Monthly Archives: April 2005

Pilocarpine Treatment of Xerostomia Induced by Psychoactive Medications

  • 4/30/2005
  • St. Simons Island, Ga.
  • Kim J. Masters, M.D.
  • Am J Psychiatry 162:1023, May 2005

Letter to the editor:

Dry mouth (xerostomia) is a frequent complication of psychoactive medications with antimuscarinic and anticholinergic side effects. The lack of saliva is annoying to patients, impairs their ability to masticate and digest food, and is a potential source of dental morbidity, including increased risk for caries and oral infection. Pilocarpine is a cholinergic muscarinic agonist. It has been used to treat xerostomia induced in cancer patients by head and neck radiotherapy (1). It has recently been found to be effective in doses of 20 mg/day in a randomized, placebo-controlled dose-adjustment study in the treatment of dry mouth and dry eyes in patients with Sjogren’s syndrome (2). It has been used to treat dry mouth as a complication of opioid treatment (3). Toxicity has been infrequently reported (4). However, it is contraindicated in patients with angle-closure glaucoma.

We have empirically used pilocarpine in doses of 10–30 mg/day, divided into dosing of two or three times a day. We have used it with our acute psychiatric inpatients, ages 20–69, who complained of dry mouth after they had been started on psychoactive medication. These included atypical antipsychotic agents, particularly clozapine and olanzapine; anticholinergic agents, primarily benztropine; and antidepressants, particularly tricyclic antidepressants and mirtazapine. Substantial relief of dry mouth was achieved in most patients. Side effects were mainly sweating and increased urination. We did not observe any adverse impact on psychiatric symptoms. The patients were generally pleased that their dry mouth symptoms responded rapidly, usually within 1 day, to pilocarpine treatment. Further investigation into the use of pilocarpine for the treatment of xerostomia induced by psychoactive medication seems warranted.

References:

Haddad P, Kanimi M: A randomized double-blind, placebo controlled trial of concomitant pilocarpine with head and neck irradiation for prevention of radiation-induced xerostomia. Radiother Oncol 2002; 64:29–32[CrossRef][Medline]
Papas AS, Sherrer YS, Charney M, Golden HE, Medsger TA, Walsh DO, Trivedi M, Goldlust B, Gallagher SC: Successful treatment of dry mouth and dry eye symptoms in Sjogren’s syndrome patients with oral pilocarpine. J Clin Rheumatol 2004; 10:169–177
Gotrick B, Akerman S, Erickson D, Torstenson R, Tobin G: Oral pilocarpine for treatment of opioid-induced dryness in healthy adults. J Dent Res 2004; 83:393–397[Abstract/Free Full Text]
Hendrickson RG, Morocco AP, Greenberg MI: Pilocarpine toxicity and the treatment of xerostomia. J Emerg Med 2004; 26:429–432[CrossRef][Medline]

April, 2005|Archive|

Nanoparticles offer new hope for cancer detection and treatment

  • 4/30/2005
  • Schmieder AH et al.
  • Magnetic Resonance in Medicine, 2005;53:621-627.

as reported by Medical News Today (www.medicalnewstoday.com)

Specially designed nanoparticles can reveal tiny cancerous tumors that are invisible by ordinary means of detection, according to a study by researchers at Washington University School of Medicine in St. Louis.

The researchers demonstrated that very small human melanoma tumors growing in mice-indiscernible from the surrounding tissue by direct MRI scan-could be “lit up” and easily located as soon as 30 minutes after the mice were injected with the nanoparticles.

Because nanoparticles can be engineered to carry a variety of substances, they also may be able to deliver cancer-fighting drugs to malignant tumors as effectively as they carry the imaging materials that spotlight cancerous growth.

“One of the best advantages of the particles is that we designed them to detect tumors using the same MRI equipment that is in standard use for heart or brain scans,” says senior author Gregory Lanza, M.D., Ph.D., associate professor of medicine. “We believe the technology is very close to being useful in a hospital setting.”

Lanza and his colleague Samuel Wickline, M.D., professor of medicine, are co-inventors of this nanoparticle technology. The effectiveness of the nanoparticles in diagnosis and therapy in humans will be tested in clinical trials in about one and a half to two years.

The spherical nanoparticles are a few thousand times smaller than the dot above this “i,” yet each can carry about 100,000 molecules of the metal used to provide contrast in MRI images. This creates a high density of contrast agent, and when the particles bind to a specific area, that site glows brightly in MRI scans.

In this study, MRI scans picked up tumors that were only a couple of millimeters (about one twenty-fifth of an inch) wide.

Small, rapidly growing tumors cause growth of new blood vessels, which feed the tumors. To get the particles to bind to tumors, the researchers equipped them with tiny “hooks” that link only to complementary “loops” found on cells in newly forming blood vessels. When the nanoparticles hooked the “loops” on the new vessels’ cells, they revealed the location of the tumors.

Nanoparticles are particularly useful because of their adaptability, according to Lanza, who sees patients at Barnes Jewish Hospital. “We can also make these particles so that they can be seen with nuclear imaging, CT scanning and ultrasound imaging,” Lanza says.

In addition, the particles can be loaded with a wide variety of drugs that will then be directed to growing tumors. “When drug-bearing nanoparticles also contain an imaging agent, you can get a visible signal that allows you to measure how much medication got to the tumor,” Lanza says. “You would know the same day you treated the patient and if the drug was at a therapeutic level.”

Using nanoparticles, drug doses could be much smaller than doses typically used in chemotherapy, making the procedure potentially much safer.

“The other side of that is you have the ability to focus more drug at the tumor site, so the dose at the site might be ten to a thousand times higher than if you had administered the drug systemically,” Lanza says.

The nanoparticles also may permit more effective follow up, because a doctor could use them to discern whether a tumor was still growing after radiation or chemotherapy treatments.

Although this study focused on melanoma tumors, the researchers believe the technology should work for most solid tumors, because all tumors must recruit new blood vessels to obtain nutrients as they grow.

Nevertheless, melanoma has unique traits that make it especially interesting as a target for nanoparticle therapy. Melanoma has a horizontal phase, when it spreads across the skin surface, and a vertical phase, when it goes deep into the body and grows quickly.

“Once melanoma has moved into its vertical phase, it is almost untreatable because by the time the tumors are large enough to detect, it’s too late,” Lanza says. “With the nanoparticles, we believe we would be able to see the smallest melanoma tumors when they are just large enough to begin new blood vessel formation. Plus, we should be able to deliver chemotherapeutic drugs right to melanoma cells, because melanoma tumors create blood vessels using their own cells.”

Original Source:
Molecular MR imaging of melanoma angiogenesis with anb3-targeted paramagnetic nanoparticles.
Magnetic Resonance in Medicine, 2005;53:621-627.

Authors:
Schmieder AH, Winter PM, Caruthers SD, Harris TD, Williams TA, Allen JS, Lacy EK, Zhang H, Scott MJ, Hu G, Robertson JD, Wickline SA, Lanza GM.

Authors Affiliations:
Washington University School of Medicine

April, 2005|Archive|

Medical care-seeking and health-risk behavior in patients with head and neck cancer: the role of health value, control beliefs and psychological distress

  • 4/30/2005
  • D. M. Tromp et al.
  • Health Education Research, doi:10.1093/her/cyh031

Health behavior plays an important role in the development, detection and course of cancer of the head and neck. Relevant health behavior includes prompt medical care seeking, and smoking and drinking cessation after diagnosis. This study examines the relationship between these health behaviors and health value and control beliefs, as well as psychological distress. Two hundred and sixty-four recently diagnosed head and neck cancer patients were interviewed about their health behavior, and they filled in a questionnaire on health beliefs and psychological distress. The results showed that one-quarter (25%) of the patients had waited more than 3 months before seeking medical care, 50% had continued to smoke and 80% had continued to drink after the diagnosis.

The patients, particularly those who smoked and drank before diagnosis, reported lower levels of health value and perceived health competence than a general population sample with which they were compared. Patients who engaged in patient delay reported a lack of perceived health competence. Psychological distress and lack of perceived health competence were found to be more common among patients who continued to smoke. The implications of these findings are discussed with regard to interventions aimed at promoting these specific health behaviors.

Authors:
D. M. Tromp 1, X. D. R. Brouha 2, G. J. Hordijk 2, J. A. M. Winnubst 1, W. A. Gebhardt 3, M. P. van der Doef 3, and J. R. J. De Leeuw 1

Authors Affiliations:
1 Julius Center for Health Sciences and Primary Care, Section Medical and Health Psychology, University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands
2 Department of Otorhinolaryngology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
3 Department of Clinical and Health Psychology, Leiden University, PO Box 9555, 2300 RB Leiden, The Netherlands

April, 2005|Archive|

Chemotherapy and Repeat Radiation Effective for Recurrent Head and Neck Cancer

  • 4/28/2005
  • Memphis, TN
  • Hehr, T. et al.
  • International Journal of Radiation Oncology, Biology and Physics. 2005; 61: 1423-1431

Reported by Cancer Consultants Oncology Resource Center
(professional.cancerconsultants.com)

Researchers from Germany have developed a tolerable regimen of alternated docetaxel (Taxotere®)-cisplatin (Platinol®) for the re-treatment of patients with recurrent head and neck cancer. The details of this report appeared in the April 1, 2005 issue of the International Journal of Radiation Oncology, Biology and Physics .

Re-irradiation of patients who have failed radiation therapy for head and neck cancer can be associated with severe complications and high-doses can rarely be achieved. The study evaluated a regimen where chemotherapy was delivered on days 1-3 and radiation therapy on days 8-12 for a total of 3 cycles. Chemotherapy was Taxotere® and Platinol® and total radiation dose was 40 Gy. This trial included 27 patients with inoperable, recurrent head and neck cancer who had received prior radiation therapy. The overall response rate was 80%. The average time to cancer progression at or near the site of cancer was 10 months, the overall average duration of survival was 10 months, and survival at 3 years was 18%. Full doses of radiation therapy were delivered to 81% of patients, and between 73% and 83% of patients received full doses of the chemotherapy agents. The main side effects were leucopenia and mucositis.

The researchers concluded that alternating chemotherapy and radiation therapy may improve tolerability of therapy in patients with recurrent head and neck cancer, potentially improving long-term outcomes in a small fraction of patients.

Comments: This study is of interest because relatively large doses of repeat radiation were apparently well tolerated.

Reference:
Hehr T, Classen J, Belka C, et al. Reirradiation alternating with docetaxel and cisplatin in inoperable recurrence of head-and-neck cancer: A prospective phase I/II trial. International Journal of Radiation Oncology, Biology and Physics. 2005; 61: 1423-1431.

April, 2005|Archive|

Making Sense Of Medical News

  • 4/25/2005
  • as reported by www.pccoaltion.com
  • Consumer Reports on Health

Following the back and forth of medical news is enough to give you whiplash. Supplemental estrogen, portrayed in the media for decades as a veritable fountain of youth, ends up being anything but when definitive studies show it can increase the risk of breast cancer, heart attack, and stroke. Initially heralded as safer than existing drugs, the pain relievers rofecoxib (Vioxx) and celecoxib (Celebrex) make the front pages again when later studies show they increase heart-attack risk. After riding a long wave of good press, the reputation of the antidepressant paroxetine (Paxil) crashes amid reports that the drug may make some teenagers suicidal.

Indeed, medical news often seems to follow an all-too-familiar pattern: New drugs or therapies are introduced with glowing reports, followed a few years later by headlines blaring their dangers. “That pattern leaves many people confused or even angry,” says Steven Woloshin, M.D., a professor at the Dartmouth Medical School’s Center for Evaluative Clinical Sciences.

Some people react to that uncertainty by dismissing all medical news, while others overreact by adopting-or abandoning-medicines too soon. For example, in the 1990s many people stopped taking certain blood-pressure medications after a pair of studies linked them to increased heart-attack risk; subsequent research refuted that evidence, but only after some patients suffered adverse events because they stopped taking their medication.

While some of the confusion stems from the natural unfolding of scientific knowledge, some comes from shortcomings in the way medical research is published and the way the mass media present medical news. Woloshin and others have identified crucial shortcomings in medical news reports about everything from dietary and exercise habits to new drugs and surgical procedures. This report suggests questions you should keep in mind when reading medical news with a critical eye.

HOW GOOD IS THE RESEARCH?

* Has the study been published? News reports often trumpet tantalizing results of preliminary research presented at medical meetings, relying only on the investigator’s description of ongoing studies. A 2002 review of such reports found that only half ever get published in respected journals.

For example, after studies suggested that celecoxib (Celebrex) increased heart-attack risk, a Pfizer-funded scientist cited unpublished research that linked similar risks to the related drug naproxen (Aleve). While that comment received much attention in the press, subsequent data from the study, released in February 2005, cleared naproxen of the supposed heart risk.

* Who funded-and promoted-the study? The vast commercial machinery behind the publication of scientific information can sometimes overcome even the vigilance of peer-reviewed medical journals, which are supposed to screen for biases.

For example, The New York Times and other papers published reassuring articles about the safety of the diet-drug combination known as phen-fen based on a study and an editorial published in the Journal of the American College of Cardiology in 1999. It turned out, however, that both the study and editorial were written by paid consultants to Wyeth, a maker of one-half of the phen-fen combination.

Because pharmaceutical companies help fund much medical research, it’s unreasonable to dismiss all industry-related studies. It is vital, however, to know about the potential conflict of interest of the researchers involved. Be leery of any news account that omits that crucial information.

* How good is the study? The gold standard in medical research is the double-blind, controlled clinical trial, in which subjects are randomly assigned to a control (placebo) or an experimental (the real thing) group. Neither the subjects nor the researchers know who is in which group until the study is over and the code is broken.

Observational studies, on the other hand, compare people who independently chose a particular health intervention against others who didn’t. These studies can suggest a probable link but can’t prove a causal effect. Other factors, such as lifestyle habits, can influence results. For example, estrogen’s reputation took a nosedive when clinical trials failed to confirm the apparent heart and other benefits suggested by numerous, previously published observational studies.

PUT IT IN CONTEXT

Despite the “Eureka!” enthusiasm often expressed in headlines, the process of gaining scientific knowledge more often resembles the creation of a pointillist painting: If you concentrate too much on individual dots, you’ll miss the big picture. That means seeing not only how the research fits in with what was known before, but also how relevant it is to you as an individual.

What’s the supporting evidence? A single study seldom constitutes strong evidence of anything. Look for descriptions of previous research that pointed in the same direction or at least provided a plausible biological explanation for the finding.

What do others have to say? Don’t rely on a single news report. Check whether other sources give additional details or perspectives that provide a fuller picture. Also, look for responses of governmental agencies and reputable organizations, which can often help you gauge how seriously to take the news. For example, the fact that the National Institutes of Health, the American Cancer Society, and the American Heart Association all chimed in with concerns about estrogen was a strong sign that the news was unusually significant.

Is the study relevant to you? Many drugs that show promise in the early test-tube stage or in animal research don’t work safely or effectively on humans. In human trials, some treatments are tested only in men or women, others only in young, healthy, or sick people. The less you resemble the subjects, the more reason to temper your enthusiasm.

What does it cost? New drugs often cost more, though their benefits are often described as though money is no issue. For example, the new drug omalizumab (Xolair) may indeed revolutionize treatment of asthma and rhinitis by targeting the immune-system flaw that often underlies both disorders. But it costs $1,000 or more a month, a significant limitation.

What do you and your doctor think? Your individual health needs may make even relevant-seeming research moot. So talk with your doctor before rushing to judgment.

NEW . . . BUT IMPROVED?

News reports are far more likely to describe the possible benefits of a new therapy than their potential risks. And research into new drugs or treatments is likely to underestimate the risks they pose and overestimate the potential benefits.

Only the good survive. Positive studies are far more likely than negative ones to make it to print, and thus far more likely to get media attention. For example, the makers of paroxetine (Paxil) withheld from publication two studies that showed the drug was ineffective in children. (Consumers Union, publisher of this newsletter, believes drugmakers should be mandated to publish results of all clinical trials; see the “Prescription for Change” initiative at www.prescriptionforchange.org.)

Stacked studies. Studies testing new treatments are often conducted by only the best doctors and in the best hospitals, skewing the results. For example, complication rates for prostate-cancer surgery initially seemed reasonably low because studies testing the procedure were performed by experts; follow-up studies that measured complication rates in the real world found much higher rates.

Also, study groups are often filled with patients most likely to benefit from the treatment and least likely to be harmed. For example, only 1 in 200 or 300 potential patients are accepted into clinical trials of breast cancer or carotid endarterectomy treatments, according to some research. Studies need to target ideal candidates to make expensive clinical trials cost-efficient. But as a result such studies might not reflect the real risks and benefits of that therapy in the general population.

No long-term data. Finally, even the best research of new therapies can’t provide evidence of their long-term safety and efficacy. Indeed, one study found that over a five-year period the Food and Drug Administration had to pull roughly 5 percent of newly approved medications off the shelves because of unexpected risks. According to another study, the FDA later issued more stringent warnings on about 10 percent of new drugs.

“50 PERCENT DECREASE!” DRAMATIC STATISTICS CAN BE MISLEADING

* The statistics used to report the findings of medical studies can often distort, rather than clarify, health benefits and risks. That’s because such reports often rely on something called “relative difference,” a statistical formulation that can lead to dramatic headlines but misrepresent the real-life importance of the research. For that, you’re better off knowing the “absolute difference” instead.

Consider, for example, news stories about the increased heart risks of celecoxib (Celebrex), which announced that the drug “more than tripled” the risk of heart attack and stroke. That does sound scary-but does it accurately convey the threat posed by the drug?

Let’s look a little closer. In the celecoxib study, 1 percent of people taking a placebo pill over a three-year period died of coronary disease compared with 3.4 percent of those taking 400 milligrams of the drug twice a day. If the results are presented as a relative difference, or a ratio, those on the drug were indeed 240 percent more likely to die of heart attack or stroke-or at more than triple the risk-than people on a placebo.

But what was the actual risk of taking the drug? To find that out, the placebo result is subtracted from the experimental result to get the absolute difference: In this example, 2.4 percent of patients actually suffered a heart attack or stroke because of the medication. That’s still important news-but not nearly as dramatic a headline.

Just as relative risk can make some problems seem bigger than they are, they can also overstate the benefits of drugs. For example, in a landmark trial of the cholesterol-lowering drug simvastatin (Zocor), 11.5 percent of patients on a placebo died of a heart attack compared with 8.2 percent on the drug. That’s an absolute difference of 3.3 percent-but a much more impressive-sounding 29 percent decline in relative mortality.

Finally, relative risk can be used to make rare problems seem much more important than they are. For example, one study found that a vigorously active person is 2.4 times more likely to have a heart attack during exercise than at rest, a finding that seems to suggest you should hang up your gym bag.

But those attacks are extremely rare; the absolute risk of having a heart attack while you’re working out is only about 1 in 2 million, so the fact that exercise multiplies the risk to that level is nearly meaningless. Moreover, knowing that regular exercise can cut the risk of heart attack the rest of the time roughly in half should be enough to get you confidently back onto the treadmill.

April, 2005|Archive|

Cuban Monoclonal Antibody Registered in China

  • 4/25/2005
  • Cuba
  • Cubasi
  • Cuba Travel Explorer

TheraCIM h-R3, a humanized monoclonal antibody, received the certificate of first-category drug granted by the State Food and Drug Administration of China, for its production and commercialization in that Asian nation.

According to Prensa Latina news agency, the drug is prescribed for the combined treatment of advanced head and neck epithelial cancer, of bad prognosis and resistant to the chemotherapy, explained PhD. Patricia Sierra, responsible on the Cuban side of this project.

The h-R3 is a new type of drug obtained through biotechnology, with high effectiveness in the marking and specificity, and little side effect, that has been patented in other countries, including the United States.

This drug will be produced and commercialized by Biotech Pharmaceutical, Chinese-Cuban Company constituted in 2000 by the CIMAB (representative of the Molecular Immunology Center) and three Chinese companies.

Sierra, also general submanager of Biotech Pharmaceutical, pointed out that the industrial-scale cultivation of the recombinant antibody would kick off next September.

To obtain that certificate, it was necessary to carry out clinical trials for more than one year with 120 patients affected by head and neck cancer in six hospitals of Beijing, capital of China, following strict protocols set for that aim.

The studies wound up with very good results, with full response in 70% of the cases, without evidences of severe clinic toxicity, Prensa Latina assures in its note.

That was the first time in which a humanized monoclonal antibody was subject to clinical test in China, country that does not have this production technology at large scale.

It was released that in addition to the h-R3, three other drugs conceived by CIM scientists are completing different phases of development, among them the CD6, a monoclonal antibody destined for the treatment of different types of lymphomas, that is currently in its phase of clinical trial; the c5, for ovarian tumors, under humanization process and works are underway for the development of the EGF anti-cancer vaccine.

April, 2005|Archive|

Losing your voice can be sign of something serious

  • 4/25/2005
  • Seattle, WA
  • Bruce Taylor Seeman
  • Seattle Times

Chuck McDowell gave speeches. He sang with a band. But everything changed when his voice disappeared, leaving McDowell feeling frightened and isolated.

“I was having to speak into an amplifier just to have a conversation at home,” said the 46-year-old financial adviser from Duluth, Ga. “If I was in a restaurant, I could not be heard unless I put my amplifier on the table and turned it up.”

Eventually, McDowell had a growth removed from his vocal cords, a procedure he now jokingly recalls as easier than some haircuts. But in the 18 months it took to summon the courage for surgery, he experienced the unsettling questions familiar to nearly everyone at least once in a lifetime: Where did my voice go? How do I get it back?

Experts believe that at any given time, more than 7 million Americans suffer from voice disorders, and that number is likely to grow. Longer lives may result in more voices muted by age-related fatigue. Meanwhile, the modern era — with so many service-sector jobs such as sales, and so much yapping on cellphones — is a recipe for voice strain.

“Some people have a hypothesis, that the cellphone is the vocal endurance test for the new millennium,” said voice-disorder specialist Dr. Michael Johns, director of the Emory Voice Center of Emory University in Atlanta.

The key to effective voice production is healthy vocal cords, which experts call vocal folds. They lie horizontally in the throat just behind the Adam’s apple — a side-by-side pair in the larynx, or voice box, atop the windpipe.

During speech, air is pushed upward from the lungs and through the windpipe. The air streams between the vocal cords, which spread apart and close together like a pair of sliding doors over a porthole. Sound is made when the vocal cords vibrate — about 110 times per second in men, and nearly twice that rate in women. That sound is turned into words by the workings of the mouth, nose and throat.

The vocal cords, which are about half an inch long, are made up of muscle and layers of mucosa. Many things can damage this tiny layer cake of soft tissue, and that’s when voice disorders can occur.

“If someone wakes up one morning and stays hoarse for a couple of weeks, they need to get evaluated,” said Katherine Verdolini, an associate professor of communication science and disorders at the University of Pittsburgh. “These are … symptoms that can be linked to hundreds of different pathologies.”

Susan Thibeault, a University of Utah assistant professor who researches how tissue engineering might help repair surgical scars on vocal cords, said estimates that 3 percent to 9 percent of the population has voice disorders is probably low.

“There are tons of people who have neurological voice problems who just live with them because they don’t know what to do,” Thibeault said. “I recently talked to a doctor who said someone came in with a problem (he’d had) for 15 years.”

Most disorders are treatable. In McDowell’s case, surgery was the best way to remove his polyp.

In other cases, voice exercises provide the necessary rehabilitation. Verdolini said many older people benefit from such workouts.

“A large number of problems of the aging voice are due to atrophy,” she said. “It’s clear that exercises can be done to strengthen the muscles.”

Betty Knuckey, 55, initially blamed voice overuse for chronic hoarseness she experienced in 2003. Her self-diagnosis seemed sensible; for about a week, Knuckey had carried a heavy workload at a computer-software company because three co-workers were not on the job.

“I was on the help desk,” said Knuckey, of Cumming, Ga. “I took 30 to 50 calls a day. That’s a lot of talking. It got where I couldn’t talk. (My voice) would crack. I had to use everything I had just to talk.”

Doctors initially blamed strained vocal cords, or a sinus infection. But talking less or taking antibiotics offered no relief. Eventually, a throat examination with a miniature camera showed a growth on her right vocal cord.

Johns, Knuckey’s doctor, removed the malignant tumor in November 2003.

Knuckey doesn’t enjoy the ongoing checks to make sure the cancer is gone. But they’re better than the alternative. Knuckey has known three people who died of throat cancer. One, her ex-husband, didn’t see a specialist for three or four months. The delay may have cost him his life.

“If I had waited another month, it would have been a lot worse,” Knuckey said.

April, 2005|Archive|

Gene therapy in the Management of Oral Cancer: A Review of Recent Developments

  • 4/25/2005
  • Lagos, Nigeria
  • AI Ladehinde et al.
  • Niger Postgrad Med J, March 1, 2005; 12(1): 18-22

Aims:
This article reviews the present body of knowledge regarding the principle, transfer techniques, therapeutic strategies, clinical applications and limitations of gene therapy in the management of oral squamous cell carcinoma. Materials and Methods: Scientific publications on gene therapy between 1990 and 2003 were selected for the purpose of the review. These include clinical articles, experimental studies and review articles.

Results:
Viruses are the commonly used transfer system for the delivery of gene therapy. The viral vectors commonly used are: retroviruses, adenoviruses, herpesviruses, and adenoassociated viruses (AAV). Transfection of cancer cells in vivo with gene therapy is done by intralesional injection, and sometimes by topical application. Phase I and II clinical trials have established the safety and clinical efficacy of gene therapy in the treatment of oral squamous cell carcinomas in humans, especially in combination with chemotherapy or radiotherapy. Phase III clinical trials and studies of the use of gene therapy as an adjuvant following surgery are presently underway.

Conclusions:
Gene therapy represents a new and innovative approach to the treatment of oral cancer especially in recurrent disease and adjuvant treatment. Oral squamous cell carcinoma is especially an attractive tumour target due to its frequent genetic mutations and accessibility for intra-tumoural administration of gene therapy. However, gene therapy has not yet been shown to be suitable for systemic delivery in cancer patients, hence the control of regional and metastasis is presently difficult.

Authors:
AI Ladehinde, MO Ogunlewe, WI Adeyemo, and BO Bamgbose

Authors Affiliation:
Oral and Maxillofacial Surgery Department, School of Dental Sciences, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria

April, 2005|Archive|

COX-2 inhibitors still eyed for cancer prevention

  • 4/25/2005
  • Bethesda, MD
  • Cheryl A. Thompson
  • Am. J. Health Syst. Pharm. 2005; 62(9): p. 890-894

While September 30, 2004, may be remembered as the day that clinicians and patients started reconsidering the available pain relievers, the negative news about rofecoxib sent a shock wave through the world of preventive oncology. December 17 brought bad news about celecoxib.
Researchers had been exploring the potential of long-term therapy with rofecoxib or celecoxib, both cyclooxygenase-2 (COX-2) inhibitors, to reduce the risk of colorectal cancer.

What the researchers found first was that the drugs apparently increased users’ risk for myocardial infarction, ischemic stroke, and other cardiovascular events.

The ability of COX-2 inhibitors to obstruct the activity of the inflammation-promoting enzyme and also interfere with inflammatory mediators such as interleukin-1 and nuclear factor kappa B had made that type of drug a potential chemopreventive for cancer, according to Ernest T. Hawk of the National Cancer Institute (NCI).

Buttressing this line of research was evidence that an excess of COX-2 played a role in the invasive and earlier stages of cancer at a large number of sites in the body, he explained.

Hawk is a member of the steering committee for the NCI-sponsored Adenoma Prevention with Celecoxib study, which stopped administering the drug in December 2004 after an independent committee discovered an increased cardiovascular risk among drug recipients.

He and an epidemiologist discussed the future for COX-2 inhibitors in cancer prevention at the American Society of Preventive Oncology annual meeting in San Francisco, held March 13–15.

A change in target patients

Hawk said NCI, despite the revelations about rofecoxib and celecoxib, has not abandoned the idea of using COX-2 inhibitors to reduce patients’ risk of colorectal cancer.

The Web site ClinicalTrials.gov showed in March that recruitment continued for an NCI-sponsored study of celecoxib, with or without oral eflornithine, in the prevention of colorectal cancer in patients with familial adenomatous polyposis.

Colorectal cancer develops in nearly all patients with familial adenomatous polyposis by age 40 years if they have not had the precancerous polyps surgically removed, according to the American Cancer Society.

“In high-risk cohorts,” Hawk said, “we’re attempting to continue on with the celecoxib trials because there we think . . . the potential benefits outweigh potential risks, and we’ll see if everyone shares our view.”

So far, he added, investigators and personnel at NCI and FDA “are on the same page with regard to the importance of moving that research forward.”

When NCI suspended use of the COX-2 inhibitor in the Adenoma Prevention with Celecoxib study, 86% of the 2035 patients had already taken the drug or placebo for the three years that had been planned, according to Hawk’s presentation in February to two FDA advisory committees.

All of the patients had at least one adenomatous polyp surgically removed from their colon or rectum before they started the study and had a moderate risk of colorectal adenoma, he said. Celecoxib’s ability to prevent the growth of new polyps, and hence reduce the risk of colorectal adenoma, would be assessed one and three years after the polypectomy.

Hawk said at the March meeting that the research team hopes to have the efficacy data in hand before the end of the year.

Also at the FDA-convened meeting in February, Merck Research Laboratories reported unpublished efficacy results from its Adenomatous Polyp Prevention on Vioxx study, whose cardiovascular data had prompted the company to stop marketing rofecoxib.

Daily therapy with rofecoxib 25 mg daily for three years had reduced the relative risk of colon-polyp recurrence by 24% in patients with colorectal adenoma, Merck’s Ned S. Braunstein had told FDA and its advisory committees.

As for the NCI-sponsored studies of COX-2 inhibitors in patients at lower risk of colorectal adenoma, “that line of research is not moving forward at the moment,” Hawk said.

NCI, he said, now focuses its chemoprevention efforts with COX-2 inhibitors on high-risk patients—those with a 40–100% lifetime risk of developing a specific cancer.

One goal of NCI’s continuing research is to identify patients with relatively low safety concerns from long-term exposure to COX-2 inhibitors who would benefit greatly from the reduction in cancer risk, he said.

Not the first surprise

“The trials of selective COX-2 inhibitors give us a sense of ß-carotene revisited,” said discussion moderator Michael Thun, head epidemiologist at the American Cancer Society, referring to nearly decade-old research.

The Beta-Carotene and Retinol Efficacy Trial, a large placebo-controlled study that involved patients at high risk of lung cancer, had found an increased risk of death in general and a possible increased risk of death from cardiovascular disease among supplement users. Use of the two supplements in the study stopped in early 1996 when the steering committee discovered the increased risks.

At about the same time, results of the ß-carotene component of the Physicians’ Health Study had been released. That portion of the study had found that long-term use of the supplement had no effect on the rate of death, cancer, or cardiovascular disease in the participants, half of whom were current or former smokers.

Both prospective studies of ß-carotene had been undertaken on the evidence of epidemiologic findings and laboratory investigations.

Breast cancer prevention

Twenty-one epidemiologic studies have focused on the occurrence of breast cancer and the use of nonsteroidal antiinflammatory drugs (NSAIDs), primarily aspirin, said Randall E. Harris, an epidemiologist and biostatistician at the Ohio State University in Columbus. On the basis of those studies, Harris’s research group estimated that the risk of breast cancer was reduced by 39% with the daily use of aspirin 325 mg or ibuprofen 200 mg—drugs that inhibit COX-2 and cyclooxygenase-1.

Harris directed the highly publicized Women’s Health Initiative study that found a 49% reduction in the relative risk of breast cancer with long-term use of ibuprofen, usually 200 mg three times a week, and a 21% reduction with aspirin therapy among postmenopausal women.

Preliminary findings from his university-conducted study of 300 women with breast cancer who used a pain reliever and 300 women without the diagnosis who used the same medication suggest a cancer-preventive effect from NSAID exposure, he said.

Whereas acetaminophen, which lacks an antiinflammatory effect, was associated with a 10% reduction in the relative risk of breast cancer, the NSAIDs in the study yielded better results, Harris reported. COX-2-selective NSAIDs, primarily rofecoxib and celecoxib, were associated with a 49% reduction in users’ relative risk, aspirin with a 34% reduction, and ibuprofen with a 74% reduction.

He said he was not surprised by these findings, given that the COX-2 gene and its enzyme affect cell division, the development of mutations, formation of new blood vessels, transmission of cancerous cells to secondary sites, and programmed cell death.

“I think we need to continue to explore the role of COX-2 inhibition and the combination of COX-2 inhibitors with perhaps other types of chemotherapeutic agents [in decreasing] the risk of not only cancer but also the risk of other chronic diseases,” he told the audience.

What matters more?

“The fundamental issue,” Thun said in describing what he sees as the new paradigm for drug development in cancer chemoprevention, “is that in the absence of safety, efficacy doesn’t matter.”

Safety, he added, is “especially difficult to achieve when the goal is to prevent a single type of cancer in healthy people.”

NCI’s Hawk disagreed with Thun’s paradigm.

“Clearly, safety is extremely important in [disease] prevention,” Hawk said. “Nevertheless, we wouldn’t recommend anyone take anything unless efficacy was demonstrated first. So in my view, efficacy does come first, and then safety comes second.”

April, 2005|Archive|

Reliability of sentinel lymph node biopsy with squamous cell carcinoma of the oral cavity

  • 4/25/2005
  • T Minamikawa, M Umeda, and T Komori
  • Oral Surg Oral Med Oral Pathol Oral Radiol Endod, May 1, 2005; 99(5): 532-8

Objectives:
Although sentinel lymph node biopsy (SLNB) may reduce surgery-related complications related to unnecessary lymph node dissection and is now widely used for many patients with cutaneous melanoma and breast cancer, its use for oral cancer patients remains controversial.

One of the main reasons for the reluctance to initiate SLNB for oral cancer is that the frequency of skip metastasis has not been clarified. The objectives of this study are to examine the frequency of skip metastasis and to evaluate SLNB for oral cancer.

Study design:
To shed light on these concerns, we first conducted a retrospective study of 296 patients with squamous cell carcinoma of the oral cavity who underwent neck dissection. Next, the accuracy of lymph node biopsy with and without detecting sentinel lymph node was examined.

Results:
Ten patients showed skip neck metastasis in the level III-V region without level I-II involvement. Of these patients, 7 underwent neck dissection when their initially N0 neck progressed to N+, 2 underwent neck dissection when local recurrence occurred, and only 1 underwent surgery as an initial therapy. Most patients who underwent neck dissection as the initial therapy showed skip metastasis. Intraoperative lymph node biopsy without any attempt to detect sentinel lymph nodes by means of blue dye or lymphoscintigraphy was performed on 68 patients with oral cancer. Sixty-one (90%) were diagnosed correctly, whereas 7 diagnosed as N- actually had neck metastasis. SLNB with blue dye was performed on 21 patients. In 17 of them, sentinel lymph node was easily detected, resulting in a correct diagnosis for 16 patients (94%), while 1 with a false negative result actually had micrometastasis.

Conclusion:
These findings seem to suggest that SLNB is useful and can be applied to patients with oral cancer who undergo surgery as the initial therapy.

April, 2005|Archive|