Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis.

One of the most common complications during pregnancy is gestational diabetes mellitus (GDM), hyperglycemia that occurs for the first time during pregnancy. The condition is multifactorial, caused by an interaction between genetic, epigenetic, and environmental factors. However, the underlying mechanisms responsible for its pathogenesis remain elusive. Moreover, in contrast to several common metabolic disorders, molecular research in GDM is lagging. It is important to recognize that GDM is still commonly diagnosed during the second trimester of pregnancy using the oral glucose tolerance test (OGGT), at a time when both a fetal and maternal pathophysiology is already present, demonstrating the increased blood glucose levels associated with exacerbated insulin resistance. Therefore, early detection of metabolic changes and associated epigenetic and genetic factors that can lead to an improved prediction of adverse pregnancy outcomes and future cardio-metabolic pathologies in GDM women and their children is imperative. Several genomic and epigenetic approaches have been used to identify the genes, genetic variants, metabolic pathways, and epigenetic modifications involved in GDM to determine its etiology. In this article, we explore these factors as well as how their functional effects may contribute to immediate and future pathologies in women with GDM and their offspring from birth to adulthood. We also discuss how these approaches contribute to the changes in different molecular pathways that contribute to the GDM pathogenesis, with a special focus on the development of insulin resistance.

Borderline ovarian tumors: a retrospective cohort study on single institution experience, practice patterns and outcomes.

Borderline ovarian tumours (BOTs) commonly affect young nulliparous women, thus making fertility-preserving approaches more desirable. Women who opt for conservative management should be counselled about disease recurrence. In this retrospective study, the medical records of 57 women with BOT treated at the American University of Beirut Medical Centre between January 1986 and May 2018 were reviewed. Clinical, pathologic, and demographic data were collected and analysed to identify variables associated with poor clinical outcomes including advanced disease and risk of recurrence. Younger and nulliparous women were more likely to undergo fertility-sparing surgery. The open approach was adopted for women with larger adnexal masses and was associated with more blood loss with a mean difference of 172 mL (95% CI [110-235], p-value < .001) but no significant difference in operative time and length of hospital stay compared to the laparoscopic approach. CA-125 correlated with an advanced International Federation of Gynaecology and Obstetrics (FIGO) stage (p = .004). The recurrence rate was found to be 7% with a median recurrence time of 41.5 months.IMPACT STATEMENTWhat is already known on this subject? BOTs are common in young nulliparous women who often desire fertility-sparing procedures. Prognostic factors associated with disease severity and recurrence remain controversial.What do the results of this study add? This study presents an opportunity to understand the disease behaviour and compare local practices and outcomes to what was reported in the literature. CA-125 appears to be a useful marker in predicting the stage of BOT.What are the implications of these findings for clinical practice and/or further research? Future research should focus on exploring whether BOTs with micropapillary features represent an aggressive histologic subtype more prone to recurrence.

The accuracy and clinical impact of intraoperative frozen section in determining the extent of surgical intervention in patients with early stage endometrial cancer.

The aim of this study was to compare intraoperative frozen section (FS) with the final pathology (FP), and determine its clinical impact in clinically apparent early stage endometrial cancer (EC) at the American University of Beirut Medical Center (AUBMC). Data for patients 18 years or older, with clinically apparent early stage, grade 1 or 2, endometrioid EC, who underwent hysterectomy ± lymph node dissection (LND) at AUBMC between January 1st 1996 and June 30th 2016 were retrospectively reviewed. 70 patients were included. The overall concordance between FS and FP was 92.3% for histological subtype, 77% for tumour grade, 82% for Myometrial invasion (MI) and 100% for tumour size. At a median follow up of 30 months, 8 recurrences (11.4%) were noted, with a 5-year PFS and OS of 76 and 84% respectively, with a trend towards lower recurrence and improved survival in patients who underwent FS or LND.Impact statementWhat is already known on this subject? Hysterectomy and bilateral salpingo-oophorectomy is the standard surgery for stage I endometrial cancer (EC). Intraoperative frozen section (FS) facilitates the decision on performing lymph node dissection (LND). However, its accuracy and clinical impact have been questioned.What do the results of this study add? Our objective is to compare FS with the final pathology (FP), and determine its clinical impact in clinically apparent early stage EC at the American University of Beirut Medical Center (AUBMC). There is a lack of standardisation regarding FS use and reporting at AUBMC.What are the implications of these findings for clinical practice and/or further research? The strong correlation between FS and FP can serve as a tool to guide decision to perform LND in patients with apparent early stage disease, where use of sentinel LN biopsy technique is not available.

Primary vulvar Ewing sarcoma/peripheral primitive neuroectodermal tumor with pelvic lymph nodes metastasis: A case report and review of literature.

Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumors (pPNET) are soft tissue tumors that generally affect the bones. Extraosseous ES/pPNET has been rarely reported. Our patient presented with a 6 × 4 cm right subcutaneous solid vulvar lesion causing pain and discomfort. Pathology and immunohistochemistry staining showed strong positivity for CD99 and vimentin, favoring the diagnosis of ES/pPNET. Magnetic resonance imaging showed a 6-cm lesion in the right vulvar region with enlarged bilateral inguinal and right iliac lymph nodes. Fluorescence in situ hybridization test for translocation t(11;22)(q24;q12) was positive, confirming the diagnosis. The patient received three cycles of neoadjuvant chemotherapy with vincristine, adriamycin, cyclophosphamide alternating with ifosfamide and etoposide with complete response. The patient underwent vulvar radical local excision. Residual tumor measured 1.6 cm with free margins. She received four additional cycles of adjuvant chemotherapy and 30 sessions radiotherapy. She is currently disease free after 37 months. No ES/pPNET cases with pelvic lymph nodes metastasis were ever reported.

BRCA mutation screening and patterns among high-risk Lebanese subjects.

BACKGROUND: Previous studies have suggested that the prevalence of BRCA1 and 2 mutations in the Lebanese population is low despite the observation that the median age of breast cancer diagnosis is significantly lower than European and North American populations. We aimed at reviewing the rates and patterns of BRCA1/2 mutations found in individuals referred to the medical genetics unit at the American University of Beirut. We also evaluated the performance of clinical prediction tools. METHODS: We retrospectively reviewed the cases of all individuals undergoing BRCA mutation testing from April 2011 to May 2016. To put our findings in to context, we conducted a literature review of the most recently published data from the region. RESULTS: Two-hundred eighty one individuals were referred for testing. The prevalence of mutated BRCA1 or 2 genes were 6 and 1.4% respectively. Three mutations accounted for 54% of the pathogenic mutations found. The BRCA1 c.131G > T mutation was found among 5/17 (29%) unrelated subjects with BRCA1 mutation and is unique to the Lebanese and Palestinian populations. For patients tested between 2014 and 2016, all patients positive for mutations fit the NCCN guidelines for BRCA mutation screening. The Manchester Score failed to predict pathogenic mutations. CONCLUSION: The BRCA1 c.131G > T mutation can be considered a founder mutation in the Lebanese population detected among 5/17 (29%) of individuals diagnosed with a mutation in BRCA1 and among 7/269 families in this cohort. On review of recently published data regarding the landscape of BRCA mutations in the Middle East and North Africa, each region appears to have a unique spectrum of mutations.

BRCA1 and BRCA2 mutations in ethnic Lebanese Arab women with high hereditary risk breast cancer.

PURPOSE: Breast cancer is the most common malignancy among women in Lebanon and in Arab countries, with 50% of cases presenting before the age of 50 years. METHODS: Between 2009 and 2012, 250 Lebanese women with breast cancer who were considered to be at high risk of carrying BRCA1 or BRCA2 mutations because of presentation at young age and/or positive family history (FH) of breast or ovarian cancer were recruited. Clinical data were analyzed statistically. Coding exons and intron-exon boundaries of BRCA1 and BRCA2 were sequenced from peripheral blood DNA. All patients were tested for BRCA1 rearrangements using multiplex ligation-dependent probe amplification (MLPA). BRCA2 MLPA was done in selected cases. RESULTS: Overall, 14 of 250 patients (5.6%) carried a deleterious BRCA mutation (7 BRCA1, 7 BRCA2) and 31 (12.4%) carried a variant of uncertain significance. Eight of 74 patients (10.8%) aged ≤40 years with positive FH and only 1 of 74 patients (1.4%) aged ≤40 years without FH had a mutated BRCA. Four of 75 patients (5.3%) aged 41-50 years with FH had a deleterious mutation. Only 1 of 27 patients aged >50 years at diagnosis had a BRCA mutation. All seven patients with BRCA1 mutations had grade 3 infiltrating ductal carcinoma and triple-negative breast cancer. Nine BRCA1 and 17 BRCA2 common haplotypes were observed. CONCLUSION: Prevalence of deleterious BRCA mutations is lower than expected and does not support the hypothesis that BRCA mutations alone cause the observed high percentage of breast cancer in young women of Lebanese and Arab descent. Studies to search for other genetic mutations are recommended.

Comprehensive genotype-phenotype correlations between NLRP7 mutations and the balance between embryonic tissue differentiation and trophoblastic proliferation.

BACKGROUND: Hydatidiform mole (HM) is a human pregnancy with excessive trophoblastic proliferation and abnormal embryonic development that may be sporadic or recurrent. In the sporadic form, the HM phenotype is driven by an abnormal ratio of paternal to maternal genomes, whereas in the recurrent form, the HM phenotype is caused by maternal-recessive mutations, mostly in NLRP7, despite the diploid biparental origin of the HM tissues. In this study, we characterised the expression of the imprinted, maternally expressed gene, CDKN1C (p57(KIP2)), the genotype, and the histopathology of 36 products of conception (POC) from patients with two defective alleles in NLRP7 and looked for potential correlations between the nature of the mutations in the patients and the various HM features. METHODS/RESULTS: We found that all the 36 POCs are diploid biparental and have the same parental contribution to their genomes. However, some of them expressed variable levels of p57(KIP2) and this expression was strongly associated with the presence of embryonic tissues of inner cell mass origin and mild trophoblastic proliferation, which are features of triploid partial HMs, and were associated with missense mutations. Negative p57(KIP2) expression was associated with the absence of embryonic tissues and excessive trophoblastic proliferation, which are features of androgenetic complete HMs and were associated with protein-truncating mutations. CONCLUSIONS: Our data suggest that NLRP7, depending on the severity of its mutations, regulates the imprinted expression of p57(KIP2) and consequently the balance between tissue differentiation and proliferation during early human development. This role is novel and could not have been revealed by any other approach on somatic cells.

ASPL-TFE3 translocation in vulvovaginal alveolar soft part sarcoma.

Alveolar soft part sarcoma of the vulvovaginal region is limited to only 8 reported vaginal cases and 1 vulvar case in the English literature. The histogenesis of the tumor remains intriguing with postulates favoring a myogenic versus nonmyogenic origin. A reciprocal translocation for ASPL-TFE3 gene fusion, frequently detected in ~90% of cases, combined with TFE3 protein immunoexpression are highly sensitive and specific methods for diagnostic confirmation. The current report describes a unique case of vulvovaginal alveolar soft part sarcoma showing the classic morphologic features with documentation of TFE3 protein expression and the ASPL-TFE3 gene rearrangement. Furthermore, a brief review of the literature of vulvar and vaginal alveolar soft part sarcoma cases with the various treatment modalities is outlined.

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

BACKGROUND: The 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. METHODS: Using 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. RESULTS: Between 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. CONCLUSION: The 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.

Survival outcome after radiation therapy for patients with early cervical carcinoma undergoing inadequate primary surgery.

OBJECTIVE: The aim of this study was to investigate the survival outcome after radiation therapy for patients with early cervical carcinoma undergoing inadequate primary surgery. METHODS: A retrospective analysis of medical charts of all patients with stage IA2 to IIA carcinoma who were referred with inappropriate primary surgery and treated with radiation therapy was reviewed. The collected data include age, presenting symptoms, retrospective stage, lymph node status, histology type, type of surgery, baseline radiologic status before radiotherapy, details of radiation therapy, follow-up, and details of disease recurrence, disease-free survival, and overall survival (OS). Kaplan-Meier survival curves were used to show the OS and recurrence-free survival. RESULTS: A total of 32 patients were treated. The median age of the patients was 48.2 years, with a range of 27.6 to 79.2 years. Twenty-three patients had retrospective stage IB1, and 9 had stage IIA disease. The most common type of surgery (62.5%) was total abdominal hysterectomy with or without bilateral salpingo-oophorectomy. The pelvic lymph node dissection (PLND) status was not determined in 20 patients, 11 had PLND surgical assessment (2 were positive), and 1 had bulky PLND by computed tomographic scan.Baseline assessment showed that 14 patients had no residual disease, 11 had microscopic disease, and 7 had macroscopic disease. The follow-up ranged from 3.3 to 77.8 months, with a median of 24.3 months. Eleven patients developed disease recurrence, and all of them died of their disease. Two- and 5-year OS rates were 79% and 51.7%. Univariate analysis did not show a statistically significant effect of either the disease stage or residual disease survival. CONCLUSIONS: Survival outcome after radiation therapy for patients with early-stage cervical cancer undergoing inadequate surgery seems to be markedly worse than that for patients of comparable stage treated initially with radical radiation.

The Lebanese percreta group: A retrospective cohort study of both radical and conservative management outcomes of abnormally invasive placenta.

OBJECTIVE: The aim of the present study was to illustrate the outcomes of abnormally invasive placenta (AIP) cases managed in three leading centers in Lebanon. METHODS: We conducted a retrospective multicenter cohort study. Patients managed conservatively (cesarean delivery with successful placental separation) or radically (cesarean hysterectomy) were included in the study. Data included patient characteristics, surgical outcomes (blood loss, operative time, transfusion, partial bladder resection), maternal outcomes (death, length of stay, ICU admission, postoperative hemoglobin level) and neonatal outcomes (Apgar score, neonatal weight, admission to neonatal intensive care unit, neonatal death). RESULTS: The study included 189 patients. In the radical treatment subgroup (141/189), patients were para 3 and delivered at 34 4/7 weeks in average, bled 1.5 L and were transfused with three packed red blood cells, with operative time averaging 160 min. A total of 36% were admitted to the ICU and patients stayed on average for 1 week despite partial bladder resection in 19% of cases. Unscheduled radical delivery occurred at a lower gestational age, was associated with more blood loss, higher rate and volume of transfusion, and risk of maternal and neonatal death. In addition, patients delivered in an unscheduled fashion experienced higher rates of partial bladder resection and longer interventions. In the conservative treatment subgroup, on average patients were para 2 and delivered at 36 weeks, bled 800 mL on average with low rates of transfusion (35%) and ICU admission (22.9%). With regard to neonatal outcomes, the average neonatal birth weight was 2.4 kg in the radical subgroup and 2.5 kg in the conservative subgroup. Neonatal death occurred in 5.4% of cases requiring radical management while it occurred in 2% of patients treated conservatively. CONCLUSION: Through their multidisciplinary approach, the three centers demonstrated that management of AIP in Lebanon has led to excellent outcomes with no maternal mortality occurring in scheduled radical treatment. By comparison of the three leading centers, pitfalls in each center were identified and addressed.

Feasibility of implementing cytology-based cervical cancer screening national program in Lebanon: A pilot study.

OBJECTIVE: To review our national cervical cancer screening program using existing Ministry of Public Health primary healthcare centers (PHCs) and report the impact of women's knowledge, attitude, behavior, and practices on screening uptake and outcome. METHODS: A cross-sectional study on cervical cancer screening offered to sexually active Lebanese women aged 21 years and above visiting PHCs. Exclusions were history of complete hysterectomy, gynecologic cancers, and current pregnancy. Data were collected through a questionnaire and conventional cervical smear performed by trained healthcare providers and sent to one centralized cytopathology laboratory. RESULTS: Of 12 273 eligible women, 1.7% had an abnormal cervical smear test including 161 atypical squamous cells (ASC) of undetermined significance, 6 atypical glandular cells of undetermined significance, 16 low-grade squamous intraepithelial lesion (SIL), 17 ASC-cannot rule out high-grade SIL, 11 high-grade SIL, and one invasive carcinoma. Knowledge and attitudes significantly affected participation in screening; women lacking awareness had rarely undergone a cervical smear. CONCLUSION: In Lebanon, cytology-based cervical cancer screening is feasible within the PHCs. Positive screen incidence was low. Despite previous campaigns, a low level of knowledge persists, and affects women's com with the screening guidelines. Advocacy and awareness activities by key healthcare providers may help to improve participation.

Management of Hydatid Cysts in Pregnancy: A Report of Two Cases and a Review of Literature.

Human hydatidosis is a parasitic infection by the larval stages of the Echinococcus (E.) that rarely occurs in pregnancy (1/20, 000-30 000). Canines are the definitive host while humans are the accidental host. They most often affect the liver (60%) and lungs (30%). E. granulosus causes cystic echinococcosis and is the most frequent form. E. multilocularis causes alveolar echinococcosis and is becoming increasingly more common. E. infections often remain asymptomatic for years before the cysts grow large enough to cause symptoms. Hepatic and pulmonary signs and symptoms are the most common clinical manifestations. There is no consensus on their management in pregnancy. We report two pregnancies complicated by hydatid disease of the liver and lung, discuss their problematic management, and review the recent literature.

NLRP7, a nucleotide oligomerization domain-like receptor protein, is required for normal cytokine secretion and co-localizes with Golgi and the microtubule-organizing center.

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-1ß 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-1ß indicating that normal NLRP7 down-regulates pro-IL-1ß synthesis in response to LPS. Using transient transfections, we confirm the role of normal NLRP7 in inhibiting pro-IL-1ß 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.

Burden of human papillomavirus-related cervical disease in the extended middle East and north Africa-a comprehensive literature review.

OBJECTIVE: This study aimed to analyze the burden of human papillomavirus (HPV) in the Extended Middle East and North Africa (EMENA) region and to discuss the potential impact on HPV-related diseases derived from changing sexual behaviors and perceptions. MATERIALS AND METHODS: A comprehensive retrospective review of the available epidemiological data (publications in the past 30 years until January 2011) on HPV and its related diseases (especially as they relate to the cervix) in the EMENA region was carried out. RESULTS: Analysis of the burden of HPV in the EMENA region highlights an unexpectedly high prevalence of HPV, with rates of HPV ranging from 0% to 25% in low-risk women with normal cytology and up to 98% in those with genital warts and preinvasive and invasive lesions. In addition, cervical cancer screening practices are, at best, opportunistic in most countries of the region; therefore, the observed change in social and sexual behavior in the EMENA population, particularly in youths, could lead to an increase in HPV and its related diseases especially cervical cancer. CONCLUSIONS: This article emphasizes the need for the introduction and standardization of screening practices in the region. Moreover, surveillance studies are needed to enable the identification of HPV type distribution and to determine the potential impact of the introduction of HPV vaccines. These socio-epidemiological data are of marked value to health care decision and policymakers in prioritizing available public health interventions.

Natural orifice transluminal endoscopic surgery (NOTES): assessment of peritoneal bacterial load after intraperitoneal antimicrobial wash and evaluation of hemodynamic changes in a porcine model.

AIMS: Natural orifice transluminal endoscopic surgery (NOTES) is a promising newly developed procedure; however, it is associated with many complications. The main aim of our study is to assess whether peritoneal wash with antibiotics decreases the bacterial load contamination related to the transgastric approach. METHODS: Ten female farm pigs underwent transgastric peritoneoscopy with fallopian tubal ligation. Five pigs were randomized to antibiotic wash of the peritoneal cavity and five to placebo. All animals were given one intravenous dose of antibiotic before the procedure. Hemodynamic variables were continuously monitored throughout the procedure. The next day, peritoneal cultures were taken. The fallopian tubes were inspected to determine the success of ligation and the gastric incision sites were assessed for leakage. RESULTS: No significant difference was noted between the antibiotic peritoneal wash group and the placebo group in terms of peritoneal bacterial load with respective median colony-forming units per ml (CFU/ml) of 0 [0; 1] vs. 0 [0; 4], p = 0.637. No clinically significant hemodynamic changes were noted during the procedure. CONCLUSIONS: The results of our study indicate that NOTES carries minimal risk of peritoneal bacterial contamination, regardless of the use of intraperitoneal antibiotics, and is not associated with hemodynamic compromise.

Outcomes of Human Papilloma Virus Vaccination in a Private Women Health Clinic in Lebanon.

Objectives: The study aims to report on the feasibility and associated adverse events of HPV-Vaccination (HPVV) in a private clinic setting in Lebanon and, when available, the results of subsequent cervical cancer screening. Methods: Opportunistic HPV vaccination is offered at the Women's Health Center of the AUBMC. We retrospectively reviewed the patients' demographic data, the incidence of adverse events, and their cytological screening. Results: A cohort of healthy women (n = 1013) aged 26.2 years (12-54 years) were opportunistically vaccinated with one of two HPV vaccines; 845 (83.4%) received the quadrivalent vaccine (Q4V), and 151 (14.1%) received the bivalent vaccine (B2V). The majority (75.8%) received three doses while 16% received two doses. Out of these women, 26.3% (267) became sexually active postvaccination (NS2), whereas 17% (174) were sexually active prior to vaccination (SA) and the rest 57% (572) reported no sexual activity (NS1). Among the SA group, 26% (46/147) presented with abnormal cytology at time of vaccination. As for the NS2 women, 5% (14/267) had subsequently abnormal screening within 37 (12-103) months following vaccination. Conclusions: In this observational study, we report the successful introduction of HPVV with negligible adverse events. The incidence of abnormal cervical cytology was low among our patients.

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.

Successful treatment of severe retro-peritoneal bleeding with recombinant factor VIIa in women with placenta percreta invading into the left broad ligament: unusual repeated ante-partum intra-abdominal bleeding.

We experienced unusual repeated ante-partum intra-abdominal bleedings in a woman with placenta percreta invading into the left broad ligament, in whom recombinant factor VIIa was effective for controlling severe retro-peritoneal bleeding. A 34-year-old multiparaous woman with two prior cesarean sections presented acute abdominal pain at 16 weeks of gestation. She also represented with abdominal pain at 22 weeks of gestation, and a diagnostic laparoscopy revealed hemoperitoneum, although we could not identify the exact source of bleeding. She also represented with abdominal pain without vaginal bleeding at 27 weeks of gestation, and an MRI revealed a hematoma in the lower abdomino-pelvic region and placenta percreta invading into the left broad ligament. A classical cesarean section followed by hysterectomy with partial cystectomy was performed at 32 weeks of gestation. Since the bleeding from the retro-peritoneum could not be controlled by the use of fresh frozen plasma, recombinant factor VIIa was administered, resulting in successful hemostasis.

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 node-positive 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 >or= .25. CONCLUSIONS: Our study demonstrates that ALNR is a stronger factor in predicting OS than the absolute number of positive axillary lymph nodes.