RxPG News : Esophageal

Plasma DNA is a reliable marker of recurrent oesophageal cancer

Fri, 25 Jul 2008 23:50:49 PST

( from http://www.rxpgnews.com ) New research published in the July issue of the Journal of the American College of Surgeons shows elevated plasma DNA is a reliable marker of recurrent esophageal cancer. The study also suggests that plasma DNA levels rise before clinical evidence of cancer recurrence in the majority of patients.

Esophageal cancer, one of the leading causes of cancer death worldwide, is usually diagnosed at a late stage. An accurate marker for detecting esophageal cancer that has spread (metastasized) beyond the esophagus may allow for better selection of patients for adjuvant therapy, prediction of response to therapy and early intervention when the disease does recur. Although carcinoembryonic antigen (CEA) and plasma DNA are known to be elevated in patients with esophageal cancer and are higher in patients with metastatic disease, the sensitivity and specificity of these markers in the diagnosis of recurrent cancer has not been compared.

"The diagnosis of metastatic esophageal cancer prior to surgery and recurrent disease after surgery remains challenging, as the clinical staging of esophageal cancer is difficult and current scanning technologies are limited," said Farzaneh Banki, MD, assistant professor of surgery, Department of Surgery, Keck School of Medicine at the University of California, Los Angeles. "The results of our study suggest that measuring DNA levels could improve the diagnosis of and prediction of recurrence of this disease."

The study analyzed the sensitivity and specificity of plasma DNA as a preoperative marker of metastasized disease and a postoperative marker in residual or recurrent esophageal cancer. Plasma DNA was measured in 45 patients with esophageal cancer and 44 healthy volunteers; serum CEA was measured in 31 patients.

Plasma DNA was found to be more sensitive than CEA for detecting cancer that cannot be removed through a surgical procedure (100 percent versus 40 percent) and was also more sensitive than CEA in detecting recurrent esophageal cancer (100 percent versus 33 percent). All patients with recurrent disease had elevated plasma DNA, and no patient with normal plasma DNA had recurrent disease (i.e., there were no false positives or false negatives for plasma DNA). Plasma DNA rose before there was clinical evidence of recurrence in 67 percent of patients, versus 17 percent of patients measured for CEA).

The researchers suggest the role of plasma DNA is of more value after surgical intervention in identifying patients with recurrent disease. In contrast, a normal CEA level should be interpreted cautiously, as it does not exclude recurrent disease. The researchers assert that greater numbers of patients and longer follow-up are necessary to confirm these findings.

How acid reflux leads to esophageal cancer

Thu, 17 Aug 2006 15:59:37 PST

( from http://www.rxpgnews.com ) A particular enzyme is significantly higher in cancer cells that have been exposed to acid, leading to the overproduction of hydrogen peroxide, and offering a possible explanation for how acid reflux may lead to cancer of the esophagus, according to a recent study in the Journal of Biological Chemistry.

The study found that the enzyme NOX5-S is affected by exposure to acid and that it produces stress on cells, activating genes that lead to DNA damage. For the first time, researchers have outlined the signaling pathway from cells damaged by acid, to the progression of esophageal cancer. They believe the same process may happen in the body when cells are exposed to acid reflux.

"The role of acid is controversial. But we show that by exposing cells to acid for short periods of time, that affects a particular enzyme, triggering a chain of events that possibly leads to cancer of the esophagus. Now that we have a better understanding of the signaling pathway, we can possibly identify who is at risk of developing cancer by determining the levels of this enzyme," says senior author Weibiao Cao, a researcher at Rhode Island Hospital and an assistant professor of medicine and surgery at Brown Medical School.

The study looked at human cancer cells and biopsies from patients with Barrett's esophagus (BE), a condition where cells in the esophagus have been altered by gastroesophageal reflux disease (GERD), or acid reflux. Acid reflux is believed to be a major risk factor for cancer in people with Barrett's esophagus.

However, the mechanisms of the progression to cancer have not been fully understood. In this study, researchers found that the enzyme NOX5-S is significantly higher in Barrett's esophageal tissues, which creates a pre-cancerous condition, as well as in esophageal cancer. Acid exposure leads to an increase in calcium in Barrett's esophageal cancer cells, thus activating a cAMP response element binding protein (CREB). This causes the activation of NOX5-S and overproduction of reactive oxygen species (ROS), thereby increasing cell growth and decreasing cell death optimal conditions for cancer to develop.

It was previously known that levels of ROS are increased in Barrett's Esophagus and in esophageal cancer and that ROS may play an important role in the development of cancer. However, the sources of ROS had not been defined. Researchers showed that the production of ROS begins with NOX5. When this enzyme was removed, acid-induced production of hydrogen peroxide was reduced, confirming that NOX5 is responsible. Also, when calcium was removed, the prevalence of NOX5 decreased, along with the production of hydrogen peroxide.

"Now that we know the sequence, we may be able to slow down or even block the progression of cancer by blocking these different steps," Cao says. "This may have therapeutic value if we can block this particular enzyme, NOX5, in Barrett's esophageal cancer cells."

Incidences of esophageal cancer related to BE have increased over the past three decades at a rate exceeding that of any other cancer in the past 10 years. Patients have a poor prognosis, with a median survival of less than 18 months after diagnosis. The five-year survival rate is less than 20 percent after surgery on operable tumors. The major risk factor is gastroesophageal reflux disease (GERD) complicated by Barrett's esophagus.

Approximately 10 percent of GERD patients develop Barrett's esophagus. A middle-aged person with BE for 20 years or more has a 10 to 20 percent lifetime risk of developing esophageal cancer, which is similar to the risk of lung cancer among heavy smokers or of liver cancer among chronic hepatitis-B virus carriers.

In order to prevent the progression, it may be necessary to increase treatment with proton pump inhibitors in patients with Barrett's Esophagus, the authors write.

"Elucidating the pathways leading from acid exposure to increased ROS production, increased proliferation and decreased apoptosis may provide a number of potentially useful therapeutic targets," the authors write.

Linking esophageal cancer with carbonated soft drinks is groundless

Wed, 04 Jan 2006 15:55:37 PST

( from http://www.rxpgnews.com ) Carbonated soft drink consumption was previously suggested to be linked to the 350 percent increase of adenocarcinoma of the esophagus since the mid-1970s, but researchers at Yale School of Medicine report that the link is unfounded and that there may, in fact, be a decreased risk of this cancer for diet soda drinkers.

The researchers warn that diet soft drink consumers might differ from other groups because they may engage in other unmeasured healthy behaviors. The study is published in the January 4 issue of Journal of the National Cancer Institute (JNCI).

It was hypothesized by others that carbonated soft drinks might have contributed to the development of adenocarcinoma of the esophagus. The theory was based on factors including similar time trends; acidic carbonated soft drinks causing gastric distension that might affect the lower esophagus; and association of carbonated soft drinks with heartburn at night, a known risk factor for esophageal adenocarcinoma.

"The theory that soft drinks could be causing this cancer was picked up by the media and widely disseminated," said lead author of the Yale study Susan Mayne, professor in the Department of Epidemiology and Public Health at Yale School of Medicine and associate director of the Yale Cancer Center. "However, there was no direct evidence to bear on this hypothesis, until we initiated our analysis."

Potential causes of esophageal adenocarcinoma were identified by Mayne and her colleagues in a previously completed population-based, multi-center study of 1,095 cancer patients and 687 control subjects. As part of that study, they conducted a full dietary interview and had access to available data on consumption of both regular and diet soft drinks.

"Our team analyzed that data as the first direct test of the hypothesis that soft drinks might have contributed to the increase in this cancer," said Mayne. "We found that contrary to the hypothesis put forth by other researchers, carbonated soft drink consumption was inversely associated with esophageal adenocarcinoma risk, mainly attributable to diet soda, and that high intake did not increase risk of any esophageal or gastric cancer subtype in men or women."

Other Yale authors on the study included Harvey Risch, principal investigator of the grant that supported the work, Robert Dubrow, and Mayne's former student, Lauren Borchardt. Authors from other centers included Wong-Ho Chow, Marilie D. Gammon, Thomas L. Vaughan, Janet B. Schoenberg, Janet L. Stanford, A. Brian West, Heidi Rotterdam, William J. Blot and Joseph F. Fraumeni, Jr.

Psychiatric disorders delay diagnosis of esophageal cancer

Mon, 15 Aug 2005 20:11:38 PST

( from http://www.rxpgnews.com ) Patients with psychiatric disorders are diagnosed with esophageal cancer much later and at a more advanced stage than patients with no psychiatric diagnosis, according to a study conducted by researchers in the Oregon Health & Science University Digestive Health Center. The finding is significant, according to the study's principal investigator, Blair Jobe, M.D., because life and death for cancer patients is all about early detection and intervention.

This study was prompted by observations made in Jobe's clinical practice. He and colleagues wished to determine whether psychiatric illness represented an independent risk factor for delay in diagnosis and advanced disease at the time the patient first displayed symptoms.

"Research has shown that initial diagnosis and management of a disease process is more difficult in patients with a psychiatric disorder," explained Jobe, an assistant professor of surgery in the OHSU School of Medicine, Portland Veterans Affairs Medical Center (PVAMC). "Although a delay in diagnosis of esophageal cancer did not appear to result in a reduction of overall survival -- a reflection of the lethality of esophageal cancer -- the relationship between psychiatric disorders and esophageal cancer is very important to heed, especially as we improve in our ability to make the diagnosis in the early, more curable stages."

In this study, Jobe and colleagues reviewed the medical records of 160 veterans with esophageal cancer seen at the PVAMC during a 13-year period. Fifty-two of the veterans had been diagnosed with a psychiatric disorder prior to their cancer diagnosis; the remaining 108 patients had no psychiatric disorder prior to diagnosis. Psychiatric disorders reported include depression, dementia, anxiety, schizophrenia, personality disorder and post-traumatic stress disorder.

The researchers found that no single risk factor contributed to a delay in diagnosis. Rather, they suggest that one or more variables may play a role, including provider bias or lack of awareness, patients' inability to articulate symptoms, patients' socio-economic status or their lack of access to care. Research to determine exactly which of these variables play a role and how to best rectify them is ongoing at OHSU.

"From here it will be important to understand why patients with psychiatric illness have a delay and eliminate it," said Jobe, also a member of the OHSU Cancer Institute. "In the meantime, our findings emphasize the importance of prompt evaluation of symptoms in all patient populations."

Women, Overweight Survive Longer with Esophageal and Stomach Cancer

Tue, 01 Mar 2005 17:24:38 PST

( from http://www.rxpgnews.com ) In the journal Clinical Gastroenterology and Hepatology, researchers from the University of North Carolina at Chapel Hill publish findings of a population-based, case-control study of 1,142 patients diagnosed with esophageal or gastric cancer. After seven years of follow up, survival rates for both cancers were low between 12 and 20 percent. However, three factors increased the likelihood of survival:

* Those who were overweight before diagnosis (BMI 25-30 kg/m2) had an approximately 30 percent lower risk of death compared to normal and underweight patients.
* Patients with moderate to high incomes (= $15,000 per year) had an up to 38 percent lower risk of death compared to low-income patients (<$15,000 per year).
* Women survived longer than men.

"Unfortunately, some of the characteristics associated with survival in this study are not easily modifiable, but we hope the findings will give patients more information about the possible course of their cancer," said lead study author Katrina F. Trivers, MSPH. "A better understanding of what can increase survival could help uncover preventive strategies."

While researchers are not currently able to pinpoint the underlying reasons for the study's results, they are certain the results are not attributed to traditional prognostic factors such as tumor stage or grade. In addition, age, education, cigarette smoking, alcohol intake, gastroesophageal reflux disease (GERD) and non-steroidal anti-inflammatory drug use were not predictors of survival.

Premature Birth Significantly Increases Risk of Esophageal Cancer

Tue, 01 Mar 2005 17:24:38 PST

( from http://www.rxpgnews.com ) In the journal Gastroenterology, researchers from the Karolinska Institutet in Stockholm, Sweden publish findings illustrating that premature birth is associated with an up to 11-fold increase in the relative risk of esophageal adenocarcinoma. This is the first study linking prenatal factors to the risk of developing esophageal cancer decades later.

"Gastroesophageal reflux disease is potentially the connection between premature birth and esophageal adenocarcinoma. GERD is one of the few established risk factors for esophageal cancer, and is quite common among infants born prematurely or with low birth weight," noted lead study author Magnus Kaijser, MD.

After following more than 3,000 individuals for more than 40 years, researchers found that low birth weight (less than 4.4 lbs.) significantly increases the risk for esophageal adenocarcinoma. The study also found birth before 35 weeks of gestation was associated with a more than six-fold increase in risk.

Researchers emphasize that the study findings are based on small numbers and not cause for alarm, but illustrate the need for further research to confirm or refute the link between prenatal exposures and esophageal cancer. The time window of interest for research on esophageal cancer must be broadened, since this study suggests that the disease may be initiated far earlier than previously known.

Esophageal cancer is three to four times more common among men than women and about 50 percent more common among African Americans than among whites. Because esophageal cancer is usually diagnosed at a late stage, most people with the disease eventually die. According to the American Cancer Society, 14,520 people will be diagnosed with esophageal cancer in the United States in 2005 and 13,570 will die from the disease.

At one time, stomach cancer was the leading cause of cancer deaths in the United States. Over the last few decades, the incidence has declined, partially due to increased use of refrigeration and antibiotics to treat childhood infections. Only 22 percent of patients with stomach cancer are diagnosed at an early enough stage to bring about significant survival benefit. In 2005, approximately 21,860 people will be diagnosed with stomach cancer and 11,550 are expected to die from the disease.

Zinc deficiency linked to fatal esophageal carcinoma

Wed, 16 Feb 2005 19:25:38 PST

( from http://www.rxpgnews.com ) Researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, have found that zinc deficiency in humans is associated with an increased risk of developing esophageal squamous cell carcinoma, an often-fatal form of esophageal cancer that has about 7,000 cases a year. NCI researchers used a novel approach to measure the concentration of zinc and other elements directly in the esophageal tissue. Their results, appearing in the February 15, 2005, Journal of the National Cancer Institute*, showed an inverse relationship between tissue zinc concentration and subsequent risk of esophageal squamous cell carcinoma.

Dietary deficiency of zinc, an essential mineral, has been associated with esophageal cancer in rodents. So far, though, examining this association in humans has been hampered by the difficulty of measuring zinc levels in the body through traditional methods. "Measuring zinc levels in the blood is not very sensitive," noted lead author Christian Abnet, Ph.D., of NCI's Cancer Prevention Studies Branch. "Because zinc is maintained in a state of equilibrium, just like body temperature, the readings will tend to be similar. Calculating zinc from intake of meat and other dietary sources isn't very sensitive either since other compounds, like phytates in whole grains, will inhibit zinc absorption."

Abnet turned to a different technique: X-ray fluorescence spectroscopy, which involves bombarding a sample with high-intensity X-rays, causing the elements in the sample to fluoresce, or glow, with a characteristic energy signature. "This allowed us to measure element concentrations directly in the tissue of interest," said Abnet, "so it should be the best indicator of the effects of zinc or other metals."

Esophageal tissue samples were obtained from a population in Linzhou, China, that was followed from 1985 through 2001. People in this region are at high risk for squamous esophageal cancer and tend to consume little meat and a lot of whole grain, and therefore are more likely to be zinc deficient. An earlier publication estimated that residents of this region get only 62 to 72 percent of the U.S. dietary recommendations for zinc, whereas most Americans meet current dietary recommendation levels.

A subset of the population underwent endoscopy with biopsy in 1985, and the NCI team, with the aid of Barry Lai, Ph.D., at Argonne National Laboratories, Argonne, Ill., examined these specimens. They measured zinc, copper, iron, nickel and sulfur levels in samples from 60 subjects who developed esophageal squamous cell carcinoma during the 16 year follow-up and from 72 histology-matched subjects at the start of the study who did not develop the disease.

The average tissue zinc concentration was significantly lower in subjects who developed esophageal cancer than in control subjects (44 ng/cm2 compared to 57 ng/cm2). When the researchers ranked the study participants by quartiles based on zinc concentration, they found that those in the highest quartile had a 5-fold lower risk of developing esophageal cancer than those in the lowest quartile. Overall, 90 percent of subjects in the highest quartile were alive and cancer-free after 16 years, while only 65 percent of the subjects in the lowest quartile were alive and cancer-free. There were no consistent associations with cancer risk for any of the other elements studied.

These findings establish an initial connection between zinc and esophageal squamous cell carcinoma in humans, although further research is needed to ensure this association is more than a local phenomenon in an area of extreme zinc deficiency. However, Abnet believes the technique itself holds great promise for future element studies. "X-ray fluorescence spectroscopy has many advantages," said Abnet. "You can apply it to most elements and you only need a tiny tissue sample. Also, it doesn't damage the tissue, so you can make multiple measurements on one sample." Abnet also noted that they successfully measured samples collected and embedded in paraffin in 1985, demonstrating that other researchers could apply this technique to archived tissue samples.