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Colon Cancer: Research Investigates the Role of Combined Surgery for Colon and Liver Involvement


WASHINGTON, D.C. – A single surgery to remove cancer from both the colon and the liver to which it has spread may be better in some cases than the current standard treatment of two separate surgeries with chemotherapy in between, according to a study led by Duke University Medical Center researchers. Simultaneous surgeries on the colon and liver may reduce the length of a patient's stay in the hospital and potentially lessen the risk of surgical complications without compromising long-term survival, according to the study. "In about a third of patients who are newly diagnosed with colorectal cancer, the cancer has already spread to the liver," said Bryan Clary, M.D., a surgical oncologist at Duke and senior investigator on the study. "The standard approach for these patients has been to remove the colorectal cancer and give them chemotherapy afterwards, waiting to remove liver tumors later if patients do not appear to be developing disease elsewhere in the body. These findings suggest there might be an alternative that is as safe and may even lead to better outcomes." Colorectal cancer is the third most common cancer in both men and women in the United States, and it is the second-leading cause of cancer-related deaths in this country. The researchers presented their findings on Saturday, March 17, in a plenary session at the annual meeting of the Society of Surgical Oncology in Washington, D.C. The study was funded by the National Institutes of Health and Duke's Department of Surgery. The researchers looked at outcomes for 610 patients who had undergone either simultaneous or separate surgeries for removal of colorectal cancer from the colon or rectum and from the liver, where it had spread. The patients were treated at three academic medical centers -- Duke, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University and the University of Texas M.D. Anderson Cancer Center -- between 1985 and 2006. "We looked at factors including surgical complications and survival data among the groups and found that in certain patient groups, simultaneous surgery was as safe as separate surgeries, could shorten the length of hospital stay and might lead to fewer surgery-related complications," said Srinevas Reddy, M.D., a general surgery resident at Duke and the study's lead author. Chemotherapy is used in addition to cancer surgery to kill cancer cells that may reside undetected in other parts of the body. Patients having separate surgeries commonly receive chemotherapy both after their initial colon surgery and then again after their liver surgery, Clary said. But the powerful drugs used in chemotherapy can have a toxic effect on other organs, including the liver, that may increase the risk of liver surgery, he said. The researchers also discovered that chemotherapy administered after surgical removal of cancerous liver segments favorably affected survival rates, whether or not that surgery was done alone or in conjunction with colorectal surgery. Chemotherapy administered before liver surgery showed no benefits, Clary said. The researchers found that simultaneous surgery was only as safe as standard treatment among patients who required a minimal amount of liver to be removed. But for those whose cancer was more extensive requiring larger amounts of liver to be removed, separate surgeries remain the better treatment choice. "For patients who require a great deal of liver to be removed, the complication risks associated with such extensive surgery outweigh the benefits of doing it all at once," Clary said. About half of patients with colorectal and liver tumors could be eligible for the simultaneous surgery, which could translate to about 25,000 patients per year, he said. "This study is important because it shows that patients with liver metastases at the time of their original colorectal cancer diagnosis might benefit from evaluation at a multidisciplinary center that includes not only medical oncologists and surgical oncologists skilled in colorectal surgery, but also surgeons capable of performing liver surgery," Clary said. Other Duke researchers involved in this study include Andrew Barbas, Kirk Ludwig, Michael Morse and Christopher Mantyh. Timothy Pawlik, Ana Gleisner, Lia Assumpcao and Michael Choti of Johns Hopkins and Dario Ribero, Daria Zorzi, Eddie Abdalla and Jean-Nicolas Vauthey of M.D. Anderson also participated in the research.

Blood Vessel Inhibitor Shows Promise Against Metastatic Thyroid Cancer

Blood Vessel Inhibitor Shows Promise Against Metastatic Thyroid CancerResearchers also find evidence tying a genetic mutation to clinical outcomeThyroid cancer that has spread to distant sites has a poor prognosis, but an experimental drug that inhibits tumor blood vessel formation can slow disease progression in some patients, a research team led by investigators from The University of Texas M. D. Anderson Cancer Center reports in the July 3rd edition of The New England Journal of Medicine.The investigational drug, motesanib diphosphate, is a VEGF inhibitor, a biologic agent that targets receptors on a protein known as vascular endothelial growth factor (VEGF). VEGF is instrumental in angiogenesis (formation of new blood vessels), a process that allows tumors to grow and spread. Study lead author Steve Sherman, M.D., chair and professor of M. D. Anderson's Department of Endocrine Neoplasia and Hormonal Disorders, noted strong evidence that VEGF receptors play an important role in metastatic thyroid cancer, a disease with few treatment options."There is no standard accepted chemotherapy for advanced metastatic differentiated thyroid cancer, and response rates have typically been 25 percent or less," Sherman said. "Most patients are not treated with systemic chemotherapy because the limited benefit rarely justifies the side effects. Treatment of thyroid cancer has been a completely unmet need."Sherman, colleagues in 10 countries, and scientists from Amgen, which is developing motesanib diphosphate (AMG 706), planned and conducted one of the largest clinical trials ever done for metastatic thyroid cancer. Of the 93 patients with rapidly progressing cancer who were enrolled in the study, 49 percent had a positive response. From that group 14 percent had their tumors shrink and 35 percent had their tumors stabilize for more than 24 weeks. Median progression-free survival was estimated to be 40 weeks.Genetic analyses of 25 patients indicated that those with a specific mutation known as BRAF V600E in their tumors had a better response to motesanib diphosphate than did those without the mutation. Additional research is needed on this genetic connection, but the early results are a good start, Sherman said."Finding that patients whose tumors bear a particular mutation were more likely to respond to the drug is an example of where we would like to head in our research," Sherman said. "This is the first of the various thyroid cancer trials to identify specific mutations that might allow us to individualize or personalize therapy."Only 15 percent survive for 10 yearsFor most patients, papillary or follicular thyroid carcinomas are not lethal. Surgical removal of the thyroid-often followed by treatment with radioactive iodine-and lifelong thyroid hormone therapy are usually sufficient. But about 15 percent of patients will develop distant metastases, typically to the lungs. A small percentage of these patients will respond well to radioactive iodine treatment and survive for many years. But for others, the estimated median survival duration is two to four years, with a 10-year survival rate of less than 15 percent.Multinational trialForty-two institutions internationally participated in the clinical trial, including an important collaboration with the Institut Gustave Roussy, M. D. Anderson's sister institution in Villejuif, France. The study enrolled patients with progressive, locally advanced or metastatic, radioiodine-resistant thyroid cancer. Study participants took 125 milligrams of oral motesanib diphosphate once a day for 48 weeks or until they experienced unacceptable side effects or disease progression. The primary treatment outcome was radiographic evidence of tumor shrinkage as determined by an independent review. The researchers also analyzed the duration of tumor response, progression-free survival, and drug safety.Stable Disease in 67 percent of patientsThe researchers monitored tumor response with computed tomography (CT) or magnetic resonance imaging (MRI) scans of the neck, chest, and abdomen every eight weeks or in response to signs of disease progression. Partial or complete responses to the drug were evaluated by independent review and confirmed with repeat scans four or more weeks later.Thirty-two patients completed the full 48 weeks of treatment. Motesanib diphosphate was discontinued in 35 patients because of disease progression and in 12 patients because of drug-related adverse events. Five patients died, and nine withdrew for various administrative or personal reasons.Thirteen patients (14 percent) achieved an objective partial response to the drug. Sixty-two patients (67 percent) experienced stable disease during the study; 33 of these (35 percent) achieved durable stable disease for at least 24 weeks. Nine patients (10 percent) had unconfirmed partial responses, which were classified as stable disease. Seven patients (8 percent) experienced only disease progression, and no response information was available for 11 patients (12 percent) because of incomplete or uninterpretable radiographic scans.Eighty-seven patients (94 percent) experienced at least one treatment-related adverse event. The most common events were diarrhea, hypertension, fatigue, and weight loss. In 51 patients, the adverse events were classified as severe (grade 3). Five patients had grade 4 (life-threatening) adverse events, including low calcium levels, high levels of uric acid, low potassium levels, cerebral hemorrhage, mental confusion, agitation, or decreased urine production. Two patients whose disease had progressed died of pulmonary hemorrhage.Phase I Program Revealed Drug's PotentialThe drug's potential benefit for advanced thyroid cancer was identified by researchers in M. D. Anderson's innovative Phase I Clinical Trials Program, led by Razelle Kurzrock, M.D., chair and professor of M. D. Anderson's Department of Investigational Cancer Therapeutics.The program typically has about 80 Phase I clinical trials under way, testing new targeted therapies for the first time in cancer patients. In addition to closely monitoring a new drug for safety, the program tests it against many different types of cancer."The molecular targets of new potential drugs are important for cancer in general, but at this stage the drugs aren't specific for any one type of cancer, so we include patients with different types on these early studies," Kurzrock said. "This gives us a unique opportunity to see response signals for the first time in specific cancers, flagging a drug for more extensive study in phase II or phase III clinical trials."In the Phase I trial led by Roy Herbst, M.D., Ph.D., professor in M. D. Anderson's Department of Thoracic/Head and Neck Medical Oncology, two out of five study patients with metastatic differentiated thyroid cancer responded to the drug, which was then taken directly to Sherman's phase II study. Other therapies are being rapidly transitioned from Kurzrock's program to Sherman's or other groups to establish efficacy as soon as evidence of response is seen in the phase I trial.The phase II trial was funded by Amgen, Inc. Co-authors with Sherman are Lori J. Wirth, M.D., of the Dana-Farber Cancer Institute in Boston; Jean-Pierre Droz, M.D., of the Centre Leon Berard in Lyon, France; Michael Hofmann, M.D., Ph.D., of the Medical School Bern in Bern, Switzerland; Lars Bastholt, M.D., of Odense University Hospital in Odense, Denmark; Renato G. Martins, M.D., of the University of Washington in Seattle; Lisa Licitra, M.D., of the Istituto Nazionale dei Tumori in Milan, Italy; Michael J. Eschenberg, Yu-Nien Sun, Ph.D., Todd Juan, Ph.D., and Daniel E. Stepan, M.D., all of Amgen, Inc. in Thousand Oaks, Calif.; and Martin J. Schlumberger, M.D., of the Institut Gustave Roussy, University Paris Sud in Villejuif, France, on behalf of the Motesanib Thyroid Study Group. 07/02/08

Melanoma Research: Interleukin-12 Indicates Survival Prospects for Melanoma Patients

Higher blood levels of an immune system protein predict poor survival prospects for melanoma patients with advanced disease, researchers at The University of Texas M. D. Anderson Cancer Center report today at the annual meeting of the American Association for Cancer Research.Their finding that elevated levels of interleukin-12 (IL-12) are a marker of poor prognosis also points to a molecular explanation for a long-known risk factor for melanoma patients - older age.Among 150 patients with Stage III melanoma, the study found that the highest levels of IL-12 are associated with a nearly 5-fold risk of death. Although older stage III patients also had an elevated risk of death, age was not a prognostic factor independent of IL-12."Melanoma in some cases can be vulnerable to attack by a patient's immune system," said senior researcher Jeffrey Lee, M.D., professor in M. D. Anderson's Department of Surgical Oncology. "What we've found could be evidence of a dysfunctional immune response that actually fuels the growth of melanoma."Blood-born IL-12 provides both an accessible prognostic marker and a key connection to other signaling proteins; IL-12 as well as these related proteins already have been targeted by antibody therapies in certain autoimmune disorders, Lee said.The research team examined age, stage of disease, and IL-12 levels in 658 melanoma patients - 445 with stage I or II disease, 150 with stage 3 and 63 at stage IV."First, we found that IL-12 levels increase with age," says first author and study presenter Yun Shin Chun, M.D. The mean levels of the protein increased at every age level above age 40. (See Chart) Age, disease stage and IL-12 levels were then analyzed separately as prognostic factors. Increases in all three were associated with poor overall survival."When we analyzed these three factors together, only stage of disease and IL-12 levels were independent predictors of overall survival," Chun said. Age dropped completely out of the picture. Stage of disease was the most powerful prognostic factor. Both IL-12 and IL-23 are cytokines, proteins that tell cells and other proteins what to do. Cytokines like IL-12 and IL-23 are particularly vital to immune system function. The general level of a person's immune function declines with age, Lee said, as do the levels of most cytokines. The rise of IL-12p40 with age is a relative anomaly.Chun, Lee and colleagues are investigating IL-12's connection to the tumor promoting IL-23 and about 30 other cytokines in high-risk melanoma patients. Some of the suspect cytokines, including IL-12 and IL-23, already are targeted by therapies used autoimmune disease, Lee noted.Funding for the research was provided by The Marit Peterson Fund for Melanoma Research, and the M.D. Anderson's SPORE grant in melanoma from the National Cancer Institute.

Mohs Surgery for Skin Cancer

Mohs surgery is named after its developer, Dr. Frederic E. Mohs. In the 1930’s, Dr. Mohs developed a method that “fixed” (preserved) and stained tissue directly on the patient. A chemical paste was applied to the tumor and was allowed to penetrate to a few millimeters depth. This required 6-24 hours, after which, the area was surgically removed and the entire peripheral and deep margin was examined for residual tumor. This process was repeated over days until all margins were found to be free of tumor. Defects resulting from Mohs surgery were generally allowed to granulate (fill-in) on their own and not sewn closed. This method had the disadvantages of being painful and time consuming (only one “stage” could be done per day) and the granulated wound often produced an ugly scar. Today, this technique has been modified; no chemicals are applied directly to the patient, multiple stages can be performed in hours, and the defect can be closed immediately if desired. The original concept of examining the entire peripheral and deep margin of the excised specimen remains.Background:When a routine excision is done, the specimen is processed by “breadloafing.” Like a loaf of bread is sliced, sections are taken vertically through the specimen at 3-4mm intervals and these sections are examined under the microscope. For practical reasons, only a few sections or “slices” are examined. Most skin cancers grow like the roots of a tree with extension of the tumor to the sides and downward. With breadloafing, tumor roots can be missed if they happen to grow in the 3-4mm gap between sections. In fact, less than 1% of the true peripheral and deep margin is examined by this method. This limitation is addressed by Mohs surgery.Technique:It is beyond the scope of this article to explain the Mohs procedure precisely step-by-step. However, the following are critical points that lead to the examination of theoretically 100% of the peripheral and deep surgical margin and conservation of surrounding normal tissue. After a pre-operative consultation has been completed and informed consent obtained:- The lesion is numbed with local anesthesia.- Tumor that can be seen or felt is removed with a curette or scalpel.- A thin, saucer-like layer of tissue is excised just a few millimeters around and underneath the resulting defect.- This layer is divided into pieces and inked. - A map is drawn that shows each piece in relation to the patient. - Each piece is frozen, mounted in a waxy substance and very thinly sectioned horizontally starting from the underside of the specimen. This is done by the Mohs histotechnician.- The slides are processed and examined by the Mohs surgeon. If tumor roots are seen on the slide, they extend beyond the underside of the tissue that was excised, and therefore, more tumor remains in the patient. The tumor site on the slide is matched to the previously drawn map and the precise location on the patient is identified. The process is then repeated and another saucer-like layer is removed, but only from the area that showed residual tumor. In this way, surrounding normal tissue is conserved.When no residual tumor is seen, the tumor is deemed completely removed and the defect can be repaired if desired. Often, the Mohs surgeon can repair the defect immediately. Alternatively, when the defect is more complex, closure can be coordinated with other physicians who specialize in reconstructive surgery such as plastic surgeons, facial plastic surgeons, otolaryngologists, or ophthalmologists. Cancers treatable by Mohs surgery:Mohs surgery has been used to excise many different types of skin cancer. However, BCCs and SCCs, the two most common forms of skin cancer, are the cancers most often treated by Mohs surgery. The treatment of melanoma by Mohs surgery is controversial at this time.Indications:Mohs surgery is a specialized technique that is not indicated for the treatment of every BCC or SCC and is most appropriately used under certain, well-defined circumstances. The majority of BCCs and SCCs can be treated with very high cure rates by standard methods including electrodessication and curettage (ED&C), local excision, cryosurgery (freezing) and irradiation. These are fairly quick and easy and can often be performed in the local physician’s office. Large or recurrent lesions or those that arise at sites where recurrence is more likely or where tissue conservation is important are most aptly treated with Mohs surgery. This includes many areas of the face. Training:The Mohs surgeon must be proficient in all aspects of the procedure including anesthesia, anatomy, surgery, pathology and reconstruction. Knowledge of these and other aspects of the procedure and most importantly, surgical judgement, are usually not acquired during the course of residency training and often require additional specialized fellowship training. Summary:Mohs surgery is a specialized surgical technique that results in high cure rates when used to remove skin cancers such as BCCs and SCCs. It is especially useful in lesions that, due to their size, location or other factors are at higher risk of recurrence if treated by standard methods or arise in areas where tissue conservation is important. It is not indicated for use in all cancers of the skin. Mohs surgery is labor intensive and requires a large support staff and specialized training in the technique.

Skin Cancer Research Suggests Novel way of Preventing Disease


New insight into skin-tanning process suggests novel way of preventing skin cancerFindings from a study led by researchers at Dana-Farber Cancer Institute and Children's Hospital Boston have rewritten science's understanding of the process of skin tanning – an insight that has enabled them to develop a promising way of protecting fair-skinned people from skin cancer caused by exposure to sunlight. The study, to be published by the journal Nature in its Sept. 21 issue, involved giving tans to specially engineered mice, not by exposing them to ultraviolet rays in sunlight (the usual route to a tan), but by applying a cream that switched on the tanning machinery in their skin cells. Because people who tan easily, or have naturally dark skin, are far less likely to develop skin cancer than fair-skinned individuals – who tend to get sunburns rather than tan – the findings suggests that medicinally-induced tans can protect at-risk individuals from the disease. "The study involved using a small molecule to essentially mimic the process that occurs when skin cells are struck by ultraviolet light from the sun," says the study's senior author, David E. Fisher, MD, PhD, director of the Melanoma Program at Dana-Farber and a professor in pediatrics at Children's Hospital Boston. While the compound used in the study has not yet been tested in humans, the results "demonstrate the principle that actual tanning can be 'rescued' by recognizing the normal pathway and the precise step where it is blocked in people who do not tan well," he remarks. Melanoma is the fastest-increasing form of cancer in the world, accounting for 62,000 new cases in the United States every year and nearly 8,000 deaths, according to the American Cancer Society. It occurs when pigment-making skin cells called melanocytes begin dividing rampantly as a result of damage to their DNA. If melanoma tumors are detected and surgically removed before their cells spread to other parts of the body, patients have an almost 100 percent chance of surviving. The odds drop sharply, however, if treatment doesn't begin until the disease has spread, or metastasized. One trigger for melanoma development appears to be ultraviolet (UV) light from the sun, which can damage the skin's DNA. For most of human history, fair-skinned people, who tan poorly, occupied regions with low sun exposure, such as Nordic areas with winter months of darkness. As human populations have scattered throughout the globe, increasing numbers of fair-skinned people have come to live in sunny climes, and melanoma and other skin cancer rates have shot up. The new Dana-Farber report grew out of efforts by Fisher's laboratory to study melanoma in mice whose fair skin stemmed from the same genetic roots as fair-skinned people. The researchers succeeded in generating red-haired mice whose light skin contained melanocytes, but when the mice were subjected to low levels of UV radiation, they did not tan. Nor did they tan when the UV levels were raised slightly; but when they increased slightly more, the animals got skin sunburns. "These animals couldn't tan," Fisher remarks, who is also a professor of pediatrics at Harvard Medical School. "We'd proven in a rigorous genetic system what people have known for hundreds of years: Redheads don't tan well." This suggested that the mice were a good model for fair-skinned humans. It also led researchers to propose a new theory about how sun exposure triggers pigmentation in people who tan easily. If the researchers' theory was correct, it should be possible to induce dark pigmentation in fair-skinned mice with specific, targeted drugs. The most common origin of red hair and pale skin in humans is found in a tiny pouch-like receptor, called MC1R, on the surface of melanocytes. When the hormone MSH — for Melanocyte Stimulating Hormone — drops into the pouch, it causes a surge in the melanocyte's production of the chemical cAMP. cAMP then stimulates melanocytes to turn on a large number of genes, causing a pigment called melanin to be produced. If cAMP levels are low, the melanocytes make red/blond melanin. If cAMP levels are high, they make brown/black melanin. The melanin is eventually discharged from melanocytes and taken up by keratinocytes. MC1R is shaped differently in red-haired people, so that MSH cannot stimulate it strongly. The result is that cAMP production stays at low levels. Less cAMP means less red/blond pigment production, which results in fair skin. Many scientists have theorized that tanning occurs when ultraviolet radiation strikes the nuclei of melanocytes, causing DNA damage that prompts the melanocytes to produce pigment. This supposition, however, conflicted with the results of Fisher's experiments. "Our work suggested that a peculiarity in the MC1R receptor on melanocytes is responsible for a failure to tan," Fisher relates. "But that sort of change on the cell surface shouldn't impede UV radiation from reaching the melanocyte's DNA." If Fisher's results were correct, the traditional picture of the biology of tanning was wrong. In a series of experiments, Fisher's team found evidence to bolster their theory, leading to a new model of how tanning occurs. The experiments demonstrated that, rather than acting directly on the nuclei of melanocytes, UV radiation acts on keratinocytes (the most abundant as well as superficial cells in the skin), causing them to produce and secrete MSH, which attaches to adjacent melanocytes and starts the pigment-making process. While Fisher's model adequately explains why redheads don't tan, it isn't the only possibility. "Suppose that during the embryonic or fetal period MC1R never activated cAMP production in developing melanocytes," Fisher proposes. "Would mature melanocytes then be permanently 'crippled,' unable to respond to UV, regardless of how its signals were transmitted?" One way to disprove that 'permanently crippled' scenario would be to see if melanocytes with abnormal MC1R receptors can be coaxed into producing pigment in adult mice. To attempt this, Fisher and his associates treated the skin of red-haired, fair-skinned mice with a compound known to increase cAMP levels. The compound, called forskolin, is derived from the root of the forskohlii plant found in India. The mice involved in the experiment turned dark, proving that melanocytes in redheads aren't inherently unable to make pigment if appropriately stimulated. Further experiments showed that not only can red-haired mice be given tans without exposing them to UV light, but this sunless tanning process is virtually indistinguishable from that in dark-haired mice that tan naturally."When keratinocytes absorb melanin pigment, the pigment isn't randomly distributed within them," Fisher explains. "It forms arcs that look like tiny umbrellas over the keratinocyte's nucleus. When we artificially caused our red-haired mice to tan, the pigment in their keratinocytes made the exact same umbrella-like pattern."The Dana-Farber researchers also showed that tans acquired through forskolin conferred significant protection against skin cancer caused by exposure to UV light. Fisher notes that while it is unknown whether forskolin will penetrate deeply enough in human skin to activate melanocytes, these results suggest that the search for other substances that do reach deep into the skin may well have the same pigmentation effects in people."These studies suggest that a drug-induced 'rescue' of the tanning mechanism may correspondingly rescue at least some aspect of skin cancer protection," Fisher observes. "Such sunless tanning may also dissuade sun-seeking behaviors, which undoubtedly contribute significantly to high skin cancer incidence."