Applied Biosystems, a division of Life Technologies Corporation (NASDAQ:LIFE) today announced that its research and development scientists used human disease samples from the Baylor College of Medicine Human Genome Sequencing Center to sequence an entire human genome in a single run at 17-fold coverage using the SOLiD 3 System, the only next-generation advanced genomic analysis platform to achieve this milestone to date. Data from these unprecedented throughput and sequence coverage projects was presented by the HGSC today at the Cold Spring Harbor Laboratory Biology of Genomes meeting in New York.

Scientists at the HGSC are currently equipped with 10 SOLiD Systems and are using them for a variety of human disease research programs, spanning cancer and genetic disorders. As part of two research projects, the SOLiD technology, equipped with new bead finding and quantitation genomic analysis software, was utilized to perform two sequencing runs. The mate pair run, which contained a sample from a genetic disorder, generated 50 billion mappable bases, or 17-fold sequence coverage of the human genome, which is comprised of approximately 3 billion bases. The second was a fragment run, which contained a sample from a brain cancer patient, and yielded 30 billion mappable bases, or 10-fold sequence coverage of the human genome.

Ultra-high-throughput genomic analysis systems, such as the SOLiD 3 System, will enable scientists to create a catalog of single nucleotide polymorphisms, and structural variants, or multi-base changes resulting from DNA rearrangements, and insertions or deletions. This kind of portrait of the genetic underpinnings of disease will help scientists to lay the groundwork for the molecular events that occur in the generation of diseases such as cancer.

Richard Gibbs, Ph.D., Director of the Human Genome Sequencing Center at Baylor College of Medicine

“The prospect of a single instrument run deciphering an entire human genome was unimaginable a few years ago, and now it’s a reality. My team continues to be impressed with the performance of the SOLiD System and anticipate that the inherent scalability of the platform and the depth of coverage achieved in these single instrument runs will further our human disease research projects.”

Shaf Yousaf, Life Technologies’ Head of Genomic Analysis Business

“This achievement further demonstrates that the SOLiD technology is well-suited for the analysis of complex genomes, and will play a key role in new discoveries relating to understanding the molecular basis of disease. The enhanced software is just one example of how we continue to improve the technology for use in research and medical applications.”

Applied Biosystems Leadership in Advanced Genomics Technologies

Applied Biosystems is a global leader in providing innovative instrument systems to accelerate academic and clinical research, drug discovery and development, pathogen detection and forensic DNA analysis. The technologies it markets include a robust line of DNA sequencing systems and chemistries to meet the increasing demands of the scientific community for higher throughput, more sophisticated DNA sequencing solutions. Applied Biosystems, together, with Invitrogen - a leading provider of platform independent, essential life science technologies for disease and drug research, bioproduction and diagnostics - is part of Life Technologies Corporation, which markets the life science industry’s most comprehensive portfolio of solutions for molecular and cell biology. Applied Biosystems and Invitrogen products are used in nearly every major laboratory in the world. For more information, please visit: http://www.appliedbiosystems.com and http://www.invitrogen.com.

Source
Life Technologies

Genentech, Inc. announced that the U.S. Food and Drug Administration (FDA) granted accelerated approval of Avastin® (bevacizumab) for people with glioblastoma with progressive disease following prior therapy. The effectiveness of Avastin in this aggressive form of brain cancer is based on an improvement in objective response rate. Currently, no data are available from randomized controlled trials demonstrating an improvement in disease-related symptoms or increased survival with Avastin in glioblastoma.

The new indication for Avastin was granted under the FDA’s accelerated approval program that allows provisional approval of medicines for cancer or other life-threatening diseases.

“People with this type of brain cancer have had no new treatments in more than a decade,” said Timothy Cloughesy, M.D., director, Neuro-Oncology Program of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. “After so many years with little progress in this field, Avastin was associated with a durable tumor response and doctors now have a new medicine to offer patients.”

“Today’s approval would not have been possible without the dedication of physicians, patient advocates, the FDA and most importantly the people who participated in the clinical trials and their families who had the courage to support them,” said Hal Barron, M.D., executive vice president, Global Development and chief medical officer, Genentech. “A global Phase III trial in patients with newly diagnosed glioblastoma will soon begin enrollment to further evaluate Avastin in this setting.”

Glioblastoma affects approximately 10,000 people per year in the United States and glioblastoma tumors nearly always return following initial treatment.

Avastin Efficacy in Glioblastoma

Study AVF3708g

The accelerated approval is based on independently reviewed data from an open-label, multicenter, non-comparative Phase II study that included 167 patients with glioblastoma that had progressed following initial treatment with temozolomide and radiation. Patients were randomized into two arms: Avastin alone or Avastin in combination with irinotecan. A primary endpoint of the study was objective response rate. Response was assessed by magnetic resonance imaging (MRI) and measured using World Health Organization radiographic criteria along with decreased or stable corticosteroid use. MRI does not necessarily distinguish between the tumor, swelling (edema), or tissue death (necrosis) caused by prior radiation therapy.

According to an FDA analysis of the study, tumor responses were observed in 26 percent (95% confidence interval: 17.0%, 36.1%) of the 85 patients treated with Avastin alone, and the median duration of response in these patients was 4.2 months (95% confidence interval: 3.0 months, 5.7 months).

The median age of the patients treated with Avastin alone was 54 years. Additionally, 32 percent were female, 81 percent were in first relapse, 45 percent had a Karnofsky performance status (KPS) of 90 to 100 and 55 percent had a KPS of 70 to 80. Patients with active brain hemorrhage were excluded from the study.

Study NCI 06-C-0064E

The efficacy of Avastin in glioblastoma that has progressed following prior therapy is supported by another study that used the same response assessment criteria as AVF3708g. In this single-arm study, 56 patients were treated with Avastin alone. Responses were observed in 20 percent of patients (95% confidence interval: 10.9%, 31.3%), and the median duration of response was 3.9 months (95% confidence interval: 2.4 months, 17.4 months).

Avastin Safety in Glioblastoma

In study AVF3708g, safety in patients with glioblastoma that had progressed following prior therapy was consistent with Avastin experience in other tumor types.

Safety in Patients Treated with Avastin Alone in AVF3708g

Avastin was discontinued due to adverse events in 5 percent of patients. The most frequently reported adverse events were infection (55 percent), fatigue (45 percent), headache (37 percent), high blood pressure (30 percent), diarrhea (21 percent) and nose bleeds (19 percent). Grade 3 or higher adverse events were infection (10 percent), high blood pressure (8 percent), fatigue (4 percent), headache (4 percent) and diarrhea (1 percent). There were two deaths possibly associated with adverse events including one retroperitoneal hemorrhage and one neutropenic infection.

Safety in All Patients in AVF3708g (Avastin Alone and Avastin Plus Irinotecan)

Avastin-related adverse events (Grades 1 to 4) across both arms of the study were bleeding/hemorrhage (40 percent), high blood pressure (32 percent), nose bleeds (26 percent), blood clots in the veins (8 percent), blood clots in the arteries (6 percent), wound-healing complications (6 percent), bleeding in the brain (5 percent), protein in the urine (4 percent), gastrointestinal (GI) perforation (2 percent), nervous system and vision disturbances known as reversible posterior leukoencephalopathy syndrome or RPLS (1 percent). Grade 3 to 5 adverse events across both arms of the study were blood clots in the veins (7 percent), high blood pressure (5 percent), blood clots in the arteries (3 percent), wound-healing complications (3 percent), GI perforation (2 percent), bleeding/hemorrhage (2 percent), bleeding in the brain (1 percent) and protein in the urine (1 percent).

About Avastin

Avastin is a biologic antibody designed to specifically inhibit the vascular endothelial growth factor (VEGF) protein that plays an important role in the development and maintenance of blood vessels, a process known as angiogenesis. Glioblastomas express high levels of VEGF and develop an extensive network of tumor blood vessels. VEGF is a potent activator of angiogenesis throughout the lifecycle of a tumor and is thought to be critical to a tumor’s ability to grow and spread in the body (metastasize).

Avastin was the first anti-angiogenesis therapy approved by the FDA and is now approved for the treatment of four tumor types. In addition to glioblastoma that has progressed following prior therapy, Avastin is also indicated for the first- and second-line treatment of metastatic colorectal cancer (mCRC) in combination with intravenous 5-FU-based chemotherapy; for the first-line treatment of unresectable, locally advanced, recurrent or metastatic, non-squamous, non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel; and for previously untreated, metastatic or locally recurrent HER2-negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in metastatic breast cancer is based on an improvement in progression-free survival. Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Avastin in breast cancer.

BOXED WARNINGS and Additional Important Safety Information

Patients treated with Avastin may experience side effects. In clinical trials, some patients treated with Avastin experienced serious side effects, including:

Gastrointestinal (GI) perforation:

Treatment with Avastin can result in the development of a serious side effect called GI perforation, which is the development of a hole in the stomach, small intestine, or large intestine. In clinical trials, this side effect occurred in 0.3 to 2.4 percent of patients and in some cases resulted in fatality. Avastin therapy should be permanently stopped in people with GI perforation.

Surgery and wound healing problems:

Treatment with Avastin can lead to slow or incomplete wound healing (for example, when a surgical incision has trouble healing or staying closed). In some cases this event resulted in fatality. In a clinical trial, 15 percent of patients with metastatic colorectal cancer who had surgery while receiving Avastin treatment had serious and fatal complications. Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Avastin therapy should be permanently stopped in patients with wound healing problems that require medical treatment. The appropriate waiting time between stopping treatment with Avastin and having surgery has not been determined.

Severe bleeding:

Severe or fatal bleeding, including hemoptysis (coughing up of blood), GI bleeding, hematemesis (bloody vomit), central nervous system (CNS) hemorrhage (bleeding in the brain), epistaxis (nose bleeds), and vaginal bleeding has occurred up to five-fold more frequently in patients receiving Avastin. Grade 3 or higher (severe or fatal) bleeding events have occurred in 1.2 to 4.6 percent of patients receiving Avastin. In patients with previously treated glioblastoma, intracranial hemorrhage (bleeding within the brain) occurred in eight of 163 patients and two people had Grade 3 to 4 (severe) bleeding. Some people receiving Avastin with chemotherapy for lung cancer experienced hemoptysis. In some cases, this event resulted in fatality. People with serious bleeding or recent hemoptysis should not receive Avastin.

In clinical trials, additional serious side effects seen across different cancer types, in some cases resulting in fatality, included the following: formation of an abnormal passage from parts of the body to another part (non-GI fistula formation - less than 0.3 percent), stroke or heart problems (arterial thromboembolic events - 2.6 percent), high blood pressure (5 to 18 percent), nervous system and vision disturbances known as reversible posterior leukoencephalopathy syndrome or RPLS (less than 0.1 percent), severe infusion reactions (0.2 percent), and too much protein in the urine (that may be a sign of kidney problems) was increased.

The most common adverse reactions observed in Avastin patients at a rate of more than 10 percent and at least twice the control arm rate were nose bleeds, headache, high blood pressure, irritation of the nose (rhinitis), protein in the urine, taste alteration, dry skin, rectal bleeding, tear production disorder (lacrimation), and inflammation of the skin (exfoliative dermatitis).

Avastin may cause problems getting pregnant. Women who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risks of loss of pregnancy or the potential risk of Avastin to the fetus. Nursing mothers should not breast-feed while receiving Avastin or for a short period of time after treatment is finished.

For full Prescribing Information and Boxed WARNINGS on Avastin visit http://www.avastin.com.

Source
Genentech

SAN FRANCISCO, May 6 — Long-term hypothyroidism may nearly triple the risk of developing liver cancer, researchers found.

• Explain to interested patients that the thyroid produces hormones that play an important role in lipid metabolism in the liver.
• Note that the observational study could not prove causation.

The association was independent of established hepatocellular carcinoma risk factors, but significant only among women, according to Manal M. Hassan, M.D., Ph.D., of the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues.

These case-control study findings shouldn’t be surprising, the researchers wrote in the May issue of Hepatology.

Hypothyroidism has been linked to chronic liver diseases and implicated in the pathogenesis of nonalcoholic steatohepatitis (NASH), which is considered a predisposing condition for liver cancer.

This may result from the essential role of thyroid hormones in lipid mobilization and degradation and fatty acid oxidation, Dr. Hassan’s group said. When they’re out of balance, “all of these conditions may enhance the susceptibility to chronic inflammation, DNA damage, and hepatocellular carcinoma development.”

In the study, an underactive thyroid increased hepatocellular carcinoma risk independent of hepatitis C virus (HCV) infection (adjusted odds ratio 2.0, 95% CI 1.2 to 3.3) and independent of diabetes (adjusted OR 1.9, 95% CI 1.2 to 3.3).

Together, though, these factors appeared to have more than an additive effect (adjusted OR 34.3 for hypothyroidism plus HCV and 7.9 for hypothyroidism plus diabetes, respectively).

“Screening and proper management of thyroid diseases in patients with diabetes or hepatitis C virus infection may help prevent hepatocellular cancer,” they said.

The ongoing hospital-based case-control study involved 420 hepatocellular carcinoma patients newly diagnosed at M.D. Anderson.

The controls included 1,104 healthy, genetically unrelated family members (such as spouses and in-laws) of M.D. Anderson patients with cancers other than liver, gastrointestinal, lung, or head and neck.

Overall, more of the hepatocellular carcinoma cases than controls reported a history of thyroid disease (15.0% versus 12.1%).

Likewise, a history of hypothyroidism — the most common type of thyroid disease — was significantly more common among cases than controls (11.7% versus 8.0%, P=0.03).

Long-term hypothyroidism of more than three-years duration conferred a significant, 2.1-fold excess risk of liver cancer, compared with no history of thyroid disorders.

The multivariate analysis found the association only among women.

Women with a prior, long-term history of hypothyroidism for three to 10 years had a 2.6-fold higher risk of hepatocellular carcinoma (95% CI 1.0 to 7.2). For women with a history of hypothyroidism lasting more than 10 years, the risk was 2.9 times as high (P<0.001).

The two- to threefold increased risk of liver cancer remained for hypothyroidism in analyses controlling for obesity at different ages, for all established hepatocellular carcinoma risk factors, and even in analyses restricted to nondrinkers, nonsmokers, and those without hepatitis or diabetes.

The greater susceptibility of women than men with the same condition may be partially explained by the liver’s role as a major target tissue for the proliferative effect of growth hormones, their receptors, and binding protein, the researchers suggested.

They noted that further prospective study is needed in different populations to validate the findings and to determine the underlying mechanisms.

While the self-reported thyroid disease may have been prone to recall bias, the investigators found no discrepancy in the medical records.

The study was supported by National Institutes of Health grants and the Texas Tobacco Settlement. The researchers reported no conflicts of interest.

Primary source: Hepatology

Source reference:

Hassan MM, et al “Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States” Hepatology 2009; 49: 1563-70.

Physicians should review a patient’s CT imaging history and cumulative radiation dose when considering whether to perform another CT exam, according to researchers at Brigham and Women’s Hospital, Boston, MA, and Washington University School of Medicine, St. Louis, MO.

The study included 130 patients who had at least three emergency department visits within one year in which they had a CT scan of the neck, chest, abdomen or pelvis. “We gathered the recent CT exam histories for each of these patients and found that half had undergone ten or more CT scans in the previous eight years, up to a maximum of 70 CT scans,” said Aaron Sodickson, MD, PhD. “Using typical dose values and standard risk estimation methods, we calculated that half of our group had accrued additional radiation-induced cancer risks above baseline greater than 1 in 110, up to a maximum of 1 in 17.”

“A patient’s cumulative risk of radiation-induced cancers is believed to increase with increasing cumulative radiation dose. The level of risk is further increased for patients scanned at young ages and is in general greater for women than for men. There is no absolute threshold, however, and the potential risks of radiation induced cancer must be balanced against the expected clinical benefits of the CT scan for the patient’s particular scenario,” he said.

“CT is a tremendously valuable clinical tool in a wide variety of settings and disease processes, and as a result CT utilization has grown rapidly in recent years. Continued attention will be needed to keep radiation risks in check through a combination of technological advances, optimized imaging techniques, appropriateness criteria and patient-specific risk/benefit assessments,” said Dr. Sodickson.

This study appears in the April issue of the American Journal of Roentgenology.

Click here for abstract.

Source:
Heather Curry

American Roentgen Ray Society