New Developments in Pancreatic Cancer Detection and Screening: Novel Diagnostic and Potential
Therapies
Girish Mishra MD MSc, FASGE FACG FACP
Professor & Vice Chief, Internal Medicine-Gastroenterology
Executive Director, Digestive Health Service Line
Director, Endoscopy and Clinical Services

Micrometastasis

Chari. Semin Oncol 2007

Chari. Semin Oncology 2007

K-ras
P16/CDKN2A
P53
DPC4
BRCA2
90-95%
80-95%
50-75%
50%
7%
Bardessy et al. Pancreatic cancer biology and genetics. Nat. Rev. Cancer 2002

 Which patient population is at greatest risk ?
 Are there any biomarkers on the horizon ?
 How can we improve detection in the high risk patient ?
 How can we leverage early detection with prevention ?

 Understand the known risk factors and inherited syndromes involved in pancreatic carcinoma development
 Introduce potential novel testing and a few promising biomarkers
 Understand the role of EUS in screening high risk individuals for pancreatic cancer
 Introduce novel imaging/diagnostics that may aid in earlier diagnosis in the asymptomatic patient

Wolfgang CL, et al.CA Cancer J Clin 2013

Wolfgang CL, et al.CA Cancer J Clin 2013

Clinical Features
•
Germline mutations in the p16/CDKN2A gene associated with a high lifetime risk of melanoma and pancreatic cancer
•
P16/CDKN2A have a 38-fold increased risk of developing pancreatic cancer
•
Kindreds with a 19-base pair deletion in exon 2 of this gene (the Leiden mutation) have a 17% lifetime risk of developing pancreatic cancer by age 75.

Jack's supervisor Prof. Maitra, has been quoted as saying that he believes that the test should ultimately be modified to include the ability to detect other "flagraising" cancer proteins - and that a lot more testing needs to be done and that, even if all goes well, the product probably would not be marketed for at least a decade (Tucker, 2012).




Elevated Serum miR-1290 distinguishes patients with PC from healthy and disease controls
Li A et al. Clin Cancer Res 2013

Novel Methylation Biomarker Panel for the
Early Detection of Pancreatic Cancer
Yi JM, et al. Clin Cancer Res 2013

74 y/o asymptomatic patient with strong family history of PC

Eloubedi et al. ASGE 2009.
Slides courtesy of Dr Eloubedi

Pancreatic cancer with obstructive jaundice

Patients with pancreatic cancer were more likely to have a PD/PG ratio of
≥0.4 compared to patients with Calcific pancreatitis, and Normal/NCCP groups
(80%, 14%, 0% respectively P<0.001)

4-D elastic lightscattering fingerprinting and lowcoherence enhanced backspattering spectoscopy
95% Sn
91% Sp
Liu et al. Clin Cancer Research. 2007

Turzhitsky et al. Dis Markers 2008

Wilson RH et al. Optics Express. 2009

Additive Manufacture of Minimally-Invasive Medical Devices for Pancreatic Cancer Treatment
Laura Reese 1 , Jeffrey McGuire 2 , Paulo Garcia PhD 1 , Perry Shen MD 3 ,
Girish Mishra MD 3 , Rafael Davalos PhD 1 , Chris Williams, PhD 2 ; Lissett Ramirez Bickford, PhD 1,2
1 School of Biomedical Engineering, Virginia Tech; 2 Department of Mechanical Engineering, Virginia Tech; 3 Wake Forest Baptist Medical Center
Background
• Currently, pancreatic cancer can only be cured if it can be completely resected with surgery, which is limited to less than 20% of diagnosed patients.
• Irreversible electroporation (IRE) is a technique for ablating cancerous tissue through the use of short electric pulses, which create permanent pores in the cell membrane, leading to cell death.
• While this treatment methodology has largely been evaluated for tumors accessible through open surgical or percutaneous procedures, there is a unique opportunity to create devices capable of performing IRE via adaptations of endoscopic tools currently used for pancreatic cancer biopsies.
Endoscopic Biopsy
Needle
• Our novel approach employs 3D printing to rapidly produce inexpensive prototypes that can easily be analyzed for functionality and modified as necessary to engineer the optimal design.
A
C
Results
CAD Design Prototype
D
A
B
(A) Side view of needle base with channels for wires (B)
Top down view of needle base (C)
Magnified view of needle base (D) Side
View of needle
C
5 mm
D assembly
In order to evaluate design functionality, prototypes of needle-based devices were successfully fabricated through the use of Solidworks and 3D printing. Prototypes were made of both a clinically-relevant size (comparable to a 19-gauge needle) as well as at a 5x scale up of this size
(shown above).
Electrode Configurations
Horizontal Electrodes
Electric Field [V/cm]
Vertical Electrodes
Electric Field [V/cm] Actuator
0.1 mm/s
Puncture Studies
D
B
B
0,5
0
Conclusions
• 3D printing facilitates the simple and rapid production of more complicated designs than previously established bench top manufacturing techniques.
• Finite element analysis revealed the electric field distribution and possible treatment areas accomplished by IRE, which requires an electric field of ~500
V/cm for pancreatic cancer cell death to occur.
• COMSOL modeling was used to determine the optimal electrode configuration through simulation of the electric field produced by analyzing various geometrical electrode configurations.
Simulations were also used to optimize the spacing and size of the electrodes.
• This innovative design will allow the unique integration of existing
IRE treatment modalities into a minimally-invasive endosopic
Methods
• Bipolar needle electrodes were fabricated through the use of the Objet Connex 350
PolyJet printer using additive manufacture techniques.
•
COMSOL, a multiphysics engineering simulation software, was used to optimize electrode design and spacing.
Three dimensional finite element numerical models were created to gain a better understanding of the electric
A
B field distribution and thus the potential treatment area.
C
(A) High Resolution 3D Printed Needle
(B) 19 Gauge Beveled Needle
(C) Low Resolution 3D Printed Needle
Area = 126mm 2
Area = 117mm 2
The vertical electrode configuration results in the maximum treatment area, with an electric field great than 500 V/cm.
COMSOL Optimization electrodes, the electrode spacing, and the length of only one electrode.
200
160
120
Changing the length of both electrodes has the greatest effect on treatment area.
0 Len…
As electrode size increases, treatment area becomes greater and more elongated.
Load
Cell
19-gauge 3D printed needles successfully punctured chicken breast tissue. Commercially available 19-gauge beveled needles required the least amount of force for puncture. 3D printed pointed needles were more effective at penetrating tissue than the beveled design.
Treatment Results
• Treatment: A range of
1500 – 2500 volts applied over 90 pulses with 50 μs
1500 V duration.
• 3D printed prototype (at
5x scale up of clinicallyrelevant size) was capable of damaging mock-tissue samples (potatoes) using
IRE treatment parameters.
• Increasing voltage resulted in larger treatment area.
2000 V
2500 V
The leftmost images are of entire halves of the treated potato, followed by sequential 1/8” slices through the remaining half of the potato.
• Verify the electric field distribution in a pancreatic cancer tissue phantom.
• Generate and test multiple prototypes of the 19-gauge
(clinically relevant) size.
• Investigate other printing modalities that offer higher resolution using biocompatible materials.
Acknowledgements
This work was funded by the ICTAS
Nano-Bio Seed Grant. The authors would also like to thank the Virginia Tech
Dreams Lab for their assistance with 3D printing.

 Pancreatic cancer poses diagnostic challenges unlike any other. Early detection is the key
 Understanding molecular mechanisms and developing more sensitive testing/biomarkers will be paramount to fighting this deadly disease
 EUS appears to be the best test for screening the asymptomatic patient. ?What age and frequency
 Novel, more sensitive imaging may allow for earlier detection in the asymptomatic individual