A Way to Kill Chemo-Resistant Ovarian Cancer Cells: Cut Down Their Protector

A recent study provides new insight into why ovarian cancer is often resistant to chemotherapy, as well as a potential way to improve its diagnosis and treatment.

Protein Data Base 3-D rendering of the Gelsolin protein. (Photo: Wikipedia)

Protein Data Base 3-D rendering of the gelsolin protein. (Photo: Wikipedia)

Ovarian cancer is the most lethal gynecological cancer, claiming the lives of more than 60% of women who are diagnosed with the disease. A study involving Ottawa and Taiwan researchers, published in the influential Proceedings of the National Academy of Sciences (PNAS), provides new insight into why ovarian cancer is often resistant to chemotherapy, as well as a potential way to improve its diagnosis and treatment.

It is estimated that 2,700 Canadian women will be diagnosed with ovarian cancer in 2014 and that 1,750 Canadian women will die from the disease, according to Ovarian Cancer Canada. This cancer is often diagnosed late and develops a resistance to chemotherapy.

tsang_ben

Dr. Ben Tsang

“What we’ve discovered will help clinicians to better treat women with ovarian cancer,” says Dr. Ben Tsang, senior scientist at the Ottawa Hospital Research Institute and professor at the University of Ottawa. “The key is understanding the role of a protein called “gelsolin.” With our colleagues from National Cheng Kung University in Taiwan, we found that an increased level of this protein is associated with aggressive forms of ovarian cancer that are more likely to be resistant to chemotherapy and lead to death.”

The researchers showed how gelsolin works at the molecular level to protect cancer cells against a widely used chemotherapy drug called “cisplatin.”

The findings are important because they will help clinicians to determine the most effective treatment plan based on the level of gelsolin. Work still needs to be done to determine exactly how much gelsolin indicates a cancer that is chemo-resistant and would require different treatment options.

In addition, this same protein that makes ovarian cancer cells resistant to chemotherapy can be used to overcome this treatment obstacle. By cutting gelsolin down to a specific fragment and putting it into chemo-resistant cancer cells, the international team discovered they could make these cells susceptible to the cancer-killing effects of cisplatin.

Shieh

Dr. Dar-Bin Shieh

“We believe this discovery is a promising avenue for developing a new therapy to reduce chemo-resistance in women with this deadly disease,” said Dr. Dar-Bin Shieh, collaborative partner from National Cheng Kung University of Taiwan. Shieh is currently leading the International Institute of Macromolecular Analysis and Nanomedicine Innovation (IMANI), which is focused on translating molecular discoveries to the clinic.

Based on 2009 estimates, approximately one in 72 Canadian women will develop ovarian cancer in her lifetime and one in 93 will die from it.

This study was supported by the Canadian Institutes of Health Research and the National Science Council of Taiwan.

Ottawa Hospital Research Institute
The Ottawa Hospital Research Institute is the research arm of The Ottawa Hospital and is an affiliated institute of the University of Ottawa, closely associated with its faculties of Medicine and Health Sciences. The Ottawa Hospital Research Institute includes more than 1,700 scientists, clinical investigators, graduate students, postdoctoral fellows and staff conducting research to improve the understanding, prevention, diagnosis and treatment of human disease. Research at Ottawa Hospital Research Institute is supported by The Ottawa Hospital Foundation.

University of Ottawa: A crossroads of cultures and ideas
The University of Ottawa is home to almost 50,000 students, faculty and staff, who live, work and study in both French and English. The campus is a crossroads of cultures and disciplines, where bold minds come together to inspire game-changing ideas. The University of Ottawa is one of Canada’s top 10 research universities — our professors and researchers explore new approaches to today’s challenges. One of a handful of Canadian universities ranked among the top 200 in the world, we attract exceptional thinkers and welcome diverse perspectives from across the globe.

National Cheng Kung University
National Cheng Kung University (NCKU) is a research-led comprehensive university in Tainan City, Taiwan. Since its establishment in 1931, NCKU has nurtured countless social elites and leaders under the trailblazing efforts of its former faculties and staffs. NCKU is one of the most prestigious universities in Taiwan, with a high reputation in science, engineering, medicine, management, planning and design. The university is a role model for the transformation of Taiwan’s higher-educational institutes, and is also an important pillar of the country’s economic and industrial structure.

Sources:

Stanford Researchers Create “Evolved” Protein That May Stop Breast & Ovarian Cancers From Spreading

 Early but promising tests in lab mice suggest that a bioengineered protein therapy, administered intravenously, may halt the spread of breast and ovarian cancers from their original tumor sites. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules when treated with the engineered decoy protein. This approach might one day provide an alternative to, or supplement, chemotherapy.

A team of Stanford researchers has developed a protein therapy that disrupts the process that causes cancer cells to break away from the original tumor site, travel through the bloodstream and start aggressive new growths elsewhere in the body.

stanford metastasis_news

Drs. Jennifer Cochran and Amato Giaccia led a team of researchers who have developed an experimental therapy to treat metastatic cancer. (Photo: Rod Searcey)

This process, known as “metastasis,” can cause cancer to spread with deadly effect.

“The majority of patients who succumb to cancer fall prey to metastatic forms of the disease,” said Dr. Jennifer Cochran, an associate professor of bioengineering, who describes a new therapeutic approach in Nature Chemical Biology.

Today, doctors try to slow or stop metastasis with chemotherapy, but these treatments are unfortunately not very effective and have severe side effects.

The Stanford team seeks to stop metastasis, without side effects, by preventing two proteins – Axl and Gas6 – from interacting to initiate the spread of cancer.

Axl proteins stand like bristles on the surface of cancer cells, poised to receive biochemical signals from Gas6 proteins.

When two Gas6 proteins link with two Axls, the signals that are generated enable cancer cells to leave the original tumor site, migrate to other parts of the body, and form new cancer nodules.

To stop this process Cochran used protein engineering to create a harmless version of Axl that acts like a decoy. This decoy Axl latches on to Gas6 proteins in the bloodstream and prevents them from linking with and activating the Axls present on cancer cells.

In collaboration with Dr. Amato Giaccia, who leads the Radiation & Cancer Biology Program in the Stanford Cancer Center, the researchers gave intravenous treatments of this bioengineered decoy protein to mice with aggressive breast and ovarian cancers.

The mice in the breast cancer treatment group had 78 percent fewer metastatic nodules than the untreated mice. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules when treated with the engineered decoy protein.

“This is a very promising therapy that appears to be effective and nontoxic in preclinical experiments,” Giaccia said. “It could open up a new approach to cancer treatment.”

Drs. Giaccia and Cochran are scientific advisors to Ruga Corporation, a biotechnology startup located in Palo Alto that has licensed this technology from Stanford. Further preclinical and animal tests must be done before determining whether this therapy is safe and effective in humans.

Professor, Molecular Neurobiology Laboratory,  Françoise Gilot-Salk Chair

Professor, Molecular Neurobiology Laboratory,
Françoise Gilot-Salk Chair, Salk Institute

Greg Lemke, of the Molecular Neurobiology Laboratory at the Salk Institute, called this “a prime example of what bioengineering can do” to open new therapeutic approaches to treat metastatic cancer.

“One of the remarkable things about this work is the binding affinity of the decoy protein,” said Lemke, a noted authority on Axl and Gas6 who was not part of the Stanford experiments.

“The decoy attaches to Gas6 up to a hundredfold more effectively than the natural Axl,” Lemke said. “It really sops up Gas6 and takes it out of action.”

Directed Evolution

The Stanford approach is grounded on the fact that all biological processes are driven by the interaction of proteins, the molecules that fit together in lock-and-key fashion to perform all the tasks required for living things to function.

In nature, proteins evolve over millions of years. But bioengineers have developed ways to accelerate the process of improving these tiny parts using technology called “directed evolution.” This particular application was the subject of the doctoral thesis of Mihalis Kariolis, a bioengineering graduate student in Cochran’s lab.

Using genetic manipulation, the Stanford team created millions of slightly different DNA sequences. Each DNA sequence coded for a different variant of Axl.

The researchers then used high-throughput screening to evaluate more than 10 million Axl variants. Their goal was to find the variant that bound most tightly to Gas6.

 (Video: Tim Saguinsin, Ricecooker Studios)

Kariolis made other tweaks to enable the bioengineered decoy to remain in the bloodstream longer and also to tighten its grip on Gas6, rendering the decoy interaction virtually irreversible.

Yu Rebecca Miao, a postdoctoral scholar in Giaccia’s lab, designed the testing in animals and worked with Kariolis to administer the decoy Axl to the lab mice. They also did comparison tests to show that sopping up Gas6 resulted in far fewer secondary cancer nodules.

Irimpan Mathews, a protein crystallography expert at SLAC National Accelerator Laboratory, joined the research effort to help the team better understand the binding mechanism between the Axl decoy and Gas6.

Protein crystallography captures the interaction of two proteins in a solid form, allowing researchers to take X-ray-like images of how the atoms in each protein bind together. These images showed molecular changes that allowed the bioengineered Axl decoy to bind Gas6 far more tightly than the natural Axl protein.

Next Steps

Years of work lie ahead to determine whether this protein therapy can be approved to treat cancer in humans. Bioprocess engineers must first scale up production of the Axl decoy to generate pure material for clinical tests. Clinical researchers must then perform additional animal tests in order to win approval for and to conduct human trials. These are expensive and time-consuming steps.

But these early, promising results suggest that the Stanford approach could become a nontoxic way to fight metastatic cancer.

Glenn Dranoff, M.D., a professor of medicine at Harvard Medical School and a leading researcher at the Dana-Farber Cancer Institute, reviewed an advance copy of the Stanford paper but was otherwise unconnected with the research. “It is a beautiful piece of biochemistry and has some nuances that make it particularly exciting,” Dranoff said, noting that tumors often have more than one way to ensure their survival and propagation.

Axl has two protein cousins, Mer and Tyro3, that can also promote metastasis. Mer and Tyro3 are also activated by Gas6.

“So one therapeutic decoy might potentially affect all three related proteins that are critical in cancer development and progression,” Dranoff said.

Erinn Rankin, a postdoctoral fellow in the Giaccia lab, carried out proof of principle experiments that paved the way for this study.

Other co-authors on the Nature Chemical Biology paper include Douglas Jones, a former doctoral student, and Shiven Kapur, a postdoctoral scholar, both of Cochran’s lab, who contributed to the protein engineering and structural characterization, respectively.

Cochran said Stanford’s support for interdisciplinary research made this work possible.

Stanford ChEM-H (Chemistry, Engineering & Medicine for Human Health) provided seed funds that allowed Cochran and Mathews to collaborate on protein structural studies.

The Stanford Wallace H. Coulter Translational Research Grant Program, which supports collaborations between engineers and medical researchers, supported the efforts of Cochran and Giaccia to apply cutting-edge bioengineering techniques to this critical medical need.

Sources:

 

Role For Gemcitabine As Second-line Chemotherapy in Recurrent Clear Cell Ovarian Cancer

In a recent 2014 retrospective analysis involving 72 recurrent ovarian clear cell patients who underwent second-line therapy at one of 20 Italian centers over a 16-year period, the researchers noted that a small subgroup of patients who received the drug gemcitabine (Gemzar®) appeared to have a higher rate of tumor response, as compared to women who were treated with topotecan (Hycamtin®) or pegylated liposomal doxorubicin (Doxil®).

Clear Cell Carcinoma of the Ovary

Clear Cell Carcinoma of the Ovary

In the July 2014 issue of Oncology, Italian researchers present an interesting retrospective analysis of patients with recurrent clear-cell ovarian cancer [1], a fairly chemoresistant subtype of ovarian cancer that can be difficult to treat.

This retrospective analysis included 72 recurrent ovarian clear cell patients (OCCC), who underwent second-line therapy at one of 20 Italian centers over a 16-year period (as part of the “Multicenter Italian Trial in Ovarian Cancer” or “MITO-9”).

In 56% of the OCCC patients, the clear cell histology was “pure,” meaning the predominant cell type identified within the primary tumor was classified as clear cell (i.e., a subtype of epithelial ovarian cancer) by a molecular pathologist. Twenty-five patients were platinum-resistant, 18 patients were platinum-sensitive with a platinum-free interval (PFI) of 6-to-12 months, and 29 patients had a PFI >12 months. Upon disease recurrence, 47% of patients were treated with platinum chemotherapy (e.g., carboplatin or cisplatin) based upon PFI.

The overall tumor response rate (RR) to the use of platinum drugs was 80%, with 55%, 100%, and 80% RRs in patients with PFIs of 6-to-12 months, >12 months, and >24 months, respectively. The RR to non-platinum drugs in resistant OCCC patients was 33%. Among the non-platinum drugs used in primary and secondary resistant cases, gemcitabine (Gemzar®), administered to 12 OCCC patients, produced higher anti-cancer activity (RR = 66%), as compared to topotecan (Hycamtin®) or liposomal doxorubicin (Doxil®) (number of patients = 31; RRs = 33% and 10%, respectively).

The Italian researchers concluded that the overall study results suggest that the treatment of recurrent OCCC, in general, should be based upon the duration of the patient’s PFI, as is customary in the treatment of other epithelial ovarian cancer subtypes. However, the data relating to the platinum-resistant OCCC patients evaluated in the Italian study suggest that gemcitabine (Gemzar®) was the drug that produced the greatest anti-cancer activity.

Notably, the results reported by the Italian researchers are consistent with the similar findings reported in a small number of previous studies involving an equally small number of recurrent OCCC patients. [2 – 5]

Maurie Markman, M.D.

Also appearing in the July 2014 Oncology issue is a commentary written by Maurie Markman, M.D., the President of the Medicine and Science unit of the Cancer Treatment Centers of America (CTCA).[6] Dr. Markman oversees the CTCA national clinical team, with a focus on the application of all clinical and translational research to patient care. In his commentary, Dr. Markman notes the importance of retrospective studies as a “long-established tradition in clinical cancer investigation.” Dr. Markman highlights the potential inportance of retrospective studies as noted below.

  • Single institutional data or large multicenter efforts examining past experiences can serve both as “hypothesis-generating” elements for a future prospective clinical study, an idea to be explored in a translational laboratory research project, and even as confirmation of the results of a reported study in a more heterogeneous patient population.
  • Retrospective analyses can provide critically relevant data in populations known to be poorly represented in cancer clinical trials and may identify adverse events potentially not recognized in the often highly homogenous groups of study participants.
  • The safety and the efficacy associated with longer observation periods and a more prolonged therapy than reported in many prospective clinical trials can be revealed through retrospective examinations of previously treated patients.

Within this context, Dr. Markman addresses the limitations of the Italian recurrent OCCC retrospective analyses cited above, but he also emphasizes the potential benefit of that study, as follows:

“Of course, it must be emphasized that the very limited sample size does not permit any definitive conclusions regarding the relative utility of any individual strategy, including providing a truly meaningful ‘objective response rate’. However, recognizing the rarity of this specific malignant condition (72 total [OCCC] patients identified in a period of 16 years at 20 centers), this retrospective experience will likely be of some value to individual oncologists needing to consider potential therapeutic options for a patient with recurrent clear-cell ovarian cancer. Further, in the event a multi-institutional prospective trial is ultimately undertaken in this most uncommon clinical setting, the results of this retrospective analysis should surely help to inform the planned study design.” [emphasis added]

At Libby’s H*O*P*E*, we generally recommend that recurrent OCCC patients speak to their doctor about the potential benefits (and limitations) associated with (i) molecular/genomic tumor profiling,  and (ii) chemosensistivity and resistance assay (CSRA) testing. The use of both forms of tumor testing may provide a recurrent OCCC patient and her doctor(s) with additional insights related to specific treatment options. In the event that neither form of tumor testing is possible, the results from the Italian study discussed above suggest that the use of gemcitabine (Gemzar®) to treat recurrent OCCC should be, at a minimum, considered by a recurrent OCCC patient and her doctor.

In addition, we strongly recommend that a newly-diagnosed or recurrent OCCC patient should consider the drugs being currently evaluated, as of this writing, in open OCCC patient-dedicated clinical trials, including as temsirolimus (Torisel®) [7], sunitinib (Sutent®) [8], ENMD-2076 [9], and dasatinib (Sprycel®) [10].

References:

1./ Esposito F et al. Second-line chemotherapy in recurrent clear cell ovarian cancer: Results from the Multicenter Italian Trials in Ovarian Cancer (MITO-9). Oncology 2014;86:351-358. PubMed PMID:24942520.

2./ Yoshino K, et al. Salvage chemotherapy for recurrent or persistent clear cell carcinoma of the ovary: a single-institution experience for a series of 20 patients. Int J Clin Oncol. 2013 Feb;18(1):148-53. doi: 10.1007/s10147-011-0357-5. Epub 2011 Dec 10. PubMed PMID: 22160560.

3./ Komiyama S et al. A heavily pretreated patient with recurrent clear cell adenocarcinoma of the ovary in whom carcinomatous peritonitis was controlled successfully by salvage therapy with gemcitabine. Arch Gynecol Obstet. 2008 Dec;278(6):565-8. Epub 2007 Jun 19. Erratum in: Arch Gynecol Obstet. 2009 Feb;279(2):271. Komiyama, Shin [corrected to Komiyama, Shin-ichi]. PubMed PMID: 17576588.

4./ Ferrandina G et al. A case of drug resistant clear cell ovarian cancer showing responsiveness to gemcitabine at first administration and at re-challenge. Cancer Chemother Pharmacol. 2007 Aug;60(3):459-61. Epub 2007 Apr 11. PubMed PMID: 17429624.

5./ Crotzer DR et al. Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol Oncol. 2007 May;105(2):404-8. Epub 2007 Feb 9. PubMed PMID: 17292461.

6./ Markman M. A Unique Role for Retrospective Studies in Clinical Oncology. Oncology. 2014;86(5-6):350. doi: 10.1159/000360911. Epub 2014 Jun 12. PubMed PMID:24942408.

7./ A Phase II Evaluation of Temsirolimus (CCI-779) (NCI Supplied Agent: NSC# 683864,) in Combination With Carboplatin and Paclitaxel Followed by Temsirolimus (CCI-779) Consolidation as First-Line Therapy in the Treatment of Stage III-IV Clear Cell Carcinoma of the Ovary. ClinicalTrials.gov Identifier: NCT01196429.

8./ A Phase II Evaluation of the Efficacy of Sunitinib® in Patients With Recurrent Ovarian Clear Cell Carcinoma. ClinicalTrials.gov Identifier: NCT01824615.

9./ A Phase II Study of Oral ENMD-2076 Administered to Patients With Ovarian Clear Cell Carcinomas. ClinicalTrials.gov Identifier: NCT01914510.

10./ A Phase II Trial of DCTD-Sponsored Dasatinib (NSC #732517) in Recurrent/Persistent Ovary, Fallopian Tube, Primary Peritoneal, and Endometrial Clear Cell Carcinoma Characterized for the Retention or Loss of BAF250a Expression. ClinicalTrials.gov Identifier: NCT02059265.

 

 

Ovarian Cancer Cells Are More Aggressive On Soft Tissues

When ovarian cancer spreads from the ovaries it almost always does so to a layer of fatty tissue that lines the gut. A new study has found that ovarian cancer cells are more aggressive on these soft tissues due to the mechanical properties of this environment. The finding is contrary to what is seen with other malignant cancer cells that seem to prefer stiffer tissues.

Model Release-YES

Professor Michelle Dawson and graduate student Daniel McGrail used traction force microscopy to measure the forces exerted by cancer cells on soft and stiff surfaces. (Photo Credit: Rob Felt, Georgia Institute of Technology)

“What we found is that there are some cancer cells that respond to softness as opposed to stiffness,” said Michelle Dawson, an assistant professor in the School of Chemical and Biomolecular Engineering at the Georgia Institute of Technology. “Ovarian cancer cells that are highly metastatic respond to soft environments by becoming more aggressive.”

Ovarian cancer cells spread, or metastasize, by a different method than other cancer cells. Breast cancer cells, for example, break off from a solid tumor and flow through the blood until they arrest in small blood vessels. The cancer cells then penetrate the vessel surface to form a tumor. Because ovarian tumors are in the abdomen, these cancer cells are shed into the surrounding fluid and not distributed through the blood. They must be able to adhere directly to the fatty tissue that lines the gut, called the omentum, to begin forming a tumor. The new study discovered details about how ovarian cancer cells seem to prefer the mechanical properties of this soft tissue.

The study was published in a recent advance online edition of the Journal of Cell Science and was sponsored by the National Science Foundation and the Georgia Tech and Emory Center for Regenerative Medicine.

The research team, led by Daniel McGrail, a graduate student in the Dawson lab, found that ovarian cancer cells in vitro were more adherent to a layer of soft fat cells than a layer of stiffer bone cells, and that this behavior was also repeated using gels of similar rigidities.

“All the behaviors that we associate with breast cancer cells on these more rigid environments are flipped for ovarian cancer cells,” Dawson said.

After adhering to these soft surfaces, metastatic ovarian cancer cells became more aggressive. Their proliferation increased and they were less responsive to chemotherapeutics. The ovarian cancer cells were also more motile on soft surfaces, moving nearly twice as fast as on rigid surfaces.

The team also found that less aggressive cells that do not metastasize do not exhibit any of these changes.

The researchers used techniques that haven’t been traditionally used in the study of ovarian cancer. They measured the force exerted by the cells by tracking the displacement of beads in the environment around the cells. The researchers found that the metastatic cells increased their traction forces – used to generate motion – by three-fold on soft surfaces, but no such change was present in the less aggressive cells.

“We think the behavior that metastatic ovarian cancer cells exert on these soft surfaces is representative of the mechanical tropism that they have for these softer tissues in the gut,” Dawson said.

In future work, the researchers will investigate whether ovarian cancer cells have some natural inclination towards this uniquely more aggressive behavior in softer environments.

“We’re trying to find out whether there is some internal programming that leads to this aggressive behavior,” Dawson said.

This research is supported by the National Science Foundation under award number 1032527, and the Georgia Tech and Emory Center for Regenerative Medicine under award number 1411304. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agencies.

Source:  McGrail DJ, et al., The malignancy of metastatic ovarian cancer cells is increased on soft matrices through a mechanosensitive Rho-ROCK pathway. (Journal of Cell Science, 2014). http://dx.doi.org/10.1242/?jcs.144378.

Small Study Finds Tumor-Freezing Cryoablation Treatment Extends Survival of Select Metastatic Ovarian Cancer Patients

A small study of 21 ovarian cancer patients reported that killing tumors by freezing them through cryoablation can extend the lives of select women with metastatic disease which has spread to the abdomen, liver, lung or bone, and can not be removed surgically. From the time of diagnosis of metastatic disease, the average patient survival time was more than four years and seven months.

"Cryoablation" is a minimally invasive treatment that uses extreme cold ("cyro") to freeze and destroy diseased tissue ("ablation"), including cancer cells. (Photo: Wikipedia)

Killing tumors by freezing them through cryoablation can extend the lives of women with ovarian cancer that has spread to other parts of the body and is cost-effective, according to research being presented at the 4th annual Symposium on Clinical Interventional Oncology (CIO), in collaboration with the International Symposium on Endovascular Therapy (ISET).

Cryoablation Study Results

The study included 21 patients whose tumors in the abdomen, liver, lung and bone could not be removed surgically. Cryoablation was used to treat 48 tumors, killing 47 of them (98 percent). From the time of diagnosis of metastatic disease, average patient survival time was more than four years and seven months. That’s significant because when tumors are not successfully removed surgically – which occurs in about 60 percent of cases, according to studies – women typically survive from about seven months to 2 ½ years. On average, more than three years had transpired from the time of diagnosis to the first cryoablation treatment, meaning these women had already passed their expected survival time, and yet cryoablation was able to extend their survival even further. Some patients had multiple cryoablation treatments and of 41 procedures, there were three major complications (7 percent). The complications included two deaths that were attributed to the cancer, not to the procedure.

The study also determined the treatment was extremely cost-effective, costing an average of $26,806 per life year saved, well below the current standard of $100,000.

Hyun J. Bang, M.D., Radiologist Resident, Wayne State University/Detroit Medical Center

“This study adds to the evidence that cryoablation is an effective option for patients who can’t have surgery,” said study author Hyun J. Bang, M.D., a radiologist resident at Wayne State University/Detroit Medical Center. “This procedure is often overlooked, but based on the high survival rate, cost effectiveness, consistent local control and safety of the procedure, we should be taking a closer look at cryoablation.”

In cryoablation, a small needle is inserted into the tumor using imaging guidance. High pressure argon flows to the tip of the cryoprobe where it expands in an internal chamber, causing a powerful cooling effect on the outside of the probe. This allows for rapid ice formation which freezes and kills tumor cells.

For more about CIO and ISET, visit www.ISET.org/oncology.

Cryoablation Study Shortcomings — Potential Selection Bias

“While an interesting abstract, it must be stressed that the total number of patients included is extremely limited, and it is not appropriate to make any statement regarding the impact of this strategy on survival,” cautioned Maurie Markman, M.D., the senior vice president of clinical affairs and national director of medical oncology at the Cancer Treatment Centers of America Eastern Regional Medical Center in Philadelphia, Pennsylvania, in an interview with Medscape Medical News.

“Any observed outcome could very easily reflect bias in the selection of patients who have been included in this series. Considerable additional clinical evaluation must be undertaken to include far larger patient populations before any statement can be made regarding the potential of this approach to be a reasonable alternative to the current standard of care in the management of ovarian cancer,” Dr. Markman added.

Sources:

30-Day Mortality Associated With Primary Cytoreductive Surgery In Elderly Advanced Ovarian Cancer Patients Much Higher Than Previously Reported

Researchers affiliated with the University of Washington have determined that the 30-day mortality rate associated with primary cytoreductive surgery in elderly patients with advanced ovarian cancer is much higher than previously reported.

Researchers affiliated with the University of Washington have determined that the 30-day mortality rate associated with primary cytoreductive surgery in elderly patients with advanced ovarian cancer is much higher than previously reported. There research is based upon the analysis of statistics obtained from the National Cancer Institue (NCI) Surveillance, Epidemiology, and End Results (SEER) database (collectively, the NCI SEER database).

Melissa M. Thrall, M.D., Lead Study Author; Fellow, Department of Obstetrics & Gynecology, University of Washington School of Medicine

The lead author of the study is Melissa M. Thrall, M.D., a Fellow in the Department of Obstetrics & Gynecology, University of Washington School of Medicine.

The researchers used the NCI SEER database to identify a cohort of 5,475 women aged 65 and older, who had primary debulking surgery for stage III or IV epithelial ovarian cancer which was diagnosed from 1995 through 2005. Women were stratified by acuity (i.e., average severity of illness) of hospital admission. Multivariable analysis was performed to identify patient-related and treatment-related variables associated with 30-day mortality.

The overall 30-day mortality rate was 8.2% for the 5,475 women who had surgery for advanced ovarian cancer. Women admitted on an elective basis experienced a 30-day mortality rate of 5.6% (251/4,517), while those patients admitted on an emergency basis experienced a 30-day mortality of 20.1% (168/835).  The researcher determined that 84.4% of patients were admitted on an elective basis, 15.6% of patients were admitted on an emergency basis, and 2.2% of patients had an unknown admission status.

Emergency admission was associated with older age (median of 76.9 vs. 75.1 for elective admission), higher comorbidity scores, and stage IV disease (41.9% vs. 32.9%). Women admitted on an emergency basis had surgery performed more frequently in low-volume hospitals, by low-volume surgeons, and by surgeons other than gynecologic oncologists (p value <0.001). Emergency admission was also associated with significantly less use of neoadjuvant chemotherapy (2.99% vs. 13.39%, p <0.001).

Advancing age, increasing disease stage, and increasing comorbidity score were all associated with an increase in 30-day mortality (p <.05) among elective admissions. The mortality risk was not influenced significantly by race, income, marital status and other demographic and clinical factors.

A group of women at high risk who were admitted on an elective basis included those aged 75 or older with stage IV disease, and women aged 75 or older with stage III disease and a comorbidity score of 1 or more. The high risk group experienced a 30-day mortality rate of 12.7% (95% confidence interval: 10.7%–14.9%), and accounted for 25.7% of the study population and approximately 50% of the deaths.

Low-risk patients were defined by age 65 to 74, stage III or IV disease, and a morbidity score of less than or equal to one. The low-risk patients accounted for 48.7% of the study population and experienced a 30-day mortality rate of 3.64%. The remaining intermediate patients experienced a mortality rate of 6.05%.

Based upon their analyses, the researcher concluded that age, cancer stage, and comorbidity scores may be helpful to stratify patients admitted on an elective basis by predicted postoperative mortality risk. If validated in a prospective cohort study, these factors may help identify women who may benefit from alternative treatment strategies, such as neoadjuvant chemotherapy.

The study was supported by the Marsha Rivkin Center for Ovarian Cancer Research and by the National Cancer Institute.

Sources:

Related WORD of HOPE Ovarian Cancer Podcast

Mesothelin Antibodies Occur In Some Women With An Epidemiologic Risk For Ovarian Cancer.

Researchers at Rush University Medical Center discover mesothelin antibodies in the bloodstream of infertile women, who possess a higher risk of ovarian cancer.

Using a new approach to developing biomarkers for the very early detection of ovarian cancer, researchers at Rush University Medical Center have identified a molecule in the bloodstream of infertile women, who possess a higher risk of ovarian cancer. This finding may be relevant in the future for screening women at high risk for the disease — or even those with early-stage ovarian cancer.

The molecule — an antibody that the human body manufactures — is an autoimmune response to mesothelin. Mesothelin a well-characterized ovarian cancer antigen and protein which is found in abundance on the surface of ovarian cancer cells, but present only in limited amounts in normal human tissue.

The study is published in the August 16 online version issue of Cancer Epidemiology, Biomarkers & Prevention, published by the American Association for Cancer Research (AACR).

Judith Luborsky, Ph.D., Lead Study Author; Professor, Pharmacology, Obstetrics & Gynecology and Preventive Medicine, Rush Medical College

“The finding is extremely important because at present medical tests are unable to detect ovarian cancer in its early stages, which is why death rates from this disease are so high,” said Judith Luborsky, Ph.D., professor of pharmacology, obstetrics and gynecology and preventive medicine at Rush and the lead author of the study.

“Our approach to discovering cancer biomarkers was unique in this study. Instead of investigating molecules specific to ovarian cancer alone, we asked what molecules women with a risk of ovarian cancer and those with ovarian cancer had in common,” Luborsky said.

The study may have enabled the researchers to explain, in part, the link between infertility and ovarian cancer that has been established in numerous epidemiological surveys.

“More important, with the discovery of the mesothelin antibody, we now have what appears to be a biomarker that can potentially be used in screening tests to help us conquer ovarian cancer,” Luborsky said.

According to the American Cancer Society’s most recent estimates, it is anticipated that 21,900 new cases of ovarian cancer will be diagnosed in the U.S. in 2011, and approximately 15,460 deaths will occur in connection with the disease. Ovarian cancer is the ninth most common cancer in women (not counting skin cancer) and ranks as the fifth highest cause of cancer death in women. It is the most lethal gynecologic cancer. The poor prognosis for women with ovarian cancer is due to the lack of both clinical symptoms when the cancer first develops and the absence of laboratory tests specific to the disease.

In the study at Rush, researchers tested for mesothelin antibodies in the bloodstream of 109 women who were infertile; 28 women diagnosed with ovarian cancer, 24 women with benign ovarian tumors or cysts, and 152 healthy women. Causes of infertility included endometriosis, ovulatory dysfunction, and premature ovarian failure. Some causes of infertility were unexplained.

Significant levels of mesothelin antibodies were found in women with premature ovarian failure, ovulatory dysfunction and unexplained infertility, as well as in women with ovarian cancer. The same results were not found in women with endometriosis, good health, or benign disease. Endometriosis is generally associated with the clear cell and endometrioid subtypes of epithelial ovarian cancer, as compared to other forms of the disease associated with infertility, which may explain why mesothelin antibodies were not found in the endometriosis cases.

It is important to emphasize that the explanation as to why the presence of mesothelin antibodies in the bloodstream should be linked with ovarian cancer is not clear.

“It has been hypothesized that an autoimmune response precedes or somehow contributes to the development and progression of malignant tumors,” Luborsky said. “We think that antibodies may arise in response to very early abnormal changes in ovarian tissue that may or may not progress to malignancy, depending on additional triggering events. Or, alternatively, antibodies may bind to normal cells in the ovary, causing dysfunction and leading to infertility — and, in a subpopulation of women, to the development of ovarian cancer.”

Other researchers involved in the study were Yi Yu, MS, and Seby Edassery, MS, both from Rush, as well as a group led by Ingegerd Hellstrom, M.D., Ph.D., and Karl Eric Hellstrom, M.D., Ph.D., which included Yuan Yee Yip, BS, Jade Jaffar, BS, and Pu Liu, Ph.D. from Harborview Medical Center at the University of Washington.

The study was supported by funding from the National Institutes of Health and Fujirebio Diagnostics, Inc.

About Rush

Rush is a not-for-profit academic medical center comprising Rush University Medical Center, Rush University, Rush Oak Park Hospital and Rush Health.

Rush’s mission is to provide the best possible care for its patients. Educating tomorrow’s health care professional, researching new and more advanced treatment options, transforming its facilities and investing in new technologies—all are undertaken with the drive to improve patient care now, and for the future.

Sources:

  • Luborsky JL, et al. Autoantibodies to Mesothelin in Infertility. Cancer Epidemiol Biomarkers Prev. 2011 Aug 16. PubMed PMID: 21846819 [Epub ahead of print]
  • Researchers at Rush University Medical Center Discover Antibody That May Help Detect Ovarian Cancer in its Earliest Stages, News Release, Rush University Medical Center, August 16, 2010.