Publications by authors named "Muhieddine Seoud"

51 Publications

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

J Obstet Gynaecol Res 2020 Oct 5;46(10):2185-2192. Epub 2020 Aug 5.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon.

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.
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http://dx.doi.org/10.1111/jog.14399DOI Listing
October 2020

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

Hered Cancer Clin Pract 2019 18;17. Epub 2019 Jan 18.

2Division of Hematology-Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

Background: Previous studies have suggested that the prevalence of and 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 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 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 or genes were 6 and 1.4% respectively. Three mutations accounted for 54% of the pathogenic mutations found. The c.131G > T mutation was found among 5/17 (29%) unrelated subjects with 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 mutation screening. The Manchester Score failed to predict pathogenic mutations.

Conclusion: The 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 and among 7/269 families in this cohort. On review of recently published data regarding the landscape of mutations in the Middle East and North Africa, each region appears to have a unique spectrum of mutations.
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http://dx.doi.org/10.1186/s13053-019-0105-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339325PMC
January 2019

Treatment of cervical cancer metastatic to the abdominal wall with reconstruction using a composite myocutaneous flap: A case report.

Gynecol Oncol Rep 2019 Feb 12;27:38-41. Epub 2018 Dec 12.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Lebanon.

A 43-year-old woman treated with radical hysterectomy 1 year ago for cervical cancer presented with a suprapubic abdominal mass. A 15 cm necrotic mass from the abdominal wall along with 2 small bowel loops and the dome of the bladder were resected. The peritoneal defect was reconstructed with a pedicled anterolateral thigh and Vastus Lateralis muscle composite flap. Pathology showed invasive non-keratinizing moderately differentiated squamous cell carcinoma, consistent with metastatic cervical cancer, involving urinary bladder, bowel and soft tissue. With advancement in reconstructive surgery, extensive resection with defect closure in properly selected cases of metastatic cervical cancer to the abdominal wall may be considered in an attempt at improving quality of life and overall survival.
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http://dx.doi.org/10.1016/j.gore.2018.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302027PMC
February 2019

Contribution of Human papillomavirus in neuroendocrine tumors from a series of 10,575 invasive cervical cancer cases.

Papillomavirus Res 2018 06 17;5:134-142. Epub 2018 Mar 17.

Hospital del Mar, Parc de Salut Mar, Barcelona, Spain.

Aims: Neuroendocrine tumors (NET) of the cervix are rare tumors with a very aggressive course. The human papillomavirus (HPV) has been linked to its etiology. The objective of this study is to describe HPV prevalence and genotype distribution of NET.

Methods And Results: Forty-nine tumors with histological neuroendocrine features were identified among 10,575 invasive cervical cancer (ICC) cases from an international study. HPV DNA detection was done using SPF10/DEIA /LiPA system. Immunohistochemical (IHC) staining for neuroendocrine markers (chromogranin A, synaptophysin, CD56) and for p16 as a surrogate for HPV transforming infection was performed. In 13 samples with negative IHC for all 3 neuroendocrine markers studied, it was possible to conduct electron microscopy (EM). NET represented 0.5% of the total ICC series and HPV was detected in 42 out of 49 samples (85.7%, 95%CI:72.8%,94.1%). HPV16 was the predominant type (54.8%), followed by HPV18 (40.5%). p16 overexpression was observed in 38/44 cases (86.4%). Neuroendocrine IHC markers could be demonstrated in 24/37 (64.9%) cases. EM identified neuroendocrine granules in 8 samples with negative IHC markers.

Conclusions: Our data confirms the association of cervical NET with HPV and p16 overexpression. Specifically, HPV16 and 18 accounted together for over 95% of the HPV positive cases. Current HPV vaccines could largely prevent these aggressive tumors.
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http://dx.doi.org/10.1016/j.pvr.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909066PMC
June 2018

Vocal Symptoms and Acoustic Findings in Menopausal Women in Comparison to Pre-menopause Women with Body Mass Index as a Confounding Variable.

J Menopausal Med 2017 Aug 31;23(2):117-123. Epub 2017 Aug 31.

Department of Obstetrics & Gynecology, American University of Beirut-Medical Center, Beirut, Lebanon.

Objectives: To compare the prevalence of phonatory symptoms in menopausal women compared to pre-menopause women with body mass index (BMI) as a confounding variable.

Methods: A total of 69 women, 34 menopausal and 35 pre-menopausal were invited to participate in this study. Demographic variables included age, smoking, and BMI. All subjects were asked about the presence hoarseness, loss of high or low frequencies, pitch breaks, throat clearing, dryness in the throat and vocal fatigue. Acoustic analysis was performed and the Voice Handicap Index (VHI)-10 was filled by all the subjects.

Results: There was a significantly higher prevalence of throat clearing and dryness in the menopausal group compared to the pre-menopause group with a value of 0.035 and 0.032 respectively. When BMI was taken into account, there was no statistically significant difference in the prevalence of any of the phonatory symptoms in menopausal women with high BMI and pre-menopause. There was no statistically significant difference in the means of any of the acoustic parameters between the menopausal group and pre-menopausal group. There was no significant difference in the mean VHI-10 between the menopause group and the pre-menopause ( = 0.652).

Conclusions: The results of this investigation substantiate the importance of fat as an alternative source of estrogen which can mask some of the phonatory symptoms.
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http://dx.doi.org/10.6118/jmm.2017.23.2.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606909PMC
August 2017

Effect of Hormonal Replacement Therapy on Voice.

J Voice 2018 Jan 27;32(1):116-121. Epub 2017 Mar 27.

Department of Obstetrics & Gynecology, American University of Beirut-Medical Center, Lebanon.

Objective: This study aimed to investigate the effect of hormonal therapy (HRT) on voice in a group of menopausal women, taking into consideration body mass index (BMI) as a confounding factor and its potential role as a substitute for HRT.

Subjects And Methods: A total of 53 menopausal women, 34 not on HRT and 19 on HRT, were recruited. Demographic variables included age, gender, smoking, and BMI. All subjects were asked about the presence or absence of the following symptoms: hoarseness, deepening of the voice, pitch breaks, throat clearing, dryness in the throat, and vocal fatigue. Acoustic analysis was performed, and Voice Handicap Index-10 was also completed.

Results: The mean BMI was 25.90 ± 5.39 and 25.77 ± 4.26 in patients on HRT and not on HRT, respectively. There was no statistical difference in the Voice Handicap Index-10 score and the prevalence of any of the phonatory symptoms in menopausal women not on HRT compared with menopausal women on HRT. However, menopausal women not on HRT had significantly lower habitual pitch than those on HRT (P value of 0.022). On the other hand, the jitter was significantly higher in those on HRT (P value of 0.033).

Conclusion: Hormonal therapy has an impact on the habitual pith in menopausal women with comparable BMI. Those on HRT have a higher habitual pitch than those not on HRT.
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http://dx.doi.org/10.1016/j.jvoice.2017.02.019DOI Listing
January 2018

Cost-effectiveness of increasing cervical cancer screening coverage in the Middle East: An example from Lebanon.

Vaccine 2017 01 22;35(4):564-569. Epub 2016 Dec 22.

Harvard T. H. Chan School of Public Health, Center for Health Decision Science, Boston, MA 02115, USA.

Background: Most cervical cancer (CC) cases in Lebanon are detected at later stages and associated with high mortality. There is no national organized CC screening program so screening is opportunistic and limited to women who can pay out-of-pocket. Therefore, a small percentage of women receive repeated screenings while most are under-or never screened. We evaluated the cost-effectiveness of increasing screening coverage and extending intervals.

Methods: We used an individual-based Monte Carlo model simulating HPV and CC natural history and screening. We calibrated the model to epidemiological data from Lebanon, including CC incidence and HPV type distribution. We evaluated cytology and HPV DNA screening for women aged 25-65years, varying coverage from 20 to 70% and frequency from 1 to 5years.

Results: At 20% coverage, annual cytologic screening reduced lifetime CC risk by 14% and had an incremental cost-effectiveness ratio of I$80,670/year of life saved (YLS), far exceeding Lebanon's gross domestic product (GDP) per capita (I$17,460), a commonly cited cost-effectiveness threshold. By comparison, increasing cytologic screening coverage to 50% and extending screening intervals to 3 and 5years provided greater CC reduction (26.1% and 21.4, respectively) at lower costs compared to 20% coverage with annual screening. Screening every 5years with HPV DNA testing at 50% coverage provided greater CC reductions than cytology at the same frequency (23.4%) and was cost-effective assuming a cost of I$18 per HPV test administered (I$12,210/YLS); HPV DNA testing every 4years at 50% coverage was also cost-effective at the same cost per test (I$16,340). Increasing coverage of annual cytology was not found to be cost-effective.

Conclusion: Current practice of repeated cytology in a small percentage of women is inefficient. Increasing coverage to 50% with extended screening intervals provides greater health benefits at a reasonable cost and can more equitably distribute health gains. Novel HPV DNA strategies offer greater CC reductions and may be more cost-effective than cytology.
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http://dx.doi.org/10.1016/j.vaccine.2016.12.015DOI Listing
January 2017

Targeted therapy in gynecologic cancers: Ready for prime time?

Int J Gynaecol Obstet 2015 Oct;131 Suppl 2:S150-2

Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan.

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http://dx.doi.org/10.1016/j.ijgo.2015.06.012DOI Listing
October 2015

Principles of chemotherapy.

Int J Gynaecol Obstet 2015 Oct;131 Suppl 2:S146-9

Department of Obstetrics and Gynecology, Gynecologic Oncology, American University of Beirut Medical Center, Beirut, Lebanon.

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http://dx.doi.org/10.1016/j.ijgo.2015.06.011DOI Listing
October 2015

Impact of Preoperative Anaemia and Blood Transfusion on Postoperative Outcomes in Gynaecological Surgery.

PLoS One 2015 6;10(7):e0130861. Epub 2015 Jul 6.

Department of Surgery, American University of Beirut Medical Centre, Beirut, Lebanon.

Objective: To evaluate the effect of preoperative anaemia and blood transfusion on 30-day postoperative morbidity and mortality in patients undergoing gynecological surgery.

Study Design: Data were analyzed from 12,836 women undergoing operation in the American College of Surgeons National Surgical Quality Improvement Program. Outcomes measured were; 30-day postoperative mortality, composite and specific morbidities (cardiac, respiratory, central nervous system, renal, wound, sepsis, venous thrombosis, or major bleeding). Multivariate logistic regression models were performed using adjusted odds ratios (ORadj) to assess the independent effects of preoperative anaemia (hematocrit <36.0%) on outcomes, effect estimates were performed before and after adjustment for perioperative transfusion requirement.

Results: The prevalence of preoperative anaemia was 23.9% (95%CI: 23.2-24.7). Adjusted for confounders by multivariate logistic regression; preoperative anaemia was independently and significantly associated with increased odds of 30-day mortality (OR: 2.40, 95%CI: 1.06-5.44) and composite morbidity (OR: 1.80, 95%CI: 1.45-2.24). This was reflected by significantly higher adjusted odds of almost all specific morbidities including; respiratory, central nervous system, renal, wound, sepsis, and venous thrombosis. Blood Transfusion increased the effect of preoperative anaemia on outcomes (61% of the effect on mortality and 16% of the composite morbidity).

Conclusions: Preoperative anaemia is associated with adverse post-operative outcomes in women undergoing gynecological surgery. This risk associated with preoperative anaemia did not appear to be corrected by use of perioperative transfusion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130861PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492675PMC
April 2016

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

Oncologist 2015 Apr 16;20(4):357-64. Epub 2015 Mar 16.

Division of Hematology-Oncology, Department of Internal Medicine, and Departments of Pharmacology and Toxicology, Surgery, and Obstetrics and Gynecology, American University of Beirut, Lebanon; University of Auvergne and Laboratoire Diagnostique Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; Sidney Kimmel Comprehensive Cancer Center and Department of Gynecology and Obstetrics, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

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.
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http://dx.doi.org/10.1634/theoncologist.2014-0364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391767PMC
April 2015

Chronic lymphocytic leukemia of the genital tract.

Eur J Obstet Gynecol Reprod Biol 2015 Jan 20;184:126. Epub 2014 Nov 20.

Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon. Electronic address:

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http://dx.doi.org/10.1016/j.ejogrb.2014.11.017DOI Listing
January 2015

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

J Med Genet 2014 Sep 5;51(9):623-34. Epub 2014 Aug 5.

Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1136/jmedgenet-2014-102546DOI Listing
September 2014

ASPL-TFE3 translocation in vulvovaginal alveolar soft part sarcoma.

Int J Gynecol Pathol 2014 May;33(3):263-7

Departments of Pathology and Laboratory Medicine (M.N.J., G.S.Z.) Obstetrics and Gynecology (M.S.), American University of Beirut Medical Center, Beirut, Lebanon Department of Pathology (H.AL-A), Memorial Sloan-Kettering Cancer Center, New York, New York Department of Anatomic Pathology (F.W.A-K), Cleveland Clinic, Cleveland, Ohio.

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.
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http://dx.doi.org/10.1097/PGP.0b013e318290407cDOI Listing
May 2014

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

Popul Health Metr 2014 Mar 4;12(1). Epub 2014 Mar 4.

Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, P,O Box 11-0236, Riad el Solh, Beirut 1107 2802, Lebanon.

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.
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http://dx.doi.org/10.1186/1478-7954-12-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996020PMC
March 2014

Intimate Partner Violence in a Lebanese Population Attending Gynecologic Care: A Cultural Perspective.

J Interpers Violence 2014 Sep 12;29(14):2592-2609. Epub 2014 Feb 12.

Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon

Occurrence of intimate partner violence (IPV) against women in the Lebanese society has been largely ignored by local legal and religious authorities. Our aim is to estimate the prevalence of IPV among married Lebanese women, and investigate perception of abuse, referral patterns, and measures taken to deal with abusive situations. In this cross-sectional study, married women aged 20 to 65 presenting to the American University of Beirut Medical Center for gynecological care were interviewed on various forms of IPV. Out of 100 women invited to participate, 91 consented to take part in the survey of whom 37 (40.67%) gave a history of physical abuse, 30 (33.0%) of sexual abuse, 59 (64.8%) of verbal abuse, and 17 (18.7%) of emotional abuse. Spouse-imposed social isolation was reported in 20 (22.0%) women, and economic abuse in 30 (33.0%). Reasons for deciding to stay in an abusive relationship were "lack of any family or social support" (40.5%), "lack of financial resources" (40.5%), and "fear that the partner may take away the children" (37.8%). Women expressed satisfaction with their spouse's treatment irrespective of the existence of various forms of violence. A significant increase in the risk of weapon use against wife was correlated with decreased monthly income of the household, whereas a protective effect was conferred by an increased number of children. This study highlights the need for routine screening in health care settings for better identification of victims of violence. The selective conventional perception of abuse and the reactive normalization of violence observed indicate the necessity for culturally informed interventional strategies to complement screening.
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http://dx.doi.org/10.1177/0886260513520507DOI Listing
September 2014

Extended Middle East and North Africa: cervical cancer and human papillomavirus: can we make the case for prevention in this "relatively" low prevalence region?

Authors:
Muhieddine Seoud

Vaccine 2013 Dec;31 Suppl 6:vii-viii

Professor and Vice Chairman, Department Obstetrics and Gynecology, Gynecologic Oncology, American University of Beirut, Medical Centre, Hamra District, P.O. Box: 113-6044, Beirut, Lebanon. Electronic address:

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http://dx.doi.org/10.1016/j.vaccine.2012.05.038DOI Listing
December 2013

Model-based impact and cost-effectiveness of cervical cancer prevention in the Extended Middle East and North Africa (EMENA).

Vaccine 2013 Dec;31 Suppl 6:G65-77

Department Obstetrics and Gynecology, Gynecologic Oncology, American University of Beirut, Medical Center, Beirut, Lebanon.

To date, no studies have evaluated the cost-effectiveness of human papillomavirus (HPV) vaccination in countries in the Extended Middle East and North Africa (EMENA) region. We synthesized population and epidemiologic data for 20 EMENA countries using a model-based approach to estimate averted cervical cancer cases and deaths, disability-adjusted life years (DALYs) and cost-effectiveness ratios (I$ [international dollars] per DALY averted) associated with HPV vaccination of pre-adolescent girls. We utilized additional epidemiologic data from Algeria, Lebanon, and Turkey to evaluate select cervical cancer screening strategies either alone or in combination with vaccination. Results showed that pre-adolescent vaccination of five consecutive birth cohorts at 70% coverage has the potential to prevent over 180,000 cervical cancer cases. Cases averted varied by country, largely due to differences in cancer burden and population size; 69% of cases averted occurred in the three GAVI-eligible countries in EMENA. Despite the low cervical cancer incidence in EMENA, we found that HPV vaccination was cost-effective using a threshold of each country's gross domestic product per capita (a common metric for evaluating cost-effectiveness) in all but five countries at a cost per vaccinated girl of I$25 ($5 per dose). However, cost-effectiveness diminished with increasing vaccine cost; at a cost of I$200 per vaccinated girl, HPV vaccination was cost-effective in only five countries. When the cost per vaccinated girl exceeded I$50 in Lebanon and Turkey and I$150 in Algeria, screening alone was most attractive. We identified opportunities to improve upon current national screening guidelines, involving less frequent screening every 3-5 years. While pre-adolescent HPV vaccination promises to be a cost-effective strategy in most EMENA countries at low costs, decision makers will need to consider many other factors, such as affordability, acceptability, feasibility, and competing health priorities, when making decisions about cervical cancer prevention. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Extended Middle East and North Africa Region" Vaccine Volume 31, Supplement 6, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.
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http://dx.doi.org/10.1016/j.vaccine.2012.06.096DOI Listing
December 2013

Overview of cervical cancer screening practices in the extended Middle East and North Africa countries.

Vaccine 2013 Dec;31 Suppl 6:G51-7

Department Obstetrics and Gynecology, Gynecologic Oncology, American University of Beirut, Medical Center, Beirut, Lebanon.

National Organized Cervical Cancer Screening (NOCCS) programs are lacking in most of the "Extended Middle East and North Africa" (EMENA) countries. Consequently, most cervical cancers are diagnosed late and are associated with high mortality. In fact, in most of these countries, national mortality data are unknown due to the absence of population-based mortality registries. Most countries of the EMENA practice more or less limited opportunistic, cytology-based, screening tests, which often lack quality assurance and follow-up care. A few countries, within the initiation of a National Cancer Control Plan, have just started to implement organized screening programs using, for cervical cancer detection, visual inspection with acetic acid (Morocco) or cytology (Turkey). Moreover, most countries of the EMENA lack national guideline, as well as resources for the management of abnormal cytologic screening (or any other screening test). The main obstacle for the implementation of NOCCS is a lack of political understanding to support such public health programs and provide the necessary resources. Other obstacles that hinder the participation of women in cervical screening include a lack of knowledge of the disease, socio-religious and cultural barriers, and geographic and economic difficulties in accessing medical services. These countries are already convinced that prevention of cervical cancers in women who have cervical intraepithelial neoplasia is possible through various screening and treatment algorithms, but most countries still need to invest in well organized programs that can reduce cervical cancer incidence and mortality in women. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Extended Middle East and North Africa Region" Vaccine Volume 31, Supplement 6, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.
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http://dx.doi.org/10.1016/j.vaccine.2012.06.046DOI Listing
December 2013

Burden of human papillomavirus infections and related diseases in the extended Middle East and North Africa region.

Vaccine 2013 Dec;31 Suppl 6:G32-44

Obstetrics and Gynecology, Gynecologic Oncology, American University of Beirut, Medical Center, Beirut, Lebanon.

In this chapter, we present the available information on the burden of human papillomavirus (HPV)-related cancers (cancers of the cervix, anogenital cancers, and cancers of the oral cavity and pharynx), as well as available data on the prevalence and distribution of HPV types in women with and without cervical cancer, for the countries of the Extended Middle East and North Africa region (EMENA). The EMENA region is characterized by societies that share similar cultures and religions and that are considered to have a more conservative sexual behaviour compared to Western societies. The incidence of cervical cancer is estimated to be relatively low, although it is difficult to assess precisely because systematic and national cancer registries are lacking in many countries of the EMENA region. In these countries, nationwide programs of cervical cancer screening do not exist or are based on a limited opportunistic cytology-based screening, which often lacks quality assurance. The incidence of anogenital cancers other than cervix is very low. The incidence of cancers of the oral cavity and pharynx is relatively high in some countries, particularly in Pakistan. Relatively low levels of HPV prevalence have been observed in the several surveys conducted in the EMENA region, although only few young women were included in these studies. Possible changes in lifestyle and sexual behaviour in younger generations might, however, change this scenario. Thus, improving the information on the burden of HPV-related cancers and on the HPV prevalence in the general population is essential to develop a comprehensive intervention policy for future management of cervical cancer in this area. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Extended Middle East and North Africa Region" Vaccine Volume 31, Supplement 6, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.
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http://dx.doi.org/10.1016/j.vaccine.2012.06.098DOI Listing
December 2013

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

Int J Gynecol Cancer 2014 Jan;24(1):124-9

*Department of Obstetrics and Gynecology, Jordan University of Science and Technology, Irbid, Jordan; †Departments of Surgery and ‡Radiation Therapy, King Hussein Cancer Center, Amman, Jordan; and §Department of Radiation Oncology and ∥Department of Obstetrics & Gynecology, American University of Beirut Medical Center, Beirut, Lebanon.

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.
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http://dx.doi.org/10.1097/IGC.0000000000000016DOI Listing
January 2014

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

Eur J Cancer 2013 Nov 22;49(16):3450-61. Epub 2013 Jul 22.

Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; CIBER en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejca.2013.06.033DOI Listing
November 2013

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

Authors:
Muhieddine Seoud

J Low Genit Tract Dis 2012 Apr;16(2):106-20

Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon.

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.
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http://dx.doi.org/10.1097/LGT.0b013e31823a0108DOI Listing
April 2012

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

J Biol Chem 2011 Dec 24;286(50):43313-23. Epub 2011 Oct 24.

Department of Human Genetics, McGill University Health Center, Montreal H3G 1A4, Canada.

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.
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http://dx.doi.org/10.1074/jbc.M111.306191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234874PMC
December 2011

Cervical adenocarcinoma: moving towards better prevention.

Vaccine 2011 Nov 6;29(49):9148-58. Epub 2011 Oct 6.

American University of Beirut Medical Center, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Bliss Street, Hamra District, Box: 113-6044/30C, Beirut, Lebanon.

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.
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http://dx.doi.org/10.1016/j.vaccine.2011.09.115DOI Listing
November 2011

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

Minim Invasive Ther Allied Technol 2012 Jul 16;21(4):265-70. Epub 2011 Sep 16.

Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

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.
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http://dx.doi.org/10.3109/13645706.2011.607828DOI Listing
July 2012

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.

Indian J Surg Oncol 2010 Dec 29;1(4):305-12. Epub 2011 Mar 29.

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.
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http://dx.doi.org/10.1007/s13193-011-0062-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372966PMC
December 2010

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

Lancet Oncol 2010 Nov 15;11(11):1048-56. Epub 2010 Oct 15.

IDIBELL, Institut Català d'Oncologia-Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.

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.
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http://dx.doi.org/10.1016/S1470-2045(10)70230-8DOI Listing
November 2010

A phase II randomized trial comparing radiotherapy with concurrent weekly cisplatin or weekly paclitaxel in patients with advanced cervical cancer.

Radiat Oncol 2010 Sep 23;5:84. Epub 2010 Sep 23.

Department of Radiation Oncology, The American University of Beirut Medical Center, Bliss Street, Beirut, Lebanon.

Purpose/objective: This is a prospective comparison of weekly cisplatin to weekly paclitaxel as concurrent chemotherapy with standard radiotherapy for locally advanced cervical carcinoma.

Materials/methods: Between May 2000 and May 2004, 31 women with FIGO stage IB2-IVA cervical cancer or with postsurgical pelvic recurrence were enrolled into this phase II study and randomized to receive on a weekly basis either 40 mg/m² Cisplatin (group I; 16 patients) or 50 mg/m² paclitaxel (group II; 15 patients) concurrently with radiotherapy. Median total dose to point A was 74 Gy (range: 66-92 Gy) for group I and 66 Gy (range: 40-98 Gy) for group II. Median follow-up time was 46 months.

Results: Patient and tumor characteristics were similar in both groups. The mean number of chemotherapy cycles was also comparable with 87% and 80% of patients receiving at least 4 doses in groups I and II, respectively. Seven patients (44%) of group I and 8 patients (53%) of group II developed tumor recurrence. The Median Survival time was not reached for Group I and 53 months for group II. The proportion of patients surviving at 2 and 5 years was 78% and 54% for group I and 73% and 43% for group II respectively.

Conclusions: This small prospective study shows that weekly paclitaxel does not provide any clinical advantage over weekly cisplatin for concurrent chemoradiation for advanced carcinoma of the cervix.
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http://dx.doi.org/10.1186/1748-717X-5-84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955593PMC
September 2010