Nitrates Linked to Pancreatic Cancer - Mayo Clinic

Uploaded by mayoclinic on Jan 17, 2012

Dr. Mitesh Borad, oncologist at Mayo Clinic in Arizona, appears on 12 News to discuss recent research findings published in the British Journal of Cancer linking nitrate consumption and increased risk of pancreatic cancer.

Randy Pausch: Life. Lessons. Legacy.

Uploaded by lustgartenfoundation on Apr 8, 2008

Public service announcement of The Lustgarten Foundation for Pancreatic Cancer Research featuring Dr. Randy Pausch.

Pancreatic Cancer Genome Project: Clinical Implications

http://www.youtube.com/watch?v=LEotceWK_hw&list=UUg6VIQOQLVpzNqxaH01gugg&index=1&feature=plcp&noredirect=1

Aspirin May Lower the Risk of Pancreatic Cancer

ScienceDaily (Apr. 4, 2011) — The use of aspirin at least once per month is associated with a significant decrease in pancreatic cancer risk, according to results of a large case-control study presented at the AACR 102nd Annual Meeting 2011, held in Orlando, Florida, April 2-6.

Xiang-Lin Tan, Ph.D., M.D., a research fellow at Mayo Clinic in Rochester, Minn., said the findings from this large collaborative study are preliminary and do not encourage widespread use of aspirin for this purpose.
"The results are not meant to suggest everyone should start taking aspirin once monthly to reduce their risk of pancreatic cancer," said Tan. "Individuals should discuss use of aspirin with their physicians because the drug carries some side effects."


For the current study, Tan and colleagues enrolled 904 patients who had documented pancreatic cancer and compared them with 1,224 healthy patients. All patients were at least 55 years old and reported their use of aspirin, NSAIDs and acetaminophen by questionnaire.


Results showed that people who took aspirin at least one day during a month had a 26 percent decreased risk of pancreatic cancer compared to those who did not take aspirin regularly. The effect was also found for those who took low-dose aspirin for heart disease prevention at 35 percent lower risk, according to Tan.


The researchers did not see a benefit from non-aspirin NSAIDs or acetaminophen. "This provides additional evidence that aspirin may have chemoprevention activity against pancreatic cancer," said Tan. He added that more data must be gathered before we can prove a real benefit.

Screening for Pancreatic Cancer in High-Risk Populations

ScienceDaily (July 25, 2011) — Researchers from New England report in a new study that using a tumor marker, serum CA 19-9, combined with an endoscopic ultrasound if the tumor marker is elevated, is more likely to detect stage 1 pancreatic cancer in a high-risk population than by using the standard means of detection. The study appears in the July issue of GIE: Gastrointestinal Endoscopy, the monthly peer-reviewed scientific journal of the American Society for Gastrointestinal Endoscopy (ASGE).

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Advanced disease at diagnosis correlates directly with worse overall survival. Symptoms of abdominal pain, jaundice, and/or weight loss often do not appear until the tumor is locally advanced or metastatic, at which point effective treatment options are very limited. By contrast, detection and resection of pancreatic cancer, when it is confined to the pancreas (stage 1 disease), improves overall survival. An effective screening protocol is urgently needed to detect earlier stage tumors. Imaging methods that have been used for pancreatic cancer screening include endoscopic ultrasound (EUS), CT, endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance imaging/MRCP.


There has been limited success in screening younger populations using the tumor marker CA19-9, so more recent pancreatic cancer screening protocols have focused on high-risk populations. It is estimated that 10 percent of patients in whom pancreatic cancer develops have at least one first-degree relative with the disease. Multiple cohort and case-control studies have demonstrated that a family history of a first-degree relative with pancreatic cancer significantly increases a patient's risk of the development of pancreatic cancer, approximately two to five-fold. The risk of the development of pancreatic cancer increases significantly as the number of affected family members increases. Advanced age is also a significant risk factor, and 93 percent of patients with pancreatic cancer present after the age of 50.


"Our hypothesis was that a high-risk population identified by age and at least one first-degree relative with pancreatic cancer can be successfully screened. Our objective was to determine whether early pancreatic neoplasia can be detected in a high-risk population by using tumor marker CA 19-9 followed by targeted endoscopic ultrasound. We also sought to determine whether this protocol was more likely to detect early stage pancreatic cancer than standard means of detection," said study lead author Richard Zubarik, MD, Fletcher Allen Health Care, University of Vermont. "Our results showed that potentially curative pancreatic adenocarcinoma can be identified with this screening protocol. Stage 1 pancreatic cancer is more likely to be detected by using this screening protocol than by using standard means of detection."


Methods
This prospective cohort study was conducted at the University of Vermont (UVM) and the Dartmouth-Hitchcock Medical Center (DHMC). Patients were enrolled from September 2006 to July 2009. Patients included were between the ages of 50 and 80 and had at least one first-degree relative (parent, sibling, or child) with pancreatic cancer. Enrollment was initiated at age 45 if a patient had two first-degree relatives with pancreatic cancer and at age 40 if the person had a BRCA2 mutation or Peutz-Jeghers syndrome.
Serum CA 19-9 testing was performed on all patients. It was chosen as the initial screening method because it is acceptable to patients, easily obtainable, widely available, inexpensive, and relatively sensitive for the disease. Endoscopic ultrasound was performed only in patients with an elevated CA 19-9 level (a CA 19-9 value greater than 37 U/mL was considered elevated) regardless of whether only one or more than one family member was affected with pancreatic cancer.


Patients who were diagnosed with pancreatic cancer at UVM (but were not enrolled in the CA 19-9/EUS study) during the same period were prospectively identified and used as the comparison group. These patients were identified by the Cancer Data Registry at the University of Vermont. Charts were then reviewed to verify tumor type, staging data and survival.


Results
A total of 546 patients were enrolled in the study. CA 19-9 was elevated in 27 patients (4.9 percent). Neoplastic or malignant findings were detected in five patients (0.9 percent), and pancreatic cancer in one patient (0.2 percent). The patient with pancreatic cancer detected as part of this study was one of two patients presenting to the University of Vermont with stage 1 cancer. One-year follow-up contact was performed by telephone in 519 patients (95 percent), by chart review in 24 patients (four percent), and by review of the social security death index in three patients (less than one percent). Pancreatic cancer was not detected at the one-year follow-up in any additional patients.


In the comparison group, a total of 124 patients received a diagnosis of pancreatic cancer between September 2006 and July 2009. Staging of the comparison group at the time of presentation was as follows: stage 1, one patient (0.9 percent); stage 2, 52 patients (45.6 percent); stage 3, 20 patients (17.5 percent); stage 4, 41 patients (36 percent). The patient detected in the CA 19-9/EUS study had stage 1 disease, whereas only 0.9 percent of patients in the comparison group presented with stage 1 disease. This difference was statistically significant despite only having one patient with pancreatic cancer detected in the study group because the detection of stage 1 cancer in the comparison group was so rare. Median survival for the 122 subjects in the comparison group was seven months, with a 2-year survival rate of 10 percent.


The results conclude that potentially curative pancreatic cancer can be identified with CA 19-9 and targeted EUS. Stage 1 pancreatic cancer is more likely to be detected by using this screening protocol than by using standard means of detection. Potential advantages include acceptable rates of disease diagnosis and exclusion as well as acceptable costs (cost to detect 1 pancreatic neoplasia was $8,431, while the cost to detect 1 pancreatic cancer was $41,133). In particular, the patient with pancreatic cancer detected with this screening protocol is alive without evidence of recurrence three years after surgical resection and is the longest survivor of pancreatic cancer detected in a published screening protocol. Also, evidence of pancreatic cancer did not develop in subjects with negative screening studies, at least in short-term follow-up.


The researchers note that the sample size is adequate only to demonstrate the feasibility of this approach, but summarized that this trial successfully screened a high-risk patient population for pancreatic cancer based on age and genetic predisposition. Early pancreatic cancer, associated with prolonged disease-free survival, can be detected as part of this pancreatic screening protocol. Stage 1 pancreatic cancer was more likely to be detected with CA 19-9 and targeted EUS, and it appears to be superior to the standard means of pancreatic cancer detection.

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Story Source:

The above story is reprinted from materials provided by American Society for Gastrointestinal Endoscopy, via EurekAlert!, a service of AAAS.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Celebrate growing older

Written by a 90 year old 

This is something we should all read at least once a week!!!!! Make 
sure you read to the end!!!!!! 

Written by Regina Brett, 90 years old, of the Plain Dealer, Cleveland , Ohio . 

To celebrate growing older, I once wrote the 45 lessons life taught 
me. It is the most requested column I've ever written. 

1. Life isn't fair, but it's still good. 

2. When in doubt, just take the next small step. 

3. Life is too short – enjoy it. 

4. Your job won't take care of you when you are sick. Your friends and 
family will. 

5.Don't buy stuff you don't need. 

6. You don't have to win every argument. Stay true to yourself. 

7. Cry with someone. It's more healing than crying alone. 

8. It's OK to get angry with God. He can take it. 

9. Save for things that matter. 

10. When it comes to chocolate, resistance is futile. 

11. Make peace with your past so it won't screw up the present. 

12. It's OK to let your children see you cry. 

13. Don't compare your life to others. You have no idea what their 
journey is all about. 

14. If a relationship has to be a secret, you shouldn't be in it. 

15. Everything can change in the blink of an eye But don't worry; God 
never blinks. 

16. Take a deep breath. It calms the mind. 

17. Get rid of anything that isn't useful. Clutter weighs you down in many ways. 

18. Whatever doesn't kill you really does make you stronger. 

19. It's never too late to be happy. But it’s all up to you and no one else. 

20. When it comes to going after what you love in life, don't take no 
for an answer. 

21. Burn the candles, use the nice sheets, wear the fancy lingerie. Don't 
save it for a special occasion. Today is special. 

22. Over prepare, then go with the flow. 

23. Be eccentric now. Don't wait for old age to wear purple. 

24. The most important sex organ is the brain. 

25. No one is in charge of your happiness but you. 

26. Frame every so-called disaster with these words 'In five years, will 
this matter?' 

27. Always choose life. 

28. Forgive but don’t forget. 

29. What other people think of you is none of your business. 

30. Time heals almost everything. Give time time. 

31. However good or bad a situation is, it will change. 

32. Don't take yourself so seriously. No one else does. 

33. Believe in miracles. 

34. God loves you because of who God is, not because of anything you 
did or didn't do. 

35. Don't audit life. Show up and make the most of it now. 

36. Growing old beats the alternative -- dying young. 

37. Your children get only one childhood. 

38. All that truly matters in the end is that you loved. 

39. Get outside every day. Miracles are waiting everywhere. 

40. If we all threw our problems in a pile and saw everyone else's, we'd 
grab ours back. 

41. Envy is a waste of time. Accept what you already have not what you need. 

42. The best is yet to come... 

43. No matter how you feel, get up, dress up and show up. 

44. Yield. 

45. Life isn't tied with a bow, but it's still a gift.

New hope for pancreatic and non-small cell lung cancers

Clavis and Clovis collaboration to tackle problem of Gemzar (gemcitabine) resistance - New hope for pancreatic and non-small cell lung cancers

11th March 2010 16:47

According to our 2009 feature Commercial Insight: Cytotoxic Therapies, the cytotoxics market was worth $13.8 billion in 2008 across the seven major pharmaceutical markets, and is forecast to grow to $18.7 billion by 2018, achieving a CAGR of 3.1%.

In 2008, Taxotere (docetaxel; Sanofi-Aventis), Eloxatin (oxaliplatin; Sanofi-Aventis) and Gemzar (gemcitabine; Eli Lilly) were the top three cytotoxics, with sales over $1 billion.

Today’s editorial focuses on one of these blockbuster cytotoxics, gemcitabine, or to be more precise, a fatty acid derivative of this agent, CP-4126 which is currently being developed by Clavis Gemcitabine was initially launched in the 1990’s as a treatment for non-small cell lung cancer (NSCLC) and pancreatic cancer and it is now part of first line treatment for both. Gemcitabine is also indicated for other cancers such as metastatic breast cancer, ovarian cancer and bladder cancer.

The cancer pipeline is burgeoning, driven by the continued incidence of the disease, continued unmet needs and patent expiries. The majority of the cancer pipeline is comprised of targeted therapies and improved cytotoxics. Gemcitabine is a good example of the current status of oncology R&D. With generics already on the market following patent expiration in some markets and acquired drug resistance limiting the continued efficacy of gemcitabine the clinic is ready for a super-gemcitabine. This is particularly the case given continued unmet needs for improved treatments of indications for this drug.

Our 2008 feature Pipeline Insight: Non-Small Cell Lung Cancer - Emerging Therapies highlights the problems around NSCLC. In 2008, the incidence of NSCLC was estimated to have exceeded 367,000 new cases in the seven major pharmaceutical markets. The prognosis for patients with the disease remains poor. In one pivotal study median survival time was just 9 months in combination with cisplatin.

Pancreatic cancer is far less common than NSCLC but remains a significant problem all the same. Estimated incidence is 91,000 across the 7 major markets. According to a report published last year Pancreatic Cancer - Gemzar Dominance Will Continue Among High Levels of Persistent Unmet Needs, only 15-20% of pancreatic cancer patients have resectable disease, therefore most receive systemic therapy. Gemcitabine forms the current standard of care for advanced disease. Despite this, no treatment is truly effective, with five-year survival at 5% for all stages of disease. Gemzar is only associated with median overall survival of 5.7 months and a one-year survival rate of 18%, statistics even more dismal than for NSCLC.

It is therefore clear that treatment of NSCLC and pancreatic cancer continues to be plagued by high levels of unmet need. Clavis is taking this need to task with CP-4126.

Activation of gemcitabine requires phosphorylation by deoxycytidine kinase; the active metabolite is incorporated into DNA and RNA. After its incorporation into DNA one or some more nucleotides can be added, after DNA polymerization stops. The nucleotide dFdCDP is also a potent inhibitor of DNA-synthesis inhibiting ribonucleotide reductase, which is the only enzyme providing the cells with deoxynucleotides which are essential for DNA synthesis. Resistance to gemcitabine may occur because it is hydrophilic therefore requiring active transport into tumor cells. One way of circumventing this problem is to develop fatty acid ester cytotoxic derivatives

Clavis Pharma has already gained success through this approach with esterified cytarabine derivative, CP-4055 which is in Phase 2 development for AML. Today we focus on CP-4126, a fatty acid derivative of gemcitabine. Both molecules were developed using the company's lipid vector technology.

In the January issue of Investigational New Drugs, Bergman et report the preclinical profile of CP-4126. Across a wide variety of cancer cells CP-4126 and gemcitabine displayed similar potencies (IC50 approximated to 100nM). Of importance, while inhibition of nucleoside transport decreased sensitivity to gemcitabine by up to 200-fold, CP-4126 suffered little effect.

The authors proceeded to evaluate CP-4126 in various xenograft models and found efficacy similar to gemcitabine in melanoma, sarcoma, lung, prostate, pancreatic and breast cancer xenografts. Importantly and in contrast to gemcitabine, CP-4126 could be administered orally.

We have seen a recent trend towards developing orally active forms of existing oncology agents. For example, Capecitabine, has been developed as an oral version of 5-fluorouracil. CP-4126 might show significant benefit as a future oral alternative for gemcitabine in addition to its ability to circumvent resistance resulting from cellular access. Clavis has been developing CP-4126 clinically as oral and iv formulations. CP-4126 has recently received orphan drug designation in the US and EU (Press Release) and is currently in a phase 2 trial (link to clinicaltrials.gov entry) of newly diagnosed, advanced pancreatic cancer. The study was initiated in April 2009 and results are expected in H1 2012. Of interest we understand that Clavis has been exploring the development of a biomarker diagnostic method for determining which patients would benefit from the drug. We presume that this test will probe the nucleoside transporter. 

LeadDiscoveryexpects investigation in other indication to follow and this is likely to be accelerated given recent news that Clavis and Clovis Oncology has signed a US$380 million partnership agreement for the development and commercialisation of CP-4126. Under the terms of the agreement, Clovis Oncology will take over responsibility for product development and manufacturing of CP-4126 as CO-101, and for filing of marketing approvals in the United States, Europe, Canada, Central and South America. Clovis Oncology will also be responsible for commercialisation of CP-4126/CO-101 in those territories.

http://www.leaddiscovery.co.uk/editorials/7/clavis-and-clovis-collaboration-to-tackle-problem-of-gemzar-(gemcitabine)-resistance---new-hope-for-pancreatic-and-non-small-cell-lung-cancers-

Duke study elucidates why stress causes DNA damage:

NCI Cancer Center News

Duke study elucidates why stress causes DNA damage:

For years, researchers have published papers that associate chronic stress with chromosomal damage. Now researchers at Duke University Medical Center have discovered a mechanism that helps to explain the stress response in terms of DNA damage... In the study, mice were infused with an adrenaline-like compound that works through a receptor called the beta adrenergic receptor... The scientists found that this model of chronic stress triggered certain biological pathways that ultimately resulted in accumulation of DNA damage.

Click here to read full press release from Duke University Medical Center .

###

Among the research institutions NCI funds across the United States, it currently designates 66 as Cancer Centers. Largely based in research universities, these facilities are home to many of the NCI-supported scientists who conduct a wide range of intense, laboratory research into cancer’s origins and development. The Cancer Centers Program also focuses on trans-disciplinary research, including population science and clinical research. The centers’ research results are often at the forefront of studies in the cancer field.

TGen/Virginia G. Piper Cancer Center publish results of new drug for pancreatic cancer patients

Public release date: 4-Oct-2011
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Contact: Steve Yozwiak
syozwiak@tgen.org
602-343-8704
The Translational Genomics Research Institute

TGen/Virginia G. Piper Cancer Center publish results of new drug for pancreatic cancer patients

Results lead to Scottsdale oncologists heading a large phase III study being conducted worldwide

SCOTTSDALE, Ariz. -- Patients at Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare were the first in the nation to participate in a clinical trial to determine the safety, tolerability and effectiveness for usage of a new drug combination consisting of a standard drug called gemcitabine and a drug called nab-paclitaxel for patients with advanced pancreatic cancer.

The results of this study, headed by renowned pancreatic cancer expert Dr. Daniel Von Hoff, were published online Oct. 3, 2011, in the prestigious Journal of Clinical Oncology.
Nab-paclitaxel (Abraxane), an albumin-bound formulation of paclitaxel, is a drug manufactured by Abraxis BioScience a wholly-owned subsidiary of Celgene and is approved for the treatment of patients with advanced breast cancer. The use of this agent in patients with pancreatic cancer is investigational.

Virginia G. Piper Cancer Center Clinical Trials is a partnership between Scottsdale Healthcare and the Translational Genomics Research Institute (TGen) to rapidly bring new discoveries in the laboratory to patients.

"This is a great example of rapid bench to bedside development," said Dr. Von Hoff, TGen's Physician-In-Chief and Chief Scientific Officer for the Scottsdale Healthcare Research Institute.

Scientists at TGen and the International Genomics Consortium, in collaboration with Abraxis scientists, found that in pancreatic cancer an albumin-binding protein called SPARC was present at high levels in cells within the pancreatic tumor microenvironment. It was hypothesized that the albumin formulation of nab-paclitaxel may be taken up by tumor cells with high SPARC expression. Based on these findings, Dr. Von Hoff -- joined by colleagues from Johns Hopkins University Hospital, Baltimore; University of Alabama, Birmingham; and South Texas Oncology-Hematology, San Antonio -- conducted a clinical trial in patients with advanced pancreatic cancer.
The results of this pilot study in which 67 patients were treated showed impressive results. Following completion of a safety and dose finding phase, 44 patients were treated in the phase II group. About half the patients showed reductions in tumor size measured by CT scans, and about 50 percent lived at least a year.

"Compared to the average survival of 6 months seen typically in this group of patients, this is very encouraging," said Dr. Ramesh Ramanathan, medical director, Virginia G. Piper Cancer Center Clinical Trials. He added that the results of this study need to be confirmed. A large worldwide study of 842 patients comparing the standard treatment of gemcitabine to the new regimen of gemcitabine and nab paclitaxel is underway, led by Dr. Von Hoff and Dr. Ramanathan.

According to Dr. Ron Korn, the lead radiologist and a co-author on this paper, the study also provided important information on the role of PET scans. "If we can find early in the course of treatment if a patient will respond to treatment or not, then we can change course quickly, this study showed that patients who had a decrease in intensity of 'hot spots' on a PET scan after 6 weeks of treatment were more likely to have a good outcome." Dr. Korn added that this approach is being further investigated in clinical trials with targeted agents in collaboration with the Virginia G. Piper Cancer Center.

Individuals seeking information about eligibility to participate in clinical trials at the Virginia G. Piper Cancer Center at Scottsdale Healthcare may contact the cancer care coordinator at 480-323-1339; toll free at 1-877-273-3713 or via email at clinicaltrials@shc.org.

###

About the Virginia G. Piper Cancer Center at Scottsdale Healthcare
The Virginia G. Piper Cancer Center at Scottsdale Healthcare in Scottsdale, Ariz. offers comprehensive cancer treatment and research through Phase I clinical trials, diagnosis, treatment, prevention and support services in collaboration with leading scientific researchers and community oncologists. Scottsdale Healthcare is the nonprofit parent organization of the Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale Healthcare Research Institute, Scottsdale Healthcare Osborn Medical Center, Scottsdale Healthcare Shea Medical Center and Scottsdale Healthcare Thompson Peak Hospital. For more information, visit http://www.shc.org.
Press Contact:
Keith Jones
Public Relations Director
Virginia G. Piper Cancer Center
480-323-1383
kjones@shc.org


About TGen
The Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the translational process. TGen is affiliated with the Van Andel Research Institute in Grand Rapids, Michigan. For more information, visit: http://www.tgen.org.
Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
syozwiak@tgen.org

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Laparoscopic Surgeons Develop Fluorescent Light Technique to Improve Pancreatic Cancer Detection

Early approach shows promise over conventional laparoscopy with no evidence of side effects

SAN FRANCISCO, Oct. 24, 2011 /PRNewswire-USNewswire/ -- More than 80 percent of people with pancreatic cancer are diagnosed after the cancer has metastasized, and by then the prognosis for long-term survival is dismal.  However, surgeons and scientists at the University of California-San Diego (UCSD) are developing a laparoscopic technique that uses fluorescent light to improve pancreatic cancer staging and treatment.  Their findings were presented today at the 2011 Clinical Congress of the American College of Surgeons.

The UCSD researchers compared a standard xenon laparoscope with a laparoscope using a light emitting diode (LED) source.  Surgeons took two antibodies that are commonly expressed by pancreatic cancer and tagged them with a fluorescent marker, thus, making the cancerous tumors "light up" in colors of bright green or red, reported study leaders, Michael Bouvet, MD, FACS, and Robert M. Hoffman, Ph.D., both UCSD professors of surgery.

The surgeons and scientists then administered fluorescent antibodies into six-week old female mice.  The researchers were able to see primary and metastatic tumors more vividly with the LED light, at a sensitivity rate of 96 percent, than with traditional laparoscopy, which had a sensitivity rate of 40 percent.  Moreover, fluorescent laparoscopy rendered fewer false positives than traditional laparoscopy, and the researchers were able to clearly see the surrounding anatomy in the abdominal cavity of the mice.  Fluorescent laparoscopy was also sensitive enough to illuminate metastatic lesions smaller than one millimeter, which are not visible with a standard laparoscope.

"Laparoscopy is used for staging in patients with cancer, often before we make a big incision," said Dr. Bouvet.  "Now, we've made it even better with the LED light source.  We modified it so you can see both the normal background of the anatomy plus the fluorescent tumor signal at the same time.  We were able to perform LED fluorescence laparoscopy in mice with small, three millimeter laparoscopes."

The fluorescent marker did not show evidence of toxicity or side effects in the mice.  The combination of LED light and fluorescent markers for malignant tumors could potentially sharpen how surgeons detect and treat pancreatic cancer in human patients.  If patients have received the fluorescent antibodies prior to an operation, the surgeon can insert the LED laparoscope through a small incision and determine if the cancer has metastasized to other areas of the abdomen.  "If it has spread, then we can biopsy those areas and better determine if the best initial treatment should be chemotherapy and save the patient the large incision," Dr. Bouvet said.  "If there's no or limited metastases, then we can more completely remove the primary and metastatic tumors because we can see the edges better.  We're hoping for a lower rate of local recurrence."

Once the cancerous tumors are illuminated, Dr. Bouvet explains, the surgeons are able to more precisely remove the tumor and any surrounding malignant tissue without injuring the aorta and other nearby blood vessels.  Furthermore, another potential application for this technique could involve medically treating pancreatic cancer: "You could tag a specific drug or isotope to target tumor cells.  Since the fluorescent antibodies bind specifically to cancer cells, you could deliver certain payloads of drugs that would kill the cancer cells more effectively," Dr. Bouvet said.

The technique could also be applied to staging and treating colon cancer, which often is expressed through the same antibodies as pancreatic cancer and treated with the same laparoscopic technology.  Within the next four years, Dr. Bouvet plans to work with OncoFluor, Inc., a biotech company that develops fluorescent compounds for malignant tumors, on securing FDA approval for clinical trials of the fluorescent antibodies in humans.

Other members of the research team included Cristina Angela Metildi Raimo, MD; Sharmeela Kaushal, Ph.D.; Chanae Hardamon, BSc, Hop Tran Cao, MD; Cynthia S. Snyder, MD; George A. Luiken, MD; and Mark A. Talamini, MD, FACS, all from theUniversity of California-San Diego, San Diego, CA;  OncoFluor, Inc., San Diego, CA; and AntiCancer, Inc., San Diego, CA.

NOTE: The UCSD research team worked with AntiCancer, Inc. on the mouse model and with laparoscope technicians at Stryker Corporation.  The research is funded by a five-year grant to UCSD and AntiCancer, Inc. from the National Cancer Institute.

SOURCE American College of Surgeons

Molecular markers can predict spread of cancer, guide treatment

December 13, 2011 

Molecular markers found in cancer cells that have spread from a primary tumor to a limited number of distant sites can help physicians predict which patients with metastatic cancer will benefit from aggressive, targeted radiation therapy.

In a study to be published online Dec. 13, 2011, in the journal PloS One, researchers from the University of Chicago and the University of Illinois at Chicago show that if cells from metastatic tumors have high levels of a particular type of microRNA -- a tool cells use to silence certain genes-- not even aggressive treatment of those tumors would help. But if the cells have lower levels of that biological marker, then focused local treatment could be effective, even curative.

"We previously demonstrated that we could provide lasting disease-free survival to a percentage of patients with metastatic disease," said study author Ralph Weichselbaum, MD, professor and chair of radiation and cellular oncology and Director of the Ludwig Center for Metastasis Research at the University of Chicago. "This finding means we can have a pretty good sense in advance of which patients we can help. Patients unlikely to benefit from focused, local therapy can receive systemic treatment immediately."

Yves Lussier, MD, professor of medicine at the University of Illinois at Chicago and co-senior author of the study, added that "the biological differences between locally curable metastases or potentially fatal widespread metastases can also be targeted for drug development."

When patients die from cancer, it is usually caused by distant metastases, numerous cancer sites established by malignant cells that split off from the primary cancer and began growing in new settings. In 1994, Weichselbaum and colleague Samuel Hellman proposed that there was a potentially curable intermediate state between cancer that had not spread at all and cancer that had spread extensively. They named this phenomenon "oligometastasis," meaning cancer that had spread to a few distant sites.

In 2004, they began a small clinical trial to test that theory. Patients with stage IV cancer with one to five distant metastases and no tumors bigger than 10 centimeters in diameter were enrolled. The results, published in 2008, showed that precisely targeted radiation therapy could eradicate all evidence of disease in about 20 percent of those patients.

"We were pleased to get such encouraging results in patients with stage IV cancers that had spread to distant sites," Weichselbaum said. "This was proof of principle in patients who had already failed standard therapies."

A follow-up study, published in October 2011, found that 18 percent of the patients in that initial trial had seen no progression of their cancers for the duration of the study and 27 percent developed no new tumor sites.

The next step was to determine in advance which patients were most likely to benefit from such targeted therapy and which ones should move on to whole-body treatments, such as chemotherapy. So they compared cells from secondary tumors from patients who did well in the original studies with those whose cancers went on to establish multiple metastatic sites.

They found that tumors that were highly proliferative, producing many metastases, had patterns of microRNA expression that differed from those that produced only a few. The tumors most likely to spread had high levels of a small nucleic acid known as microRNA-200c.

This came as a surprise. MicroRNA-200c was thought to suppress metastasis. But when the researchers boosted microRNA-200c levels in a mouse model of cancer, it significantly increased metastasis. The researchers subsequently showed that microRNA-200c reduced the activity of other genes that acted to prevent the spread of cancer.

Further tests in mouse models showed that boosting microRNA-200c levels significantly increased the metastatic potential of tumors that were not as prone to spread.

"Our findings are an initial step in discriminating between patients with a few treatable sites where the tumor has spread and those who will develop widespread metastasis, which is not curable with focused radiation therapy," Weichselbaum said. "It is encouraging to find a common molecular basis for this treatable state across a broad variety of metastases from solid tumors."

Oligometastases are "more common than generally recognized," the authors note. "Potentially, 50 percent of patients with metastatic non-small cell lung cancer, the leading cause of cancer death in men and women, may be oligometastatic."

When combined with other factors -- the number and size of metastasis, the interval from treatment of a primary tumor to the appearance of metastasis, the microscopic structure and appearance of tumor tissue -- the presence of microRNA-200c could become a key element of patient selection for targeted radiation therapy, Weichselbaum said, distinguishing between patients who have treatable tumors and those who have widespread metastasis, including many tumors too small to detect.

This project was collaborative effort by three research groups. Weichselbaum and colleagues Michael Hasselle, Renuka Malik, Kimberly Corbin, Mitchell C. Posner, Steven J. Chmura, and Samuel Hellman at the University of Chicago, with Joseph Salama of Duke University Medical Center, developed the idea and perfumed the clinical studies. Biological modeling was co-led by H. Rosie Xing, with Qingbei Zhang, and Hanli Fan, and Weichselbaum with Nikolai Khodarevi, Sajid Khan, Thomas Darga, Samantha Perakis and Matthew Filippo at the University of Chicago. The bioinformatics and genomic modeling was led by Lussier, with Yong Huang, Xinan Yang, and Younghee Lee at the University of Illinois at Chicago.

The National Institutes of Health, the Ludwig Center for Metastasis Research, the University of Chicago Center for Radiation Therapy, the Chicago Tumor Institute, Dr. Lloyd Old, Mr. and Mrs. Vincent Foglia and the Foglia Foundation, the Lung Cancer Research Foundation, the University of Chicago Cancer Research Foundation, the University of Chicago Comprehensive Cancer Center and the National Center for the Multi Scale Analysis of Genomic and Cellular Networks supported this study.

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Public release date: 29-Dec-2011
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Contact: Jeremy Moore
Jeremy.Moore@aacr.org
215-446-7109
American Association for Cancer Research

Gene identified in increasing pancreatic cancer risk

PHILADELPHIA — Mutations in the ATM gene may increase the hereditary risk for pancreatic cancer, according to data published in Cancer Discovery, the newest journal of the American Association for Cancer Research.

Pancreatic cancer is one of the most morbid cancers, with less than 5 percent of those diagnosed with the disease surviving to five years. Approximately 10 percent of patients come from families with multiple cases of pancreatic cancer.

"There was significant reason to believe this clustering was due to genetics, but we had not, to this point, been able to find the causative genes that explained the cluster of pancreatic cancer for a majority of these families," said lead author Alison Klein, Ph.D., associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and director of the National Familial Pancreas Tumor Registry.
Klein and colleagues used next-generation sequencing, including whole genome and whole exome analyses, and identified ATM gene mutations in two kindreds with familial pancreatic cancer.

When these initial findings were examined in a large series for patients, ATM mutations were present in four of 166 subjects with pancreatic cancer but were absent in 190 spousal control subsets.

Klein said that knowledge of the presence of the ATM gene could lead to better screening for pancreatic cancer, the fourth most common cause of cancer-related death. However, there are currently no recommended screening tests.

Many doctors use endoscopy as a screening tool for pancreatic cancer, but researchers are still evaluating this technique in clinical trials.

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Public release date: 21-Dec-2011
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Contact: Steve Graff
stephen.graff@jefferson.edu
215-955-5291
Thomas Jefferson University 

Researchers identify potential target to delay metastatic pancreatic cancer and prolong survival

Cell-surface protein N-cadherin represents a promising therapeutic target for the treatment of pancreatic cancer, say researchers at Jefferson's Center for Translational Medicine

PHILADELPHIA -- Often, and without much warning, pancreatic cancer cells slip through the endothelial cells, head into the blood and out to other parts of the body to metastasize, making it one of the deadliest and hardest to treat cancers today.

Now, researchers from Thomas Jefferson University's Center for Translational Medicine have found that reducing levels of a well-known, cell-surface protein known as N-cadherin in those cancer cells can interfere with that activity. The disruption slowed down the pancreatic cancer cells' mobility, they found, and prolonged survival in mice.

The findings, published online in December in Nature's Oncogene, support a critical role for N-cadherin in pancreatic ductal adenocarcinma (PDA). Because this cancer does not typically produce symptoms until after it has metastasized, the mortality rate is very high—its five-year survival rate is less than 5 percent. Thus, strategies that specifically target and prevent the spreading of the cancer cells have the potential to significantly improve the prognosis for patients.

"Previous studies demonstrated the importance of this cell surface protein for tumor cell growth," said Glenn Radice, Ph.D., an Associate Professor in the Department of Medicine at Jefferson's Center for Translational Medicine, and co-author of the study. "However, it was not clear from those studies whether interfering with N-cadherin levels would increase survival of animals genetically engineered to develop highly metastatic pancreatic cancer."

Using the mouse model, researchers found that reducing N-cadherin expression delayed tumor progression and prolonged survival in mice by 25 percent.

These studies implicate N-cadherin as a key regulator of multiple signaling pathways critical for cancer progression, a mechanism that can be exploited, the researchers point out.

This is another example of how researchers from the Center are bridging basic scientific discoveries with physicians' needs for their patients—by discovering and improving upon new targeted therapies for pancreatic cancer that may eventually be tested in clinical trials.

"Our survival results are very exciting because a drug, known as ADH-1, that specifically targets N-cadherin is already in clinical trial for melanoma" Dr. Radice said. "The next step is to test this N-cadherin-function blocking drug or a similar compound in the pancreatic cancer mouse model to see if it can prolong survival."

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