Are we managing our patients correctly following treatment for cervical glandular intraepithelial neoplasia? A review of practice at the Jessop Wing Colposcopy Unit.

OBJECTIVE: Women diagnosed with cervical glandular intraepithelial neoplasia (CGIN) remain at risk of further pre-malignant and malignant disease and require rigorous post-treatment follow-up. We assess the effectiveness and safety of community cervical sampling follow-up in women treated for CGIN. METHODS: A retrospective study was conducted of women diagnosed with CGIN between April 1, 2013, and March 31, 2019, at Jessop Wing Colposcopy Unit, Sheffield, UK. RESULTS: Of 140 women diagnosed with CGIN, 76 had co-existing cervical intraepithelial neoplasia (CIN). Cytologists were significantly more likely to report glandular neoplasia in the absence of co-existing CIN, and high-grade dyskaryosis in its presence (Ps < 0.0001). Co-existing CIN was significantly more likely to be present with high or low-grade compared to normal colposcopy findings (P < 0.0001). The 6-month test of cure (TOC) was attended by 67% of women (84% within 12 months), and the 18-month post-treatment sampling by 52.5% of women (70% within 24 months). Colposcopy recalled 96% of women correctly for the 18-month sampling, but 20% of women undertaking primary care samples were incorrectly recalled at 3 years instead. CONCLUSIONS: When CGIN is diagnosed, two dates for recall should be provided at 6 and 18 months post-treatment to the Cervical Screening Administration Service and the centralised screening laboratory ensuring the 18-month post-treatment sample is correctly appointed, preventing women with HPV-negative TOC samples being returned to 3-year recall. Follow-up of CGIN should be closely audited by the centralised laboratories ensuring women with CGIN are not put at additional risk.

Surgical prevention strategies in ovarian cancer.

Given the current lack of effective screening for ovarian cancer, surgical removal of at-risk tissue is the most successful strategy to decrease risk of cancer development. However, the optimal timing of surgery and tissues to remove, as well as the appropriate patients to undergo preventive procedures are poorly understood. In this review, we first discuss the origin and precursors of ovarian epithelial carcinomas, focusing on high-grade serous carcinomas and endometriosis-associated carcinomas, which cause the majority of the mortality and incidence of ovarian cancer. In addition, we summarize the implications of current understanding of specific pathogenic origins for surgical prevention and remaining gaps in knowledge. Secondly, we review evidence from the epidemiologic literature on the associations of various surgical prevention strategies, including endometriosis excision, tubal procedures, and bilateral salpingo-oophorectomy, with risk of future ovarian cancer development, as well as the short- and long-term consequences of these strategies on women's health and quality and life. We conclude with recommendations for surgical prevention in women with high-risk genetic mutations and average-risk women, and a brief discussion of ongoing research that will help clarify optimal surgical approaches that balance risk-reduction with maintenance of women's quality of life.

Sanguinarine inhibits epithelial ovarian cancer development via regulating long non-coding RNA CASC2-EIF4A3 axis and/or inhibiting NF-κB signaling or PI3K/AKT/mTOR pathway.

OBJECTIVE: This study aimed to investigate the antitumor effects and possible regulatory mechanisms of sanguinarine in epithelial ovarian cancer. MATERIAL AND METHODS: The effects of sanguinarine on the malignant behaviors of epithelial ovarian cancer SKOV3 cells and the expression of long non-coding RNA CASC2 were investigated. The expression of CASC2 and EIF4A3 in epithelial ovarian cancer tissues and cells were detected, and the potential mechanisms of sanguinarine were explored by investigating the interactions between CASC2 and EIF4A3. Furthermore, the regulatory relationship between sanguinarine and nuclear factor-κB (NF-κB) signaling or PI3K/AKT/mTOR pathway was explored. RESULTS: Sanguinarine exhibited antitumor effects in SKOV3 cells by significantly inhibiting cell viability, migration and invasion and promoting cell apoptosis. Moreover, sanguinarine induced CASC2 expression and silencing of CASC2 reversed the effects of sanguinarine in epithelial ovarian cancer cells. CASC2 was significantly lowly expressed in ovarian cancer tissues and cells, while EIF4A3 was highly expressed. EIF4A3 was identified as a CASC2 binding protein. Knockdown of EIF4A3 reversed the effects of sanguinarine plus CASC2 silencing. Besides, sanguinarine markedly inhibited the activation of NF-κB signaling or PI3K/AKT/mTOR pathway, which was reversed by CASC2 silencing. And the effects of sanguinarine plus CASC2 silencing on the activation of these pathways were further reversed after knockdown of EIF4A3 at the same time. CONCLUSIONS: Our findings reveal that sanguinarine exhibits antitumor effects in epithelial ovarian cancer cells possible via regulating CASC2-EIF4A3 axis and/or inhibiting NF-κB signaling or PI3K/AKT/mTOR pathway. Sanguinarine may serve as a potential therapeutic reagent for epithelial ovarian cancer.

The origin of endometriosis-associated ovarian cancer from uterine neoplastic lesions.

Endometriosis is a risk factor for type I epithelial ovarian cancer but an issue to be clarified is the site of origin of endometriosis associated ovarian cancer. Here we proposed that the uterus may be the organ of origin of ovarian endometrioid cancer associated with endometriosis. Thus, the first neoplastic transformation would characterize the uterine cells migrating in the pelvis via retrograde menstruation and they would implant secondarily on the ovary. Supporting this hypothesis, an higher incidence of synchronous precancerous and cancerous endometrial pathology in patients affected by ovarian endometrioid cancer associated with endometriosis was showed. Moreover, uterine endometrial type I carcinoma resembles endometriosis associated endometrioid ovarian cancer in behavior and prognosis. This hypothesis is also supported by epidemiologic evidence showing a protective effect for tubal ligation and oral contraceptive use for endometriosis associated endometrioid ovarian cancer. Endometriosis and endometrioid ovarian carcinoma might represent two distinct biological entities characterized by the same organ of origin (the uterus), the same pathogenetic mechanism (transtubal reflux) and the same target organ (the ovary). By shifting the early events of ovarian carcinogenesis to the endometrium, prevention approaches as salpingectomy/tubal ligation and intervention at uterine corpus level may play an important role.

Setting the Threshold for Surgical Prevention in Women at Increased Risk of Ovarian Cancer.

The number of ovarian cancer cases is predicted to rise by 14% in Europe and 55% worldwide over the next 2 decades. The current absence of a screening program, rising drug/treatment costs, and only marginal improvements in survival seen over the past 30 years suggest the need for maximizing primary surgical prevention to reduce the burden of ovarian cancer. Primary surgical prevention through risk-reducing salpingo-oophorectomy (RRSO) is well established as the most effective method for preventing ovarian cancer. In the UK, it has traditionally been offered to high-risk women (>10% lifetime risk of ovarian cancer) who have completed their family. The cost-effectiveness of RRSO in BRCA1/BRCA2 carriers older than 35 years is well established. Recently, RRSO has been shown to be cost-effective in postmenopausal women at lifetime ovarian cancer risks of 5% or greater and in premenopausal women at lifetime risks greater than 4%. The acceptability, uptake, and satisfaction with RRSO at these intermediate-risk levels remain to be established. Prospective outcome data on risk-reducing salpingectomy and delayed-oophorectomy for preventing ovarian cancer is lacking, and hence, this is best offered for primary prevention within the context and safe environment of a clinical trial. An estimated 63% of ovarian cancers occur in women with greater than 4% lifetime risk and 53% in those with 5% or greater lifetime-risk. Risk-reducing salpingo-oophorectomy can be offered for primary surgical prevention to women at intermediate risk levels (4%-5% to 10%). This includes unaffected women who have completed their family and have RAD51C, RAD51D, or BRIP1 gene mutations; first-degree relatives of women with invasive epithelial ovarian cancer; BRCA mutation-negative women from high-risk breast-and-ovarian cancer or ovarian-cancer-only families. In those with BRCA1, RAD51C/RAD51D/MMR mutations and the occasional families with a history of ovarian cancer in their 40s, surgery needs to be considered at younger than 45. In other moderate-risk gene mutation carriers and those with polygenic risk, RRSO needs be considered at 50. There is need for establishment/expansion of well-defined pathways to increase clinical access to RRSO. It is time to lower the risk threshold for RRSO to enable introduction of a targeted primary prevention approach, which could significantly impact the future burden of ovarian cancer.

Protective effect of aspirin against mitomycin C-induced carcinogenicity, assessed by the test for detection of epithelial tumor clones (warts) in Drosophila melanogaster.

The present study assessed the protective effect of aspirin against carcinogenicity induced by mitomycin C (MMC) by the test for detection of warts/epithelial tumor clones in Drosophila melanogaster. Larvae were treated with different concentrations of aspirin alone (10, 20 or 40 mg/mL) or aspirin in association with MMC. MMC and ultrapure water were employed as the positive and negative control, respectively. Antioxidant activity was determined using the DPPH method. For performing cytotoxicity assay on HeLa cells, the aspirin concentrations used ranged from 200 mmol/L to 3,125 mmol/L. For assessment of apoptosis and necrosis, cells were incubated for 24 h with complete medium in the absence (control group) or presence of aspirin (12.5 mmol/L and 25 mmol/L). The results obtained in the assessment of the possible carcinogenic effects of aspirin at the three concentrations tested indicate no statistically significant increase in tumor frequency compared to the negative control. The anticarcinogenic activity assessment, where the larvae of D. melanogaster were previously induced to tumor formation by MMC and later treated with aspirin, showed a statistically significant reduction in the number of tumors compared to the positive control. Antioxidant activity across the three aspirin concentrations (10, 20 or 40 mg/mL) ranged from 20.81% to 26.5%. It was observed that aspirin reduced growth viability of HeLa cells in a concentration-dependent manner in comparison with the control. These results indicate that aspirin did not induce tumors in Drosophila and reduced MMC-induced carcinogenicity. The antioxidant activity and apoptosis induction appear to be the main mechanisms involved in reducing the frequency of tumors.

Opportunistic bilateral salpingectomy during benign gynecological surgery for ovarian cancer prevention: a survey of Gynecologic Oncology Committee of Japan Society of Obstetrics and Gynecology.

OBJECTIVE: Recent evidence has supported the concept that epithelial ovarian cancer (EOC) arises from the cells of the fallopian tube or endometrium. This study investigated current practice in Japan with respect to performing opportunistic bilateral salpingectomy (OBS) during gynecological surgery for benign disease for Ovarian Cancer Prevention. METHODS: We mailed a questionnaire to 767 hospitals and clinics, comprising 628 accredited training institutions of the Japan Society of Obstetrics and Gynecology (JSOG), Japan Society of Gynecologic Oncology (JSGO), or Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy (JSGOE) and 139 private institutions with at least one JSGOE-certified licensed gynecologic laparoscopist. RESULTS: Among the 767 institutions, 444 (57.9%) provided responses, including 91 (20.6%) that were both JSGOE and JSGO accredited, 71 (16.0%) that were only JSGO accredited, 88 (19.8%) that were only JSGOE accredited, and 194 (43.7%) that were unaccredited. It was found that awareness and performance of OBS largely depended on the JSGO and/or JSGOE accreditation status. OBS was only performed at 54.0% of responding institutions and just 6.8% of the institutions were willing to participate in randomized controlled trials to validate this method for reducing the incidence of ovarian cancer. CONCLUSION: The JSOG Gynecologic Tumor Committee will announce its opinion on salpingectomy for ovarian cancer prevention to all JSOG members and will develop a system for monitoring the number of OBS procedures in Japan.

Risk-reducing salpingectomy: Let us be opportunistic.

Because there is no screening test for ovarian cancer, effective prevention strategies may be the best way to reduce the mortality of this most lethal gynecologic malignancy. Increasing evidence supports the hypothesis that the fallopian tube is the site of origin for the vast majority of high-grade serous carcinomas. Our growing understanding of the pathogenesis of this disease offers a rare opportunity to explore new preventive measures, such as bilateral salpingectomy, which may provide great benefit without compromising ovarian function. If the tubal paradigm is accurate, then the impact of bilateral salpingectomy could extend to BRCA1 and BRCA2 mutation carriers, high-risk noncarriers, and average-risk women. The authors present a review of the literature on the role of risk-reducing salpingectomy in all women and in high-risk groups, with a focus on morbidity, ovarian function, potential clinical applicability, and epidemiological considerations. Cancer 2017;123:1714-1720. © 2017 American Cancer Society.

Role of Fallopian Tubes in the Development of Ovarian Cancer.

Ovarian cancer is the leading cause of death from gynecologic malignancy and the fifth cause of cancer death in women in the United States. The most common and lethal histologic subtype of epithelial ovarian cancer is high-grade serous carcinoma (HGSC), which generally presents at an advanced stage. HGSC may be associated with BRCA1 and BRCA2 mutations. Historically, HGSC was believed to originate from the ovarian epithelial cells. However, more recent evidence supports the idea that most ovarian cancers originate in the fallopian tube epithelium in both high-risk women and in the general population. Serous tubal intraepithelial carcinomas may ultimately evolve into ovarian or peritoneal cancer. As a result, prophylactic salpingectomy with conservation of the ovaries has become an increasingly more common practice for premenopausal women undergoing risk-reducing surgery. Because the fallopian tube is now recognized as the most common potential site of origin of ovarian carcinoma, there is ongoing research to explore molecular and genetic factors that may be critical in the development of this disease. Further research is needed to identify novel opportunities for early detection and screening of ovarian cancer with the ultimate goal of increasing overall survival.

The Association between Endometriosis, Tubal Ligation, Hysterectomy and Epithelial Ovarian Cancer: Meta-Analyses.

To investigate the association between endometriosis, tubal ligation, hysterectomy and epithelial ovarian cancer. Relevant published literatures were searched in PubMed, ProQuest, Web of Science and Medline databases during 1995-2016. Heterogeneity was evaluated by I² statistic. Publication bias was tested by funnel plot and Egger's test. Odds ratio and 95% CI were used to assess the association strength. The statistical analyses in this study were accomplished by STATA software package. A total of 40,609 cases of epithelial ovarian cancer and 368,452 controls in 38 publications were included. The result suggested that endometriosis was associated with an increased risk of epithelial ovarian cancer (OR = 1.42, 95% CI = 1.28-1.57), tubal ligation was associated with a decreased risk of epithelial ovarian cancer (OR = 0.70, 95% CI = 0.60-0.81), while hysterectomy show no relationship with epithelial ovarian cancer (OR = 0.97, 95% CI = 0.81-1.14). A stratified analysis showed there were associations between endometriosis and the increased risk of epithelial ovarian cancer for studies conducted in USA and Europe. Meanwhile, there were associations between tubal ligation and the decreased risk of epithelial ovarian cancer for studies conducted in USA, Asia, Europe and Australia. The result indicated that endometriosis was a risk factor of epithelial ovarian cancer whereas tubal ligation was a protective risk factor of epithelial ovarian cancer, hysterectomy may have no relationship with epithelial ovarian cancer.

Inhibition of microRNA-383 has tumor suppressive effect in human epithelial ovarian cancer through the action on caspase-2 gene.

BACKGROUND: MicroRNAs are important cancer regulators. In this work, we examined the expression pattern and mechanistic implications of microRNA-383 (miR-383) in human epithelial ovarian cancer (EOC). METHODS: Gene expression level of miR-383 was compared by qRT-PCR between EOC cell lines and normal ovarian epithelial cell line, and between clinical EOC tumors and adjacent non-tumor ovarian epithelial tissues. Endogenous miR-383 was downregulated through lentiviral infection. Its effects on regulating EOC proliferation, cell cycle, invasion and in vivo explant development were assessed. Possible downstream target of miR-383 in EOC, human caspase-2 gene (CASP2), was evaluated by luciferase assay and qRT-PCR. CASP2 was then genetically knocked down by siRNA to assess its functional relationship with miR-383 in regulating EOC development both in vitro and in vivo. RESULTS: MiR-383 was overexpressed in both immortal EOC cell lines and human EOC tumors. In stably miR-383-downregulated EOC cell lines, cancer proliferation, cell cycle progression, invasion and in vivo explant development were significantly suppressed. CASP2 was confirmed to be downstream of miR-383 in EOC. SiRNA-mediated CASP2 downregulation had reverse relationship with miR-383 downregulation in regulating EOC development both in vitro and in vivo. CONCLUSION: Inhibition of miR-383 has profound tumor suppressing effect on EOC development. And the functional regulation of miR-383 in EOC is very likely inversely associated with CASP2 gene.

Very high uptake of risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers: A single-center experience.

OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is the only effective surgical strategy to reduce the increased risk of epithelial ovarian cancer in BRCA1/2 mutation carriers. Given the long-term health consequences of premature surgical menopause, we need insight in uptake and timing of RRSO to guide us in improving healthcare. METHODS: A single-center retrospective cohort study of BRCA1/2 mutation carriers diagnosed and counseled at the multidisciplinary Family Cancer Clinic of the Radboud university medical center in Nijmegen, The Netherlands, between 1999 and 2014. Descriptive statistics were used to analyze uptake and timing of RRSO. RESULTS: Data of 580 BRCA1/2 were analyzed. The uptake of RRSO among mutation carriers who are currently above the upper limit of the recommended age for RRSO, is 98.5% and 97.5% for BRCA1 and BRCA2 mutation carriers, respectively. The vast majority undergoes RRSO ≤40 (BRCA1) or ≤45 (BRCA2) years of age, provided that mutation status is known by that age: 90.8% and 97.3% of BRCA1 and BRCA2 mutation carriers, respectively. CONCLUSIONS: The uptake of RRSO among BRCA1/2 mutation carriers who were counseled at our Family Cancer Clinic is extremely high. High uptake might be largely attributed to the directive and uniform way of counseling by professionals at our Family Cancer Clinic. Given the fact that RRSO is often undergone at premenopausal age in our population, future research should focus on minimizing long-term health consequences of premature surgical menopause either by optimization of hormone replacement therapy or by investigating alternative strategies to RRSO.

Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer.

The hypothesis on the pathogenesis of epithelial ovarian cancer continues to evolve. Although epithelial ovarian cancer had been assumed to arise from the coelomic epithelium of the ovarian surface, it is now becoming clearer that the majority of serous carcinomas arise from epithelium of the distal fallopian tube, whereas clear cell and endometrioid cancers arise from endometriosis. Molecular and genomic characteristics of epithelial ovarian cancer have been extensively investigated. Our understanding of pathogenesis of the various histologic types of ovarian cancer have begun to inform changes to the strategies for management of epithelial ovarian cancer, which represent a paradigm shift not only for treatment but also for prevention, which previously had not been considered achievable. In this article, we will discuss novel attempts at the prevention of high-grade serous ovarian cancer and treatment strategies for two distinct entities in epithelial ovarian cancer: low-grade serous and clear cell ovarian carcinomas, which are relatively rare and resistant to conventional chemotherapy.

Recommendations in the management of epithelial appendiceal neoplasms and peritoneal dissemination from mucinous tumours (pseudomyxoma peritonei)

The epithelial appendiceal neoplasms are uncommon and are usually detected as an unexpected surgical finding. The general surgeon should be aware of the diversity of its clinical manifestations and biological behaviors along with the significance of the surgical treatment on the progression of the illness and the prognosis of the patients. The operative findings and, especially, tumor histology, determine the type of surgery. Intestinal histologic subtype behaves and should be treated similarly to the right colon neoplasms; while mucinous tumors, often discordant between histology and its aggressiveness, can be treated with a simple appendectomy or require complex oncological surgeries. Mucinous tumors are often associated with the presence of mucin or tumor implants in the abdominal cavity, being the clinical syndrome known as pseudomyxoma peritonei (PMP). PMP tends to present an indolent but deadly evolution and requires a multimodal approach as a single treatment with curative potential: complete cytoreductive surgery plus hyperthermic Intraperitoneal chemotherapy (CCRS ? HIPEC) now considered the standard of care in this pathology. The general surgeon should be aware of the governing principles of the treatment of appendiceal neoplasms with or without peritoneal dissemination, know the therapeutic frontiers in every situation (avoiding unnecessary or counterproductive surgeries) and sending early these patients to specialised centres in the radical management of malignant diseases of the peritoneum in the conditions and with the necessary information to facilitate a possible radical treatment (AU)

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Impact and mechanistic role of oral contraceptive pills on the number and epithelial type of ovarian cortical inclusion cysts; a clinicopathology and immunohistochemical study.

BACKGROUND: Ovarian epithelial cancers are among the most lethal women's cancers. There is no doubt about the preventive role of oral contraceptive pills (OCPs) in development of ovarian cancers. But, there are limited numbers of studies to address the effect of these agents on the number of cortical inclusion cysts (CICs), their epithelial type and suppression of the metaplastic phenomenon by these pills. The aim of this study was to clarify the role of these agents in the prevention of these cyst formation and tubal metaplasia and also examine the mesenchymal-epithelial transition theory in this context by immunohistochemical methods. METHODS: The representative section(s) of ovarian cortex from a total number of 201 consecutive total abdominal hysterectomy with bilateral or unilateral salpingo-oophorectomy specimens were examined for mean number of CICs and their epithelial type between two groups of the patients. Group A included the patients who were on oral contraceptive pills for more than 5 years. All of the subjects with other contraceptive methods or a history of less than 5 years contraceptive pills usage were stratified in group B. Sections from 20 cases in which more than five inclusion cysts were found, were selected for IHC staining with calretinine and PAX8 as markers for mesothelium and mullerian epithelium respectively. RESULTS: The mean age of the patients was 51.67 years with no significant differences between two groups. The mean number of cysts were 1.27 and 3.23 in group A and B respectively (P =0.0001). Similarly the mean number of CICs, lined by tubal epithelium, was significantly different between two groups (0.65 vs 2.65, P =0.0001). In IHC staining 123 out of 150 CICs (82 %) were PAX+ while only 7 CICs (4.8 %) showed positive reaction for calretinin irrespective of type of epithelium. CONCLUSION: Our findings showed that the use of OCP for more than five years in women, significantly prevents development of cortical inclusion cysts in the ovaries which lined by tubal (PAX8 positive) type epithelium. These findings may explain the alternative mechanism of oral contraceptive pills or long time use of progesterone in suppression of tubal type overgrowth and subsequently prevention of ovarian epithelial cancers.

Italian cancer figures--Report 2015: The burden of rare cancers in Italy.

OBJECTIVES: This collaborative study, based on data collected by the network of Italian Cancer Registries (AIRTUM), describes the burden of rare cancers in Italy. Estimated number of new rare cancer cases yearly diagnosed (incidence), proportion of patients alive after diagnosis (survival), and estimated number of people still alive after a new cancer diagnosis (prevalence) are provided for about 200 different cancer entities. MATERIALS AND METHODS: Data herein presented were provided by AIRTUM population- based cancer registries (CRs), covering nowadays 52% of the Italian population. This monograph uses the AIRTUM database (January 2015), which includes all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to the International Classification of Diseases for Oncology (ICD-O-3). Data underwent standard quality checks (described in the AIRTUM data management protocol) and were checked against rare-cancer specific quality indicators proposed and published by RARECARE and HAEMACARE (www.rarecarenet.eu; www.haemacare.eu). The definition and list of rare cancers proposed by the RARECAREnet "Information Network on Rare Cancers" project were adopted: rare cancers are entities (defined as a combination of topographical and morphological codes of the ICD-O-3) having an incidence rate of less than 6 per 100,000 per year in the European population. This monograph presents 198 rare cancers grouped in 14 major groups. Crude incidence rates were estimated as the number of all new cancers occurring in 2000-2010 divided by the overall population at risk, for males and females (also for gender-specific tumours).The proportion of rare cancers out of the total cancers (rare and common) by site was also calculated. Incidence rates by sex and age are reported. The expected number of new cases in 2015 in Italy was estimated assuming the incidence in Italy to be the same as in the AIRTUM area. One- and 5-year relative survival estimates of cases aged 0-99 years diagnosed between 2000 and 2008 in the AIRTUM database, and followed up to 31 December 2009, were calculated using complete cohort survival analysis. To estimate the observed prevalence in Italy, incidence and follow-up data from 11 CRs for the period 1992-2006 were used, with a prevalence index date of 1 January 2007. Observed prevalence in the general population was disentangled by time prior to the reference date (≤2 years, 2-5 years, ≤15 years). To calculate the complete prevalence proportion at 1 January 2007 in Italy, the 15-year observed prevalence was corrected by the completeness index, in order to account for those cancer survivors diagnosed before the cancer registry activity started. The completeness index by cancer and age was obtained by means of statistical regression models, using incidence and survival data available in the European RARECAREnet data. RESULTS: In total, 339,403 tumours were included in the incidence analysis. The annual incidence rate (IR) of all 198 rare cancers in the period 2000-2010 was 147 per 100,000 per year, corresponding to about 89,000 new diagnoses in Italy each year, accounting for 25% of all cancer. Five cancers, rare at European level, were not rare in Italy because their IR was higher than 6 per 100,000; these tumours were: diffuse large B-cell lymphoma and squamous cell carcinoma of larynx (whose IRs in Italy were 7 per 100,000), multiple myeloma (IR: 8 per 100,000), hepatocellular carcinoma (IR: 9 per 100,000) and carcinoma of thyroid gland (IR: 14 per 100,000). Among the remaining 193 rare cancers, more than two thirds (No. 139) had an annual IR <0.5 per 100,000, accounting for about 7,100 new cancers cases; for 25 cancer types, the IR ranged between 0.5 and 1 per 100,000, accounting for about 10,000 new diagnoses; while for 29 cancer types the IR was between 1 and 6 per 100,000, accounting for about 41,000 new cancer cases. Among all rare cancers diagnosed in Italy, 7% were rare haematological diseases (IR: 41 per 100,000), 18% were solid rare cancers. Among the latter, the rare epithelial tumours of the digestive system were the most common (23%, IR: 26 per 100,000), followed by epithelial tumours of head and neck (17%, IR: 19) and rare cancers of the female genital system (17%, IR: 17), endocrine tumours (13% including thyroid carcinomas and less than 1% with an IR of 0.4 excluding thyroid carcinomas), sarcomas (8%, IR: 9 per 100,000), central nervous system tumours and rare epithelial tumours of the thoracic cavity (5%with an IR equal to 6 and 5 per 100,000, respectively). The remaining (rare male genital tumours, IR: 4 per 100,000; tumours of eye, IR: 0.7 per 100,000; neuroendocrine tumours, IR: 4 per 100,000; embryonal tumours, IR: 0.4 per 100,000; rare skin tumours and malignant melanoma of mucosae, IR: 0.8 per 100,000) each constituted <4% of all solid rare cancers. Patients with rare cancers were on average younger than those with common cancers. Essentially, all childhood cancers were rare, while after age 40 years, the common cancers (breast, prostate, colon, rectum, and lung) became increasingly more frequent. For 254,821 rare cancers diagnosed in 2000-2008, 5-year RS was on average 55%, lower than the corresponding figures for patients with common cancers (68%). RS was lower for rare cancers than for common cancers at 1 year and continued to diverge up to 3 years, while the gap remained constant from 3 to 5 years after diagnosis. For rare and common cancers, survival decreased with increasing age. Five-year RS was similar and high for both rare and common cancers up to 54 years; it decreased with age, especially after 54 years, with the elderly (75+ years) having a 37% and 20% lower survival than those aged 55-64 years for rare and common cancers, respectively. We estimated that about 900,000 people were alive in Italy with a previous diagnosis of a rare cancer in 2010 (prevalence). The highest prevalence was observed for rare haematological diseases (278 per 100,000) and rare tumours of the female genital system (265 per 100,000). Very low prevalence (<10 prt 100,000) was observed for rare epithelial skin cancers, for rare epithelial tumours of the digestive system and rare epithelial tumours of the thoracic cavity. COMMENTS: One in four cancers cases diagnosed in Italy is a rare cancer, in agreement with estimates of 24% calculated in Europe overall. In Italy, the group of all rare cancers combined, include 5 cancer types with an IR>6 per 100,000 in Italy, in particular thyroid cancer (IR: 14 per 100,000).The exclusion of thyroid carcinoma from rare cancers reduces the proportion of them in Italy in 2010 to 22%. Differences in incidence across population can be due to the different distribution of risk factors (whether environmental, lifestyle, occupational, or genetic), heterogeneous diagnostic intensity activity, as well as different diagnostic capacity; moreover heterogeneity in accuracy of registration may determine some minor differences in the account of rare cancers. Rare cancers had worse prognosis than common cancers at 1, 3, and 5 years from diagnosis. Differences between rare and common cancers were small 1 year after diagnosis, but survival for rare cancers declined more markedly thereafter, consistent with the idea that treatments for rare cancers are less effective than those for common cancers. However, differences in stage at diagnosis could not be excluded, as 1- and 3-year RS for rare cancers was lower than the corresponding figures for common cancers. Moreover, rare cancers include many cancer entities with a bad prognosis (5-year RS <50%): cancer of head and neck, oesophagus, small intestine, ovary, brain, biliary tract, liver, pleura, multiple myeloma, acute myeloid and lymphatic leukaemia; in contrast, most common cancer cases are breast, prostate, and colorectal cancers, which have a good prognosis. The high prevalence observed for rare haematological diseases and rare tumours of the female genital system is due to their high incidence (the majority of haematological diseases are rare and gynaecological cancers added up to fairly high incidence rates) and relatively good prognosis. The low prevalence of rare epithelial tumours of the digestive system was due to the low survival rates of the majority of tumours included in this group (oesophagus, stomach, small intestine, pancreas, and liver), regardless of the high incidence rate of rare epithelial cancers of these sites. This AIRTUM study confirms that rare cancers are a major public health problem in Italy and provides quantitative estimations, for the first time in Italy, to a problem long known to exist. This monograph provides detailed epidemiologic indicators for almost 200 rare cancers, the majority of which (72%) are very rare (IR<0.5 per 100,000). These data are of major interest for different stakeholders. Health care planners can find useful information herein to properly plan and think of how to reorganise health care services. Researchers now have numbers to design clinical trials considering alternative study designs and statistical approaches. Population-based cancer registries with good quality data are the best source of information to describe the rare cancer burden in a population.

Salpingectomy and Ovarian Cancer Prevention.

Ovarian cancer is a major health concern for women. Women are often diagnosed late in the course of the disease, making the mortality rate high. Currently, screening methods for ovarian cancer are limited and, therefore, prevention methods remain an area of focus for researchers. Recent research has examined the salpingectomy and tubal ligation/sterilization as a prevention method for ovarian cancer. This column takes a second look at two recent research studies that examine salpingectomy and tubal ligation/sterilization as a method of ovarian cancer risk reduction.

c-Met inhibitors attenuate tumor growth of small cell hypercalcemic ovarian carcinoma (SCCOHT) populations.

A cellular model (SCCOHT-1) of the aggressive small cell hypercalcemic ovarian carcinoma demonstrated constitutive chemokine and growth factor production including HGF. A simultaneous presence of c-Met in 41% SCCOHT-1 cells suggested an autocrine growth mechanism. Expression of c-Met was also observed at low levels in the corresponding BIN-67 cell line (6.5%) and at high levels in ovarian adenocarcinoma cells (NIH:OVCAR-3 (84.4%) and SK-OV-3 (99.3%)). Immunohistochemistry of c-Met expression in SCCOHT tumors revealed a heterogeneous distribution between undetectable levels and 80%. Further characterization of SCCOHT-1 and BIN-67 cells by cell surface markers including CD90 and EpCAM demonstrated similar patterns with differences to the ovarian adenocarcinoma cells. HGF stimulation of SCCOHT-1 cells was associated with c-Met phosphorylation at Tyr1349 and downstream Thr202/Tyr204 phosphorylation of p44/42 MAP kinase. This HGF-induced signaling cascade was abolished by the c-Met inhibitor foretinib. Cell cycle analysis after foretinib treatment demonstrated enhanced G2 accumulation and increasing apoptosis within 72 h. Moreover, the IC50 of foretinib revealed 12.4 nM in SCCOHT-1 cells compared to 411 nM and 481 nM in NIH:OVCAR-3 and SK-OV-3 cells, respectively, suggesting potential therapeutic effects. Indeed, SCCOHT-1 and BIN-67 tumor xenografts in NODscid mice exhibited an approximately 10-fold and 5-fold reduced tumor size following systemic application of foretinib, respectively. Furthermore, foretinib-treated tumors revealed a significantly reduced vascularization and little if any c-Met-mediated signal transduction. Similar findings of reduced proliferative capacity and declined tumor size were observed after siRNA-mediated c-Met knock-down in SCCOHT-1 cells demonstrating that in vivo inhibition of these pathways contributed to an attenuation of SCCOHT tumor growth.

Role of salpingectomy at the time of urogynecologic surgery.

PURPOSE OF REVIEW: This article reviews the current literature about prophylactic bilateral salpingectomy and provides guidelines for clinicians in regard to the inclusion of salpingectomy at the time of urogynecologic surgery. RECENT FINDINGS: After the Nurses' Health Study showed that all-cause mortality was increased in women undergoing oophorectomy at the time of hysterectomy for benign indications, there was a shift in focus toward ovarian conservation at the time of gynecologic surgery. As there has been continued interest in the fallopian tube as the origin of ovarian cancer, a move toward prophylactic salpingectomy has occurred. This strategy has become widely accepted in high-risk women, but is not universal in either premenopausal or postmenopausal women who are primarily served by the urogynecologic community. SUMMARY: Current literature supports that, if easily accessible, the fallopian tubes should be removed at the time of urogynecologic surgery. In premenopausal women, salpingectomy does not likely affect ovarian reserve, but this possibility should be discussed with patients. If inaccessible (i.e., at the time of a midurethral sling), there should not be additional surgery performed to access the fallopian tubes. In addition, the pathologic evaluation of the fallopian tubes should include complete examination of the fimbriae and a representative section of the nonfimbriated portion.