Long-Sought-After Anticancer Agent Synthesized By Scientists

A team of Yale University scientists has synthesized for the first time a chemical compound called lomaiviticin aglycon, leading to the development of a new class of molecules that appear to target and destroy cancer stem cells.

Chemists worldwide have been interested in lomaiviticin’s potential anticancer properties since its discovery in 2001. But so far, they have been unable to obtain significant quantities of the compound, which is produced by a rare marine bacterium that cannot be easily coaxed into creating the molecule. For the past decade, different groups around the world have been trying instead to synthesize the natural compound in the lab, but without success.

Now a team at Yale, led by chemist Seth Herzon, has managed to create lomaiviticin aglycon for the first time, opening up new avenues of exploration into novel chemotherapies that could target cancer stem cells, thought to be the precursors to tumors in a number of different cancers including ovarian, brain, lung, prostate and leukemia. Their discovery appears online today in the Journal of the American Chemical Society.

“About three quarters of anticancer agents are derived from natural products, so there’s been lots of work in this area,” Herzon said. “But this compound is structurally very different from other natural products, which made it extremely difficult to synthesize in the lab.”

In addition to lomaiviticin aglycon, Herzon’s team also created smaller, similar molecules that have proven extremely effective in killing ovarian stem cells, said Gil Mor, M.D., a researcher at the Yale School of Medicine who is collaborating with Herzon to test the new class of molecules’ potential as a cancer therapeutic.

The scientists are particularly excited about lomaiviticin aglycon’s potential to kill ovarian cancer stem cells because the disease is notoriously resistant to Taxol and Carboplatin, two of the most common chemotherapy drugs. “Ovarian cancer has a high rate of recurrence, and after using chemotherapy to fight the tumor the first time, you’re left with resistant tumor cells that tend to keep coming back,” Mor explained. “If you can kill the stem cells before they have the chance to form a tumor, the patient will have a much better chance of survival – and there aren’t many potential therapies out there that target cancer stem cells right now.”

Herzon’s team, which managed to synthesize the molecule in just 11 steps starting from basic chemical building blocks, has been working on the problem since 2008 and spent more than a year on just one step of the process involving the creation of a carbon-carbon bond. It was an achievement that many researchers deemed impossible, but while others tried to work around having to create that bond by using other techniques, the team’s persistence paid off.

“A lot of blood, sweat and tears went into creating that bond,” Herzon said. “After that, the rest of the process was relatively easy.”

Next, the team will continue to analyze the compound to better understand what’s happening to the stem cells at the molecular level. The team hopes to begin testing the compounds in animals shortly.

“This is a great example of the synergy between basic chemistry and the applied sciences,” Herzon said. “Our original goal of synthesizing this natural product has led us into entirely new directions that could have broad impacts in human medicine.”


Other authors of the paper include Liang Lu, Christina M. Woo and Shivajirao L. Gholap, all of Yale University.

DOI: 10.1021/ja200034b

Suzanne Taylor Muzzin
Yale University

View drug information on Taxol.

Heart-Assist Device Helped Ready 16-Year-Old For Successful Surgery

The wait is over for 16-year-old Francesco “Frank” De Santiago. On January 29, De Santiago received a donor heart in a nine-hour transplant operation at Texas Children’s Heart Center De Santiago made news last October as the first child ever discharged from a pediatric hospital with an implanted mechanical heart pump, or ventricular assist device (VAD). Until then, pediatric patients with VADs remained in the hospital, often in ICU, while awaiting a donor heart.

“Frank’s surgery went extremely well; he was a much better candidate for a heart transplant now than eight months ago when his heart was failing,” said Dr. David L.D. Morales, pediatric cardiovascular surgeon at Texas Children’s Heart Center who implanted Frank’s device last May and performed his recent heart transplant. “The device improved his physical health and allowed him be discharged so he could enjoy some normal teen activity during the wait for a donor heart. Texas Children’s is leading the way in using five different types of VAD technology to help pediatric patients enhance their quality of life and outlook so they are better prepared for their transplant surgery.”

De Santiago will continue to reside in Houston and undergo rehabilitation and follow-up check-ups for three months before returning to his home in south Texas. He calls his heart “a gift” and is learning how to care for himself and his new organ.

Morales said about 450 pediatric heart transplants occur annually in the United State; yet the number of pediatric heart failure cases diagnosed annually continues to rise. He believes that the future of pediatric heart care resides in VAD technology and Texas Children’s Heart Center uses the most of any pediatric hospital in the country.

“Heart failure in children is now being diagnosed at an increased rate,” said Dr. Jeffrey Dreyer, medical director of cardiac transplantation at Texas Children’s Hospital. “Advances in VAD technology provide new opportunities for treatment and recovery. Prior to VADs, a significant number of pediatric heart failure patients did not survive long enough to receive a heart transplant. We are fortunate to have this technology and expertise at Texas Children’s.”

Frank De Santiago was transferred to Texas Children’s Hospital from south Texas after experiencing a temporary stroke. He was diagnosed with dilated cardiomyopathy, a condition in which his heart was enlarged to more than twice a normal size and could not pump blood efficiently. The Texas Children’s Heart Center physician team placed him on the heart transplant list and concluded he was an excellent candidate for the HeartMate II VAD that could keep him alive until a suitable donor heart became available.

Texas Children’s Hospital is the first pediatric hospital in the world to use the HeartMate II in pediatric patients with a body surface area of at least 1.3 square meters. The device, about the size of two “D” cell batteries laid end-to-end, received U. S. Food and Drug Administration approval on April 26, 2008. Since then, Morales, also director of the Pediatric Mechanical Circulatory Support Program, has implanted the HeartMate II in five teen or pre-teen patients. All patients experienced improved heart health on the device, which allowed them to live until donor hearts became available.

Carol Wittman
Texas Children’s Hospital

No High Risk Avian Influenza Viruses Found In Canada’s Wild Birds

The Government of Canada is committed to preventing the introduction of avian influenza in Canada’s domestic poultry flocks. Canada’s 2007 Interagency Wild Bird Influenza Survey confirmed no findings of highly pathogenic avian influenza in Canada’s wild bird population.

Initially launched in 2005, the annual survey is a joint initiative between federal, provincial and territorial governments as well as the Canadian Cooperative Wildlife Health Centre (CCWHC) and Canada’s Avian Influenza Laboratory Network.

The 2007 survey included testing of wild birds along main Canadian migratory routes as well as in Iceland, where birds were sampled during their migration from Western Europe to the Canadian Arctic.

As with previous surveys, the 2007 survey found various low pathogenicity AI subtypes, including both H5 and H7. These detections are expected. Low pathogenicity influenza viruses commonly circulate in wild birds with little or no impact on the health of birds or people.

The 2008 survey is now underway. Annual monitoring of wild birds helps animal health experts track and understand the viruses circulating throughout Canada. Wild bird surveillance is one of the Government’s key AI prevention and preparedness initiatives.

A summary of results from 2005-2007 can be viewed on the CCWHC website.

For additional information on AI, please visit the Canadian Food Inspection Agency’s website at: inspection.gc

Canadian Food Inspection Agency

Lucentis Improves Vision As Well As Slowing Vision Loss

Lucentis, a drug used to treat wet age-related macular degeneration (wet AMD) was found to not only slow down vision loss in 90% of patients, but it also helped 26% of them get some of their vision back, say Lucentis makers, Genentech, Inc.

Wet AMD is the leading cause of blindness among the elderly.

Lucentis prevents the formation of abnormal, new blood vessels in the eye. It also destroys blood vessels in the eye which have started to leak.

You can read about the latest studies in The New England Journal of Medicine (NEJM).

In one study, 716 volunteers underwent an eye chart test. They all suffered from AMD. Half the group received Lucentis injection, while the other half received a placebo injection.Two years later:

– 90% of the Lucentis patients lost fewer than 15 letters on the eye chart test

– 50% of the placebo patients lost fewer than 15 letters on the eye chart test

– 26% of patients who received 0.3mg of Lucentis experienced improvement in their eyesight*

– 33% of patients who received 0.5mg of Lucentis experienced improvement in their eyesight*

– 4% of patients who received the placebo experienced improvement in their eyesight*

* Improvement = Being able to read 15 more letters on the eye chart test

Ranibizumab for Neovascular Age-Related Macular Degeneration
Philip J. Rosenfeld, M.D., Ph.D., David M. Brown, M.D., Jeffrey S. Heier, M.D., David S. Boyer, M.D., Peter K. Kaiser, M.D., Carol Y. Chung, Ph.D., Robert Y. Kim, M.D., for the MARINA Study Group
NEJM Volume 355:1419-1431 – October 5, 2006 – Number 14
Click here to see abstract online

Ranibizumab versus Verteporfin for Neovascular Age-Related Macular Degeneration
David M. Brown, M.D., Peter K. Kaiser, M.D., Mark Michels, M.D., Gisele Soubrane, M.D., Jeffrey S. Heier, M.D., Robert Y. Kim, M.D., Judy P. Sy, Ph.D., Susan Schneider, M.D., for the ANCHOR Study Group
NEJM Volume 355:1432-1444 – October 5, 2006 – Number 14
Click here to see abstract online

View drug information on Lucentis.

NanoViricides Reports Treatment With Its FluCide Drug Candidate Achieves Dramatic Full Survival In Recent H1N1 Influenza Lethality Study

NanoViricides, Inc. (OTC BB: NNVC.OB) (the “Company”) reported dramatically improved antiviral efficacy with its optimized FluCide™ drug candidates in its most recent animal study. In the influenza mouse lethal infection model, animals treated with one of the optimized FluCide™ nanoviricide drug candidates survived beyond the stated full duration of study (21 days), and those treated with two additional drug candidates survived almost the full duration of the study. Animals in these three groups survived significantly longer (20.2 to 22.2 days) as compared to the animals treated with Oseltamivir (Tamiflu®; only 8.3 days).

The studies were conducted by Dr. Krishna Menon, PhD, VMD, MRCS, at KARD Scientific, MA. One million virus particles of Influenza A Strain A/WS/33 (H1N1) were aspirated directly into the lungs of mice. The same quantity of virus infection was repeated at 22 hrs. This influenza model was designed to be uniformly fatal in 100% of the infected, untreated animals within 5 days after infection. Treatment with the FluCide candidates and Tamiflu® (Roche) commenced 24 hours after the first viral infection. The duration of study was set at 21 days in the protocol. It was extended in order to properly evaluate the longest surviving animals.

The Company had previously reported 18.3 days mean survival with its then best anti-influenza drug candidate in the same animal model. Since then the Company says its FluCide program has progressed to process chemistry optimizations that were expected to provide additional benefits in terms of efficacy and safety improvements. The Company now reports that these improvements have led to animal survival over the full defined 21 day duration of study for one drug candidate, with two additional drug candidates close behind the top candidate, at 20.2 and 20.4 days.

“We believe that we may have more than quadrupled the efficacy of our FluCide candidates since the last study, based on the survival data,” said Anil R. Diwan, PhD, President, adding, “We believe that current anti-influenza drugs would not match the efficacy levels achieved by our FluCide drug candidates, even at high dosages due to the former’s dose-limiting toxicities.”

Additional clinically important parameters including viral load and lung histopathology, are being analyzed to confirm the therapeutic potential of the FluCide drug candidates. The results of these investigations will be reported as they become available.

“We eagerly await the viral load and histopathology results to guide our next steps in this program,” said Randall Barton, PhD, Chief Scientific Officer of the Company.



View drug information on Tamiflu capsule.

New Surgery Without Incisions Shows Promise For Prostate Cancer Treatment

With a recent first of its kind surgery, physicians at Mayo Clinic in Arizona have developed a new surgical procedure for the treatment of prostate cancer using natural orifices – signaling the next step in the evolution of minimally invasive surgery.

Removing the prostate is a common treatment for patients with prostate cancer, which affects one in six men in the U.S. according to the American Cancer Society. Mitchell Humphreys, M.D., urologist at Mayo Clinic in Arizona, said that the latest advances in the surgical treatment of the disease involve using the body’s own natural orifices as access points instead of making incisions through the skin. These types of procedures, Natural Orifice Transluminal Endoscopic Surgery, or NOTES, have advanced over the past several years and now, it is believed for the first time, a NOTES procedure has been perfected to remove the prostate.

“The reason this hasn’t been done in prostate surgery before is because of the challenge of rejoining or suturing the bladder back to the urethra,” Dr. Humphreys said. “To do this, we have developed specialized techniques and instruments that allow us to do all the work through the urethra, preventing the need for any incisions in the skin whatsoever.”

The unique tools, developed in conjunction with Mayo Clinic in Arizona, are used in a procedure called Natural Orifice Transluminal Endoscopic Surgical Radical Prostatectomy or NOTES RP. The instruments are inserted through the penis and an innovative technique is used to remove the entire prostate. Surgeons then rejoin the internal tissues via specialized instruments designed to work through the urethra. Patients benefit from the procedure because there are no incisions, little risk of bleeding and are usually able to leave the hospital within 24 hours.

The first patient who had a NOTES RP has done well and has had no problems or complications throughout any part of the operation in late June.

“This really shows that the impossible is now possible and represents a paradigm shift not only in the way we look at diseases, but also how we surgically treat disease,” Dr. Humphreys said.

The recent surgery by Dr. Humphreys is a culmination of more than two and a half years of research and development between James Lingeman, M.D., of Indianapolis, and Jude Sauer, M.D., with his research team from Rochester, New York, and the team at Mayo including Paul Andrews, M.D., Chair of the Department of Urology at Mayo Clinic in Arizona.

Prostate cancer is one of the most commonly diagnosed malignancies in men. Standard surgical therapy involves removal of the prostate through open, laparoscopic, or robot-assisted laparoscopic means. Each of these approaches does the same thing by removing the entire prostate, and presumably the cancer, and then suturing (or sewing) the bladder back to the urethra to restore the continuity of the urinary system.

For decades surgical procedures have strived to become more and more minimally invasive in order to limit potential complications and speed up recovery for patients without compromising disease control. Mayo Clinic physicians in Arizona have been on the forefront of these efforts with their early involvement in laparoscopy (surgery done through multiple small incisions) and robotic-assisted surgery (using the robot system to do complex surgeries again though small incisions).


Mayo Clinic

Association Between The Frequency Of Disposable Diaper Changing And Urinary Tract Infection In Infants

UroToday – A study from Japan looked at the frequency of diaper changing in relation to urinary tract infection. The theory behind this study was that, typically, diapers are changed mostly at the time of defecation. Diaper changing just with urination seems to be a less frequent occurrence based on anecdotal observations.

A total of 131 children were studied with urine samples. These children all had temperatures greater than or equal to 38 degrees C. The ages ranged from 2 months to 2.5 years. The authors investigated the number of times diapers were changed daily in each of the patients. Of the 131 infants, 3 cases were excluded. The remaining 128 patients were divided into 2 groups. The first group was without urinary tract infections and numbered 96, while the second group had urinary tract infections and numbered 32. The authors found that those without urinary tract infections had their diapers changed 7.5 times on average per day, while those with urinary tract infections were changed 4.7 times per day. Their analysis showed that this was statically significant. They felt that based on these studies, those infants wearing disposable diapers had an increase risk of UTI as the frequency of diaper changing decreases.

Although colonization might play a role in developing a urinary tract infection, typically the frequency of urination will correlate more along with constipation than typically just diaper changing itself. It would be interesting to see how many of those children were potty trained and how often they were voiding per day. Also it would be of interest if some of these children who were approaching 2-2.5 years of age, although if they were not potty trained, could be exhibiting some early effects of self potty training with bladder holding. It would also be interesting to delineate if these children who are only being changed 4.7 times per day on average are truly bladder holders and emptying less than those that are changed 7.5 times per day. The bladder holding, regardless of age, should correlate more with urinary tract infection than just changing diapers alone.

Sugimura T, Tananari Y, Ozaki Y, Maeno Y, Tanaka S, Ito S, Kawano K, Masunaga K
Clin Pediatr (Phila). 2009 Jan;48(1):18-20.

UroToday Medical Editor Pasquale Casale, MD

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Copyright © 2009 – UroToday

Physician Conversations Have A Positive Impact On Tobacco Use

Every day approximately 1,000 U.S. teens become daily smokers. However, a study of 5,154 students, “Physician Communication Regarding Smoking and Adolescent Tobacco Use,” in the June 2011 issue of Pediatrics (published online May 16), found that physicians who talk about the dangers of smoking with their patients had a positive impact on the teens’ knowledge of the effects of smoking, tobacco use, intentions to quit and successful quitting. Intentions to smoke in five years were lower among smokers who discussed their habit with the physician.

Those who do smoke were more likely to plan on quitting and make more attempts at quitting. The authors conclude that this study underscores the value and benefits of physician communication regarding smoking for teens.


American Academy of Pediatrics

Statins Could Provide Cost-Effective Prevention Of Heart Attack And Stroke

A new analysis suggests that broader statin use among adult patients may be a cost-effective way to prevent heart attack and stroke. The Stanford University School of Medicine study also found that using a popular test – a screening for high sensitivity C-reactive protein, or CRP – to identify patients who may benefit from statin therapy would be cost-effective, but only under certain scenarios.

“If statins are really as safe and effective as they appear to be, broadening the indications for statin therapy would be an effective and cost-effective strategy,” said Mark Hlatky, MD, professor of health research and policy and of cardiovascular medicine. “But under different assumptions, targeted CRP screening would be a reasonable approach,” Hlatky is the senior author of the findings, which appear online in Circulation.

The study comes almost two years after a major clinical trial, known as the JUPITER study, showed that millions more people could benefit from taking statins, even if they have low cholesterol. That study involved patients with low cholesterol levels but elevated levels of CRP, which indicates inflammation in the body and suggests a greater risk of heart attack and stroke.

Under current clinical guidelines, statin therapy is recommended for individuals at high risk: those identified as having a 20 percent or more risk of some sort of cardiovascular event in the next 10 years. But heart attacks and stroke also occur in many people at lower risk levels, and the findings from the JUPITER study suggested that measuring CRP levels might identify patients who would benefit from statin therapy.

Still, that research did not address whether it would be cost-effective to do more screening and/or to give more people statin therapy. Accordingly, Hlatky and his colleagues sought to compare the cost-effectiveness of different strategies to prevent heart disease.

For their study, the researchers developed a model to analyze the cost-effectiveness of three approaches: following current guidelines; doing CRP screening in individuals who don’t meet the current guidelines for treatment, with statin therapy for those with elevated CRP levels; and providing statin therapy based on an individual’s cardiovascular risk alone, without CRP testing. Their model followed hypothetical patients, starting at 40 years of age, with normal lipid levels and no clinical evidence of heart disease or diabetes.

The researchers then looked at which approaches met the threshold of costing no more than $50,000 per quality-adjusted-life-year, a common metric that takes into account quality of life as well as length of survival. (Therapies costing around $50,000 or less per quality-adjusted life-year are generally considered cost-effective.)

Their conclusion? Assigning statin therapy based on risk alone, without CRP testing, was the most cost-effective strategy. The optimal strategy for men with no risk factors, for example, would be to start a statin at the age of 55.

“Initiation of statin treatment at lower risk levels without CRP testing would further improve clinical outcomes at acceptable cost, making it the optimally cost-effective strategy in our analysis,” the researchers wrote in their paper.

The researchers found, however, that the optimal strategy for prevention changed if the assumptions in the model were altered. For instance, if patients with normal CRP levels get little or no benefit from statin therapy, CRP screening would be the optimal strategy. And if harms from statin use are only slightly greater than currently thought, statin therapy would not be reasonable in low-risk individuals, and following current clinical guidelines would be the most cost-effective strategy.

Clearly, there are a lot of unknowns and assumptions – all of which tempered the researchers’ conclusion. “This is not a slam-dunk decision in terms of: You should take people at low risk and put them all on treatment,” said Hlatky. “If you run the model and change the assumptions even a little bit, you get a different answer. Our model shows that we need better data to be confident about the best approach to drug treatment of lower-risk individuals.”

For co-author Douglas Owens, MD, the study points to a high priority for determining whether statins work as well in low-risk people (i.e. those with normal CRP levels) or just high-risk ones. “That’s a big uncertainty,” he said, and the answer would inform how cost-effective both screening and broad therapy are.

The researchers also said it would be important to know whether high CRP levels do more than identify people who are at risk of developing heart disease, but also identify which people are more likely to have lower risk of heart attack or stroke when treated with a statin. (The test could then spare certain patients from unnecessary treatment.)

“Ideally, a marker would tell us who will benefit from drug treatment and who will not,” said Hlatky. “If a test could give us that information, it would be very cost-effective. But there’s not good evidence yet that CRP, or any other test, works that well.”

Hlatky said a National Heart, Lung, and Blood Institute working group is now updating the clinical guidelines for statin therapy, and he hopes this research will inform their recommendations. “Maybe the threshold for statin treatment ought to be lower than is currently recommended,” he said.

In the meantime, the researchers have developed an interactive tool that physicians can reference to determine the most cost-effective approach to statin therapy for individual patients. The calculator can be found here

Keane Lee, MD, who did the work at Stanford and is now with Kaiser Permanente of Northern California, is the lead author of the paper. Stanford co-authors include graduate student Lauren Cipriano and Owens, an investigator at the Veterans Affairs Palo Alto Health Care System and professor of medicine and of health research and policy at the medical school.

Funding for the study came from an American Heart Association-Pharmaceutical Roundtable Outcomes Research Award, the National Institutes of Health and the Social Science and Humanities Research Council of Canada.

Michelle Brandt
Stanford University Medical Center

Jefferson Starts Live Donor Liver Program

The Division of Transplantation in the Department of Surgery at Thomas Jefferson University Hospital (TJUH) has started a live donor liver transplant program. Live donor liver transplantation (LDLT) is a procedure in which a living person donates a portion of his or her liver to another person. Combined, the two operations typically take about 12 hours. Since the program began in summer 2010, three patients and their donors have successfully undergone the procedure.

“The start of this program marks the beginning of a new era in transplantation surgery here at Jefferson,” said Cataldo Doria, M.D., Ph.D., Nicoletti Family Professor of Transplant Surgery at Jefferson Medical College of Thomas Jefferson University, and director of the Division of Transplant Surgery at TJUH. “This achievement was possible due to the efforts of everyone involved in the liver transplant program and the incredible support of the Department of Surgery, Jefferson Medical College and Thomas Jefferson University Hospital Administration.” In addition to Dr. Doria, the LDLT transplant surgery team consists of Warren Maley, M.D, director of the LDLT program, and an associate professor of Surgery; Carlo Ramirez, M.D., an associate professor of Surgery; and Adam Frank, M,.D., an assistant professor of Surgery.

Jefferson has been designated a Live Donor Liver Transplant Center by the United Network for Organ Sharing (UNOS), the organization that administers the nation’s policies on organ transplantation and procurement. The designation makes Jefferson’s one of only three adult-to-adult living donor liver transplantation (LDLT) programs in the Delaware Valley.

The liver is an organ that controls metabolism and detoxification of the body. Liver failure is often caused by the intake of poisonous drugs or substances, which can damage large parts of the liver beyond repair causing it to no longer function properly. Liver failure can also be caused by certain viruses, long-term consumption of alcohol, malnutrition and genetic disorders. Most often liver failure occurs gradually and over many years.

TJUH has a long tradition of outstanding achievement in its liver transplant program — having performed the first liver transplant in the Delaware Valley more than 25 years ago and being ranked by U.S. News & World Report as among the best in the nation for digestive disorders. Our experts are also leading the field of clinical trials and research studies for viral hepatitis, medication induced liver disease; and liver cancer, through the Hepatology and Liver Surgery sections, and the Kimmel Cancer Center at Jefferson.


Thomas Jefferson University