However counterintuitive, the association between saliva and the dental environment AND pancreatic cancer continues to garner highly interesting research. One team lead by David T. Wong and colleagues at the Dental Research Institute of the UCLA School of Dentistry in Los Angeles, California first came to our attention per the Pancreatica blog on 6/23 of this year for a 2010 article in the journal Gastroenterology laying the basis for salivary biomarkers for cancer of the pancreas, and later for a 2012 article in the journal Gut postulating specific oral bacteria as associated with pancreatic cancer.
This UCLA team has now published an article in the September 13, 2013 issue of the Journal of Biological Chemistry that lays an intriguing and perhaps even likely possible predicate for the mechanism by which salivary fluid may be specifically affected by such apparently distal and unrelated diseases such as pancreatic cancer.
Before presenting the results of their research, we should discuss the concept of exosomes. Identified in the late 1980s, these are tiny (30 to 100 nanometers in diameter) durable vesicles or bubble-like structures that are found in most biological fluids. They have been found to contain proteins and other substances including messenger-RNA. In an over-simplistic statement, these structures appear to facilitate or at least affect such processes such as cell-to-cell communication throughout the body, coagulation, waste management, tumor invasion, and the immune response. The origin of exosomes is from within cells – and then in some cases, the plasma cell wall releases an exosome to extracellular space within which it can travel.
Wong and his fellow researchers in this present work, studied the role of exosomes that derived from pancreatic adenocarcinoma tumor tissue – and evaluated their presence and possible function in saliva in a mouse model. They developed a mouse that gave specific biomarkers for pancreatic cancer by implanting a pancreatic cancer cell line into the animal’s pancreas – and then identifying a selective panel of biomarkers and thereupon testing for these markers in the saliva of those mice with pancreatic cancer (which were found) as compared to those without (not found). Almost all of the components of this panel of seven gene-derived transcriptomic biomarkers were found in the affected mice tumor, serum, saliva, and exosomes.
Then the researchers used a modified tumor line that tended to suppress exosome production from the tumor tissue. They then again looked at these mice tissues and found that almost none of the components of the seven biomarker panel were found in the saliva of these affected mice. This allowed the researchers to cautiously postulate a working theory that tumor-derived exosomes may be central to the pathway that establishes salivary biomarkers that appear to be specific for (in this case) pancreatic cancer. The authors call for further research to more fully explicate the precise course of the pathways in this process.
And we could ask for nothing more as a follow-on to this growing body of evidence from this clearly talented research team.
Dale O’Brien, MD
The move away from surgical diagnosis to radiographic criteria in many and now even most efforts at the staging of cancer of the pancreas carries a number of somewhat unspoken but profound consequences, one being efforts to find ways to downstage the diagnosis so as to profitably utilize surgery in locally advanced and borderline resectable pancreatic cancer. We have thus seen the rise of the use of chemotherapy alone or in combination with other modalities in induction neoadjuvant treatment in order to accomplish this.
But this is somewhat new territory. For example, it is not clear what the optimal duration of such neoadjuvant therapy should be. Thus, it comes with great interest that Donahue, Reber and colleagues at UCLA have reviewed their experience in this realm over the past two decades – with a rather startling finding: that prolonged duration of neoadjuvant therapy appears to confer a large benefit in many cases. This work has been E-published on December 4, 2013 in the journal JAMA Surgery (formerly Archives of Surgery).
The UCLA researchers reviewed patients treated at their institution from 1992 until 2011, identifying 49 patients who were Stage III / locally advanced or who were considered borderline resectable, AND who completed preoperative treatment – with a median duration of 7.1 months. A remarkable 75.5% of these patients were able to later undergo surgery. Most of these patients were lymph node negative at the time of surgery. The median overall survival duration of this studied group was 40.1 months.
Prolonged pre-surgical therapy appears to offer large benefit to select patients. This finding requires further study, but is highly encouraging.
Dale O’Brien, MD
Since the May 12, 2011 New England Journal of Medicine article that reported the possible superiority of the 5-FU based four-drug FOLFIRINOX regimen over gemcitabine in the treatment of metastatic pancreatic cancer (and subsequent FDA approval), researchers have been at work trying to discover the best use of this information – and ways to perhaps improve on it. A case in point is the blog entry just prior to this one (FOLFIRINOX for neoajuvant therapy in pancreatic cancer).
Also, we have reported on research of chemotherapy combinations that contain similar but fewer drug agents, such as the ones termed OFF and SOX. These are essentially modified FOLFIRINOX regimens. But there has arisen the term “Modified FOLFIRINOX Regimen” by which researchers appear to mean that tiny (to date) body of research on smaller tweaks to the standard FOLFIRINOX combination: oxaliplatin – 85 mg per M2 (body-surface area); irinotecan – 180 mg/ M2; leucovorin, 400 mg/M2; and fluorouracil (5-FU) – 400 mg/M2 given as a bolus followed by 2400 mg/M2 given as a 46-hour continuous infusion.
El-Rayes and colleagues at Emory University have published a study involving such a modified FOLFIRINOX regimen in the November issue of the journal Pancreas. They postulated that eliminating the bolus portion of the 5-FU and adding hematopoietic growth factor to FOLFIRINOX might continue to provide the efficacy of the drug-combination while improving the safety profile of the side-effects. They looked at 60 patients with pancreatic cancer in various stages of disease who were treated using this modified combination.
The authors found that the median overall survival duration for these patients with metastatic pancreatic cancer treated with this modified FOLFIRINOX regimen was 9.0 months. Also, importantly, the safety profile did appear to be improved. The researchers suggest that this regimen can be given more safely than standard FOLFIRINOX, and without losing efficacy.
This is an interesting finding demanding further research.
Dale O’Brien, MD