Posts Tagged ‘image fusion’

Imaging-Biomarkers; from discovery to validation

Author: Dror Nir, PhD.


Recent technology advances such as miniaturization and improvement in electronic-processing components is driving increased introduction of innovative medical-imaging devices into critical nodes of major-diseases’ management pathways. Similarly, medical imaging bears outstanding potential to improve the process of drugs development and regulation (e.g. companion diagnostics and imaging surrogate markers. In; The Role of Medical Imaging in Personalized Medicine I discussed in length the role medical imaging assumes in drugs development.  Integrating imaging into drug development processes, specifically at the early stages of drug discovery, as well as for monitoring drug delivery and the response of targeted processes to the therapy is a growing trend. A nice (and short) review highlighting the processes, opportunities, and challenges of medical imaging in new drug development is: Medical imaging in new drug clinical development. An important aspect of drug development that is largely discussed is facilitating testing of the new drug through clinical studies. A major hurdle in development of many anti-cancer drugs is the long time that is required to determine the efficacy of the new drug through measurement of clinically meaningful endpoints; e.g. overall survival. Imaging is offering the opportunity to determine surrogate markers of clinical outcome (as a substitute for a clinically meaningful endpoints). The need for surrogate outcome markers is especially great with newer agents that may act by tumour stabilization as opposed to shrinkage.

To comply with current trends; e.g. personalized medicine and evidence-based medicine, medical imaging must support quantification of meaningful pathological phenomena; e.g. morphological deformations, enhanced/reduced chemical reactions, presence/absence of biological substances etc….


Two examples: 

Molecular imaging (e.g. PET, MRS) allows the visual representation, characterization, and quantification of biological processes at the cellular and subcellular levels within intact living organisms. In oncology, it can be used to depict the abnormal molecules as well as the aberrant interactions of altered molecules on which cancers depend. An established biological process is neoplastic angiogenesis is associated with a number of detectable changes at molecular and microcirculatory levels. In Positron emission tomographic imaging of angiogenesis and vascular function the authors are offering that direct study of angiogenic molecular biology and tumour circulation before during and after treatment may offer useful surrogate markers for vascular-targeted therapies. The paper reviews two main areas: (a) the methodology behind PET imaging of tumour blood supply with 15O-oxygen labelled compounds; and (b) newer tracers in development as markers of angiogenetic biology.

A largely sought-for application for medical imaging is Monitoring quality of surgery: Cancer patients could benefit from a surgical procedure that helps the surgeon to determine adequate tumor resection margins. Variety of applications and work-flows; e.g. Systemic injection of tumor-specific fluorescence agents with subsequent intraoperative optical imaging to guide the surgeon in the process are offered. Recently, in order to overcome the problem of tumor heterogeneity it was proposed to shift the focus of tumor targeting towards the follicle-stimulating hormone receptor (FSHR).

Imaging bio-markers

Being able to discover and clinically validate fundamental finger-prints of cancer which can be detected and quantified through medical-imaging modalities is key to transforming the potential presented by medical imaging into clinical reality. Such specific finger-prints/characteristics are usually referred to as imaging bio-markers.

A critical step in the discovery and validation of imaging bio-markers is the matching of tissue location as depicted by imaging-products (most commonly images) to their histology, as underlined by a pathologist under the microscope.

Since histology requires extraction of organ tissue and some processing, it is impossible to achieve such matching in real time. Therefore, different techniques were developed to support the retrospective matching between histology and imaging. The most prevalent one rely on image registration: i.e. the products of medical imaging are registered to images of pathology slides. The main limitation of such methods has to do with:

  1. The fact that the two images poses largely different image resolution.
  2. The form-factor (shape and dimensions) of Histological tissue-slides are distorted in comparison to their in-vivo state.
  3. Histology-reading is subjective; i.e. the concordance between readings of different pathologist is far from being satisfactory. It gets worse when it comes to staging of the cancer.
  4. There is large variation in the quality of medical imaging products.

A Workflow to Improve the Alignment of Prostate Imaging with Whole-mount Histopathology presents a robust methodology validating imaging biomarkers in the case of prostate cancer. In this paper we describe a workflow for three-dimensional alignment of prostate imaging data against whole-mount prostatectomy reference specimens and assess its performance against a standard workflow. We hypothesized that integration of image registration principles into the histological workflow for radical prostatectomy specimens would increase the alignment accuracy. In this post I will include only few excerpts from this paper which I strongly recommend to read in full.

Materials and Methods

Ethical approval was granted. Patients underwent motorized transrectal ultrasound (Prostate Histoscanning) to generate a three-dimensional image of the prostate before radical prostatectomy. The test workflow incorporated steps for axial alignment between imaging and histology, size adjustments following formalin fixation, and use of custom-made parallel cutters and digital caliper instruments. The control workflow comprised freehand cutting and assumed homogeneous block thicknesses at the same relative angles between pathology and imaging sections. The basic requirements of image registration were incorporated within the pathological protocol.

We demonstrate that the use of a simple, custom-made tissue-planer to slice the formalin-fixed prostate results in more uniform and parallel tissue blocks than conventional freehand techniques, and increases the accuracy of image alignment.  We also show that accounting for dimensional change due to formalin fixation is essential during image alignment.

Figure 1: Suggested workflow for registration of scanned histopathological data with radiological imaging


 Figure 3

A sketch of the tissue cutting device is shown (A).  The formalin-fixed prostate was placed on the space marked “X” on the device with its flat posterior surface facing down.  With the probe in the urethra to align the AP axis with the device, the base of the gland was gently pressed onto “Y”.  The probe was then removed, and a mounted microtome blade was lowered along the 4mm raised edge of the device from top to bottom to cut away the block (B).  The sliced block was put aside with its apical face facing down, and the process was repeated by gently pressing the cut surface flush against the device before each cut (C).  The thickness of each block was measured in 5 locations marked (D).



Thirty radical prostatectomy specimens were histologically and radiologically processed, either by an alignment-optimized workflow (n = 20) or a control workflow (n = 10). The optimized workflow generated tissue blocks of heterogeneous thicknesses but with no significant drifting in the cutting plane. The control workflow resulted in significantly nonparallel blocks, accurately matching only one out of four histology blocks to their respective imaging data. The image-to-histology alignment accuracy was 20% greater in the optimized workflow (P < .0001), with higher sensitivity (85% vs. 69%) and specificity (94% vs. 73%) for margin prediction in a 5 × 5-mm grid analysis.

Figure 5. Assessment of alignment accuracy between radiological images and pathological sections

The method of assessing alignment accuracy between radiological images and pathological slides is shown using an example.  Each square within the grids overlaid onto histology and radiological images were scored either as a “1”, indicating the presence of a histological or radiological margin, respectively, or “0”.  Scored pathology grids were used as the reference, and scored radiology grids were used as the index.  Hence, we determined true positives i.e. grid points score “1” in both histology and radiology (yellow squares, n=25), false positives i.e. grid points on the radiology scores “1” but not on histology (green squares, n=4), false negatives i.e. grid points on the histology scores “0” but not on radiology (red squares, n=3), and true negatives (grey squares, n=38).



A significantly better alignment was observed in the optimized workflow. Evaluation of prostate imaging biomarkers using whole-mount histology references should include a test-to-reference spatial alignment workflow.


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From AUA2013: “Histoscanning”- aided template biopsies for patients with previous negative TRUS biopsies

Reporter: Dror Nir, PhD


This year’s AUA takes place in San Diego, USA.

Wednesday, May 08, 2013 10:30 AM-12:30 PM
SDCC: Room 8
Prostate Cancer: Detection & Screening (V)
Moderated Poster
Funding: none
2209: “Histoscanning”- aided template biopsies for patients with previous negative TRUS biopsies.
Oleg Apolikhin; Andrey Sivkov; Gennady Efremov; Nikolay Keshishev; Oleg Zhukov; Andrey Koryakin

Abstract: 2209
Introduction and Objectives
One of the biggest problems in the diagnosis of prostate cancer (PCa), which distinguishes it from many other solid tumors, is the difficulty of tumor imaging by means of standard visualization techniques. A transrectal ultrasound (TRUS) biopsy is mostly performed on the basis of risen PSA and is often blind – tissue specimens are taken from standard zones. Biopsy under MRI control is technically and logistically complicated and expensive, while TRUS can`t always differentiate the suspicious areas. A TRUS-based innovative technique, “Histoscanningâ€� is used in our centre for PCa identification and targeted biopsy.

Prior to template biopsy we have performed Histoscanning to 31 patients, with previous one to six negative TRUS biopsies and persistent clinical suspicion of PCa (elevated PSA, high-grade prostatic intraepithelial neoplasia (HPIN) in 4 cores or suspicious TRUS findings). Age range was 51 – 75, with PSA values 3,8 – 14,3 ng/ml. Prostate size range 22-67cc. Most of the patients (n-26) from this group received therapy with 5α-reductase inhibitors for 6 months or more. Depending on the gland size, 10-14 standardized cores were taken + 4 additional cores from the suspicious zones marked on Histoscanning report.

Histopathology identified PCa in 13 out of 31 patients , adenocarcinomas with Gleason score ranging 6-8. In 11 patients with no signs of PCa we found HPIN or low-grade PIN. Comparing histology reports with Histoscanning mapping, in 8 PCa cases we found high correlation of this method with histopathological study on the amount and location of tumor lesions and in 5 cases Histoscanning showed greater spread of lesions, with good correlation of the tumor location.

Due to the effectiveness, ease of use and the short time required for data processing, Histoscanning is a promising method for more effective targeted biopsy of the prostate.

As a result of ongoing research, we aim to evaluate sensitivity and specificity of the method, fuse it with MRI, to create a 3D model for biopsy or surgery. In the future, this data could be used for decision making on the nerve-sparing prostatectomy and minimally invasive focal treatments such as cryoablation, high-intensity focused ultrasound, radiofrequency or laser ablation.

Date & Time: May 8, 2013 10:30 AM
Session Title: Prostate Cancer: Detection & Screening (V)
Sources of Funding: none


Personal note:

On the authors’ intention to fuse HistoScanning with MRI: The authors report a very compelling clinical benefit just from using HistoScanning for guiding their biopsies. HistoScanning itself results in a 3D mapping of the prostate and the suspicious locations inside.

3D mapping of the prostate by HistoScanning analysis following motorised TRUS. the colored locations represents tissue suspicious for being cancer.

3D mapping of the prostate by HistoScanning analysis following motorised TRUS. the colored locations represents tissue suspicious for being cancer.


Fusing ultrasound & MRI images is prone to image-registration errors (e.g. due to differences in the prostate’s shape-distortion by the probe) which are larger than the accuracy sought for when performing biopsy or nerve-sparing surgery. I recommend anyone who wishes to guide biopsies and treatment based on MRI and therefore is in need for good level of localized-MRI interpretation, to rely on dedicated MRI interpretation applications and not intra-modalities image fusion.

In addition, major benefits of using HistoScanning for managing prostate cancer patients are the accessibility; A urologist can perform himself, at any time he chooses and at any place, simplicity; it only requires routine TRUS, patient-friendly; it lasts less than a minute and does not require anesthesia and low-cost; it’s ultrasound! Mixing HistoScanning with MRI will certainly eliminate these.

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