

Validation of an immunohistochemical signature predictive of 8-year outcome for patients with breast carcinoma.

We recently reported that standardized quantitative immunohistochemical (IHC) assays allowed prediction of an adverse outcome among 572 node negative (N−) patients with breast carcinoma (BrCa). To further validate our prior findings, we repeated the IHC stains including a second series of BrCa diagnosed at Yale University. Tissue microarrays (TMAs) of two cohorts of patients with BrCa (418 Marseille University and 303 Yale University) were respectively investigated for IHC expression of 15 markers (HIF‐1α, PI3K, pAKT, pmTOR, moesin, P21, 4EBP‐1, P27, Ker5‐6, pMAPKAPK‐2, SHARP2, claudin‐1, ALDH, AF6 and CD24). Quantitative measurements of immunoprecipitates densitometry assessed with an image analyzer were correlated with 8‐year patients outcome and compared in the two cohorts. The best predictive signature consisted of a combination of five markers that included HIF‐1α, PI3K, claudin‐1, AF6 and pAKT in N− BrCa. This combination permitted an accurate prediction of outcome in 92.34% (386/418) of N− patients in the first set (Marseille) and 89.8% (158/176) in the second set (Yale). The close results in both cohorts confirmed the validity of this original IHC signature predictive of prognosis in node negative BrCa. This validation suggests that in clinical practice, it would be possible with standardized kits (i) to identify patients with poor prognosis at diagnosis time, particularly in the N− BrCa subset, who would require more aggressive adjuvant therapy and (ii) to avoid useless expensive therapies and their side effects in N− patients with favorable prognosis.

Methylation of Human Papillomavirus Type 16 CpG Sites at E2-Binding Site 1 (E2BS1), E2BS2, and the Sp1-Binding Site in Cervical Cancer Samples as Determined by High-Resolution Melting Analysis–PCR

ABSTRACT High-risk (HR) human papillomavirus (HPV)-associated carcinogenesis is driven mainly by the overexpression of E7 and E6 oncoproteins following viral DNA integration and the concomitant loss of the E2 open reading frame (ORF). However, the integration of HR-HPV DNA is not systematically observed in cervical cancers. The E2 protein acts as a transcription factor that governs viral oncogene expression. The methylation of CpGs in the E2-binding sites (E2BSs) in the viral long control region abrogates E2 binding, thus impairing the E2-mediated regulation of E7/E6 transcription. Here, high-resolution melting (HRM)–PCR was developed to quantitatively analyze the methylation statuses of E2BS1, E2BS2, and the specificity protein 1 (Sp1)-binding site in 119 HPV16-positive cervical smears. This is a rapid assay that is suitable for the analysis of cervical samples. The proportion of cancer samples with methylated E2BS1, E2BS2, and Sp1-binding site CpGs was 47%, whereas the vast majority of samples diagnosed as being within normal limits, low-grade squamous intraepithelial lesions (LSIL), or high-grade squamous intraepithelial lesions (HSIL) harbored unmethylated CpGs. Methylation levels varied widely, since some cancer samples harbored up to 60% of methylated HPV16 genomes. A pyrosequencing approach was used as a confirmation test and highlighted that quantitative measurement of methylation can be achieved by HRM-PCR. Its prognostic value deserves to be investigated alone or in association with other biomarkers. The reliability of this single-tube assay offers great opportunities for the investigation of HPV16 methylation in other HPV-related cancers, such as head and neck cancers, which are a major public health burden.

Modélisation de l’impact de la vaccination HPV quadrivalente en France

OBJECTIVEnTo assess the expected impact in France of a quadrivalent HPV 6/11/16/18 vaccine on the occurrence of genital HPV-induced lesions in women.nnnMETHODSnA Markov model based on a quadrivalent vaccination of 14-year-old girls as recommended in France was performed to assess the number of subjects needed to vaccinate to prevent an HPV-related event during their lifetime and the expected annual number of cases which could be prevented by vaccination. This model was based on prevalence data reported in four large French studies (EDiTH I-IV) reporting an HPV 6/11/16/18 prevalence of 82% (95% CI: 78.5-85.1) in cervical cancer (CC), 64% (95% CI: 59.7-68.1) in CIN2/3, 34% (95% CI: 28.9-38.1) in low-grade squamous intraepithelial lesions (LSIL) and 83% (95% CI 77.6-87.8) in female external acuminata condylomata (EAC) cases.nnnRESULTSnUsing a theoretical vaccine efficacy of 100%, 130 young women need to be vaccinated to prevent a case of CC, 17 for a case of CIN2/3 and 13 for a case of EAC. Immunization of 80% of 14-year-old girls could prevent 2495 CC (72%), 17,985 CIN2/3 (54%), 8004 CIN1 (27%), and 22,531 EAC female cases (65%) in France annually.nnnCONCLUSIONnA good adhesion to the preferentially recommended HPV quadrivalent vaccination would thus substantially reduce the burden of female genital lesions in France.

Severe perineal morbidity of instrumental deliveries using Thierry's spatulas and vacuum extraction: A prospective observational cohort study

OBJECTIVESnTo evaluate the risk of severe perineal tear following instrumental vaginal delivery (IVD) performed with spatulas and vacuum extraction. Secondary objectives were to estimate the impact of episiotomy on this risk.nnnMETHODSnFrom Decemberxa02008 to Octoberxa02012, women who underwent spatulas or vacuum were prospectively included. Each spontaneous vaginal delivery (SVD) following each included IVD were included as control cases (1-1xa0ratio). Careful perineal examination was systematically performed. Severe perineal tear was defined by the occurrence of anal sphincter rupture with or without anal mucosa tear.nnnRESULTSnA total of 761xa0patients were included in the current study: 248 (64%) spatulas, 137 (36%) vacuums and 381 (49%) SVDs. Severe perineal tear was diagnosed in 19 (2.5%) cases. Episiotomy had been performed in 276 (36.9%) patients. Only spatulas extraction was found to significantly increase the risk of severe perineal tear (AOR=7.66; 95% CI: 2.06-28; P=0.02). Although vacuum extraction seemed to increase this risk, it was not found to be significant (AOR=3.25; 95% CI: 0.65-16.24; P=0.15). No significant difference was observed between the risk of severe perineal tear following spatulas and vacuum (AOR=2.36; 95% CI: 0.63-8.82; P=0.202). Finally, neither foetal macrosomia, nor episiotomy, nor foetal extraction with the head in the deep pelvis, nor delivery at night had a significant impact on the probability of severe perineal tear.nnnCONCLUSIONSnSpatulas extraction is an independent risk factor for severe perineal tear. The practice of episiotomy was not shown to have any significant impact on this risk.OBJECTIVESnTo evaluate the risk of severe perineal tear following instrumental vaginal delivery (IVD) performed with spatulas and vacuum extraction. Secondary objectives were to estimate the impact of episiotomy on this risk.nnnMETHODSnFrom Decemberxa02008 to Octoberxa02012, women who underwent spatulas or vacuum were prospectively included. Each spontaneous vaginal delivery (SVD) following each included IVD were included as control cases (1-1xa0ratio). Careful perineal examination was systematically performed. Severe perineal tear was defined by the occurrence of anal sphincter rupture with or without anal mucosa tear.nnnRESULTSnA total of 761xa0patients were included in the current study: 248 (64%) spatulas, 137 (36%) vacuums and 381 (49%) SVDs. Severe perineal tear was diagnosed in 19 (2.5%) cases. Episiotomy had been performed in 276 (36.9%) patients. Only spatulas extraction was found to significantly increase the risk of severe perineal tear (AOR=7.66; 95% CI: 2.06-28; P=0.02). Although vacuum extraction seemed to increase this risk, it was not found to be significant (AOR=3.25; 95% CI: 0.65-16.24; P=0.15). No significant difference was observed between the risk of severe perineal tear following spatulas and vacuum (AOR=2.36; 95% CI: 0.63-8.82; P=0.202). Finally, neither foetal macrosomia, nor episiotomy, nor foetal extraction with the head in the deep pelvis, nor delivery at night had a significant impact on the probability of severe perineal tear.nnnCONCLUSIONSnSpatulas extraction is an independent risk factor for severe perineal tear. The practice of episiotomy was not shown to have any significant impact on this risk.

Is gestational diabetes an independent risk factor of neonatal severe respiratory distress syndrome after 34 weeks of gestation? A prospective study

PurposeTo evaluate if neonates delivered after 340/7 weeks from mothers diagnosed with gestational diabetes (GD) are exposed to an increased risk of neonatal severe respiratory distress syndrome (SRDS).MethodsWomen with singleton pregnancy in labour after 340/7 weeks of gestation or admitted for planned caesarean section and who had been systematically screened for GD were eligible to participate to this prospective cohort study. Diagnosis of SRDS was defined by the association of clinical signs of early neonatal respiratory distress, with consistent radiologic features and requiring mechanical ventilation with a fraction of inspired oxygen (FiO2) >0.25 for a minimum of 24xa0h and admission to neonatal intensive care unit.ResultsA total of 444 women were included. GD was diagnosed in 60 patients (13.5%). A neonatal SRDS was diagnosed in 32 cases (7.2%). Compared to others, neonatal SRDS was significantly more often observed in neonates from women diagnosed with GD: 12 (20%) vs. 20 (5.2%), respectively (pxa0<xa00.001). Women whose neonates presented neonatal SRDS were significantly more likely to be obese (pxa0=xa00.002), to have undergone a caesarean section (pxa0<xa00.001) and to have received corticosteroids therapy before 340/7 weeks (pxa0=xa00.013). In multivariate analysis, GD was identified as an independent risk factor of neonatal SRDS (aOR 3.6; 95% CI 1.5–8.6; pxa0=xa00.005). Other risk factors were maternal obesity (aOR 2.8; 95% CI 1.1–7.1; pxa0=xa00.029) and assisted vaginal delivery (aOR 5.5; 95% CI 1.9–15.9; pxa0=xa00.002).ConclusionsGD is an independent risk factor of neonatal SRDS after 340/7 weeks.

Treatment failure following excision therapy of CIN: the impact of direct colposcopic vision during procedure

PurposeTo assess whether the use of direct colposcopic vision during excision therapy of cervical intraepithelial neoplasia (CIN) has an impact on the risk of treatment failure.MethodsData from 285 patients who had had excision therapy with proven CIN at specimen histological analysis were reviewed. Primary endpoint was the occurrence of post-treatment failure defined by the histological diagnosis of CIN 2–3 during follow-up. Data were analysed according to the use of colposcopy at the time of initial therapy of CIN.ResultsThe use of direct colposcopic vision (DCV) resulted in a significant reduction in the mean height (pxa0=xa00.008) and diameter (pxa0<xa00.001) of the excised specimen. Patients’ median follow-up was 28.4 (±1.3) months. A total of 43 (15.2xa0%) patients were diagnosed with treatment failure. Compared to excisions performed without any use of colposcopy, DCV was not found to have any significant impact on the risk of treatment failure (HR: 0.58; 95xa0% CI 0.16–2.13, pxa0=xa00.412), neither when compared to excisions performed immediately after colposcopy (HR: 0.91; 95xa0% CI 0.47–1.79; pxa0=xa00.794). The only factors found to have a significant impact on the risk of treatment failure was the identification of clear margins (HR: 0.36; 95xa0%CI 0.19–0.69; pxa0=xa00.002) and the diameter of the surgical specimen (HR: 0.94; 95xa0%CI 0.89–0.99; pxa0=xa00.040).ConclusionsAlthough the use of DCV during excision therapy of CIN was associated with a significant reduction in the dimensions of the excised cervical specimen, it did not result in a significant change in the risk of treatment failure.

Relationship between HPV 16, 18, 31, 33, 45 DNA detection and quantitation and E6/E7 mRNA detection among a series of cervical specimens with various degrees of histological lesions.

Better understanding of the correlation between high‐risk HPV DNA testing, viral load quantitation, and E6/E7 mRNA detection is required. The aim of this study was to assess the relationship between these markers and the severity of cervical lesions. One‐hundred and fifty one directed cervical specimens were analysed (normal, cervical intraepithelial neoplasia, and cancer). HPV types 16, 18, 31, 33, and 45 DNA detection and quantititation and E6/E7 mRNA detection were performed. DNA was detected in 87 (57.6%) samples and increased from 0% (normal) to 93.9% (cancer). E6/E7 mRNA was detected in 65 (43%) samples and increased with the severity of the lesions from 0% (normal) to 78.8% (26/33) (cancers) (Pu2009<u20090.001). HPV DNA and E6/E7 mRNA detection were compared in the 141 samples harbouring HPV16, 18, 31, 33, or 45 infection: 45.4% (64/141) of specimens were DNA−/mRNA−, 46% (65/141) were DNAu2009+u2009/mRNA+ and 8.5% (12/141) were DNAu2009+u2009/mRNA−. The proportion of DNAu2009+u2009/mRNA+ specimens increased with the severity of the lesions (Pu2009<u20090.001). All normal cervix specimens were DNA‐/mRNA‐. Among grade 2 cervical intraepithelial neoplasia, prevalence of DNA was higher than that of mRNA: 41.6% (5/12) versus 25% (3/12), whereas it was 79.3% (46/58) versus 62% (36/58) among grade 3 cervical intraepithelial neoplasia. Full concordance was observed in cancers as all the 26 DNA+ specimens were mRNAu2009+. Median overall HPV load was higher in DNAu2009+u2009/mRNA+ than in DNAu2009+u2009/mRNA− specimens (1.41u2009×u2009106 vs. 9.1u2009×u2009102 copies per million cells, Pu2009<u20090.001). Both E6/E7 mRNA detection and concordant DNAu2009+u2009/mRNA+ detection increases with the severity of the lesions and with the HPV DNA load. J. Med. Virol. 87:1389–1396, 2015.

Comparison of pelvic and para-aortic lymphadenectomy versus para-aortic lymphadenectomy alone for locally advanced FIGO stage IB2 to IIB cervical cancer using a propensity score matching analysis: Results from the FRANCOGYN study group

INTRODUCTIONnPre-treatment evaluation of nodal status is crucial in women presenting with locally advanced cervical cancer (LACC). However, the prognostic impact of surgical staging remains to be proved, as published results comparing surgical versus radiological staging are contradictory. The aim of this study was to compare the prognosis of women with FIGO stage IB2-IIB CC who underwent surgical nodal staging including either exclusive para-aortic lymphadenectomy (PAL) or comprehensive pelvicxa0+xa0para-aortic lymphadenectomy (P-PAL).nnnMATERIALS AND METHODSnData of 314 women with FIGO stage IB2 to IIB CC treated between January 2000 and January 2015 were retrospectively abstracted from nine French institutions. The prognosis and outcomes were compared by Propensity score (PS) matching (PSM) analysis.nnnRESULTSnThe median follow-up was 33 months (2-114). When comparing women who underwent PAL vs P-PAL, the recurrence rates were 26% (37/144) and 28% (41/144), respectively (pxa0=xa00.595). The respective 3-year recurrence free survival (RFS) for P-PAL and PAL were 72.9% (95% CI, 65.7-81.0) and 70.7% (95% CI, 62.4-80.2), (pxa0=xa00.394). The respective 3-year overall survival (OS) rates for P-PAL and PAL were 86.8% (95% CI, 81.1-92.9) and 78.6% (95% CI, 70.4-87.7) (pxa0=xa00.592). In the sub-group of women with lymph node metastases, RFS was improved for women who underwent P-PAL compared to those with exclusive PAL (pxa0=xa00.027), with no difference in OS (pxa0=xa00.187).nnnCONCLUSIONSnComprehensive P-PAL does not seem to be of significant therapeutic benefit compared to exclusive PAL.