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MiRNAs Acting in Concert Impede PDCD4 and Related Genes in Pancreatic Cancer

Writing a pancreatic cancer blog is interesting. Research questions seem limited only by the level of imagination of researchers. We have addressed in our Pancreatica Blog a small body of research related to MicroRNA (MiRNA) work primarily related to seeking patterns that may aid in the eventual earlier diagnosis or even screening for pancreatic cancer (ductal adenocarcinoma of the pancreas): Here, Here, Here, and Here.

As discussed, MiRNA (alternatively, miR) are small non-coding RNA strands that appear to be related to genetic and cellular regulation that were discovered primarily in the 1990s. A number of specific miRs tend to be over-expressed in pancreatic cancer, and indeed in a number of tumor types.

Jiao and colleagues primarily from London medical institutions but also from Germany, Italy and the Netherlands, published the findings of their study on MiRs in regard to their actions in the January 2014 issue of the journal Gastroenterology. The researchers studied pancreatic cancer cell lines, mice, and tumor tissue samples from 91 human subjects diagnosed with pancreatic cancer.

The researchers used bioinformatics techniques to seek data from MiR and Messenger RNA profiles of the pancreatic cancer cell lines and tissue samples.  They identified a pattern – that three miRs (miR 21, miR23A, and miR27A) appear to act in a synergistic manner to inhibit a nexus of tumor suppressor genes including NEDD4L, BTG2, and PDCD4.  The artificial inhibition by the researchers of these three miRs both with pancreatic cancer cell lines and in pancreatic tumors in mice showed reduced tumor cell growth and reduced tumor growth, respectively.   Additionally, the authors examined the human pancreatic cancer tumor samples – quantifying levels of miR 21, miR23A, and miR27A.  They then reviewed the clinical course of the patients under study.  The results demonstrated that the clinical course of the patients whose tumors showed HIGH levels of the three miRs was associated with SHORTER survival duration after pancreatic cancer tumor resection.

This is a rather interesting study. The findings of course need to be replicated.  It they hold, new avenues of treatment options for pancreatic cancer may arise. The discovery of MicroRNA is a gift that keeps on giving.

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Dale O’Brien, MD

Including Grade Status Marker Levels in the Staging of Neuroendocrine Tumors

In a sense, the pancreatic cancer research underlying this blog posting is a bookend to the one that we discussed here in the Pancreatica Blog about a month ago.  Then, researchers had incorporated the Ki-67 cell proliferation marker into a standard Tumor-Node-Metastasis system (American Joint Committee on Cancer – AJCC) to see if the novel schema improved concurrence between staging and survival duration prediction in pancreatic adenocarcinoma – the most common form of pancreatic cancer.  It did.

In the present study, the researchers also tried to discern a relationship between a standard TNM system (European Neuroendocrine Tumor Society – ENETS) and the grade of cell proliferation as represented by Ki-67 level, but now in neuroendocrine tumors.

Ki-67 is an antigen, also known as MKI67 that appears to be essential for cell proliferation in humans. It is integral to ribosomal RNA transcription, and is encoded by the human gene MKI167.  Its name is derived by the city of its discovery (researchers in Kiel, Germany), and the number of the lab dish on which it was found. As evolved, the referent labeling index represents that portion of sample cells which are Ki-67 positive.  At its most basic level, the Ki-67 index IS a measure of cell proliferation. This index number appears to be correlated with the clinical history in a number of tumor types. The higher the index, the more aggressive the clinical course of the cancer.

Frilling and colleagues from the Imperial College London UK published the results of their work in the area of TNM staging and Ki-67 marker levels in neuroendocrine tumors on February 4, 2014 in the World Journal of Surgery, a publication of the International Society of Surgery.  In this retrospective study, the researchers reviewed the records and laboratory results of 161 patients with neuroendocrine tumors of the GI-pancreatic organ system seen at the Imperial College Healthcare Trust between the years 2010 and 2012. The patients were divided into three Ki-67 level cell differentiation categories according to ENETS recommendations: G1 (low to intermediate grade cell differentiation), G2 (well to moderate grade cell differentiation), and G3 (moderate to poor cell differentiation).

The researchers found that in patients with neuroendocrine tumors, the more advanced the stage the higher the Ki-67 index levels. This finding was tempered by the observation that the organ of origin also was strongly correlated with Ki-67 levels.

The findings of this study move our understanding forward.  One point to note is that in the United States’ SEERS cancer registry data show about 27% of patients with neuroendocrine tumors as having distal metastases, whereas the European registry databases typically show this figure at 44% to 73%. Whether this staging difference represents a different natural history, a difference in staging criteria, or a difference in diagnosis, remains to be seen.

Nevertheless, this is an interesting finding that appears to further integrate our understanding of TNM staging and cell dynamics, as we try to better integrate staging with prognosis in neuroendocrine tumors.

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Dale O’Brien, MD

More Information in the Adjuvant Chemoradiation Controversy for Pancreatic Cancer

The findings of the European Study Group for Pancreatic Cancer (ESPAC-1) clinical trial and championed by surgeon John Neoptolemos of Liverpool University more than a decade ago challenged the assumption that chemotherapy combined with radiation was a superior regimen after pancreatic cancer (ductal adenocarcinoma of the pancreas) surgery.  The chemotherapy alone arm of this trial (using bolus 5-fluorouracil with folinic acid) showed improved survival advantage over the multi-modal (chemoradiation) arm post-surgery for cancer of the pancreas.

But subsequently, aspects of the clinical trial including the conclusions of ESPAC-1 have in turn been challenged.  And the debate including dueling non-dispositive research findings back and forth has continued to rage.  We have covered this matter HERE and HERE.

Now comes an interesting study by Lipscomb and colleagues from the Department of Surgery at Emory University as published in the October 2013 issue of the Annals of Surgical Oncology.  These researchers surveyed and queried the U.S. National Cancer Data Base in terms of overall survival, reviewing the results of more than eleven thousand patients who had received pancreatic cancer surgery over a four year period (1998 – 2002). They developed propensity scores to help produce matched samples for those patients receiving adjuvant chemotherapy versus chemoradiation versus no adjuvant therapy.

The authors found that adjuvant chemoradiation offered the longest duration survival advantage (overall survival) over chemotherapy and no-adjuvant-therapy with a hazard ratio of 0.70 (95% CI of 0.61 – 8.0).

This study is pretty strong tea – and should serve as ammunition in the adjuvant therapy wars.  It is possible, as earlier research has hinted, that certain variables may mitigate toward one approach or another.  In the meantime, we expect that the debate to carry on for now.

Nevertheless, this clever research work by the Emory University group is powerful dispassionate evidence for the possible superiority of chemoradiation for the adjuvant treatment of pancreatic cancer.

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Dale O’Brien, MD

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