Tel Hashomer Medical Research

Infrastructure and Services Ltd.

Imaging and Monitoring Tools

2016

Contact : Sylvie Luria PhD., CEO

Technology Transfer Company

Tel Hashomer Medical Research, Infrastructure and Services Ltd.

Tel: +972-3-5305998 Fax: +972-3-5305944 Cell: 052-6667277

sylvie.luria@sheba.health.gov.il http://research.sheba.co.il/e/

Sheba Medical Center - Technology Transfer Company

Tel Hashomer Medical Research, Infrastructure and Services Ltd.

http://rnd.sheba.co.il/

Business:

Tel Hashomer Medical Research, Infrastructure and Services Ltd. (THM) the technology

transfer arm of Sheba Medical Center, is responsible for managing the intellectual property

assets of Sheba Medical Center and to promote the transfer of technologies, innovation and

professional know-how for society's use and benefit, and for the development of the medical and

health care delivery fields. Sheba Medical Center facilities, experience, human resources and

regulations enable the development of a novel idea from its basic science to its product

development and prototype, thus rapidly generating value to its IP for commercialization.

Main Activities:

Scientific insights and academic breakthroughs often translate into inventions for the benefit of

the marketplace. THM bridges the gap between Academia Research and Industry Needs, since

the industry is product-based, business-oriented, and focused on time-framed missions, THM

helps turn scientific progress into tangible products, while returning income to the inventor and

to Sheba Medical Center to support further research.

THM receives invention disclosures from faculty, staff and students. We evaluate the innovations

for patent applications and develop licensing strategy, consider the technical and market risks.

Patentable inventions constitute the majority of THM's licensing activities; however, we also

handle collaborations with industrial partners and Tangible Research Property (TRP) such as

Tissue Bank, Genomics and Bio-Markers, Cell Therapy, Computational Imaging and more.

THM builds a well-structured and organized “value creation” model, as well as several business

models pending on industry: (Health IT, Medical Devices, Bio-Medical, ) and on entity (start-

up, SME and Big Entity/ Pharma).

THM has several strategic support plans such as the “Micro Fund" and strategic collaboration

with other research institutes and industry to facilitate invention development.

IP strategy and managemnt

Commercialization and

licensing management

Royalties Streaming

THM Strategic Principles to the Success of our Tech Transfer

► We bridge basic research to commercial Value

► We develop close interaction with researchers and industry

► We Build Strategic Capabilities

► We are a “Learning Organization” and Flexible Organization

► We understand the stakeholders need and Value creation

► We Build Collaboration & Alliances

► Our stream: Identify Need from the bedside, Basic and applicable Research-

► We develop broad and Multi-national view

THM Intellectual property's portfolio spans over therapeutics, diagnostics, medical devices

and medical tools in the fields of Onco-Genetics, Hemato-Oncology, Epidemiology of

Malignant Diseases and Trauma, Lipids, Diabetes, Hypertension, Onco-Surgery , including

research in Breast and Colon Cancer, Regenerative medicine, Immunology, Neuro-Immunology,

Alzheimer's Disease, Multiple Sclerosis and Psychiatry.

Contact:

Sylvie Luria Ph.D. Technology Transfer and Business & Development Manager

Tel Hashomer Medical Research, Infrastructure and Services Ltd.

Tel: +972-3-5305998 Fax: +972-3-5305944 Cell: +972-052-6667277

sylvie.luria@sheba.health.gov.il http://rnd.sheba.co.il/e/

Innovations from Sheba Medical Center - Technologies for Licensing:

1. MRI- TRANS RECTAL ULTRASOUND FUSION FOR IMPROVED PROSTATE CANCER THERAPY Zvi Simon and Arlando Mayer

2. FUSION BETWEEN PRE-OPERATIVE AND INTRA-OPERATIVE BRAIN MRI FOR NEUROSURGICAL NAVIGATION

Moshe Hadani and Arlando Mayer

3. METHOD AND SYSTEM TO CONFIRM INTRAVENOUS CATHETER PLACEMENT AND POSITIONING Ilan Keidan and Arlando Mayer

4. SMARTI-SMART IMMOBILZATION FOR ADVANCED RADIATION THERAPY AND IMAGING. A

CONTROLLED PLATFORM FOR ASSESSING AND OBTAINING TARGET LESION IMMOBILIZATION

THROUGH INTEGRATED USE OF CPAP, BIOFEEDBACK AND OTHER MODALITIES. Zvi Symon, Jeff Goldstein, and Yaacov Lawrence

5 THE APPLICATION OF MRI FOR DETERMINING BBB ABNORMALITIES Yael Mardor

MRI- TRANS RECTAL ULTRASOUND FUSION FOR IMPROVED PROSTATE CANCER THERAPY

Dr. Zvi Simon and Dr. Arlando Mayer, Sheba Medical Center

Categories Image Processing , Medical Algorithm, Medical Navigation, Prostate Cancer

Development Stage Clinical Stage

Patent Status WO2015/008279 – "MRI Image Fusion Methods and uses Thereof"- Pending

Background of the Invent ion

We develop a complete framework for focal therapy of the prostate guided by TRUS-MRI image fusion.

In image guided prostate biopsy, we distinguish between the first biopsy and the recurring follow-up. In

the first biopsy it is necessary to ensure that the lesion(s) will be sampled to provide informative tissue for

the pathologist and accurate diagnosis. The accurate position of the area sampled inside the lesion is less

important by itself.

In the recurring follow up it is required to sample the prostate at the locations that were sampled at

previous biopsies in order to enable temporal evolution monitoring. Here again it is important to ensure

that the needle re-samples an area sufficiently close the previous biopsy location to provide comparable

pathology results over time. For example, if the area sampled at first biopsy was inside a lesion, it is

important that the corresponding area sampled in the recurring biopsies be inside the same lesion.

On the other hand, prostate focal therapy has much more stringent requirements in terms of accuracy.

Fusion accuracy must enable to mark the whole volume of the targeted lesion up to a predefined resection

margin. The acceptable resection margin will usually be much smaller (1-2 mm) than the tolerable biopsy

positioning error. According to Seifabadi, the maximum tolerable error in biopsy is 5 about mm, which is

the radius of a clinically significant tumor assuming that it has a spherical shape .

The technologies that are developed these days for TRUS-MRI fusion in prostate imaging are dedicated to

biopsy applications and are not designed to cope with the stringent accuracy requirements of focal therapy

that we address in this project.

Our innovation revealed that software to register and merge data from magnetic resonance imaging (MRI)

and ultrasound (US) images enables intraoperative visualization of tumors, not typically seen in a US

image. It is possible that this technology may be essential for the efficient implementation of focal

therapy techniques in which individual tumors are treated within an appropriate and safe surgical margin.

The Need

Prostate cancer is the most common cause of cancer in men in many countries. It is the second leading

cause of death from cancer in American man.

Over the last decade, more accurate localization

of cancers within the prostate

Growing interest in focal therapy

Less radical approach.

Image-guided radiation therapy (IGRT) is the process of frequent two and three-dimensional imaging,

during a course of radiation treatment, used to direct radiation therapy utilizing the imaging coordinates of

the actual radiation treatment plan.

IGRT and Precise radiation therapy offers several advantages:

1. Reduce severity and risk of therapy-induced complications.

2. Increase both quality and probability of success.

3. Broaden application of proven therapies.

4. Permit new therapies that are intolerant to geometric imprecision.

Co-localization of the target and

therapeutic dose distribution within the

human body is a significant technical

challenge.

P otent ia l Appl icat ions

parametric MRI is a powerful tool for any guided prostate cancer -Fusion between TRUS and multi

ct the sampling/treatment needle intervention whether diagnostic or therapeutic and could be used to dire

to suspicious lesions on MRI not clearly visible on TRUS alone.

therapy, photodynamic therapy, gene -high intensity focused ultrasound, cryo-These modalities include:

therapy and guided biopsies.

This fusion technology can be easily adapted to CT-MRI fusion. Thereby, it has the potential of

significantly improving the accuracy of CT-MRI fusion routinely performed in external beam

radiotherapy (EBRT). Current fusion solutions for CT-MRI fusion in EBRT are not accurate enough and

usually require much manual tweaking. The number of EBRT procedures is even larger than

brachytherapy

In Addition the automatic contouring technology we developed is also very useful in EBRT planning as ,

manual contouring takes a significant amount of time and is difficult to realize on CT scans due to poor

contrast in soft tissues. Actually, the contouring technology may be applied to other organs, leading to

additional products.

The Market

The Global market for Radiation Therapy Equipment is projected to reach US$6.8 billion by 2018, driven

by the increasing incidence of cancer around the world and by the development of Image-guided

radiation therapy tools. Additionally, technological advancements are driving the market for Radiation

Therapy Equipment, owing to the development of sophisticated screening methods that facilitate early

cancer detection.

Brachytherapy is increasingly been accepted as standard treatment for prostate cancer and gynecological

cancers including ovarian cancers, cervical cancer, and endometrial cancer among others. Brachytherapy

offers several benefits to cancer sufferers who are increasingly adopting this non-invasive alternative, and

this is predicted to continue to drive the future demand for brachytherapy. Extending applications of

brachytherapy to other locations within the body to include gliomas and intraocular melanomas, which are

a kind of brain tumor would assist in propelling the market for temporary brachytherapy devices in the

future.

Approximately 70 percent of all the cancer patients globally undergo radiation therapy. But almost 20

percent of malignant tumors are radiation-resistant. The radiation can be delivered via external-beam

radiation therapy, internal radiation therapy or systemic radiation therapy.

The market is also segmented by various technologies like intensity-modulated radiation therapy (IMRT),

image-guided radiation therapy (IGRT), cyber knife, gamma knife, proton / neutron therapy and dynamic

multi-leaf collimator (DMLC), among others, though External-beam radiation therapy (EBRT) continues

to represent the largest segment.

P atent

WO2015/008279 – "MRI Image Fusion Methods and uses Thereof"- Pending

T e c h T r a n s f e r Of f i c er

Dr. Sylvie Luria

Tel Hashomer Medical Research, Infrastructure and Services

Tel: +972-3-5305998 Fax: +972-3-5305944 ; sylvie.luria@sheba.health.gov.il

FUSION BETWEEN PRE-OPERATIVE AND INTRA-OPERATIVE BRAIN MRI FOR NEUROSURGICAL NAVIGATION

Moshe Hadani, Arlando Mayer and Eli Konen – Sheba Medical Center, Israel

Nahum Kiryati, Ori Weber – Tel Aviv University, Israel

Categories Image Processing , Medical Algorithm, Medical Navigation, Neurosergury

Development Stage Clinical Stage

Patent StatusC156-P1374-USP- "Fusion between Intraoperative and Low Field MRI and

Preoperative MRI for Improved Neurosurgical Navigation" - pending

Background of the Invent ion

Preoperative high-resolution MRI is commonly used as anatomical reference for navigation during open-

brain surgery. It can be enhanced by overlaid preoperative Functional MRI (fMRI) and diffusion tensor

imaging (DTI) data that localize critical grey and white matter areas in the vicinity of the targeted lesion.

The use of preoperative images implicitly assumes that the brain remains immobile with regard to the

skull during the entire procedure. In practice, this assumption has only a limited validity in time.

When the skull is opened (craniotomy) at the brain drift progressively with regard to the skull. This well-

known effect is called brain shift. As surgery progresses, local deformations caused by ongoing tissue

resection further increase the discrepancy between preoperative MRI and the actual brain anatomy.

Intraoperative MRI slices: Left-before surgery; Middle-during surgery; Right-overlay before

(grayscale) / during (purple) surgery. In the middle image, the yellow arrow through the skull opening

indicates the area that has been resected (black). Note in the right image the local misalignment

(yellow contour) between before and during surgery corresponding to brainshift effect and resection

induced deformations.

Pre-operative planning and intra-operative guidance in neurosurgery require detailed information

about the location of functional areas and their anatomo-functional connectivity. In particular,

regarding the language system, post-operative deficits such as aphasia can be avoided.

During the last decade, low field (~0.15 Tesla) interventional MRIs (iMRI) has been developed to

provide updated MR images during surgery, thereby helping to compensate for brain shift. It has been

shown that iMRI guided Glioma surgery helps surgeons provide the optimum extent of tumor resection.

In practice, however, due to magnetic field and physical size limitations, intra-operative MRI cannot

provide images comparable to the pre-surgical images obtained on a full size, high field scanner. The field

of view is limited to an ellipsoidal window that is usually too small to contain the whole brain and whose

position and orientation are unknown a-priori, and it is not possible to acquire functional MRI (fMRI) or

diffusion tensor imaging (DTI) intra-operatively.

Preoperative high field image (left); intraoperative low field and SNR image (right)

Currently, no existing solution gives the neurosurgeon an image quality comparable to pre-operative

MRI with the compactness, ease of use and low cost of low field MRI.

We developed and validated an algorithmic framework to perform accurate and robust registration

between high quality pre-surgical MRI and noisy intra-operative MRI images. On completion of

successful registration, pre-operative anatomical, functional and DTI tractography maps shall be projected

onto the intraoperative MRI images, thereby providing fusion between preoperative (anatomical, DTI

tractography and fMRI) and intra-operative MRI.

The Need

There is major need for Precision guidance system for surgeon with real-time updated information of

target condition . Computer Assisted Surgery based on Intraoperative Information and Navigation

Technology is in great demand for several reasons:

1. Patient safety

2. Evaluation of performance of surgeon/procedure/device

–Record, Analyze, Visualize

–By human: hard task, long time, high cost, error

–Do not disturb surgical procedure 3. Demand for Automatic Recording/Analysis/Visualization

–Quantitative digital data for computer processing

–No effect on surgical procedure and environment

Automatic analysis using navigation information4 .

Advantages:

Platform technology for accurate medical image Fusion.

Improved patient safety and procedure outcome.

The technology can be applied to MRI and iMRI images generated by equipment

produced by different vendor.

The software can be standalone and load standard DICOM images dirtectly from the

imaging devices or from a picture archiving and communication system (PACS).

The software can be fully integrated to existing iMRI navigation systems in collaboration

with the vendor.

P otent ia l Appl icat ions

The developed deformable registration between modalities with different field-of-view, such as

iMRI-MRI fusion application - is applicable to other scenarios in image guided interventions.

For example, the registration between preoperative MRI images and intraoperative optical

microscope or endoscope images can benefit of our ability to deal with partial field-of-views

(here for the microscope).

The resulting product may prove particularly useful as the intrasurgical microscope provides real-

time updates while iMRI can only provide snaphots at a given time.This is applicable not only for

Brain but virtually to any form of micro-surgery performed under microscope or endoscope.

The developed technology can be applied to the registration between MRI and CT required

for the accurate planning of image guided cancer radiotherapy. The potential use of this

application is very widespread since image guided radiotherapy is performed on a multitude of

organs affected by cancer. Accuracy is a critical factor in radiotherapy as it ensures proper

delivery of radiation to the target while sparing surrounding healthy tissues.

The developed technology can also be applied to PET-CT or PET-MRI fusion. The significant

difference in SNR between these modalities is similar to the iMRI – MRI problem addressed

specifically in our research. Here again, the potential use is very important as PET-CT / MRI is

the method of choice for cancer metabollic imaging

The Market

Neurosurgery is a complex surgical procedure that involves diagnosis, treatment, and

rehabilitation of disorders affecting any region of the nervous system. Some of the common

neurosurgeries are endovascular neurosurgery, stereotactic neurosurgery, oncological

neurosurgery, craniotomy, and neuroendoscopy. In all neurosurgery procedures, Image navigation

in real time is mandatory with millimeter accuracy. Advanced imaging maps of the brain structure

and function, using intraoperative MRI with This allows our surgeons to perform brain surgery

with precision and real-time imaging information, helps surgeons identify vital areas of the

brain, and these are key success factors. Brain Tumors pose particular challenges because of

edema, displacement effects on brain tissue and infiltration of white matter. Under these

conditions, standard fiber tracking methods reconstruct pathways of insufficient quality.

Therefore, robust global or probabilistic approaches are required.

The global MRI market is currently valued in the region of US$5.5 billion (2010) and is estimated

to rise to US$7.5 billion by the year 2015. Of this the US market is estimated at US4.5 million

(2010) rising to US$5.8 million by 2015 (GIA, 2010; Reportlinker 2010). The leading MRI

producers are GE (Signa brand), Siemens (Magnetom), Philips (Achieva, Intera, Panorama),

Hitachi (Aaltaire, Airis) and Toshiba (Vantage, Opart, Ultra). Products range from Low Field

systems (<0.5T) through Mid Field (0.5-1T) High Field (usually 1.5T) to Very High Field

(usually 3T).

Procedure Types Currently the greatest demand for MRI procedures in the US is for Brain, Head and Neck scans

with spine and extremity scans running a close second. The following chart shows a breakdown

of procedure types in the years 2010 and 2007.

Procedure types 2010, 2007

MRI Procedure Type

2010 2007

Procedure

numbers

(millions)

% of all

procedure

s

% of sites

performin

g

Procedure

numbers

(millions)

% of all

procedure

s

% of sites

performin

g

Spine 7.5 25% 97% 7.1 27% 100%

Brain Head and Neck 8.7 29% 89% 8.5 32% 94%

Extremity 7.3 24% 99.5% 5.3 20% 99%

Vascular (MRA) 2.3 8% 99% 2.4 9% 88%

Pelvic & Abdominal 2 7% 91% 1.9 7% 91%

Breast 1.1 4% 55% 0.5 2% 26%

Chest, other cardiac 1.1 4% 19% 0.8 3% 34%

Other (inc

interventional) 0.2 1% 5% 0.2 1% 5%

Total 30.2

26.7

Our technology will have an impact to other procedures that require real time imaging for

precision procedures.

P atent

"Fusion between Intraoperative and Low Field MRI and Preoperative MRI for Improved Neurosurgical

Navigation" 61/984,988, pending

Method and System to Confirm Intravenous Catheter Placement and Positioning

Dr. Ilan Keidan, Sheba Medical Center, Israel

Categories Method and Algorithm

Development Stage Clinical Stage

Patent Status

PCT/IB2012/052288 :

"PROVIDING EVIDENCE WHETHER AN INTRAVASCULAR

CONDUIT ISCORRECTLY POSITIONED"

Background and Technology

INFILTRATION AND EXTRAVASATION are common complications of intravenous (I.V.) infusion

therapy. Extravasation can cause accidental administration of intravenously infused medicinal drugs into

the surrounding tissue, either by leakage (e.g., because of brittle veins in very elderly patients), or direct

exposure (e.g. because the needle has punctured the vein and the infusion goes directly into the arm

tissue). For example, Extravasation of medicinal drugs highly irritating solutions, such as those containing

calcium, potassium, contrast media, some antibiotics, vasopressors, or chemotherapeutic agents.during

intravenous therapy is a side effect that should be avoided. In mild cases, extravasation can cause pain,

reddening, or irritation on the arm with the infusion needle. Severe damage may include tissue necrosis. In

extreme cases, it even can lead to loss of an arm. The best "treatment" of extravasation is prevention.

While there is no real treatment per se, there are some techniques that can be applied in case of

extravasation, though their efficacy is modest. We have developed a simple method and system to

monitor intravenous position of catheters via periodically administration of a simple composition and a

monitoring device. (Sodium bicarbonate solution and end-tidal carbon dioxide monitor). The rationale for

using bicarbonate is based on the well-known phenomenon of increased exhaled carbon dioxide (CO2)

after its IV administration.

The Need

Extravasation is a serious condition that warrants special attention from the healthcare professionals

involved in administering intravenous medications. Over 100,000 doses of chemotherapy and in excess of

1,000,000 intravenous (IV) infusions given every day around the world, keeping adverse events and

complications of these procedures to a minimum is important both for the patients receiving them and the

healthcare systems in which they take place. It is critical that an extravasation is recognized and diagnosed

early. The tools available today to recognize and detect extravasation in its early stages are mainly

subjective and awareness to all relevant signs and symptoms. Infiltration rates were reported to be high,

with as many as 20-30% of IV catheters in adults resulting in infiltration, with higher rates seen in

children. Analysis of the American Society of Anesthesiologists Closed Claims database revealed 2% of

all claims were related to peripheral IV catheterization and over half of these were due to extravasation,

and higher rates could be expected with other health care providers given the presumed expertise of

anesthesiologists in IV cannulation.

Development Stage and Technology

We developed a novel technique that can differentiate between an infiltrated and a correctly sited IV

catheter in both anesthetized ventilated and spontaneously breathing volunteers. We have demonstrated

the efficacy of the novel method as very useful in providing information to monitor and assist in

determining whether or not an intravenous conduit is in a correct position. The method is simple to

integrate in various monitoring systems in the hospital set-up. We have initiated clinical studies that

demonstrate the efficacy and specificity of the concept and system in patients from age 2-35 years old.

Currently we are expending the study to the general patient's population. We target those patients which

extravasations/ infiltration rate is high and the consequences are grave.

Advantages

The technology relates to a specific tool to be implemented in clinical monitors. Our technology is simple

to integrate into existing monitoring devices, Capnometers and monitoring systems with critical added

value of CO2 monitoring..

The Market

The market is add on capnometry devices for the determination of the end-tidal partial pressure of carbon

dioxideThe carbon dioxide (CO2) monitors market is witnessing an increasing trend over the last few

years, primarily driven by enhanced requirements in patient monitoring for safety and disease

management. Although majority of capnography applications are in the operating rooms for detecting and

identifying the end-tidal CO2 levels, new and emerging applications including critical care units, recovery

rooms, labor and delivery rooms, emergency rooms, post-anesthesia care units, intensive care units and

daily care units in Oncology and autoimmune diseases are instigating the use of capnography equipment.

Capnography market worldwide is presently considered a segment with rich opportunities, increasing

simultaneously with the continuously evolving ways and methods of patient care. Our new feature to be

incorporated into an existing commercial end-tidal CO2 monitor may contribute the market growth, with

the rise of aging population as well as increasing IV bio-pharmaceutical therapies and the augmented

safety regulations.

The worldwide markets for Carbon Dioxide (CO2) Monitors include the following Product Segments:

End-tidal Carbon Dioxide (EtCO2) Monitors, and Transcutaneous Carbon Dioxide (tcpCO2) Monitors.

There are 40 companies including many key and niche players such as B. Braun Melsungen AG, CAS

Medical Systems, Inc., Criticare Systems, Inc., Dräger Medical AG & Co. KG, GE Healthcare Life

Support Solutions, Heinen + Löwenstein GmbH, Invivo Corporation, Ivy Biomedical Systems, Inc.,

Mindray North America, Nellcor Puritan Bennett, LLC, Nihon Kohden Corporation, Nonin Medical, Inc.,

Oridion Systems, Ltd., OSI Systems, Inc., Philips Healthcare, Physio-Control, Inc., Radiometer Basel AG,

Radiometer Medical ApS, Respironics, Smiths Medical, Thames Medical, Weinmann Geräte Für Medizin

GmbH + Co. KG, and Welch Allyn Inc.

The global market for intravenous therapy and vein access was $19.3 billion in 2013. The market reached

$20.3 billion in 2014 and is expected to reach about $27.2 billion in 2019, registering a compound annual

growth (CAGR) of 6.0% over the next five years.

The next generation market for capnometry devices will be at each bed station in the hospitals.

P atent

METHODS AND DEVICES USEFUL FOR DETERMINING CORRECT PLACEMENT OF INTRA-VASCULARTURE "

CONDUIT "

A controlled platform for assessing and obtaining target lesion immobilization through

integrated use of CPAP, biofeedback and other modalities.

Zvi Symon, Jeff Goldstein and Yaacov Lawrence, Sheba Medical Center

Categories Radiotherapy, Target Lesion Immobilization, Imaging, Medical

Device

Development Stage First prototype

Patent Status Pending

BACKGROUND AND TECHNOLOGY

Organ movement is troublesome in many areas of interventional and diagnostic medicine where

precision is vital to success. The concept ‘motion management’ has especially been developed in

radiation oncology in order to avoid missing the target (e.g. a lung tumor) and to minimize

radiation exposure of normal tissues. Currently various strategies of motion management exist

(e.g. abdominal compression, gating of the X ray beam, breath hold) and are employed

empirically depending upon physician preference and availability. No predictive algorithms exist

that predict what the optimal motion management should be employed.

We have developed a novel approach and Smart iMmobilzation device that incorporate multiple

inputs for measuring organ movement / respiratory phase and have the ability to control multiple

interventions to minimize organ movement. The device is an individualized ‘organ-stabilization’

strategy based upon 1) a preliminary dummy run testing how each individual patient/tumor reacts

to each intervention and 2) an inbuilt algorithm that predicts the impact of respiration based upon

tumor location and body habitus.

The multiple interventions that are used to decrease tidal volume include: CPAP, Air Pressure for

delivering CPAP will be under computer control (or other respiratory mode, biofeedback of size

of tidal volume supplementary oxygen, abdominal compression under computer control,

breathing control, and use of pharmaceutical agents .

The device will incorporate number of sensors to probe the depth of respiration, and tumor

movement as well as other parameters: respiratory rate, pulse oximeter, spirometer including

pressure volume measurement, lung compliance and volume, mechanical measure of chest

expansion using wearable sensors a mechanism for distinguishing different patterns of breathing

(e.g. thoracic vs abdominal breathing), blood pressure and pulse, panic button, and ultrasound.

The device will be able to control/trigger LINAC gating (or other device e.g. PET scan). The

patient will have a hand control that will enable manual adjustment of pressure (and measure

pulse oximtery), incorporating a panic button.

A control station can adjust CPAP volume, oxygen concentration, visual feedback and

abdominal pressure in order to help the patient minimize tidal volume. The system includes an

algorithm that optimizes the above interventions based upon real-time feedback , e.g. of chest

movement. The algorithm predicts the optimal strategy for organ mobilization based upon

clinical and anatomical parameters, previously collected clinical data. The machine will also be

used during delivery to ensure consistent care.

This device will employ allow assessment and use of both widely used (e.g. abdominal

compression, breath hold) and novel (e.g. CPAP) methods of motion management. Further more

it will provide a platform for further development.

DEVELOPMENT STAGE:

CPAP as an individual modality is already being developed and is protected by a patent

pending registered by Sheba.

We are performing on-going clinical studies to understand the optimal duration and

pressure for CPAP use and these will form the basis of the algorithm, which will be

implemented within the device.

We are submitting an IRB proposal to investigate the effect of CPAP and abdominal

compression on tidal volume and respiratory rate.

THE NEED

Radiation therapy uses controlled high-energy rays to treat tumors and other diseases. The goal

of radiation therapy is to maximize the dose to the target lesion within the organ with the

following general principles

Precisely locate the target

Hold the target still - Patient and Machine alignment

Accurately aim the radiation beam

Shape the radiation beam to the target

Deliver a radiation dose that damages abnormal cells yet spares normal cells

Immobilization devices are needed for precise treatments:

Stereotactic

Radiosurgery (SRS)

Fractionated Stereotactic

Radiotherapy (FSR)

Conventional

Radiotherapy

Locate target Uses stereotactic

localization

Uses stereotactic localization Uses standard diagnostic

scans

Immobilization

device

Uses a rigid

stereotactic head or

body frame

Uses a repositionable stereotactic

mask or body mold

May use a mask or body

mold

Accurately aim

radiation beam

Most precise

Uses laser, infrared and

x-ray body tracking

Very precise, Uses laser, infrared

and x-ray body tracking

Larger target area that

includes normal brain

margin

Immobilization devices need to be improved to control for precise treatments in real time. Smart

immobilization devices will affect treatment efficacy and safety. Our novel system and general

platform will address the need in every radiotherapy clinic and for every patient in the clinic.

The need for smart immobilization devices will grow with market growth of proton therapy.

Additional possible applications: radiology for improving contrast between lesions and normal

lung tissue, screening for lung cancer, invasive radiology- performing biopsies (e.g. kidney,

liver biopsy), urology (lithotripsy) and to optimize imaging e.g. PET (which is degraded through

organ movement)or MRI.

ADVANTAGES

Current strategies of motion management are ‘dumb’, e.g. abdominal compression used to limit

breath size consists of a simple belt or plastic paddle that is adjusted by hand prior to treatment

and not connected to any electronic device. Our ‘smart’ device will both measure movement and

intervene to minimize breath size before and during treatment, allowing real-time monitoring,

and inform a self-learning algorithms to the benefit of subsequent subjects.

THE MARKET

Radiation therapy is one of the advanced treatment and diagnostic procedures to kill tumor cells

using focused energy with an intension to limiting harmful effects to the neighboring healthy

cells. Radiotherapy is generally applied either alone or along with the combination of surgery or

chemotherapy.

The global radiotherapy devices market is classified into external radiotherapy, internal

radiotherapy (brachytherapy) and systemic radiotherapy. The radiation therapy market is

expected to grow at a faster rate with a CAGR of 5.3% from 2013 to 2018.

The global radiotherapy market has seen challenging and dynamic market conditions, but still

remains strong, with a size of approximately $4.4 billion in 2011, at an estimated annual growth

rate of 5.3% over the next five years.

Major players in the market include Varian Medical System (U.S.), Elekta AB (Sweden) and

Accuray (U.S.), IBA Group (Belgium), Eckert & Ziegler BEBIG (Belgium), iCAD, Inc. (U.S.),

GE Healthcare (U.K.), Covidien, PLC (Ireland), C.R. Bard, Inc. (U.S.), Nordion, Inc. (Canada),

Theragenics Corporation (U.S.), Oncura, Inc. (U.S.) among others.

The market for treatment solutions to support radiotherapy include software and hardware,

including immobilization devices.

Beam shaping IMRT or 3D conformal IMRT or 3D conformal IMRT or 3D conformal

Optimal dose Very high dose

delivered during one

treatment session

Moderate “fractions” of the

complete high dose delivered over

multiple treatment sessions

Moderate “fractions” of

the complete dose

delivered over multiple

treatment sessions

The successful clinical implementation of radiotherapy modalities requires precise positioning of

the target to avoid a geographical miss. Effective reduction in target positional inaccuracies can

be achieved with the proper use of immobilization devices.

Immobilization devices are applicable to any interventional procedures in the chest and abdomen

where respiration-induced organ movement is detrimental, e.g. Optimization of internal patient

anatomy for radiation treatment planning and delivery, other ablative modalities ( Focused

ultrasound, radiofrequency ablation, nano-knife and other ablative modalities), interventional

radiology for performing biopsies (e.g. kidney, liver biopsy), urology (lithotripsy) and to

optimize imaging e.g. PET (which is degraded through organ movement)or MRI.

The immobilization device market includes stereotactic frame, Talon system, thermoplastic

molds, Alpha Cradles, and Vac-Lok system. Main players are VARIAN, Elekta, Orfit Industries,

Bionix Radiation Therapy , Kobold , Qfix and others. The overall market reaches over 430 M

USD during 2013. The driving force of this market will be precise treatment and proton therapy

using immobilization with real time controlled operation systems.

FUTURE OUTLOOK

New therapeutic approaches to disease are increasingly minimally invasive and non-operative.

All require precision, and if located within the chest or abdomen, they are negatively affected by

respiratory motion. Hence there is a growing need for “organ stabilization” techniques.

IP STATUS- NEW APPLICATION , PENDING

AUTOMATIC DECISION SUPPORT SYSTEM FOR CONTRAST ENHANCED DIGITAL MAMMOGRAPHY

Dr. Miri SklairLevy and Dr. Arnaldo Mayer , Sheba Medical Center

Categories Digital Mammography, Breast Cancer, Imaging, Medical Device

Development Stage First prototype

Patent Status Pending

BACKGROUND AND TECHNOLOGY

Mammography is a well-established, cost-effective imaging technique for breast cancer

detection that has been clinically available since 1970. It is the only screening technology that

was proved to reduce mortality and the only one with FDA clearance.

In the last decade, full-field digital mammography has progressively replaced the film-based

mammogram. Solid-state detectors, directly converts X-rays into a high resolution digital

image.

The lack of visibility in dense breasts remains a major limitation of mammography even in its

digital form. 40 to 50% of women below 50 years have dense breasts as well as a significant

proportion of women older than 50 years. The overall sensitivity range of mammography is

63%-98% and drops to 30%-58% for dense breast.

MRI proved to be a very sensitive tool in breast cancer detection even with dense breast by

leveraging the complementary information provided by contrast administration. In particular,

contrast-enhanced MRI is extremely sensitive to angiogenesis. Unfortunately, breast MRI

remains very expensive in comparison to digital mammography and with limited availability.

Contrast enhanced digital mammography (CEDM) was developed in the very recent years as

a low cost technique for the detection of abnormal focal areas with increased micro vessel

density.

We have developed an automatic decision support system that will help the radiologist reach

a confident classification of CEDM breast lesions as benign or malignant. Our goal is to

increase the radiologist diagnostic specificity so that a significant amount of unnecessary

biopsies will be avoided without compromising sensitivity. In a unique approach, the

developed system will integrate both visual data (pixels) and patient background information

(risk stratification system )into a joint supervised learning scheme.

The developed technology can be applied to other breast imaging techniques such as MRI

that would also benefit from the contextual patient information in obtaining a higher

diagnostic confidence and potentially reduce the amount of unnecessary biopsies.

Also, the developed technology may be applied to other organs where contrast enhancement

MRI is performed for the detection of malignant lesions such as the prostate.

We propose imaging tools for Contrast-enhanced digital mammography (CEDM) and contrast-

enhanced tomosynthesis (CET). CET and CEDM may be considered as an alternative modality to

MRI for following up women with abnormal mammography. .

DEVELOPMENT STAGE

1) Development of a lesion classification system in CEDM images: The algorithm developed

is enhanced to include additional visual features into the learning and classification process.

The enhanced algorithm is validated on retrospective set of at least 200 CEDM lesions for

which manual contour will be provided by an expert breast radiologist and lesion

classification available from prior biopsy.

2) Enhanced classification by joint visual and contextual features learning : Contextual

information describing the patient medical background such as age, genetically background

(BRCA gene), previous/family history of disease, lesion palpability, etc is included to

complement the "pixel" based information in the classification system. For this purpose,

contextual information will be collected for each of the 200 CEDM of point 1.

3) Development of an Online learning capability architecture for continuous performance

improvement: Online learning enables the incremental update of a learning system model

parameters each time new training data is available. We leverage the routine reading work of

breast radiologists on CEDM to add automatically new cases to the training set and update

the classifier parameters to account for the newly available data. For this purpose incremental

learning techniques is investigated and compared to standard batch re-training of the

classifier.

4) Integration of the developed system with the radiologist workflow: The developed system

is implemented on a virtual machine. .

5) Clinical validation of the integrated system in Sheba: Using the integrated workflow

described above, the developed system is evaluated on a set over 100 new CEDM lesion for

which ground truth is available. The automatic classification results is compared to ground

truth (biopsy) and statistical analysis will be performed.

THE NEED

The main problem with mammography is its unacceptably high rate of false positives.

If a mammogram detects an abnormal spot in a woman's breast, the next step is typically a

biopsy. In addition, early stage cancer like ductal carcinoma in situ, or D.C.I.S., can be very

hard to diagnose. Many of the tests that produce false positives, lead to many unnecessary

biopsies and other invasive medical procedures. Vast research demonstrate that biopsies

performed for 70% to 80% of all positive mammograms do not show any presence of cancer.

According to some estimates, 90% of these call backs are because of unclear readings due to

dense overlying breast tissue.

Estrogen replacement therapy (ERT) obscures mammogram results. According to a study of

8,800 postmenopausal women aged 50 and older, the use of ERT leads to a 71% increased

chance of receiving a false positive from a mammogram. It was also found that women on ERT

were more likely to get more false-negative readings.

Safer methods of breast cancer screening is needed, and some technologies are becoming

available, however more studies are needed to enable these technologies as a screening tests.

ADVANTAGES OF OUR NOVEL APPROAC H:

Our Innovation enables several advantages for the patient, for radiologists and for clinics:

We have demonstrated very high sensitivity. This low cost CEDM technology has an excellent

growth potential that will benefit to any decision support systems relying on it.

Using an "online" learning approach, the performances will benefit from the increasing number of

processed cases over time.

The technology is easily applied to the characterization of MRI lesions.

The technology developed in this project is purely software based and therefore "vendor

agnostic". Alternatively, the software can be integrated to existing CEDM systems in

collaboration with the vendor.

The developed technology can be applied to other breast imaging techniques such as MRI that

would also benefit from the contextual patient information in obtaining a higher diagnostic

confidence and potentially reduce the amount of unnecessary biopsies.

The developed technology may be applied to other organs where contrast enhancement MRI is

performed for the detection of malignant lesions such as the prostate.

THE MARKET

Breast Imaging Market worth 4.14 Billion USD by 2021 at a CAGR of 8.5% from 2016 to 2021.

Based on type, the global breast imaging market is segmented into ionizing breast imaging

technologies and non-ionizing breast imaging technologies. The ionizing breast imaging

technologies segment is subsegmented into analog mammography, full-field digital

mammography (FFDM), 3D breast tomosynthesis, positron emission tomography/computed

tomography (PET/CT), molecular breast imaging/breast-specific gamma imaging (MBI/BSGI),

cone-beam computed tomography (CBCT), positron emission mammography (PEM), and

electric impedance tomography. The non-ionizing breast imaging technologies segment includes

breast MRI, breast ultrasound, optical imaging, automated whole-breast ultrasound (AWBU),

and breast thermography.

Growth in the breast imaging market is driven by factors such as the rising incidence of breast

cancer globally; growing government investments and funding for breast cancer treatment and

related research; increasing awareness about early detection of breast cancer; rising geriatric

population; technological advancements in breast imaging modalities; and launch of advanced

breast imaging systems capable of detecting cancer in women with dense breast tissues. In

addition, the growing demand for breast imaging in emerging Asian countries, and technological

advancements in breast cancer detection are expected to offer high growth opportunities for

market players. However, factors such as high installation cost of breast imaging systems, side-

effects of radiation exposure, and errors in breast cancer screening and diagnosis are restricting

the growth of the global breast imaging market.

North America is estimated to be the largest regional segment in the global breast imaging

market in 2016, followed by Europe. However, the Asia-Pacific market is expected to grow at

the highest CAGR of 9.5% from 2016 to 2021. A number of factors, such as the growing patient

population, increasing healthcare expenditure, improving healthcare infrastructure, growing

government spending on breast cancer research studies, and implementation of several initiatives

to create awareness about the early detection of breast cancer are expected to drive the market in

the Asia-Pacific region.

Hologic, Inc. (U.S.), GE Healthcare (U.K.), Siemens Healthcare (Germany), Philips Healthcare

(Netherlands), Fujifilm Holdings Corporation (Japan), Gamma Medica, Inc. (U.S.), Toshiba

Corporation (Japan), Sonocine, Inc. (U.S.), Aurora Imaging Technology, Inc. (U.S.),

Technologies, Inc. (U.S.) , and Toshiba are some of the key players operating in the global breast

imaging market.

FUTURE OUTLOOK

Breast cancer is identified by the WHO as the leading cause of cancer in women.

According to the estimates of WHO (World Health Organization), approximately 1.5 million

cases of breast cancer were diagnosed in 2010 and this number is expected to double by 2030.

Such rapidly rising incidence rates of breast cancer will serve the global mammography

equipment market as a significant growth rendering driver.

The history of breast imaging continues to evolve with the introduction of new applications, such

as computed tomography, breast-specific gamma imaging, and positron emission mammography.

However, the higher radiation doses associated with these new technologies deserves close

attention as the relative benefits and risks of these modalities are evaluated in the clinical setting.

The 3D mammography equipment is identified as the fastest growing market. Better image

clarity aiding in accurate diagnosis and the implementation of PACS (Picture Archiving and

Communication Systems) eliminating costs associated with the usage and storage of X-ray fimls

are some of the factors attributing to its high growth rates.

North America is expected to dominate the market throughout the forecast period. The presence

of sophisticated reimbursement frameworks and high patient awareness levels account for the

aforementioned conclusion. The European mammography equipment market follows North

America in terms of market share on account of the presence of high breast cancer prevalence in

countries such as Belgium, Denmark and France coupled with high per capita healthcare

expenditures in this region.

IP STATUS- NEW APPLICATION , PENDING