Chemotalk Newsletter

Chemotalk Newsletter, Vol. 76: August 1, 2014

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Hello, Everyone...

Starting off with an article of universal interest:


Despite impressive medical strides, CANCER remains a leading killer and overwhelming burden to healthcare systems, causing well over a half million fatalities per year with a projected cost of $174 billion by 2020, according to the National Cancer Institute. Reducing the human and economic toll will require diagnosis and intervention at early stages of illness, when the best prognosis for a cure exists.

In recent years, aggressive research and substantial financial investments have been directed at discovering pre-symptomatic indicators of cancer, known as biomarkers. But as lead author Phillip Stafford and his colleagues at Arizona State University's Biodesign Institute emphasize in a new study, the quest for cancer biomarkers has been stymied by a number of factors.

In research appearing in the current issue of the journal Proceedings of the National Academy of Science, Stafford and his team describe an innovative technique for early disease detection, which they call immunosignaturing.

"For years we've seen remarkable results from immunosignatures, but introducing the technology to the scientific community has required a lot of patience," Stafford says. Stafford is a researcher in Biodesign's Center for Innovations in Medicine which is co-directed by Stephen Albert Johnston, who is also one of the new study's co-authors.

To date, only a handful of cancer biomarkers have received FDA approval for clinical use and even approved biomarkers are sometimes of limited utility. The problems are numerous. The body's immune response to cancer is complex, heterogeneous and differs from patient to patient, as well as depending on depending on cancer type and stage.

Individual biomarkers often lack the sensitivity and resolution for positive diagnosis and diagnostic molecules, including RNA, DNA, proteins or peptides are often present in vanishingly slight amounts, after diluting in the bloodstream, making accurate detection especially challenging. Vast research efforts notwithstanding, efforts to establish better pre-symptomatic beacons of disease have been disappointing.

Immunosignatures take a different approach. Rather than using a reductionist biomarker paradigm, it relies on a multiplexed system in which the entire population of antibodies circulating in blood at a given time is profiled.

The technique relies on a microarray consisting of thousands of random sequence peptides, imprinted on a glass slide. (The peptides used are 20 unit amino acid chains, randomly composed.)

When a tiny droplet of blood, (less than a microliter is needed), is spread across the microarray, antibodies in the blood selectively bind with individual peptides, forming a portrait of immune activity‹an immunosignature.

Because the peptide sequences are random and not related to any naturally occurring disease antigens, the authors refer to immunosignatures as "disease agnostic," which means that a single platform is potentially applicable to multiple disease types. This is a substantial improvement over highly specific bioassays that can only test for a single biomarker antibody, often with substantial misidentification or inadequate sensitivity.

The current study puts immunosignatures to the test, evaluating the technique's ability to identify multiple disease types. The team first "trained" the system to calibrate results and establish reference immunosignatures, using 20 samples each from five cancer patient cohorts, along with 20 non-cancer patients. Once reference immunosignatures were established, the technique was tested in blind evaluation of 120 independent samples covering the same diseases. The results demonstrate 95 percent accuracy.

To further assess the diagnostic power of immunosignaturing, over 1500 historical samples comprising 14 different diseases, including 12 cancers were tested. In this case, 75 percent of the samples were used in the training phase and the remaining 25 percent subjected to blind test.

Remarkably, an average diagnostic accuracy of over 98 percent was achieved, demonstrating the suitability of immunosignaturing for the simultaneous classification of multiple diseases.

Specifically, in one experimental trial, researchers were able to detect and distinguish a complex, heterogeneous disease‹stage IV breast cancer, relative to 4 other cancers and healthy controls. In the second trial, 14 separate diseases were distinguished from one another as well as from healthy controls, through immunosignatures. Among the cancers tested were 3 different stages of breast cancer, 4 different brain cancers, 2 pancreatic diseases, ovarian cancer and 2 different blood cancers.

The study emphasizes the fact that incidence of cancer constitutes an unprecedented global challenge to healthcare infrastructure, particularly in the face aging populations. Early detection and treatment of cancer must be given highest priority in order to adequately address projected increases in cancer cases.

Immunoisignatures provide an attractive means of capturing disease complexity, offering a marked improvement in detection over traditional methods in which one-to-one molecular recognition events are measured and only one or a small number of analytes can be evaluated.

In addition to the problem of dilution of measurable analytes in conventional tests, the authors stress the considerable heterogeneity of cancer, which results in complexity at the molecular level that tends to evade characterization when only a few target analytes are evaluated.

The microarray chip used for the current study contains 10,000 imprinted peptides, of random sequence, which serve the role of artificial disease antigens used to poll the antibodies present in blood. The fact that the random sequence peptides are structurally unrelated to natural antigens allows the array to perform as a sort of all-purpose diagnostic, capable of producing an antibody profile or immunosignature, regardless of the underlying disease in question.

When a particular immunosignature is recorded, some of the antibody activity observed pertains to binding signals present in most individuals; some are unique to particular individuals. In the case of underlying disease however, a subset of binding signals will be the result of disease-related antigens common to most individuals with the same disease, making the results highly reproducible.

The presence of 10,000 peptides on each microarray chip allows for enhanced sensitivity, owing to the large number of different possible signals elicited. The technology is also highly flexible in terms of handling and processing. A dried sample of blood, collected on filter paper and mailed to a study facility can be used to generate an immunosignature, permitting frequent health monitoring at low cost.

Further, a significant improvement in immunosignaturing sensitivity and accuracy can be achieved through new chip technology. The group is currently developing a peptide imprinted with >100,000 peptides.

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As the fields of medicine and science advance and researchers become closer to finding cures for human disease, so has the need for reliable biological materials increased. Today, rather than collect specimens from individual subjects, laboratories and research facilities are relying more on biobanks to get the materials they need.

Biobanking involves collecting, processing and storing biological samples for use in scientific research. The biological samples are usually human in origin, but could also be from animal sources. Some biobanks also analyze the material and make the resultant data available for research purposes.

Prior to the widespread use of biobanks, scientists would collect their own biological specimens and use them in their research. The big problem with this method was that those samples were not available for widespread use, which lead to less reliable results when other scientists tried to replicate the experiments.

For example, Scientist A is doing a genetic study on CERVICAL CANCER, and collects cancer cells from patient A for his research. He shares his results with Scientist B, who then tries to replicate the experiment. However, Scientist B does not have the biological materials from Patient A, so he collects his own materials from Patient B, who had the same form of cancer. Unfortunately, the cancer cells from Patient B are slightly different than the cells from Patient A, and the experiment does not yield the same result.

Biobanks store enough quantities of material that both Scientist A and Scientist B can use the exact same samples, which means more accurate results.

Biobanks also have a broad range of genetic specimens, so that scientists conducting genetic research can have access to an entire genome, instead of just one specimen from one donor. This is important because doing genetic research using just one sample is like trying to understand how an elephant works but just looking at the tail.

Biobanks get their materials from a variety of sources.  Some organizations, like the Personal Genomes Project, take voluntary donations from individuals around the world, and store them in biobanks for future research.  Some hospitals, and other medical facilities, collect specimens from patients. Some organizations collect tissues from cadavers, and tissue samples could also be collected from prison inmates.

There has been some controversy over the ownership of biological materials, specifically the question of whether the individual from whom the samples are taken still retains ownership ­ especially if they have died since the specimens were collected.

The case of Henrietta Lacks, and the HeLa immortal cell line, is a good example. Back in 1951 Henrietta Lacks had an aggressive form of cervical cancer from which she died at the age of 31. Prior to her death, her doctor collected some of the cancerous cells and gave them to scientists for study. The cells continued to grow, and are still alive to this day. They have been used in the development of vaccines, including the polio vaccine, and in research for AIDS and other diseases.

Neither Henrietta Lacks, nor her family, was aware that her cells had been taken and used for research. It wasn¹t until twenty-five years later, when scientists contacted them requesting genetic material for the purpose of mapping the HeLa genome, that her family learned what had happened.

The case of the HeLa cells brought to light ethical questions regarding biological materials, and brought changes in the way specimens are collected, stored, and disseminated.

Today, research organizations are looking into more ethical methods of collecting biological materials, such as getting informed consent from potential donors. In addition to consent, biobanks also work to protect donor privacy, including health records and personal information. As in the case of the HeLa cells, it could also mean involving the donor¹s family in the process of reviewing and deciding who should have access to the genetic information.

Biobanks serve a vital purpose in today¹s scientific landscape. They allow researchers access to a variety of specimens, to help them find cures and treatments for major diseases, and learn more about human genetics.

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A previous post touched on this topic.  Now there's more ...


By Pam Belluck

New evidence adds strength to arguments that doctors should be extremely cautious about using a procedure performed on about 50,000 women a year during surgery to remove the uterus because of the risk that it may spread CANCER.

The procedure, power morcellation uses a deice to cut uterine tissue into pieces before removal through small incisions made durin minimally invasive surgery.  It is also used to remove fibroid tumors.

Revent reports indicate that wome wome have been harmed when the device, a morcellator, sliced into tumors they and their doctors did not know existed and spread cancer cels through the abdomen.

Now, a new study published in The Journal of the American Medical Association, found that undetected tumors in women having hysterectomies are more common than many experts had thought, a conclusion that is likely to fuel calls to limit or eliminate the procedure.

The Food and Drug Administration said in April that the procedure should be discouraged and this month held hearings to evaluate morcellation.

The study analyzed a large insurance database that included 155 of hospitalizations nationwide from 2006 to 2012.  The researchers found 232,882 cases im which women at 500 hospitals underwent minimally invasive hysterectomies using various approaches, including 36,470 wome who had power morcellation.

Of those, 99 women had uterine cancer that was detected afterward.  (If doctors had known about the cancer, they would not have used morcellation.) That means one in 368 women undergoing a hysterectomy had cancerous tumors that risked being spread by morcellation, said Dr Jason D. Wright, the lead author and chief of gynecologic oncology at Columbia University College of Physicians and Surgeons.

Previous estimates suggested that unsuspected cancer was much rarer, ranging from one in 500 to one in 10,000 cases.  But the F.D.A. recently released an analysis estimating that one in 352 women undergoing hysterectomy or fibroid removal have sarcomas: aggressive, hard-to-detect cancers.

"The new numbers are coming all in the same ballpark -- higher than eople anticipated," said Dr Suzanne George, an oncologist at Dana-Farber Cancer Institute, who was not involved in the research.

The researchers found that age was the biggest risk factor for the uterine cancers, with cases increasing steeply from 50-year-old women to those 65 and older.

They also identified small numbers of other malignancies and several hundred women with a possible precancerous condition among those who underwent power morcellation.  Dr. Kimberly Kho, an obstetrician- gynecologist at the University of Texas Southwestern Medical Center who was not involved in the research, said some of those could be detected with tests like pap smears or endometrial screening, so "part of this research shows there are preventable complications we can find with a more systematic approach to preoperative testing."

The researchers ould not determine how women fared after morcellation. But recent cases suggest that it can spray pieces of tumor around, worsening the cancer.  A review of cases at Dr. George's center found that cancer spread significantly faster after morcellation than after major abdominal surgery to remove the uterus.

Dr. George said another finding of the new stuy, that morcellation was used in only 165 of minimally invasive hysterectomies, meant there were other options, including, in some cases, removing the uterus through the vagina.  "Minimally invasive surgery does not equal morcellation," she said.

As for whether any women should undergo morcellation, Dr. Wright said, "I don't know that necessarily morcellation should be banned.  But this data is important to allow people to make decisions."

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I can relate.  See you next month.

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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