Utility of Mesothelin, L1CAM and Afamin as Biomarkers in Primary Ovarian Cancer.

Jan 2013

Aktas B, Kasimir-Bauer S, Wimberger P, Kimmig R, Heubner M.

Source

Department of Gynecology and Obstetrics, University of Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany. bahriye.aktas@uk-essen.de.

Abstract

BACKGROUND:

We evaluated the prognostic value of the new serum biomarkers mesothelin (cell surface glycoprotein and tumor differentiation antigen), L1 cell adhesion molecule (L1CAM) and afamin (vitamin D-binding protein) alone and in combination with cancer antigen 125 (CA125) in serum samples of 154 patients with first-diagnosis of primary ovarian cancer, before surgery and after platinum-based chemotherapy. We correlated these findings with clinical parameters and evaluated their prognostic value with regard to overall survival (OS).

MATERIALS AND METHODS:

Blood (9 ml) was obtained before surgery (n=154) and after chemotherapy (n=82) for the measurement of serum markers using commercial Enzyme Linked Immunosorbent Assay (ELISA) kits for mesothelin, L1CAM, afamin and CA125. Mesothelin positivity was defined as >2.0 nM, L1CAM as >10 ng/ml, afamin as <45 mg/l and CA125 as >35 U/ml, respectively.

RESULTS:

Before surgery, mesothelin positivity significantly correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.002), residual postoperative tumor (p<0.0001), serous histological subtype (p<0.0001) and higher age (p=0.013). Elevated CA125 levels significantly correlated with advanced FIGO stage (p<0.0001) and grading (p=0.012). After chemotherapy, mesothelin as well as CA125 levels, were significantly associated with FIGO stage (p=0.041 and p=0.017) and residual tumor (p=0.022 and p=0.002) while L1CAM correlated with platinum sensitivity (p=0.041). In contrast, afamin at all determined time points showed no correlation with any of these parameters. The combination of markers did not add any significant power to their use.

CONCLUSION:

Mesothelin and L1CAM appear to correlate with clinical prognostic parameters and might be useful biomarkers for therapy monitoring and, thus, could serve as attractive targets for therapy of ovarian cancer.

Anticancer Research

Prognostic role of E-cadherin in patients with advanced serous ovarian cancer.

Dec 2012

Bačić B, Haller H, Mrklić I, Košta V, Carić A, Tomić S.

Source

Department of Obstetrics and Gynaecology, Split University Hospital Centre and School of Medicine, Spinčićeva 1, 21000, Split, Croatia, boris.bacic@st.t-com.hr.

Abstract

PURPOSE:

To analyse correlation between expression of E-cadherin and clinical and pathological features and overall survival in advanced-stage serous ovarian carcinoma.

METHODS:

The expression of E-cadherin was analysed immunohistochemically in formalin-fixed, paraffin-embedded samples from 54 patients with advanced-stage serous ovarian cancer and related to clinicopathological characteristics and patients survival. The clinicopathological characteristics included the stage according to the International Federation of Gynecology and Obstetrics (FIGO), tumour differentiation, number of mitoses per 10 high-power fields (HPF), residual tumour size, and vascular invasion. Only patients with serous ovarian cancer FIGO stages III-IV were included. Overall survival (OS) was defined as time from surgery to the last follow-up date on 01.10.2010. OS was evaluated using Kaplan-Meier method, and log-rank test was used to asses the differences between the positive and E-cadherin negative group. Multivariate analysis was completed using the Cox proportional hazard regression model.

RESULTS:

E-cadherin immunoreactivity was not associated with FIGO stage, tumour grade, number of mitotic figures per 10 HPF, residual tumour volume or vascular invasion. Negative E-cadherin expression significantly predicted shorter OS (p < 0.001). The multivariate analyses showed that negative E-cadherin (p < 0.001), FIGO stage (p = 0.012) and residual tumour size >1 cm after the initial cytoreductive surgery (p < 0.001) were predictors of shorter OS.

CONCLUSION:

Negative E-cadherin expression like presence of residual tumour after primary cytoreductive surgery and higher FIGO stage seem to predict unfavourable clinical outcome in patients with advanced-stage serous ovarian cancer. Negative expression of E-cadherin was shown to be a significant independent predictor of poorer OS. E-cadherin as marker has prognostic value.

Springerlink

Nail toxicity associated with Paclitaxel treatment for ovarian cancer.

Jan 2103

Swenson KK, Bell EM, Nissen J.

Source

Park Nicollet Institute, St. Louis Park, MN.

Abstract

A 57-year-old woman named C. B. began experiencing abdominal pain and bloating. She presented to her primary physician with these symptoms, and her physician palpated an adenexal mass on pelvic examination. That prompted a computed tomography (CT) scan of the abdomen and pelvis, which demonstrated omental thickening as well as a mildly enlarged left ovary. After initial consultation with a gynecologic oncologist, C. B. was taken to surgery and a total abdominal hysterectomy bilateral salpingo-oophorectomy omentectomy partial bowel resection, and pelvic and periaortic lymph node dissection were performed. C. B. was diagnosed with stage IV ovarian cancer involving the omentum, pelvic lymph nodes, and bowel wall and was subsequently referred for postoperative chemotherapy.

PubMed

Ovarian cancer Images

Ban Back Together - Ovarian Cancer Resources




Highly recommend this site and in particular the article on staging.

National Ovariance Cencer Network




MD Guidelines

Gonadatrophin Suppression to Prevent Chemotherapy-Induced Ovarian Damage: A Randomized Controlled Trial.

Jan 2013

Elgindy EA, El-Haieg DO, Khorshid OM, Ismail EI, Abdelgawad M, Sallam HN, Abou-Setta AM.

Source

Al-Banoon Fertility Centre, the Departments of Obstetrics and Gynecology and Clinical Oncology, Zagazig University School of Medicine, Zagazig, the Department of Medical Oncology, National Cancer Institute, Cairo University School of Medicine, Cairo, and the Department of Obstetrics and Gynecology, Alexandria University School of Medicine, and the Alexandria Regional Centre for Women's Health, Alexandria, Egypt; and the George and Fay Yee Centre for Healthcare Innovation, University of Manitoba/Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada.

Abstract

OBJECTIVE: To estimate the effectiveness of gonadotropin-releasing hormone (GnRH) analogues cotreatment in preventing chemotherapy-induced amenorrhea in young breast cancer patients undergoing cyclophosphamide-based chemotherapy. 

METHODS: One hundred hormone-insensitive breast cancer participants (aged 18-40 years) were recruited from two university-affiliated oncology centers in Egypt. Opting for type of cotreatment was based on available timeframe until start of chemotherapy. Fifty women ready for early chemotherapy were randomized to receive either chemotherapy alone (arm I) or chemotherapy after downregulation (estradiol less than 50 pg/mL) by GnRH antagonist and agonist (arm II). Then, GnRH antagonist was discontinued and agonist was continued until the end of chemotherapy. When chemotherapy was to start later than 10 days after study inclusion, 50 women were randomized to receive either chemotherapy alone (arm III) or chemotherapy after downregulation with GnRH agonist (arm IV). Resumption of menstruation at 12 months after end of chemotherapy was the primary outcome. Postchemotherapy hormonal and ultrasound changes were secondary outcomes. 

RESULTS: Twelve months after termination of chemotherapy, there were no differences in menstruation resumption rates between GnRH-treated patients and control group individuals in either early (80% in arms I and II, risk ratio 1, 95% confidence interval 0.7-.32; P=1.00) or delayed chemotherapy groups (80% and 84% in arms III and IV, risk ratio 0.95, 95% confidence interval 0.73-1.235; P=.71). There were no differences in hormonal and ultrasound markers between GnRH analogue users and control group individuals. The use of GnRH analogue cotreatment did not predict independently the odds of menstruating at 12 months. 

CONCLUSION: GnRH analogue cotreatment does not offer a significant protective effect on ovarian function in patients treated by cyclophosphamide-based chemotherapy. CLINICAL TRIAL REGISTRATION:: Australian New Zealand Clinical Trials Registry. www.anzctr.org.au, ACTRN12609001059257. LEVEL OF EVIDENCE:: I.

PubMed

Update on gynecopathology.

[Article in German]

Schmidt D.

Source

Referenzzentrum für Gynäkopathologie, Institut für Pathologie, A 2, 2, 68159, Mannheim, Deutschland, dischmi57@gmail.com.

Abstract

Recent years have witnessed significant achievements in light microscopic, immunohistochemical and molecular diagnostics in gynecopathology. In this article four topics will be discussed as examples. The squamous precancerous and carcinomatous lesions of the female anogenital tract and the cervix are caused by a transforming high risk human papillomavirus (HPV) infection. No differences in morphological findings can be found between the different locations. In contrast to the current WHO classification a new categorization into low grade and high grade precancerous lesions is suggested. Only some cervical adenocarcinomas are related to high risk HPV infection. Nevertheless, some of these unusual variants demonstrate p16 overexpression. Uterine leiomyosarcomas are clinically aggressive neoplasmsindependent of the histological grade and in most cases curative treatment is not feasible. It is most important to distinguish leiomyosarcoma from those leiomyoma variants which mimic uterine leiomyosarcoma. Pelvic and ovarianserous carcinomas can be separated into low grade and high grade types which differ significantly in formal pathogenesis, molecular features and pathomorphological findings. Significant differences are also obvious in clinical behavior and response to chemotherapy regimens.

PubMed

Many have ovary surgery even with negative gene test

Dec 18, 2012

Many women who test negative for gene mutations that heighten the risk of ovarian cancer still get their ovaries removed despite a lack of evidence that it reduces the risk of dying, says a new study.

"A higher number than expected went through with the surgery, and it probably has to do with doctors in the community not having enough information on their patients' risk levels," said Dr. Gabriel Mannis, the study's lead author.

According to Mannis and his colleagues, who published their study in the Archives of Internal Medicine on Monday, the average woman's risk of developing ovarian cancer is about 2 percent, but women with BRCA1 and BRCA2 gene mutations have a 40 percent and 20 percent risk, respectively.

For women that test positive for the gene mutations, the American Congress of Obstetricians and Gynecologists (ACOG) says, if they choose to have their ovaries removed, it should be when they are done having children and near 40 years old.

There are no guidelines, however, on ovary removal and screening for women whose blood tests don't show the gene mutations but who may still be at an increased risk of cancer based on their family's medical history.

"We don't have a clear sense of what their risk level is, or what the role of screening should be," said Mannis, of the division of oncology at the University of California, San Francisco.

For the new study, the researchers surveyed women at two hospitals about 4 years after they were tested for the gene mutations to see if they decided to be screened or have their ovaries removed.

Of 1,077 women surveyed, about 19 percent tested positive for a BRCA mutation, about 10 percent had no mutation, and the rest had unclear results.

The researchers found that about 70 percent of the women who tested positive for a mutation had their ovaries removed by the time they took the survey.

But, despite a lack of evidence that they should have their ovaries removed, about 12 percent of the women with unclear results still had the surgery.

Ovarian cancer screening

The researchers also found that despite the U.S. Preventive Services Task Force recommending against screening for ovarian cancer in women without the gene mutations, about 20 percent of women whose test results didn't clearly show the mutations still ended up getting screened in the year before taking the survey.

In a previously published study, women screened annually for ovarian cancer were no less likely to die from the disease than those who didn't get regular screening.

Aside from not being shown to help, the tests are also imperfect, said Dr. Jed Delmore, chair the Gynecologic Oncology Sub-committee for ACOG.

"I can simply say that as of today we don't have a good screening," said Delmore, of the University of Kansas School of Medicine in Wichita.

"At this point if doctors are going to proceed with screening in this group of women, there needs to be a conversation that we don't really know if this will prevent you from dying sooner of ovarian cancer or that it may come back as a false positive," said Mannis.

In that previous study, about one in ten screened women had a false positive result, and of those a third had one or both ovaries removed.

That means some women had both ovaries removed even though they were not at an increased risk for cancer, which needlessly put them in danger of a complication and forced them into menopause.

Plus, the removing an ovary can cost over $3,000.

Delmore told Reuters Health that it seems like an intermediate ground has been reached with a majority of BRCA-positive women having surgery to reduce their risk, and fewer BRCA-negative women having it.

He agreed with Mannis that doctors need to be honest with their patients about the limitations of today's screenings and treatments.

"We have pretty solid information for women who are BRCA positive and clearly BRCA negative," he said. "It's just that group in the middle."

Mannis told Reuters Health that the next step would be to identify that group's risk levels, but both he and Delmore said that won't be easy.

Fox News

Longitudinal Algorithm May Detect Ovarian Cancer Earlier

Dec 2012

(HealthDay News) – Compared with a single-threshold (ST) rule, a parametric empirical Bayes (PEB) longitudinal screening algorithm can identify ovarian cancer earlier and at a lower concentration of CA125, according to research published online Dec. 17 in the Journal of Clinical Oncology.

Charles W. Drescher, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues compared an ST rule with a PEB longitudinal screening algorithm in a retrospective evaluation of preclinical CA125 values measured annually in 44 participants with incident ovarian cancer from the Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial.

The researchers found that, in many cases, ovarian cancer was detected earlier using the PEB algorithm, compared to using an ST rule. At a specificity of 99%, corresponding to an ST rule CA125 cut-off of ≥35U/mL used in the PLCO trial, use of the PEB algorithm would have identified 20% of cases earlier. The PEB indicated abnormal CA125 values among these cases 10 months earlier and at a lower CA125 concentration (42% lower; 20U/mL) than an ST rule cut-off. As the specificity of screening was reduced, there was an increase in the proportion of cases detected earlier by PEB.

"Our results demonstrated that, for ovarian cancer screening by using CA125, the PEB longitudinal algorithm detected ovarian cancer earlier than an ST rule in a statistically significant and meaningful proportion of cases," the authors write. "This observation was consistent across a range of specificities relevant for a first-line test in a multimodal screening program."

Journal of Clinical Oncology

BRCA testing impact on ovarian cancer prevention revealed

Published on December 24, 2012 at 9:15 AM

By Lynda Williams, Senior medwireNews Reporter

Research shows that women without a confirmed BRCA mutation are choosing to undergo screening or surgery to prevent ovarian cancer, despite little evidence to support their use in this population.

After BRCA mutation testing and genetic counseling, a significant proportion of women with an uninformative result underwent risk-reducing salpingo-pophorectomy (RRSO; 12.3%), screening transvaginalultrasonography  (TVUS; 37.3%), or serum cancer  antigen (CA)-125 testing (33.8%).

"For most women with uninformative BRCA results, RRSO and ovarian cancer screening may not be appropriate, barring strong family histories of ovarian cancer," caution Gabriel Mannis (University of California, San Francisco, USA) and co-workers in the Archives of Internal Medicine.

The team followed up 1077 women for a median of 3.7 years after genetic counseling and BRCA testing. A positive BRCA test was confirmed in 18.7% of the patients, 9.6% had a true-negative result, and 71.8% had an uninformative test.

Compared with an uninformative result, a positive BRCA test strongly and significantly predicted the likelihood a woman would undergo RRSO (odds ratio [OR]=28.1), TVUS (OR=9.5), and serum cancer antigen (CA)-125 screening (OR=13.0).

This is in line with guidelines from the American College of Obstetricians and Gynecologists that recommend RRSO in BRCA-positive women aged over 40 years or after childbearing is complete, Mannis et al observe.

Conversely, a true-negative result was associated with a significantly reduced risk for RRSO (OR=0.1), TVUS (OR=0.2), and serum CA-125 screening (OR=0.3) compared with an uninformative test.

With a low 1-2% lifetime risk for ovarian cancer and the potential harm associated with false-positive test screening results, the team says these findings are in line with the knowledge that there is "insufficient evidence to recommend ovarian cancer screening for women with true-negative BRCA results."

Recognizing that the long-term risk for ovarian cancer in women with an uninformative BRCA test result is unknown, the researchers comment: "Because this population likely represents a heterogeneous group… it is possible that certain subgroups, such as women with strong family histories of ovarian cancer, may be at higher-than-average risk.

"In the face of such uncertainty, patients and physicians may opt to obtain screening tests despite the absence of evidence-based guidelines and the questionableefficacy. of these tests."

News MedicalNet

Scientists discover gene linked to breast and ovarian cancer

17 December 2012

A team of researchers led by the Institute of Cancer Research, London, have found that rare mutations in a gene called PPM1D are linked to an increased risk of breast and ovarian cancer. The mutations are not inherited, and the discovery potentially reveals a new mechanism of cancer development.

The study suggests that around one in five women with PPM1D mutations will develop breast or ovarian cancer in the course of their lifetime, almost double the breast cancer risk and more than ten times the ovarian cancer risk of women in the general population. The discovery could have implications for genetic testing and targeted prevention, in particular for ovarian cancer, which is often diagnosed at an advanced stage.

The team analysed 507 genes involved in DNA repair in 1150 women with breast or ovarian cancer, identifying PPM1D gene mutations in five women. They then sequenced the PPM1D gene in 7781 women with breast or ovarian cancer and 5861 people from the general population.

There were 25 faults in the PPM1D gene in women with cancer and only one in the general population, a highly statistically significant difference.

The study found that the mutated genes were not passed down from parent to child and were not present in every cell. Even more surprisingly, there were no PPM1D mutations in the cancer cells or in the normal breast or ovarian cells; they were found only in blood cells. The findings suggest that PPM1D works in a completely different way to other genes known to increase the risk of breast and ovarian cancer, such as BRCA1 and BRCA2, potentially highlighting a new cancer-causing mechanism.

The team found that the mutations made the molecule that is produced from the PPM1D gene shorter than usual. Such truncating mutations are usually thought to cause a loss of function; however, the team were surprised to find that in this case the PPM1D mutations seem to make it more active.

Study leader Professor Nazneen Rahman, head of genetics at the Institute of Cancer Research (ICR) and head of the cancer genetics clinical unit at the Royal Marsden NHS Foundation Trust, said: "This is one of our most interesting and exciting discoveries.

"At every stage the results were different from the accepted theories. We don't yet know exactly how PPM1D mutations are linked to breast and ovarian cancer, but this finding is stimulating radical new thoughts about the way genes and cancer can be related."

"The results could also be useful in the clinic, particularly for ovarian cancer, which is often diagnosed at an advanced stage. If a woman knew she carried a PPM1D mutation and had a one in five chance of developing ovarian cancer, she might consider keyhole surgery to remove her ovaries after completing her family."

Professor Alan Ashworth, chief executive of The Institute of Cancer Research and one of the study researchers, said: "This discovery really does turn conventional wisdom about the way genetic mutations can lead to cancer on its head. We are likely to gain many valuable insights into how cancers can occur as we continue to unravel this puzzle."

New genetic sequencing technologies that allow much deeper analysis of genes were crucial to enable the team to make the link between the PPM1D mutations and cancer. The discovery that the mutations were only present in some cells, a so-called mosaic pattern, would have been extremely difficult to detect with older sequencing methods.

It is possible that similar mosaic mutations in other genes, and in patients with other types of cancer, will emerge as more research groups are now using these deep sequencing techniques, the authors say.

Dr Michael Dunn, head of molecular and physiological sciences at the Wellcome Trust, said: "This study is an fantastic example of the power of next-generation sequencing to discover new cancer predisposing genes, offering opportunities for better diagnosis. The discovery also opens up a very exciting new avenue of research in the study of cancer development."

WelcomeTrust

Diabetes drug may treat ovarian cancer

Kathy Boltz, PhD

December 17, 2012

Patients with ovarian cancer who took the drug metformin for diabetes had a better survival rate than patients who did not take the drug. These findings may play an important role for researchers as they study the effectiveness of existing medications in treating different or new diseases.

Metformin is widely prescribed for managing diabetes, and previous research by others has shown its promise for other cancers. This study adds ovarian cancer to the list.

The research team compared the survival of 61 patients with ovarian cancer who were taking metformin and 178 patients who were not taking metformin. After 5 years, 67% of the patients who took metformin were still surviving, compared with 47% of those who did not take the medication. When the researchers analyzed factors such as the patients' body mass index, the severity of the cancer, type of chemotherapy, and quality of surgery, the patients taking metformin were nearly four times more likely to survive compared with those not taking the medication.

“Our study demonstrated improved survival in women with ovarian cancer that were taking metformin,” says coauthor Sanjeev Kumar, MBBS, a Mayo Clinic gynecologic oncology fellow. “The results are encouraging, but as with any retrospective study, many factors cannot be controlled for us to say if there is a direct cause and effect. Rather, this is further human evidence for a potential beneficial effect of a commonly used drug which is relatively safe in humans. These findings should provide impetus for prospective clinical trials in ovarian cancer.”

The researchers explained that the results may pave the way for using metformin in large-scale randomized trials of ovarian cancer. The high rate of mortality in ovarian cancer indicates the great need to develop new therapies. Metformin may potentially be one of those options

Oncology Nurse Advisor

Initial report on differential expression of sprouty proteins 1 and 2 in human epithelial ovarian cancer cell lines.

2012

Moghaddam SM, Amini A, Wei AQ, Pourgholami MH, Morris DL.

Source

Cancer Research Laboratories, Department of Surgery, St. George Hospital, The University of New South Wales, Sydney, NSW 2217, Australia.

Abstract

Sprouty (Spry) proteins, modulators of receptor tyrosine kinase signaling pathways, have been shown to be deregulated in a variety of pathological conditions including cancer. In the present study we investigated the expression of Spry1 and Spry2 isoforms in a panel of human ovarian cancer cell lines in vitro. Our western blot analysis showed nonuniform patterns of Spry expression in the cancer cells, none of which conformed to the pattern observed in the normal ovarian epithelial cells employed as the control. Among the seven cancer cell lines studied, Spry1 was expressed lower in four cell lines and higher in one as compared with the control. As for Spry2, four cell lines showed lower and two exhibited higher expression. Results from RT-PCR assay raised the possibility that Spry protein levels may not necessarily correspond with its expression at mRNA level. Our immunostaining study revealed that Spry2 was predominantly distributed within the whole cytoplasm in vesicular structures whereas Spry1 was found in both the cytoplasm and nucleus. This might provide clues to further investigation of Spry mode of action and/or function. Collectively, our study unveiled the differential expression of Spry1 and Spry2 proteins in various ovarian cancer cell lines.

PubMed

Current status and implications of microRNAs in ovarian cancer diagnosis and therapy

Current status and implications of microRNAs in ovarian cancer diagnosis and therapy

Ovarian cancer is the fifth most common cancer among women and causes more deaths than any other type of female reproductive cancer. Currently, treatment of ovarian cancer is based on the combination of surgery and chemotherapy.

While recurrent ovarian cancer responds to additional chemotherapy treatments, the progression-free interval becomes shorter after each cycle, as chemo-resistance increases until the disease becomes incurable. There is, therefore, a strong need for prognostic and predictive markers to help optimize and personalize treatment in order to improve the outcome of ovarian cancer.

An increasing number of studies indicate an essential role for microRNAs in ovarian cancer progression and chemo-resistance. MicroRNAs (miRNAs) are small endogenous non-coding RNAs (~22bp) which are frequently dysregulated in cancer.

Typically, miRNAs are involved in crucial biological processes, including development, differentiation, apoptosis and proliferation. Two families of miRNAs, miR-200 and let-7, are frequently dysregulated in ovarian cancer and have been associated with poor prognosis.

Both have been implicated in the regulation of epithelial-to-mesenchymal transition, a cellular transition associated with tumor aggressiveness, tumor invasion and chemo-resistance. Moreover, miRNAs also have possible implications for improving cancer diagnosis; for example miR-200 family, let-7 family, miR-21 and miR-214 may be useful in diagnostic tests to help detect ovarian cancer at an early stage.

Additionally, the use of multiple target O-modified antagomirs (MTG-AMO) to inhibit oncogenic miRNAs and miRNA replacement therapy for tumor suppressor miRNAs are essential tools for miRNA based cancer therapeutics. In this review we describe the current status of the role miRNAs play in ovarian cancer and focus on the possibilities of microRNA-based therapies and the use of microRNAs as diagnostic tools.

Author: Mohd Saif ZamanDiane M MaherSheema KhanMeena JaggiSubhash C Chauhan
Credits/Source: Journal of Ovarian Research 2012, 5:44

7th Space Interactive

The molecular biology of epithelial ovarian cancer.

Dec 2012

Leary A, Pautier P, Tazi Y, Morice P, Duvillard P, Gouy S, Uzan C, Gauthier H, Balleyguier C, Lhommé C.

Source

Institut Gustave-Roussy, département de médecine, comité pluridisciplinaire de gynécologie, 114, rue Édouard-Vaillant, 94800 Villejuif, France.

Abstract

Epithelial ovarian cancer frequently presents at an advanced stage where the cornerstone of management remains surgery and platinum-based chemotherapy. Unfortunately, despite sometimes dramatic initial responses, advanced ovarian cancer almost invariably relapses. Little progress has been made in the identification of effective targeted-therapies for ovarian cancer. The majority of clinical trials investigating novel agents have been negative and the only approved targeted-therapy is bevacizumab, for which reliable predictive biomarkers still elude us. Ovarian cancer is treated as a uniform disease. Yet, biological studies have highlighted the heterogeneity of this malignancy with marked differences in histology, oncogenesis, prognosis, chemo-responsiveness, and molecular profile. Recent high throughput molecular analyses have identified a huge number of genomic/phenotypic alterations. Broadly speaking, high grade serous carcinomas (type II) display significant genomic instability and numerous amplifications and losses; low grade (type I) tumors are genomically stable but display frequent mutations. Importantly, many of these genomic alterations relate to known oncogenes for which targeted-therapies are available or in development. There is today a real potential for personalized medicine in ovarian cancer. We will review the current literature regarding the molecular characterization of epithelial ovarian cancer and discuss the biological rationale for a number of targeted strategies. In order to translate these biological advances into meaningful clinical improvements for our patients, it is imperative to incorporate translational research in ovarian cancer trials, a number of strategies will be proposed such as the acquisition of quality tumor samples, including sequential pre- and post-treatment biopsies, the potential of liquid biopsies, and novel trial designs more adapted to the molecular era of ovarian cancer research.

PubMed

Gold nanorods detect ovarian cancer, improve surgical removal in mice

Gold nanorods detect ovarian cancer, improve surgical removal in mice
Dec. 2012

Nanowerk News) Using gold nanorods that are visible using two different types of imaging techniques, researchers at the Stanford University Center for Cancer Nanotechnology Excellence and Translation, (Stanford CCNE-T) have developed a promising new method that may be able to detect early stage ovarian cancer and help surgeons completely remove the detected tumor. The researchers have successfully tested this imaging agent in an animal model of human ovarian cancer and are already working on an improved agent that may be able to discriminate between malignant and benign ovarian masses. The Stanford CCNE-T team, led by Sanjiv Sam Gambhir, reported its findings in the journal ACS Nano ("Gold Nanorods for Ovarian Cancer Detection with Photoacoustic Imaging and Resection Guidance via Raman Imaging in Living Mice").

Ovarian cancer is the fifth most common cancer among women, and it causes more deaths than any other type of female reproductive cancer, largely because ovarian cancer symptoms are vague and it most often goes undiagnosed until it has spread to other parts of the body. However, when detected early, the five-year survival rate is as high as 95 percent, so the development of non-invasive and inexpensive technology to detect early stage ovarian cancer could have a profound impact on patient survival.

To create their new imaging agent, Dr. Gambhir’s team took advantage of the unique properties of gold nanorods, which interact strongly with light in a variety of useful ways. For example, gold nanorods will absorb near-infrared light and produce heat that creates a pressure wave that can be detected with standard ultrasound devices that are already used widely in doctor’s offices. This technique is known as photoacoustic spectroscopy. Gold nanorods will also generate a well-defined optical emission that can be detected using surface-enhanced Raman spectroscopy (SERS), another well-established measurement technology.

Another useful property of nanorods in general is that their shape somehow enables them to accumulate more effectively than spherical particles around tumors. Researchers assume that the long, thin shape enables the rods to more easily penetrate and escape the leaky blood vessels that surround tumors.

To assess the imaging capabilities of gold nanorods, the investigators created three different batches that varied in the ratio of their length to width, also known as the aspect ratio. Based on the intensity of the photoacoustic signal and the Raman signal, the researchers settled on a gold nanorod with an aspect ratio of 3.5 (756 nm absorbance) for further testing. When injected intravenously into mice bearing human ovarian tumors, these gold nanorods were readily detected through the skin in and around tumors in live animals. The researchers noted that the photoacoustic signal from the injected nanorods remained stable for three days, while signal from nanorods circulating in blood returned to baseline levels within 24 hours, a desirable trait for a clinically useful imaging agent.

Next, Dr. Gambhir and his colleagues used the SERS signal to guide surgical removal of the tumors. Presurgical images clearly showed the location and edges, or margins, of even small tumors, and post-surgical imaging confirmed that all traces of tumor were removed.

Though the photoacoustic signal from the gold nanorods can be detected through as much as 4 centimeters (just over 1.5 inches) of tissue, Dr. Gambhir and his colleagues are developing photoacoustic catheters that will further increase the number of accessible sites. They are also developing nanorods targeted specifically to malignant ovarian tumors that would not only accumulate better in tumors, but may also be able to distinguish malignant from benign ovarian masses.

Source: National Cancer Institute

Immune Response Evaluation Through Determination of Type 1, Type 2, and Type 17 Patterns in Patients With Epithelial Ovarian Cancer.

Dec 2012

Cândido EB, Silva LM, Carvalho AT, Lamaita RM, Filho RM, Cota BD, Silva-Filho AL.

Source

1Department of Obstetrics and Gynecology, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Abstract

Innate and adaptive immune cells secrete different cytokines, which participate through distinct mechanisms in cell-mediated immunity and humoral immune responses. The aim of this study was to evaluate the immune response through analysis of type 1 (Th1), Th2, and Th17 cells in patients with epithelial ovarian cancer (EOC). Our study included 44 patients with EOC (study group) and 32 gynecological patients with no ovarian disease (control group). Fragments of ovarian tissue and blood samples were collected in both groups and aliquots of intracystic fluid and peritoneal fluid were recovered from the EOC patient group. Interleukin (IL)-2/IL-4/IL-6/IL-10/IL-17/tumor necrosis factor (TNF)-α/interferon (IFN)-γ levels were measured by cytometric bead array. Statistical analysis included chi-squared, Student t, Mann-Whitney, Kruskal-Wallis tests, and Cox regression model. Patients with EOC were associated with higher levels of TNF-α/IL-4/IL-6/IL-10 compared to the control group. Both IL-10 and TNF-α concentrations were higher in patients with stage III/IV EOC and also associated with higher levels of cancer antigen 125. Higher Th1-mediated immune response was observed when the cytoreduction was considered optimal. 

However, patients with EOC with unsatisfactory cytoreductive surgery and undifferentiated tumors were associated with higher concentrations of Th2 cytokines in the 4 sites studied. Higher IL-6/IL-10 and lower IFN-γ concentrations were also associated with a lower overall survival rate in patients with EOC. The EOC group presented a predominantly Th2 response and an immunosuppressant standard and had association between IL-6/IL-10/IFN-γ and prognosis.

PubMed