Posts Tagged ‘stage’

Breast conserving therapy shows survival benefit compared to mastectomy in early-stage patients with hormone receptor positive disease

The study findings defy the conventional belief that the two treatment interventions offer equal survival, and show the need to revisit some standards of breast cancer practice in the modern era.

The research was presented at the 2014 Breast Cancer Symposium by Catherine Parker, MD, formerly a fellow at MD Anderson, now at the University of Alabama Birmingham.

In the 1980s, both US-based and international randomized clinical studies found that BCT and mastectomy offered women with early stage breast cancer equal survival benefit. However, those findings come from a period in time when very little was understood about breast cancer biology, explains Isabelle Bedrosian, M.D., associate professor, surgical oncology at MD Anderson.

“Forty years ago, very little was known about breast cancer disease biology — such as subtypes, differences in radio-sensitivities, radio-resistances, local recurrence and in metastatic potential,” explains Bedrosian, the study’s senior author. “Since then, there’s been a whole body of biology that’s been learned — none of which has been incorporated into patient survival outcomes for women undergoing BCT or a mastectomy.

“We thought it was important to visit the issue of BCT versus mastectomy by tumor biology,” Bedrosian continues.

The researchers hypothesized that they would find that patients’ surgical choice would matter and impact survival with tumor biology considered.

For the retrospective, population-based study, the researchers used the National Cancer Database (NCDB), a nation-wide outcomes registry of the American College of Surgeons, the American Cancer Society and the Commission on Cancer that captures approximately 70 percent of newly-diagnosed cases of cancer in the country. They identified 16,646 women in 2004-2005 with Stage I disease that underwent mastectomy, breast conserving surgery followed by six weeks of radiation (BCT), or breast conserving surgery without radiation (BCS). Bedrosian notes that it was important that the study focused solely on women with Stage I disease in order to keep the study group homogenous and because in this cohort few would be ineligible for BCT.

Since estrogen receptor (ER) and progesterone receptor (PR) data were available and HER2 status was not, the researchers categorized the tumors as ER or PR positive (HR positive), or both ER and PR negative (HR negative). Patients were rigorously matched using propensity-score for a broad range of variables, including age, receiving hormone therapy and/or chemotherapy, as well as type of center where patients were treated and comorbidities.

Of the 16,646 women: 1,845 (11 percent) received BCS; 11,214 (67 percent) received BCT and 3,857 (22 percent) underwent a mastectomy. Women that had BCT had superior survival to those that had a mastectomy or BCS — the five-year overall survival was 96 percent, 90 percent and 87 percent, respectively. After adjusting for other risk factors, the researchers again found an overall survival benefit for BCT compared to BCS and mastectomy. In a matched cohort of 1,706 patients in each arm, the researchers still found an overall survival benefit with BCT over mastectomy in the HR positive subset but not in the HR negative subset.

While provocative, Bedrosian cautions that the findings are not practice changing, as the study is retrospective. Still, the research complements other recent studies that showed BCT was associated with a survival benefit compared to mastectomy. Also, she points to the delivery of radiation therapy as the possible driver of the overall survival benefit.

“We’ve historically considered surgery and radiation therapy as tools to improve local control,” says Bedrosian. Yet recent studies suggest that there are survival-related benefits to radiation in excess of local control benefits. Therefore, radiation may be doing something beyond just helping with local control. Also, we know hormone receptive positive tumors are much more sensitive to radiation, which could explain why we found the survival benefit in this group of patients.”

As follow up, Bedrosian and her team hope to mine the randomized controlled trial findings from the 1980s, matching those cohorts to current NCDB patients to see if a similar survival benefit could be observed.

“While retrospective, I think our findings should give the breast cancer community pause. In the future, we may need to reconsider the paradigm that BCT and mastectomy are equivalent,” she says. “When factoring in what we know about tumor biology, that paradigm may no longer hold true.”

source : http://www.sciencedaily.com/releases/2014/09/140904103336.htm

Trapped: Cell-invading piece of virus captured in lab by scientists

This achievement sets the stage to use x-ray crystallography to develop complete images of HIV that include integrase, which in turn will help scientists develop new treatments for the illness.

Duane Grandgenett, Ph.D., professor at SLU’s Institute of Molecular Virology and senior author of the study, discovered integrase in 1978, little knowing the piece of virus would provide the basis for an entire class of drugs that now treats HIV.

“In 1974, we hadn’t heard of HIV yet,” Grandgenett said. “We did, however, study retroviruses, the class of viruses that includes HIV. Retroviruses spread by taking over your cell’s DNA.

“And the way the virus does this is with integrase. It’s responsible for inserting the genetic information of the virus, the DNA, into our chromosomes establishing the viral reservoir. Then, it uses our cells to replicate.

“Integrase is a key component that makes HIV pathogenic.”

When a person is infected with HIV, there is an initial burst of virus production. This is when integrase inserts the virus DNA into many human cells, including CD4 T-immune cells, brain cells and other lymph cells. HIV is particularly devastating to the immune system’s T-cells, which protect the body from infection.

“Most people do not die from virus replication but from secondary causes,” Grandgenett said. “Their immune system collapses and opportunistic infections and cancer are what really kill the person.”

Now, scientists have developed drugs that are very successful at managing HIV. Combinational drug therapy is particularly effective. The virus mutates so that it can quickly become resistant to a drug. But when three different drugs aim at three different targets, as in combination drug therapy, the probability of drug resistance is much smaller.

There is one catch, however. Patients must take the drugs every day. If they do not, the virus starts cycling again and within a few weeks the viral levels are back up.

Scientists continue to try to stay a step ahead of the virus, both to combat drug resistance and to develop better treatments.

To develop better drugs, scientists want to use a process called x-ray crystallography to develop a complete picture of how integrase inhibitors — the class of HIV drugs that target integrase– interact with the virus.

“We’re aiming to develop newer, better medicines,” Grandgenett said. “We want to better understand how the integrase inhibitor drugs interact with integrase.

“So far, everybody has failed to produce HIV integrase-DNA images via high resolution x-ray crystallography,” Grandgenett said. “No one has ever captured the mother load.”

This is Grandgenett’s goal.

“Now, we’re going after full length integrase protein with DNA,” Grandgenett said. “This is what I’ve wanted to do since 1978, even before HIV was identified.”

To do this, Grandgenett and his team, including investigators Krishan Pandey, Ph.D., and Sibes Bera, Ph.D., needed to develop an integrase-DNA complex and then kinetically stabilize the complex in the presence of the drug.

Researchers used a surrogate virus to take a shortcut. Because integrase structures are similar in all retroviruses, Grandgenett tried his approach in Rous sarcoma virus (RSV), whose integrase is more readily manipulated than HIV integrase.

All current clinical integrase inhibitors work in the same way: They block integrase which prevents HIV from replicating. Specifically, they do this by stopping viral DNA strand transfer with STIs — strand transfer inhibitors.

Those inhibitors work by binding three components together: viral DNA; viral integrase; and the drug itself. Before this study, no one had been able to produce a synaptic complex (SC) in solution, the place where these three elements meet.

The researchers developed conditions where the HIV strand transfer inhibitors (STIs) trapped the SC of the surrogate RSV integrase. Grandgenett reports that this experiment is first time anyone has ever captured an integrase-DNA-inhibitor SC in solution.

“We’ve isolated it and now we want to do x-ray crystallography on it to get a better image of HIV integrase,” Grandgenett said. “That’s the next step. Hopefully, that crystal structure will better explain how integrase drugs and DNA interact at the nanometer level.

“This will help us to design new drugs. There will be a lot of uses for this information.”

source : http://www.sciencedaily.com/releases/2014/08/140806095153.htm

Lung cancer diagnosis tool shown to be safe and effective for older patients

Half of all lung cancer patients are over 70 years old when first diagnosed, but studies have shown that these older patients are less likely to receive an accurate diagnosis.

A correct assessment of the stage of a patient’s disease — how much their tumor has grown and spread — is key to ensuring they receive the right treatment.

Non-invasive methods of checking whether a patient’s cancer has spread to their lymph nodes have limited sensitivity and until recently the only way to obtain a tissue sample was under general anaesthetic — limiting its use in elderly patients who often present with other conditions that may restrict the use of general anaesthesia.

Now researchers at University Hospital of South Manchester NHS Foundation Trust and The University of Manchester — part of the Manchester Cancer Research Centre — have looked at a newer technique: endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). This method is carried out under sedation while the patient is still conscious and uses ultrasound to guide a sampling needle down and through the airways of the lungs.

Dr Richard Booton, Consultant Respiratory Physician at the North West Lung Centre and senior lecturer at the University’s Institute of Inflammation and Repair who led the study, said: “We wanted to see if there were any differences between patients aged less than 70 years old and those older than 70, in terms of both the safety of the technique and how useful it was for diagnosis.

“The team recently published their results in the Journal of Thoracic Oncology and found that the procedure was well tolerated at all ages — even in those patients aged over 80 years old. They also showed that EBUS-TBNA is effective for assessing whether a patient’s tumor had spread to the lymph nodes.

“Being able to safely take tissue samples will also allow us to test for specific tumor sub-types and better decide the most appropriate treatment for each individual patient,” added Dr Booton.

source : http://www.sciencedaily.com/releases/2014/08/140804065948.htm