Map of Pancreatica Walks and Runs

Electroporation for the Treatment of Locally Advanced Cancer of the Pancreas

Nilsson and colleagues from Uppsala University in Sweden in an interesting Phase I pilot study evaluated the irreversible electroporation procedure for the treatment of locally advanced (ostensibly unresectable) pancreatic cancer, publishing the results in the January 2014 issue of the journal, Anticancer Research.

Cells are the fundamental unit of biological life. And we know that the membrane that separates the intracellular from the extracellular world is a complicated selectively porous phospholipid bilayered structure that that functions in part as an insulator. The ion channels and other pores in the cell membrane allow electrical currents to flow between the charged fluids on the inside and outside of the cell. Thus, there is electrical potential across the cell membrane.  Electroporation (sometimes called electropermeabilization) is the process whereby an externally applied electrical field can cause increased electrical conductivity and permeability of the cell membrane.

A frequent use of electroporation is to improve permeability in order to introduce an external substance into the cell (e.g., a probe, a drug, DNA).  However, there is another use of electroporation (so-called irreversible electroporation) in that exceeding the maximum electroporation threshold level will cause inevitable cell death. This second use is that of the research herein discussed.

The researchers identified five patients who met their inclusion criteria.  Under general anesthesia, the researchers used ultrasound to guide thin needles placed in percutaneously fashion around the pancreatic cancer tumor in each of these patients. Short bursts of direct current above the level of the electroporation threshold were administered, causing irreversible electroporation (cell death) – presumably primarily in the tumor tissue.

The authors found that one patient now became eligible for and was able to undergo a pancreaticoduodenectomy (Whipple procedure with portal vein resection).  Also, two patients showed no sign of recurrence by scan or ultrasound at six months post-procedure.  Finally, there were no serious untoward side-effects related to the procedure in any of the patients noted during and after the course of the treatment.

The researchers found that the treatment efficacy of percutaneous irreversible electroporation for locally advanced cancer of the pancreas appears to be promising, with a good safety profile.

This is a very positive finding that demands replication and confirmation. It would be interesting to follow the patient outcomes for a longer period – to more fully assess efficacy.  The minimally invasive (percutaneous) aspect of the treatment modality adds a special interest to this approach.

 

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Dale O’Brien, MD

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: 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 tumor resection.

This is a rather interesting study. The findings of course need to be replicated.  It they hold, new avenues of treatment options 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.

 

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Dale O’Brien, MD

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