publication date: Jan. 12, 2018

Clinical Roundup

Yale study demonstrates four-fold superiority of academic level diagnostic accuracy

Specialty diagnostics company Precipio Inc. announced preliminary data from an ongoing study on the impact of academic pathology expertise on diagnostic accuracy.

The purpose of the study was to independently evaluate the effect of academic pathology on the massive problem of misdiagnosis, and determine the impact of Precipio’s business model as a solution to this problem.

Initial data shows that of the biopsy samples that Yale specialist pathologists provided a second opinion on and arrived at different diagnoses, ~73% arrived at a diagnosis that either definitely or possibly changed the patient treatment plans.

This is strengthening industry data on the problem of misdiagnosis, providing powerful evidence to the consequences to patient care, and validating Precipio’s business model as the only innovative solution of its kind to combat the problem of misdiagnosis.

This data is further strengthened by the comparative data generated internally by Precipio, demonstrating that in the first 100 cases initially diagnosed by academic expert pathologists at Yale and then sent to an outside pathologist for a second opinion, in 99% of those cases, the second opinion confirmed the primary diagnosis arrived at by Yale.

The study’s purpose, launched July 2017, is to evaluate the hypothesis that academic pathologists’ expertise result in a higher rate of diagnostic accuracy than the current industry is providing. The study was designed to retrospectively evaluate the concordance in two sets of data in order to demonstrate this hypothesis.

The first cohort consists of patients who received their primary diagnoses non-academic community hospitals or national reference labs (representative of the industry), and were then referred to an academic pathology institution (Yale University) for a second opinion consultation. The purpose of evaluating this cohort was to re-assess the diagnosis received outside of an academic institution, and then have an academic expert specialist evaluate its accuracy.

The second cohort consists of patients initially diagnosed at Yale University, and then referred to another academic institution for a second opinion consultation, (for example at the Brigham & Women’s Hospital in Boston, or at Memorial Sloan Kettering Cancer Center in New York).

The purpose of evaluating this cohort was to review the diagnosis rendered by an academic expert, and assess its accuracy by having it reviewed by a peer academic expert – thus, subject to the same scrutiny as the first cohort.

In the cases where there is a disagreement between primary diagnosis and the second opinion evaluation, the patient sample will be submitted to a third party academic institution to act as the arbiter (a process which currently does not exist in the industry).

For the purpose of this study, academic expert pathologists at University of Pennsylvania will review each of the discordant cases and determine the correct diagnosis.

Study investigators at Yale anticipated the first cohort would show a significant rate of misdiagnosis with meaningful consequences to the patient; while the second cohort would show minimal discordance, reflecting an overall substantially higher level of diagnostic accuracy rendered by academic pathologists.

To date, a total of 315 cases have been reviewed, 213 of which belong to the first cohort of the study, consisting of patients initially diagnosed at a non-academic facility, and then receiving a second opinion consult at Yale University.

The preliminary data reveals that, of the cohort of patients initially diagnosed at a non-academic institution, in 45 patients (21% of the cases) the academic pathologist arrived at a different conclusion during their second opinion assessment.

Furthermore, in 33 of those cases (>73%), the change in diagnosis had a potential substantial impact on patient treatment plan and is considered a material discordance.

In the remaining 102 cases reviewed that belong to the second cohort, in only 5% of the patients that were initially diagnosed by an academic expert, the second opinion diagnosis differed from the primary diagnosis. However, in 0% of those cases, did the change impact the patient treatment plan and is therefore not considered a material discordance.

The study will ultimately include at least 1,000 patients to further demonstrate the value of academic expertise in the diagnostic process. It is expected to be completed by the end of Q1-2018, after which the results will be compiled and published in a peer-reviewed industry journal.


Researchers demonstrate RAS dimers are essential for cancer

Researchers at UT Southwestern’s Simmons Cancer Center have shown that RAS molecules act in pairs, known as dimers, to cause cancer, findings that could help guide them to a treatment.

The question of RAS dimerization has been debated, according to Kenneth Westover, assistant professor of radiation oncology and biochemistry with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center.

The UT Southwestern team led by Westover used X-ray crystallography data to predict what a RAS dimer might look like, then tested the model in cells using a method called fluorescence resonance energy transfer to show when RAS forms dimers and when it does not.

The study, published in the journal Cell, provides a foundation for further studies that delve into RAS biology and could potentially pave the way to develop new cancer drugs that target RAS dimerization.

Members of the Westover research lab teamed up with researchers from the Dana Farber Cancer Institute to show that RAS dimers are essential in a number of cancer cell systems and animal models of cancer.

This work was supported by The US Department of Defense, V Foundation for Cancer Research, and the Cancer Prevention and Research Institute of Texas.


Xenoestrogens in foods may counteract breast cancer treatment

Scientists from The Scripps Research Institute discovered two estrogen-mimicking compounds found in many foods appear to potently reverse the effects of palbociclib/letrozole, a popular drug combination for treating breast cancer.

The study, published in the journal Cell Chemical Biology, suggests that exposure to xenoestrogens may significantly reduce the effectiveness of anti-estrogen treatments for cancer.

“Breast cancer patients taking palbociclib/letrozole should consider limiting their exposure to foods that contain xenoestrogens,” says Gary Siuzdak, the study’s senior author and senior director of TSRI’s Scripps Center for Metabolomics.

The palbociclib/letrozole combination therapy was approved by FDA in 2015 after a clinical trial showed it doubled the progression-free survival time in postmenopausal women with estrogen receptor positive, metastatic breast cancer. The palbociclib/letrozole is one of the standard therapies for ER-positive breast cancers.

Siuzdak and colleagues, including first and lead author Benedikt Warth, then a visiting Erwin-Schrödinger Fellow in the Siuzdak Lab, used advanced metabolomics technology to analyze the effects of palbociclib/letrozole on breast cancer cells.

Their analysis revealed that neither palbociclib alone nor letrozole alone had a strong effect on metabolites in an ER-positive breast cancer cell line. However, the combination had a strikingly large impact.

Cancer researchers are increasingly concerned that xenoestrogens in food and water may enhance the growth of estrogen-fueled cancers, and may also hamper the effectiveness of anti-estrogen drugs such as letrozole. TSRI scientists therefore examined breast cancer cells treated with palbociclib/letrozole to see how their metabolite populations changed when they were also exposed to two common dietary xenoestrogens: zearalenone and genistein.

Zearalenone has been linked to birth defects and abnormal sexual development in pigs and other livestock, and is suspected of having caused an outbreak of early breast development among girls in Puerto Rico in the 1970s. Genistein is produced in certain plants including soybeans and is often highly concentrated in phytoestrogen-rich food supplements.

Even using very low doses, similar to typical dietary exposures, the researchers found that both model xenoestrogens largely reversed the metabolomic impact of the cancer drug combination.

Under the influence of either xenoestrogen, the breast cancer cells also resumed proliferating at a rate comparable to that seen in the absence of drug treatment. The results indicate that these dietary xenoestrogens do have the potential to affect cancer therapy outcomes—and genistein and zearalenone are just two of the many xenoestrogens commonly found in the human diet.

The impact of xenoestrogens on health and on hormonally-targeted therapies is nevertheless an understudied, underfunded area of research, the researchers emphasized.

Other co-authors of the study, “Metabolomics reveals that dietary xenoestrogens alter cellular metabolism induced by palbociclib/letrozole combination cancer therapy,” were Philipp Raffeiner, Ana Granados, Tao Huan, Mingliang Fang, Erica Forsberg, and H. Paul Benton, all of The Scripps Research Institute at the time of the study; as well as Caroline H. Johnson at Yale University and Laura Goetz of the Scripps Clinic Medical Group.

Funding for the research came from the Austrian Science Fund (Erwin-Schrödinger fellowship awarded to Benedikt Warth), the George E. Hewitt Foundation for Medical Research and the National Institutes of Health (grants R01 GMH4368 and PO1 A1043376-02S1).

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