Loss of EIF4G2 mediates aggressiveness in distinct human endometrial cancer subpopulations with poor survival outcome in patients.

The non-canonical translation initiation factor EIF4G2 plays essential roles in cellular stress responses via translation of selective mRNA cohorts. Currently there is limited and conflicting information regarding its involvement in cancer development and progression. Here we assessed its role in endometrial cancer (EC), in a cohort of 280 EC patients across different types, grades, and stages, and found that low EIF4G2 expression highly correlated with poor overall- and recurrence-free survival in Grade 2 EC patients, monitored over a period of up to 12 years. To establish a causative connection between low EIF4G2 expression and cancer progression, we stably knocked-down EIF4G2 in two human EC cell lines in parallel. EIF4G2 depletion resulted in increased resistance to conventional therapies and increased the prevalence of molecular markers for aggressive cell subsets, altering their transcriptional and proteomic landscapes. Prominent among the proteins with decreased abundance were Kinesin-1 motor proteins, KIF5B and KLC1, 2, 3. Multiplexed imaging of the EC patient tumor cohort showed a correlation between decreased expression of the kinesin proteins, and poor survival in patients with tumors of certain grades and stages. These findings reveal potential novel biomarkers for Grade 2 EC with ramifications for patient stratification and therapeutic interventions.

Case of fetal ovarian juvenile granulosa cell tumor: Complications and management.

A prenatal ovarian juvenile granulosa cell tumor (JGCT) is a rare entity which may present as an intra-abdominal cyst. Due to its low incidence, optimal management and timing for intervention remain uncertain. This report presents a case of an intra-abdominal cystic structure in a female fetus, one of the two fetuses in a dichorionic-diamniotic twin pregnancy, detected during routine fetal sonographic surveillance at 30 weeks of gestation. Further fetal evaluation detected the sonographic triad of an ovarian cystic mass, polyhydramnios and signs of fetal virilizations, requiring us to consider the presence of an atypical, ovarian androgen secreting tumor. Following delivery, acute ovarian torsion and intracystic hemorrhage required emergent surgical intervention, confirming the diagnosis of JGCT. Following surgical treatment, laboratory, clinical, and morphological features improved progressively.

Does long-term treatment with Doxil® predispose patients to oral cancer?

We present a possible adverse reaction related to long-term use of Doxil(®) in female patients. We believe that long-term use of Doxil(®) may predispose female patients to oral squamous cell carcinoma. The patients in this report were not exposed to the common risk factors related to oral cancer formation such as smoking or alcohol consumption. Both patients were 59-year-old females. The first patient was diagnosed in 2001 with stage IIIC ovarian cancer. Seven years following treatment with Doxil(®), she was diagnosed with stage III squamous cell carcinoma of the right maxilla. The second patient was diagnosed with Kaposi's sarcoma with evidence of spread to the lungs. Four years following treatment with Doxil(®) she was diagnosed with stage I squamous cell carcinoma of the left maxilla. A literature review did not reveal any report on Doxil(®) and predisposition to oral cancer; however, we found an abstract that was presented at the last annual meeting of the American Society of Clinical Oncology (ASCO) by Cannon et al. When we combine the data from Cannon et al. and the data presented here, a total of six female patients developed an epithelial carcinoma of the oral cavity following long-term treatment with Doxil(®). We believe that a large-scale study should be initiated on patients that were treated with Doxil(®) for more than 3 years, since these patients might be at risk for developing secondary cancer of the oral cavity.

Evaluating the epidemiology and morbidity burden associated with human papillomavirus in Israel: accounting for CIN1 and genital warts in addition to CIN2/3 and cervical cancer.

BACKGROUND: Human papillomavirus (HPV) infection is mostly associated with cervical cancer (CC). However, it can cause other illnesses as well, all of which impact on people's wellbeing and consume healthcare resources. Measures for prevention or early detection of these conditions differ in their effectiveness and cost. An informative evaluation of the projected benefit of these measures depends on understanding the current unmet need, not only limited to CC. OBJECTIVE: To evaluate the burden of HPV-related conditions in Israel, including CC, cervical precancerous lesions and genital warts. METHODS: A retrospective database analysis was conducted for the second largest health management organization (HMO) in Israel, covering approximately 1.8 million people. Records were drawn following a search for key words indicative of related diagnoses, lab results, medications, or procedures for the time period of 2006-2008. Prevalence, incidence and resource utilization were analysed. Findings were extrapolated to the whole Israeli population using age and gender incidence rates. RESULTS: Incidence of CC was found to be 5 per 100,000 females. Incidences of cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3 were 74, 27 and 36 per 100,000 females, respectively. Incidence of genital warts was 239 and 185 per 100,000 for men and women, respectively. The overall annual economic burden was calculated to be $US48,838,058 (year 2010 values). CONCLUSIONS: HPV poses a significant burden in terms of health (clinical and quality of life) and in monetary terms, even for conditions that are sometimes regarded as benign, such as CIN1 or genital warts. Current findings should be used for proper evaluation of measures to reduce HPV-related morbidity and mortality, such as regular screening and vaccination.

[Persistent low levels of human chorionic gonadotropin in the serum: investigation and management].

Persistent low levels of human Chorionic Gonadotropin-hCG, the pregnancy hormone, in the serum in the absence of pregnancy or any evidence of Gestational Trophoblastic Disease (GTD) is a diagnostic and therapeutic dilemma. This condition mostly presents during follow-up after patients with a history of GTD or hydatidiform mole or an incidental pregnancy test. Many physicians are not aware of the broad differential diagnosis of this condition which is mostly benign. Therefore, many women with this condition have received chemotherapy and hysterectomy for assumed malignancy which were ineffective and unwarranted. The most common etiologies are: 1. Pituitary hCG: A condition mostly found in older women, completely benign and can be resolved using hormone replacement therapy or oral contraceptives. 2. False positive hCG: this condition has no clinical meaning, it can be identified by the absence of hCG in a parallel urine sample or using a better hCG test with no past reports of false positive. 3. Quiescent GTD: This is a benign trophoblastic disease in which the hyperglycosylated hCG accounts for a small percentage of the total hCG in the serum. Due to its premalignant nature, a follow-up of the hCG levels and the hyperglycosylated hCG percentage is needed. The hCG molecule has many forms. Different hCG tests detect different forms identified as heterogeneous in nature. For each etiology mentioned above there is a characteristic dominant form. If it was known which test to use, the diagnosis could be made.

[Radical trachelectomy as a fertility-preserving option--operative methods, outcomes and fertility rates].

Radical trachelectomy is a relatively new procedure, performed in early stage cervical cancer in young women who choose to preserve their fertility. Two different techniques have been described in the past few years, vaginal and abdominal radical trachelectomy. This review aims to describe and compare the two procedures with regard to: surgical technique, complications, patient survival and fertility. A Medline search was performed, using radical trachelectomy and cervical cancer as the keywords. We included only large series published in the English literature. Case reports were excluded. We believe that since the oncologic outcome is not altered as compared with the traditional approach, this new surgical treatment (radical trachelectomy) for early cervical cancer in young patients desiring to preserve their fertility, should be considered in relevant patients.

Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer.

PURPOSE: To evaluate the long-term survival of ovarian cancer (OvC) patients in total and by BRCA1/2 mutation status. PATIENTS AND METHODS: In a nationwide case-control study on OvC conducted in Israel between 1994 and 1999, 779 Jewish women with epithelial invasive OvC were tested for the three Ashkenazi Jewish founder mutations in BRCA1 (185delAG; 5382insC) and BRCA2 (6174delT) genes and followed for survival up to 2003. Of the 605 women of Ashkenazi origin, 213 (35.2%) carried a mutation in the BRCA1/2 genes. Clinical characteristics were abstracted from the patients' medical records. The Kaplan-Meier method, log-rank tests, and stepwise Cox regression model were used for survival analyses. RESULTS: The 5-year survival rate for the entire group was 39%. Median survival for carriers was significantly longer than for noncarriers (53.7 v 37.9 months, respectively; P = .002). This differential survival was pronounced among women diagnosed at stages III to IV (5-year survival rates of 38.1% and 24.5% for carriers and noncarriers, respectively; P < .001) and for women with poor grade (45.4% v 31.5%, for carriers and noncarriers, respectively; P < .001). These results remained significant after controlling for age at diagnosis, grade, and morphology. This benefit in prognosis was seen for both BRCA1 and BRCA2 carriers compared with noncarriers. During the study period (median follow-up, 6.2 years), being a BRCA1/2 mutation carrier decreased the mortality rate by 28%. CONCLUSION: This study confirms that, among Ashkenazi OvC patients, BRCA1/2 mutations are associated with improved long-term survival. This may be due to distinct clinical behavior and/or to a better response to chemotherapy.