Muhieddine Seoud

Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study

BACKGROUND Knowledge about the distribution of human papillomavirus (HPV) genotypes in invasive cervical cancer is crucial to guide the introduction of prophylactic vaccines. We aimed to provide novel and comprehensive data about the worldwide genotype distribution in patients with invasive cervical cancer. METHODS Paraffin-embedded samples of histologically confirmed cases of invasive cervical cancer were collected from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Inclusion criteria were a pathological confirmation of a primary invasive cervical cancer of epithelial origin in the tissue sample selected for analysis of HPV DNA, and information about the year of diagnosis. HPV detection was done by use of PCR with SPF-10 broad-spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridisation line probe assay. Sequence analysis was done to characterise HPV-positive samples with unknown HPV types. Data analyses included algorithms of multiple infections to estimate type-specific relative contributions. FINDINGS 22,661 paraffin-embedded samples were obtained from 14,249 women. 10,575 cases of invasive cervical cancer were included in the study, and 8977 (85%) of these were positive for HPV DNA. The most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58 with a combined worldwide relative contribution of 8196 of 8977 (91%, 95% CI 90-92). HPV types 16 and 18 were detected in 6357 of 8977 of cases (71%, 70-72) of invasive cervical cancer. HPV types 16, 18, and 45 were detected in 443 of 470 cases (94%, 92-96) of cervical adenocarcinomas. Unknown HPV types that were identified with sequence analysis were 26, 30, 61, 67, 69, 82, and 91 in 103 (1%) of 8977 cases of invasive cervical cancer. Women with invasive cervical cancers related to HPV types 16, 18, or 45 presented at a younger mean age than did those with other HPV types (50·0 years [49·6-50·4], 48·2 years [47·3-49·2], 46·8 years [46·6-48·1], and 55·5 years [54·9-56·1], respectively). INTERPRETATION To our knowledge, this study is the largest assessment of HPV genotypes to date. HPV types 16, 18, 31, 33, 35, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed, and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines. Our results also suggest that type-specific high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45.

Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva

BACKGROUND Human papillomavirus (HPV) contribution in vulvar intraepithelial lesions (VIN) and invasive vulvar cancer (IVC) is not clearly established. This study provides novel data on HPV markers in a large series of VIN and IVC lesions. METHODS Histologically confirmed VIN and IVC from 39 countries were assembled at the Catalan Institute of Oncology (ICO). HPV-DNA detection was done by polymerase chain reaction using SPF-10 broad-spectrum primers and genotyping by reverse hybridisation line probe assay (LiPA25) (version 1). IVC cases were tested for p16(INK4a) by immunohistochemistry (CINtec histology kit, ROCHE). An IVC was considered HPV driven if both HPV-DNA and p16(INK4a) overexpression were observed simultaneously. Data analyses included algorithms allocating multiple infections to calculate type-specific contribution and logistic regression models to estimate adjusted prevalence (AP) and its 95% confidence intervals (CI). RESULTS Of 2296 cases, 587 were VIN and 1709 IVC. HPV-DNA was detected in 86.7% and 28.6% of the cases respectively. Amongst IVC cases, 25.1% were both HPV-DNA and p16(INK4a) positive. IVC cases were largely keratinising squamous cell carcinoma (KSCC) (N=1234). Overall prevalence of HPV related IVC cases was highest in younger women for any histological subtype. SCC with warty or basaloid features (SCC_WB) (N=326) were more likely to be HPV and p16(INK4a) positive (AP=69.5%, CI=63.6-74.8) versus KSCC (AP=11.5%, CI=9.7-13.5). HPV 16 was the commonest type (72.5%) followed by HPV 33 (6.5%) and HPV 18 (4.6%). Enrichment from VIN to IVC was significantly high for HPV 45 (8.5-fold). CONCLUSION Combined data from HPV-DNA and p16(INK4a) testing are likely to represent a closer estimate of the real fraction of IVC induced by HPV. Our results indicate that HPV contribution in invasive vulvar cancer has probably been overestimated. HPV 16 remains the major player worldwide.

Effects of young age at presentation on survival in breast cancer

BackgroundYoung age remains a controversial issue as a prognostic factor in breast cancer. Debate includes patients from different parts of the world. Almost 50% of patients with breast cancer seen at the American University of Beirut Medical Center (AUBMC) are below age 50.MethodsWe reviewed 1320 patients seen at AUBMC between 1990 and 2001. We divided them in three age groups: Below 35, 35–50, and above 50. Data and survival were analyzed using Chi-square, Cox regression analysis, and Kaplan Meier.ResultsMean age at presentation was 50.8 years. 107 patients were below age 35, 526 between 35–50 and 687 patients above age 50. Disease stages were as follows: stage I: 14.4%, stage II: 59.9%, stage III: 20% and stage IV: 5.7%. Hormone receptors were positive in 71.8% of patients below 35, in 67.6% of patients 35–50 and in 78.3% of patients above 50. Grade of tumor was higher as age at presentation was lower. More young patients received anthracycline-based adjuvant chemotherapy. Of hormone receptor-positive patients, 83.8% of those below age 35 years, 87.76% of those aged 35–50 years, and 91.2% of those aged above 50 years received adjuvant tamoxifen. The mean follow up time was 3.7 +/- 2.9 years. Time to death was the only variable analyzed for survival analysis. Excluding stage IV patients, tumor size, lymph node, tumor grade and negative hormone receptors were inversely proportional to survival. Higher percentage of young patients at presentation developed metastasis (32.4% of patients below 35, as compared to 22.9% of patients 35–50 and 22.8% of patients above 50) and had a worse survival. Young age had a negative impact on survival of patients with positive axillary lymph nodes, and survival of patients with positive hormonal receptors, but not on survival of patients with negative lymph nodes, or patients with negative hormonal receptors.ConclusionYoung age at presentation conferred a worse prognosis in spite of a higher than expected positive hormone receptor status, more anthracycline-based adjuvant chemotherapy and equivalent adjuvant tamoxifen hormonal therapy in younger patients. This negative impact on survival was seen in patients with positive lymph nodes and those with positive hormonal receptors.

A familial case of recurrent hydatidiform molar pregnancies with biparental genomic contribution.

Hydatidiform mole is a benign trophoblastic neoplasia characterized by an abnormal development of the embryo and proliferation of placental villi. Using microsatellite markers amplified by the polymerase chain reaction, we have performed a genetic study on eight independent molar tissues occurring in two sisters. Karyotype and genotype data demonstrate a diploid and biparental constitution in seven of the analyzed moles suggesting a common mechanism underlying the etiology of the various molar pregnancies in this family. The data reported here suggest that complete and partial hydatidiform moles are not always separate entities and that women with familial recurrent hydatidiform moles are homozygous for an autosomal recessive mutation.

Recurrent molar pregnancies in a family with extensive intermarriage: Report of a family and review of the literature

Background Familial recurrent molar pregnancies are exceedingly rare. The genetic basis for recurrent moles is not well understood, and its association with major human lymphocytic antigen histocompatibility is debatable. The purpose of this report is to present a family with extensive intermarriage and recurrent molar pregnancies with some emphasis on the result of the human lymphocytic antigentyping. Case Two sisters, both married to first-degree cousins, had three and five pathologically confirmed molar pregnancies, respectively. A second-degree cousin, also married to her first-degree cousin, is also reported to have had five consecutive moles. Chromosomal analysis and human lymphocytic antigen-typing on the two sisters and their spouses was performed. Human lymphocytic antigen-typing was compared to a cross-sectional sample of our population. This showed a high incidence of unusual human lymphocytic antigens in these family members. Conclusion In families with extensive intermarriage and recurrent molar pregnancies, patients and their spouses may have unusual human lymphocytic antigen histocompatibility, which supports the possibility of a strong genetic predisposition expressed at the level of major histocompatibility class I and li gene translation.

NLRP7, a Nucleotide Oligomerization Domain-like Receptor Protein, Is Required for Normal Cytokine Secretion and Co-localizes with Golgi and the Microtubule-organizing Center

Background: NLRP7 is responsible for recurrent hydatidiform moles, but its functional role is unknown. Results: NLRP7 mutations impair IL-1β and TNF secretion but do not affect IL-1β processing. NLRP7 co-localizes with the microtubule organizing center, and mutations impair cytokine trafficking. Conclusion: Patients with NLRP7 mutations have abnormal tolerance to aberrant pregnancies. Significance: We unravel a new mechanism for reproductive wastage. A hydatidiform mole (HM) is a human pregnancy with hyperproliferative placenta and abnormal embryonic development. Mutations in NLRP7, a member of the nucleotide oligomerization domain-like receptor family of proteins with roles in inflammation and apoptosis, are responsible for recurrent HMs. However, little is known about the functional role of NLRP7. Here, we demonstrate that peripheral blood mononuclear cells from patients with NLRP7 mutations and rare variants secrete low levels of IL-1β and TNF in response to LPS. We show that the cells from patients, carrying mutations or rare variants, have variable levels of increased intracellular pro-IL-1β indicating that normal NLRP7 down-regulates pro-IL-1β synthesis in response to LPS. Using transient transfections, we confirm the role of normal NLRP7 in inhibiting pro-IL-1β and demonstrate that this inhibitory function is abolished by protein-truncating mutations after the Pyrin domain. Within peripheral blood mononuclear cells, NLRP7 co-localizes with the Golgi and the microtubule-organizing center and is associated with microtubules. This suggests that NLRP7 mutations may affect cytokine secretion by interfering, directly or indirectly, with their trafficking. We propose that the impaired cytokine trafficking and secretion caused by NLRP7 defects makes the patients tolerant to the growth of these earlier arrested conceptions with no fetal vessels and that the retention of these conceptions until the end of the first trimester contribute to the molar phenotype. Our data will impact our understanding of postmolar choriocarcinomas, the only allograft non-self tumors that are able to invade maternal tissues.

Ratio Between Positive Lymph Nodes and Total Excised Axillary Lymph Nodes as an Independent Prognostic Factor for Overall Survival in Patients with Nonmetastatic Lymph Node-Positive Breast Cancer

Background.The status of the axillary lymph nodes in nonmetastatic lymph node-positive breast cancer (BC) patients remains the single most important determinant of overall survival (OS). Although the absolute number of nodes involved with cancer is important for prognosis, the role of the total number of excised nodes has received less emphasis. Thus, several studies have focused on the utility of the axillary lymph node ratio (ALNR) as an independent prognostic indicator of OS. However, most studies suffered from shortcomings, such as including patients who received neoadjuvant therapy or failing to consider the use of adjuvant therapy and tumor receptor status in their analysis.Methods.We conducted a single-center retrospective review of 669 patients with nonmetastatic lymph nodepositive BC. Data collected included patient demographics; breast cancer risk factors; tumor size, histopathological, receptor, and lymph node status; and treatment modalities used. Patients were subdivided into four groups according to ALNR value (<.25, .25–.49, .50–.74, .75–1.00). Study parameters were compared at the univariate and multivariate levels for their effect on OS.Results.On univariate analysis, both the absolute number of positive lymph nodes and the ALNR were significant predictors of OS. On multivariate analysis, only the ALNR remained an independent predictor of OS, with a 2.5-fold increased risk of dying at an ALNR of ≥.25.Conclusions.Our study demonstrates that ALNR is a stronger factor in predicting OS than the absolute number of positive axillary lymph nodes.

Cancer trends in Lebanon: a review of incidence rates for the period of 2003–2008 and projections until 2018

BackgroundThe analysis of cancer incidence trends is essential to health care planning. The aim of this study is to examine variations in cancer incidence rates in Lebanon between 2003 and 2008 and use the observed trends to project cancer incidence until 2018.MethodsUsing secondary data with a cumulative caseload of 45,753 patients from the National Cancer Registry database of the Ministry of Public Health in Lebanon, we estimated sex- and site- specific incidence of cancer for each year of the six-year period between 2003 and 2008. Logarithmic regressions were fitted to estimate the cancer incidence for the forecast years until 2018.ResultsBetween 2003 and 2008, males and females presented with an overall 4.5% and 5.4% annual increase, respectively. Significant increases were observed for cancers of the liver and prostate among males, and for cancers of the liver, thyroid, and corpus uteri among females. By 2018, incidence rates were projected to approach 296.0 and 339.5 cases per 100,000 for males and females, respectively. The most common five types of cancer are expected to be prostate, bladder, lung, non-Hodgkin, and colon among males; and breast, ovarian, non-Hodgkin, lung, and colon among females.ConclusionThe increased availability of screening programs and a growing smoking epidemic, most notably in women, are the most likely explanations behind the increased cancer incidence in the past decade. An aging population and higher proportion of older people suggest further increases in the cancer caseload in the future. The health care system in Lebanon will be required to adapt to the growing burden of cancer in our population.

Cervical adenocarcinoma: moving towards better prevention.

OBJECTIVE Although cervical screening has led to a significant decline of invasive cervical cancer (ICC) in developed countries, it remains the third leading cause of cancer in women worldwide. While the majority of the decline in ICC can be attributed to a reduction in squamous cell carcinoma (SCC), the incidence of cervical adenocarcinoma (ADC), absolute and relative to SCC, has been rising steadily, especially in younger women. This paper examines oncogenic human papillomavirus (HPV) infections, the risk of developing cervical ADC and its prognosis. It analyzes differences between ADC and SCC and considers current and future methods for prevention. METHODS PubMed, publicly available websites and congress abstracts were searched for data and literature. RESULTS HPV-16, -18 and -45 account for approximately 90% of ADC worldwide. Typically, α-7 genotypes, which include HPV-18 and -45, are more commonly associated with ADC than SCC. The difficulty in detecting ADC through screening as well as changing sexual habits and increased HPV transmission may account for its increase; an increase in SCC may not be observed because of improved detection of pre-malignant SCC compared with pre-malignant ADC. HPV testing shows promise for screening women ≥30years of age, but α-7 genotypes may be underrepresented in precancerous lesions. Clinical trial data indicate that current vaccines have high efficacy against HPV-16/18-related cervical intraepithelial neoplasia. Moreover, these vaccines also demonstrate a different level of protection beyond the HPV vaccine types, therefore increasing the overall vaccine efficacy. Such broad coverage could translate into a considerable reduction in the incidence of ADC. CONCLUSION Prophylactic HPV vaccination may have a significant impact on the prevention of ADC and may significantly impact future strategies for primary and secondary prevention of cervical cancer.

Bone mineralization in newborns whose mothers received magnesium sulphate for tocolysis of premature labour.

Prolonged maternal magnesium sulphate infusion therapy for tocolysis of premature labour may result in secondary fetal hypermagnesaemia, which has been associated with bony abnormalities in the newborn. We report on four infants, members of two twin pregnancies, who were exposed to prolonged fetal hypermagnesaemia. Three of the infants, all appropriate for gestational age, showed abnormal radiological findings consisting of abnormal mineralisation of long-bone metaphyses owing to fetal hypermagnesaemia. The fourth infant, who was growth retarded, had normal bones. Intrauterine growth restriction appears to be protective against magnesium sulphate-induced abnormal bone mineralisation in the newborn.