New Developments in Pancreatic Cancer Detection and Screening: Novel Diagnostic and Potential

TherapiesGirish Mishra MD MSc, FASGE FACG FACP

Professor & Vice Chief, Internal Medicine-Gastroenterology

Executive Director, Digestive Health Service Line

Director, Endoscopy and Clinical Services

An ounce of prevention is …

We are in for a long haul for a cure

Pancreatic CancerClinical

Cancer Diagnosis Balance

Early Detection Treatment

Pancreatic Cancer

Early Detection

Early MetastasisMicrometastasis

Chari. Semin Oncol 2007

Pancreatic Cancer Radiologic Window

Chari. Semin Oncology 2007

Can we take advantage of a molecular window?

K-ras 90-95%

P16/CDKN2A 80-95%

P53 50-75%

DPC4 50%

BRCA2 7%

Bardessy et al. Pancreatic cancer biology and genetics. Nat. Rev. Cancer 2002

Clinical Strategies 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 ?

Objectives

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

Risk Factors

Wolfgang CL, et al.CA Cancer J Clin 2013

Inherited Risk Factors

Wolfgang CL, et al.CA Cancer J Clin 2013

FAMM SyndromeClinical 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.

How can we improve detection?

Boy Wonder!!

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 "flag-raising" 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).

Promising Biomarkers

miR-1290

Novel Methylation Biomarkers

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

How should we screen patients at high risk for

pancreatic cancer?

Results

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

EUS Features-Normal ratio

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

Pancreatic cancer with obstructive jaundice

Ratio to adopt

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)

Optical Markers in the Duodenal Mucosa Predict the Presence of

Pancreatic Cancer

Liu et al. Clin Cancer Research. 2007

4-D elastic light-scattering fingerprinting and low-coherence enhanced backspattering spectoscopy

95% Sn

91% Sp

How about screening in high risk individuals?

Turzhitsky et al. Dis Markers 2008

Optical Spectroscopy and Pancreatic Cancer

Wilson RH et al. Optics Express. 2009

EUS-FNA/FNI

• 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 field distribution and thus the potential treatment area.

Methods

Results

• 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 design.

Conclusions

Acknowledgements

Background

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.

Additive Manufacture of Minimally-Invasive Medical Devices for Pancreatic Cancer Treatment

Laura Reese1, Jeffrey McGuire2, Paulo Garcia PhD1, Perry Shen MD3, Girish Mishra MD3, Rafael Davalos PhD1, Chris Williams, PhD2; Lissett Ramirez Bickford, PhD1,2

1School of Biomedical Engineering, Virginia Tech; 2Department of Mechanical Engineering, Virginia Tech; 3Wake Forest Baptist Medical Center

• 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.

• 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.

• 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.

Future Work

CAD Design Prototype

COMSOL Optimization Studies

Changing the length of both electrodes has the greatest effect on treatment area. As electrode size increases, treatment area becomes greater and more elongated.

Treatment Results

Puncture StudiesElectrode Configurations

• Treatment: A range of 1500 – 2500 volts applied over 90 pulses with 50 μs duration.

• 3D printed prototype (at 5x scale up of clinically-relevant size) was capable of damaging mock-tissue samples (potatoes) using IRE treatment parameters.

• Increasing voltage resulted in larger treatment area.

The leftmost images are of entire halves of the treated potato, followed by sequential 1/8” slices through the remaining half of the potato.

Actuator

0.1 mm/s

Load Cell

0

0.2

0.4Force Re-

quired to

Punc-ture

Tissue

Fo

rc

e

[N

]

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.

A

D

B

C

5 mm

BA

DC

(A)High Resolution 3D Printed Needle(B) 19 Gauge Beveled Needle

(C)Low Resolution 3D Printed Needle

A

B

C

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).

Horizontal Electrodes Electric Field [V/cm]

Vertical Electrodes Electric Field [V/cm]

The vertical electrode configuration results in the maximum treatment area, with an electric field great than 500 V/cm.

Analyzed the effect of changing the size of both electrodes, the electrode spacing, and the length of only one electrode.

(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 assembly

B

D

Area = 126mm2 Area = 117mm2

Endoscopic Biopsy Needle

0 2 4 6 8 10100

140

180

Length

(mm)

Are

a

>5

00

V/c

m

(mm

2)

1500 V

2500 V

2000 V

Conclusions 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