Existing methodology
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Existing Methodology. Question: Will we be able to do this?. Question: What is “normal” tissue?. Surrogate Anatomic Sites for Evaluating Cancer Risk. Vadim Backman, Ph.D. Biomedical Engineering Department Northwestern University. Colorectal Cancer (CRC).

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Existing methodology

Existing Methodology


Question will we be able to do this

Question: Will we be able to do this?


Question what is normal tissue

Question: What is “normal” tissue?


Surrogate anatomic sites for evaluating cancer risk

Surrogate Anatomic Sites for Evaluating Cancer Risk

Vadim Backman, Ph.D.

Biomedical Engineering Department

Northwestern University


Colorectal cancer crc

Colorectal Cancer (CRC)

  • #2 cause of cancer deaths, ~155K cases annually and ~57K deaths – stagnant for 20 years

  • 90%+ survival rate if caught early but today the majority (61%) are later stage

  • Colonoscopy detects and removes a precursor to colon cancer, adenomatous polyp, thus decreasing future occurrence of CRC by 75-90%


Existing methodology

Why Colon Cancer Screening Program Does Not Work?

  • Problem:

    • Current guidelines: everybody over age 50 is recommended to undergo colonoscopy at least once every 10 years.

    • There are >90 million Americans over age 50.

    • 70-80% of colonoscopies are negative and unnecessary

    • Colonoscopic screening of this entire eligible population is impossible due to

  • - expense (annual cost would be ~$50 billion)

  • - insufficient number of endoscopists

  • - patient reluctance (hate prep!)

  • - complication rate.

    • 85% of the population receives no colonoscopic CRC screening.

  • Solution: Develop a minimally invasive technology to identify patients who are at risk for CRC and would benefit from colonoscopy.

    Precedent: Cervical cancer screening with Pap smear in the last 50 years reduced mortality from #1 cancer in women to #13!


Factors for a successful screening test inexpensive no prep sensitive

Bowel

Bowel

Technique

Technique

Expensive?

Expensive?

preparation

preparation

Sensitivity*

required?

required?

100%**

Colonoscopy

Colonoscopy

Yes, >$1,000

Yes, >$1,000

Yes

Yes

FOBT

FOBT

No

No

No

No

10%

Fecal DNA

Fecal DNA

Yes, $700

No

No

18%

18%

Virtual

Virtual

55-80%

Yes, ~$1,000

Yes

Yes

colonoscopy

colonoscopy

Imaging

Imaging

Not yet approved

Not yet approved

Yes, >$2,000

Yes, >$2,000

Yes

Yes

capsule

capsule

for colon imaging

for colon imaging

Factors for A Successful Screening Test: Inexpensive, No Prep, & Sensitive

  • Requirements for a population screening test:

  • No bowel preparation

  • Performed by a PCP

  • Sensitive

  • Inexpensive

*Sensitivity relative to colonoscopy for precancerous advanced adenomas (polyps >1cm). Precancerous polyps, not cancer, is the most clinically relevant for the screening population.

**Gold standard with assumed sensitivity of 100%. Colonoscopy is estimated to miss up to 10% of advanced lesions (>1cm) and up to 35% of smaller lesions


Exploiting the field effect

Exploiting the Field Effect

Field Effect: the genetic/environmental milieu that results in a neoplastic lesion in one area of the colon exists throughout the organ.

  • Conventional wisdom: tissue in a tumor is abnormal, tissue surrounding tissue is normal.

  • This is only an approximation

  • New methodology: detection of carcinogenesis by analysis of normal appearing cells in an accessible part of an organ.


Commonly used biomarkers of field effect in crc

Commonly Used Biomarkers of Field Effect in CRC

  • Focal Neoplastic Lesions to predict Proximal Neoplasia

    • Adenoma on flexible sigmoidoscopy

      (Arch Intern Med. 2004 1881-7).

    • Rectal aberrant crypt foci

      (Takayama et al N Engl J Med. 1998; 339:1277.)

  • Diffuse Alterations in the Histologically Normal Mucosa

    • Decreased apoptosis

      (Bernstein et al. Cancer Res. 1999 59:2353-7)

    • Increased proliferation

      (Ponz de Leon, et al Cancer Res. 1988 ;48:4121).


Novel biomarkers of field effect in crc

Novel Biomarkers of Field Effect in CRC

Microarray evidence

Proteomic evidence

TUMOR

Polley et al. Cancer Res 2006

Chen et al. Cancer Res 2004


Optically detectable markers of the field effect

Optically-detectable Markers of the Field Effect

  • Our approach: sensing changes in tissue that CANNOT be detected by histopathology, spatially outside the extent of a neoplastic lesion.

  • Tissue physiology: Increased mucosal microvascular blood supply

  • Tissue morphology: Alterations in tissue fractal microarchitecture

  • Intracellular morphology: Alterations in intracellular nanoscale architecture


Lessons from animal studies

Lessons from Animal Studies

  • AOM-treated rat and MIN-mouse models

  • Early increase in microvascular blood supply (EIBS) and alterations in tissue micro and nano-architecture develop prior to ACFs and microadenomas.

  • These alterations can be detected at a distance from the neoplastic focus.

  • Diffusely present in ~90% of tissue sites.

  • Depth-resolution is crucial: changes are only in the mucosa (top 100 m).

  • EIBS is caused in part by iNOS upregulation.

Gastroenterology, 126, 1071-1081 (2004)

Clinical Cancer Research, 19, 961-968 (2006)

FEBS, 581, 3857-3862 (2007)

Gut, 54, 654-660 (2005)


Optically detectable markers of the field effect1

Optically-detectable Markers of the Field Effect

  • Tissue physiology: Increased microvascular blood supply

  • Tissue morphology: Alterations in tissue microarchitecture

  • Intracellular morphology: Alterations in intracellular nanoscale architecture


Eibs in vivo clinical validation

EIBS: In Vivo Clinical Validation

  • Technology: polarization-gated spectroscopy sensitive to mucosal microcirculation

  • Design: in vivo, during colonoscopy

  • Patient characteristics:

    • 220 average risk screening patients

    • 51 with adenomas: 30 non-advanced adenomas, 9 multiple non-advanced adenomas,12 advanced

    • 169 patients with no neoplasia including 26 with hyperplastic polyps

colonoscope

EIBS fiber-optic probe


Eibs in vivo clinical validation1

EIBS: In Vivo Clinical Validation

*

*

*

*


Rectal eibs is indicative of presence of adenomas throughout the colon

Rectal EIBS is Indicative of Presence of Adenomas Throughout the Colon

*

*

Patients with no dysplasia vs. patients with advanced adenomas

Area under ROC curve =90%

Rectal EIBS

EIBS reading: rectum only

Adenoma location: throughout the colon

Sensitivity = 100%

Specificity = 75%


Optically detectable markers of the field effect2

Optically-detectable Markers of the Field Effect

  • Tissue physiology: Increased microvascular blood supply

  • Tissue morphology: Alterations in tissue (fractal) microarchitecture

  • Intracellular morphology: Alterations in intracellular nanoscale architecture


Alterations in mucosal microarchitecture clinical study results

Alterations in Mucosal Microarchitecture: Clinical Study Results

  • Technology: low-coherence enhanced backscattering (LEBS) spectroscopy

  • Design: rectal biopsy

  • Patient characteristics:

    • 233 patients undergoing screening colonoscopy

    • Mean age 56.8 ±10.7

    • 47% female

    • 60 with adenomas (17 advanced adenomas)

    • 9 with previous h/o adenomas but none on present colonoscopy

    • 158 with no current, prior or family history of adenomas


Human clinical study results

Human Clinical Study Results

80%


Potential confounding factors do not appear to affect lebs diagnosis

Potential Confounding Factors Do Not Appear to Affect LEBS Diagnosis


Optically detectable markers of the field effect3

Optically-detectable Markers of the Field Effect

  • Tissue physiology: Increased microvascular blood supply

  • Tissue morphology: Alterations in tissue microarchitecture

  • Intracellular morphology: Alterations in cell nanoscale architecture


Alterations in epithelial nanoarchitecture clinical study results

1 µm

1 µm

Alterations in Epithelial Nanoarchitecture: Clinical Study Results

  • Technology: partial wave spectroscopic (PWS) microscopy

  • Design: rectal mucosal brushings

  • Patient characteristics:

    • 35 patients

    • 21 with no neoplasia

    • 14 with adenomas, 4 advanced


Human clinical study results1

x 10-7

13

*

12

* p-value < 0.0001

11

Disorder strength Ld (mm)

*

10

9

8

7

Adenoma

Advanced

Control

adenoma

Human Clinical Study Results

no neoplasia

neoplasia

Disorder in nanoscale density fluctuations in endoscopically-normal rectal mucosa is increased in patients with sporadic adenomas


Existing methodology

Colonoscopy-free Screening for Colon Cancer Using Optical Detection of the Field Effect

Annual population screening by PCP’s during an annual exam without colonoscopy and preparation

_

+

Colonoscopy

  • Only patients with adenomas receive colonoscopies

  • Most (all) patients with adenomas are screened

  • Patients are more compliant

  • Better allocation of colonoscopic resource

LEBS probe


Existing methodology

Does LEBS Work in Other Organs?


Existing methodology

Does LEBS Work in Other Organs?

Example: Pancreatic Cancer

  • No existing technique is capable of accurate diagnosis of pancreatic carcinogenesis in preinvasive (PanIN) or resectable stage.

  • 95% mortality within a year after diagnosis.

  • Problem: pancreatic duct exam is not suitable for screening due to a high rate of complications including acute pancreatitis (~5-20%).

  • Solution: PWS analysis of duodenal periampullary cells brushed during upper endoscopy.


Existing methodology

Prospect of Pancreatic Cancer Screening

PWS (Nanoarchitecture):

LEBS (Microarchitecture):

204 patients total

84 Healthy control

26 Family History

29 Cyst

45 Pancreatic Adenocarcinoma

20 Other diseases

35 patients total

26 Healthy control

9 Pancreatic Adenocarcinoma

Testing set:

Sensitivity = 85%

Specificity = 80%

Sensitivity = 90%

Specificity = 81%


Example iii lung cancer

Example III: Lung Cancer

  • >80% of lung cancer patients had altered nuclear texture features

  • Us-Krasovec et al., Anal Quant Cytol Histol. 2005 Oct;27(5):254-62

  • Automated Quantitative cytology of buccal nuclei correlated with lung cancer

    • 66% sensitivity and 70% specificity for lung cancers

    • 61% sensitivity for stage 1

  • Turic et al, Chest 2005 (abstract)

  • Increased incidence of head and neck cancer in patients with lung cancer

  • Johnson et al., B. J. Natl. Cancer Inst., 1998

  • Genetic changes in the histologically normal large-airway epithelial cells obtained at bronchoscopy.

  • Guo, M. et al. Clin. Cancer Res. 2004.

  • 80% sensitivity and 84% specificity

  • Spira et al., Nat Med 2006.


Lung cancer screening by pws analysis of buccal cells

Lung Cancer Screening by PWS Analysis of Buccal Cells

  • Normal - Nonsmokers - 5

  • Cancer - Nonsmokers- 3

  • COPD (smokers)- 31

  • COPD – Family Hx- 7

  • Lung cancer (smokers)- 53

  • Other cancers- 4

  • Smokers (no COPD or cancer)- 5

Number of Patients: 108


Pws images are different for non cancer and cancer patients

PWS Images are Different for Non-cancer and Cancer Patients

Bright field

Non-cancer (COPD) patients

PWS

Disorder strength (Ld), um

Bright field

Lung cancer patients

PWS


Disorder in nanoarchitecture is increased in buccal cells in lung cancer patients

P<0.001

Control

(COPD)

Lung

cancer

Disorder in Nanoarchitecture is Increased in Buccal Cells in Lung Cancer Patients

Area under ROC curve = 84%

Sensitivity = 90%

Specificity = 77%


Potential confounding effects

Potential Confounding Effects

  • Can the differences in cell nanoarchitecture be simply due to difference in age among COPD and lung cancer patients?

  • Can the differences be due to different smoking history?


Conclusions

Conclusions

  • What we call “histologically normal tissue” is not entirely normal in patients with neoplasia

  • Not only neoplastic lesions but also tissue outside neoplastic lesions is abnormal

  • Biophotonics can detect field effects associated with carcinogenesis in the colon, pancreatic and lung

  • Optically-detectable markers of the field effect include increased mucosal blood supply, micro and nano-architectural changes in the mucosa

  • Potential for colon, pancreatic and lung cancer screening/risk-stratification through biophotonics detection of the field effect


Acknowledgements

Northwestern University

Vladimir Turzhitsky

Andrew Gomez

Hariharan Subramanian

Sarah Ruderman

Jeremy Rogers, Ph.D.

Young Kim, Ph.D.

Yang Liu, Ph.D.

Prabhakar Pradhad, Ph.D.

Xu Li, Ph.D.

Alexei Kromine

Acknowledgements

Funding

National Institutes of Health

R01CA128641, R01 CA109861,

R01 EB003682, R01 CA112315,

R01 CA118794, R33CA122017,

R21 EB006742, U01 CA11125

National Science Foundation

CBET- 0733868, CBET-0238903

V Foundation

Coulter Foundation

AACR

Evanston Hospital

Hemant Roy, M.D.

Ramesh Wali, Ph.D.

Randall Brand, M.D.

M. Goldberg, M.D.


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