Neoplasms

All Conditions

Wounds and Injuries

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Digestive System Diseases

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Liver Neoplasms

Kidney Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Hematinics

All Drugs and Chemicals

Herbal and Botanical

Liver Extracts

Cola

The RFA Loosely wound thermal coil electrode will be inserted directly or percutaneously into the lesion, depending on the imaging modality (US or CT guidance) and deployed with same method as previously described in the 'delayed group'. Energy will be delivered using the single timed heating cycle. Treatment will be monitored with B mode US. Once the cycle is completed, the probe will be removed and the planned surgery will continue with partial or radical nephrectomy.

Using an electrically insulated 12ga introducer with trocar is inserted percutaneously into the renal tumor. The needle tip will be placed 20mm from the center of the target. The trocar is removed and co-axially (i.e. within the introducer), a core biopsy of the lesion is performed with a 14-18 gauge needle. The radiofrequency applicator with a 14ga cannula containing the RFA Loosely wound thermal coil electrode is then optimally positioned and locked into the introducer. On approximately day 6-10, a partial or radical nephrectomy will be performed in the usual way.

This new device uses radiofrequency energy to destroy kidney or liver tumours. It is called radiofrequency ablation.

This type of energy is simply an alternating current that passes from a coil (electrode) into the tissue causing heating of the tissue in the vicinity of the electrode.

RFA Loosely wound thermal coil

Michael Jewett, M.D.

This is a clinical research study designed to determine the safety and efficacy of the application of a unique interstitial radio frequency thermal therapy for the treatment of large tumours in the kidney or liver. The novel device offers patients a more effective therapy than conventional RFA and for patients with large tumours fewer number of treatments and needle insertion sites. The clinical treatment volumes (or sites of focal tumours) will be determined by a combination of biopsy and contrast enhanced CT imaging.

The study will assess if novel device can produce lesions in the liver or kidney in a controlled and predictable manner and with sufficient size to effectively manage disease progression in the organ. The extent of lesion size at a delivered power setting and treatment time will be measured with post-treatment CT or MRI and biopsy as measures of tissue response

Our group has developed a novel, interstitial induction coil device that has been designed to coagulate large tumours (≥3cm) through a single needle insertion using heat in the range 55-90 ◦C. \[31\]Our system consists of a helical coil that is loosely wound inside the tumour tissue or phantom and excited with radiofrequency energy at 27.12 MHz. The coil is constructed from Nitinol, a shape memory alloy, to permit percutaneous deployment of the device from a cannulating delivery needle into the tumor target. This novel monopolar device has the potential to treat larger tumours with larger ablation zones (6cm x 4cm) with shorter treatment time, in both ex vivo and in vivo settings. In our previous pig studies our group has not seen a decrease in ablation volume compared to the ex vivo studies. The intent of this research proposal is to determine the safety and efficacy of the application of a unique interstitial coil electrode RF thermal therapy device for ablating large human renal and hepatic tumors under US or CT guidance.

2. Hypothesis

Interstitial thermal therapy in the form of RF energy delivered percutaneously under US or CT guidance with our newly developed novel coil electrode is a safe and effective method to ablate large renal and hepatic tumors. This is an alternative to immediate surgery or to surveillance with possible delayed treatment.

3. Objectives

3.1 To use the novel RF device and technique in liver tumor as developed in the porcine model to patients with heptacellular carcinoma by:

3.1.1 Establishing that RF electrodes can be accurately and safely placed in the desired location.

3.1.2 Establish the safety of energy application with the RF coil device including assessing effect on surrounding liver tissue.

3.1.3 Verifying that large (\>2cm) liver tumors are effectively ablated with RF energy.

3.2 To apply the novel RF device and technique in kidney tumor ablation as developed in the porcine model to patients with renal cell carcinoma by:

3.2.1 Establishing that RF electrodes can be accurately and safely placed in the desired location.

3.1.4 Establish the safety of energy application with the RF coil device including assessing effect on surrounding kidney tissue.

3.2.2 Verifying that large (RFA Loosely wound thermal coil2cm) kidney tumors are effectively ablated with RF energy.

4. Sample Size and Methods

4.1 RF ablation of renal tumor by:

4.1.1 Sample

Six patients with a large (large T1a and T1b N0 M0 RCC ,\> 2 cm in diameter), solid renal mass who are undergoing partial or radical nephrectomy deemed suitable for additional RFA will be eligible.

The patients will be evenly split between two groups, namely the 'acute' and 'delayed'. With the acute group, the study can meet its study objectives while minimizing the number of procedures and evaluate the safety of the device with the patient in an OR suite. However, it is difficult to predict tumor viability accurately based on cellular effects of the RF treatment when the lesion is excised immediately after. The purpose of a delayed group examines the full extent of histological thermal changes which do not occur until 6-7 days after the treatment. This group will also validate the feasibility of the device within the intended clinical setting of an interventional CT suite.

Patients who might be considered eligible for standard RFA or with irreversible coagulation defects, urinary tract infection and/or morbid obesity will be excluded.

Only patients eligible for surgery for tumour resection will be enrolled. Patients will not be randomised. The first 3 patients will go into the acute group (immediate arm). The reason for this is to have a controlled setting should an incidence arise. The patient will already be prepared for surgery, which will provide a more controlled environment, should there be a patient safety issue.

4.1.2 Methods (Delayed Group)

The patient is admitted in the morning to the Medical Surgical Day Unit at the Toronto General Hospital. Initial nursing assessment includes the documentation of vital signs and allergies, and obtaining intravenous access. The patient is transported to the Department of Medical Imaging, where care is provided by the Interventional Radiology team consisting of a Radiologist, Radiology Nurse, and Radiology Technologist. Informed consent and satisfactory blood work results (platelet count, INR, and PTT) are confirmed. Pre-treatment CBC and creatinine will be measured and a urinalysis will be performed. Intravenous sedation is given (midazolam, fentanyl, meperidine, and/or dimenhydrinate) during the continuous monitoring of the patient, which includes pulse oximetry and blood pressure readings.

The appropriate area is aseptically prepared and draped, and the procedure is performed under real-time US and CT guidance. Local anesthesia (e.g. 10 ml of 1% lidocaine) is administered via a 25 gauge needle.

To ensure surrounding structures are protected from thermal injury, a "hydro-dissection technique" may be applied which acts as a "thermal blanket" around the kidney proven to be safe, effective, reproducible and inexpensive.

Using an electrically insulated 12ga introducer with trocar is inserted percutaneously into the renal tumor. The needle tip will be placed 20mm from the center of the target. The trocar is removed and co-axially (i.e. within the introducer), a core biopsy of the lesion is performed with a 14-18 gauge needle. The radiofrequency applicator with a 14ga cannula containing the loosely wound coil electrode is then optimally positioned and locked into the introducer. Applicator is rotated to line up target with coil trajectory. Coil 'introducer pliers' are used to deliver the coil into the tissue. Four dispersive electrodes (grounding pads) are adhered on the thighs of the patient. The applicator is connected to the generator and grounding pads. Energy will be applied in a single heating cycle for 4-10 minutes at a power rating set between 125-200W based on manual feedback and size of target. Development of the thermal lesion will be monitored with real time B mode US. At the end of the procedure the coil electrode is retracted with aid of the 'rectractor pliers' and then applicator with introducer is removed.

US or CT imaging is used during and immediately after RF to ensure accuracy of the thermal lesion created and to exclude complications. After completion of the procedure, the patient is transported to the Medical Surgical Day Unit for observation, recovery, and further pain control as required. Immediate post-treatment CBC and serum creatinine levels will be measured. Urinalysis will be performed. The patient is discharged home accompanied by a relative or a friend approximately 4 hours after completion of the RF procedure.

A follow-up contrast-enhanced spiral CT scan will be performed on approximately post-treatment day 6-10 (prior to the surgery) to assess possible complications and to measure the size of the lesion and degree of enhancement. In addition, CBC, serum creatinine and urinalysis will be performed.

On approximately day 6-10, a partial or radical nephrectomy will be performed in the usual way. In the cases of partial nephrectomy, it is assumed that clear margins will be grossly visible around the tumors to aid in the resection through normal tissue.

The specimen will be sent to pathology where thermal lesion sizes will be measured by gross inspection. Histo-pathology using standard H\&E and NADH will establish the boundaries of the thermal lesion and detect any viable cells within this region. It will also establish the extent of coagulative necrosis in the normal surrounding kidney tissue. Further follow-up of the patient will continue as per standard protocol for RCC.

4.1.3 Methods (Acute Group)

In either the image guided therapy operating room (MPOR) or in the routine operating room at Toronto General Hospital the patient will be put under general anaesthesia.. A needle core biopsy will be taken from the lesion and sent to pathology for routine examination to ensure that an accurate diagnosis can be made if the subsequent thermal therapy alters the appearance of the tissue. A "hydro-dissection technique" is then applied to ensure surrounding structures are protected from thermal injury, which acts as a "thermal blanket" around the kidney.

The RF electrode will be inserted directly or percutaneously into the lesion, depending on the imaging modality (US or CT guidance) and deployed with same method as previously described in the 'delayed group'. Energy will be delivered using the single timed heating cycle. Treatment will be monitored with B mode US. Once the cycle is completed, the probe will be removed and the planned surgery will continue with partial or radical nephrectomy.

The specimen will be sent to pathology and processed as above.

For patients that have an ultrasound guided procedure, the RFA procedure will be done in the routine operating room in an open fashion, the kidney will be exposed surgically in the usual way in anticipation of the partial or radical nephrectomy. The kidney tumour will be located by gross inspection, palpation and with the aid of intraoperative US if required. In this case, the RFA probe will be inserted directly into the lesion. For those patients that have a CT guided procedure along with US, the procedure will be done in the MPOR and the RFA probe will be inserted percutaneously into the lesion, prior to opening and exposing the kidney. If the surgery is unable to be performed in the MPOR, the patient will transferred to a routine operating room, while under general anesthetic, to have their surgery. They will be accompanied by the anesthesiologist.

Thermal Ablation in Larger Liver and Kidney Tumours

Thermal Ablation With a Loosely Wound Helical Coil for Radiofrequency Treatment of Large Renal and Hepatic Tumors in Patients Undergoing Partial or Total Nephrectomy or Heptectomy

this will be assessed during the surgery and once the tumour is removed and examined

This will be assessed during the surgery and once the tumour is removed and examined

Once the tumour is removed, the ablation field can be fully examined.

University Health Network, Toronto

Symptoms and General Pathology

Hemorrhage

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Waterjet induced dissection of the liver during resection.Waterjet dissection device mechanically separates hepatic tissue from bile ducts and vessels, the latter two to be separately ligated.

CUSA transection of the liver. Ultrasound based destruction of the liver parenchyma to allow separate ligation of the bile duct and intrahepatic vessels.

Waterjet induced dissection

Ultrasound based destruction of the liver

CUSA induced dissection

Anders Jansson, MdPhd

Lars Lundell, Professor

Before liver transection patients are allocated to either waterjet or CUSA to divide the liver parenchyma.

Transection time, bloodloss, total operation time and postoperative complication rates are registered.

Waterjet Versus Ultrasound Dissection During Hepatic Transection

Peroperative bloodloss in ml during liver transection by use of either waterjet or CUSA.

Bengt Isaksson

Jansson, Anders, M.D.

Karolinska University Hospital

Professor

Heart and Blood Diseases

Ischemia

Reperfusion Injury

Hepatic Insufficiency

Liver Failure

Vascular Diseases

Postoperative Complications

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Anti-Infective Agents

Respiratory System Agents

Amino Acids

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Prednisolone

Glucocorticoids

Methylprednisolone

Acetylcysteine

N-monoacetylcystine

Cortisone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Hormones

Hormone Antagonists

Protective Agents

Antineoplastic Agents, Hormonal

Antiviral Agents

Expectorants

Antioxidants

Antidotes

Cysteine

Patients were randomized to this arm will receive a bolus of N-acetylcysteine in an hour of 150 mg/kg after the beginning of the operation. After the bolus will start a 6-hour infusion of 50mg/kg/h of N-acetylcysteine.

Patients were randomized to this arm will receive a bolus of methylprednisolone in an hour of 500 mg after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).

Patients were randomized to this arm will receive placebo (Ringer's acetate) in an hour after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).

Methylprednisolone is a glucocorticoid, which is an adrenocortical steroid. The chemical name for methylprednisolone is pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6-methyl-, (6α,11β)-and the molecular weight is 374.48. It is an analog of naturally occurring glucocorticoid (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Methylprednisolone is used for their potent anti-inflammatory effects in disorders of many organ systems, it modify the body's immune responses to diverse stimuli. The usual dosage of medication varies in relation to pathology for which is prescribed: normally varies from about 40-60 mg per day up to very high doses of 30 mg/kg bolus as used in spinal cord injury.

Acetylcysteine is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine. Chemically, it is N-acetyl-L-cysteine. The compound is a white crystalline powder which melts at 104°-110°C and has a very slight odor. Acetylcysteine may form cysteine, disulfides, and conjugates in vivo (N, N'-diacetylcysteine, N-acetylcysteine- cysteine, N-acetylcysteine-glutathione, N-acetylcysteine-protein, etc). No metabolites were identified. Acetylcysteine likely protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.

N-acetylcysteine

Guido Torzilli, PhD

Giovanni Bordone, PhD

This is a prospective double-blind randomized phase II clinical trial, with two groups of intervention (one with administration of N-acetylcysteine and the other with administration of methylprednisolone), and one group of placebo. The purpose of this study is to investigate the role of N-acetylcysteine and Methylprednisolone in the modulation of warm ischemia of the liver during hepatic resection. In fact to avoid massive blood loss in liver surgery, continuous or intermittent vascular clamping of the hepatic hilum ('Pringle maneuver') is generally used with good results. However, as a consequence, ischemia and subsequent reperfusion result in complex metabolic, immunological, and microvascular changes, which together might contribute to hepatocellular damage and dysfunction. This phenomenon, known as ischemia-reperfusion (IR) injury of the liver, is a complex multi-path process leading to the activation of some inflammatory pathways. Any patient candidate to liver resection will be enrolled in the study based on the aforementioned criteria. The primary objective of the study is to assess the real efficacy of Methylprednisolone and N-acetylcysteine in reducing the secondary damage from ischemia reperfusion injury in liver resection and in reducing inflammatory response. Secondary objective of the study is whether the reduction of ischemia-reperfusion injury results in: lower incidence of postoperative liver failure, improvement of postoperative liver function, and reduction of blood components transfusions. The randomization will be done the day before the operation. The drugs will be prepared in a blind fashion by the hospital pharmacy. The hospital pharmacy will provide to each patient a drip to make bolus of about an hour before the start of the liver resection and a syringe pump for an infusion of approximately 6 hours. If the patient is enrolled and randomized in the placebo arm, he/she will receive 250 ml of glucose 5% plus the infusion of 100 ml of glucose 5% If the patient is randomized in the Methylprednisolone arm, he/she will receive a dose of 500 mg in 250 ml of glucose 5% plus 100 mg of glucose 5%. If the patient is randomized in the N-acetylcysteine arm, he/she will receive a dose of 150 mg/kg in 250 ml of glucose 5% plus N-acetylcysteine 50 mg/kg in 100 ml glucose 5%. Systematic sampling of liver function tests will be done the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7.

Elective liver resection is performed mainly for benign and malignant liver tumors. The malignant tumors may arise primarily within the liver (hepatocellular carcinoma and cholangiocarcinoma) or represent metastases from malignancies of other organs. During hepatic resection, the risk of severe intraoperative bleeding represents a major risk. To avoid massive blood loss, continuous or intermittent vascular clamping of the hepatic artery and portal vein ('Pringle maneuver') is an efficient method to reduce hemorrhage. However, as a consequence, ischemia and subsequent reperfusion result in complex metabolic, immunological, and microvascular changes, which together might contribute to hepatocellular damage and dysfunction. This phenomenon, known as ischemia-reperfusion (IR) injury of the liver, is a complex multi-path process leading to the activation of inflammatory pathways, in which cellular injury results from events occurring during both the ischemic and reperfusion phases. The key mechanism of tissue injury is the intense and excessive inflammatory response to reperfusion. Although initially considered a condition mediated by innate immune responses, IR injury also triggers adaptive immunity, such as activated Kupffer cells that express cytokines and chemokines thereby leading to further neutrophils activation and recruitment. Neutrophils inflict tissue damage on the liver through the generation of some reactive oxygen-species (ROS) and of some proteolytic enzymes. Various methods and many pharmacological agents have been attempted to decrease the IR injury associated with prolonged duration of vascular occlusion, no one is a standard of care in protocols for liver resection. After a tough review of the literature we considered the most promising data on two drugs: N-acetylcysteine (NAC) and Methylprednisolone (MET). NAC seems more active in ischemic phase and in the early reperfusion period. In fact when blood flow is interrupted cellular adenosine triphosphate (ATP) is depleted and there is a buildup of adenosine monophosphate, which is catabolized to hypoxanthine that is oxidized to xanthine by the enzyme xanthine oxidase, generating ROS in the process. Glutathione (GSH), that is an antioxidant present in the liver, offers protection against oxygen free radicals. During hypoxia, GSH stores are consumed, which predisposes to oxidative injury. N-acetylcysteine (NAC) serves as a precursor to GSH and can replenish intracellular GSH stores, it directly scavenge hydrogen peroxide. It has also been shown to impair the chemo taxis and generation of oxygen radicals by human phagocytic cells through an anti-inflammatory action, inhibit cytokine-mediated induction of nitric oxide synthase in human hepatocytes in vitro and have probably an anti-inflammatory mechanism of hepatoprotection against oxidative injury from nitric oxide (NO). So there is a substantial body of experimental work evaluating the role of NAC in liver I/R injury, but these studies are small in terms of patients, and more importantly they utilize a widely disparate range of protocols of administration. Yet, there is only one small study describing the outcome of a randomized controlled trial in patients undergoing liver resection. Thus, we decide, after the 'a priori' sample power calculation, to investigate the effect of NAC in patients submitted to hepatic resection systematically performed with the 'Pringle maneuver' using the same loading dose and subsequent infusion of some Randomized Clinical Trial in liver transplantation. Together with NAC we decide to investigate the effects of MET, which is a glucocorticoid steroid that acts as an anti-inflammatory agent, reducing inflammatory markers and apoptotic cell count in experimental liver IR injury. To our knowledge, there are only three published studies that evaluated the role of MET in liver resection, but only one of those was associated to a significant decrease of transaminase enzymes (AST and ALT). The basic hypothesis is that the protective effects of Methylprednisolone may become more apparent as the extent of liver resection and/or the duration of vascular occlusion increases. Therefore, the investigators designed a randomized controlled trial with adequate sample size with the aim to recognize in the intervention groups, one with NAC and one with MET, a statistically significant reduction of ALT and AST (100U/L) compared with the placebo group. No stratifications are planned. Two comparisons are planned Experimental (MET+NAC) vs. Standard and MET vs. NAC. A randomization ratio MET:NAC:STD=1:1:1 is planned; for the Experimental (EXP) Vs Standard (STD) comparison the allocation ratio is therefore 2:1. In order to verify the superiority of EXP (MET+NAC) it was assumed that with the standard treatment the mean value of ALT was 800 units with a standard deviation (SD) of 100, as reported in literature. the investigators decided to consider of interest a reduction of 100 for the experimental treatments leading to consider a value of 700 as desirable. Considering α value of 0.025 (one-sided) and a power of 90%, a total of 48 evaluable patients are required (16 in each arm). If the test results in a statistical significant advantage for EXP arms (MET+NAC), the study will continue the accrual for MET and NAC only, with the aim of comparing MET vs. NAC, considering a difference of interest of 50 units, with α value of 0.05 (two-sided) and a power of 80%. Further 94 Pts need to be enrolled for a total of 126 evaluable patients available for the comparison of MET vs. NAC. The total sample size will be 142 (63 treated with MET, 63 treated with NAC and 16 treated with standard therapy).

Methylprednisolone N Acetylcysteine in Hepatic Resections

Phase II Randomized Double Blind Trial of Methylprednisolone and N-acetylcysteine in Hepatic Resections.

The primary endpoint of the study is the modulation of the IR injury made by NAC and/or MET in patients undergoing liver surgery. For this purpose a decrease of 100 UI/L of AST and ALT is expected compared with placebo.

This secondary endpoint want to assess difference in total bilirubin expression between the intervention groups and the placebo group.

This secondary endpoint want to assess difference in blood transfusion between the intervention groups and the placebo group.

Istituto Clinico Humanitas

Neoplasm Metastasis

Central Nervous System Depressants

Anesthetics

Doxorubicin

Liposomal doxorubicin

Anesthetics, General

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

All participants in Part I received:

Pre-LTLD Biopsy of Target Liver Tumour ThermoDox® (LTLD) Post-LTLD Biopsy of Target Liver Tumour Focused Ultrasound of Target Liver Tumour Thermometry of Target Tumour Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver Tumour

Part I of the study was designed to identify optimal focused ultrasound (FUS) exposure parameters for a range of tumour locations within the liver, using real-time thermometry data from an implanted thermometry device (a thermistor or thermocouple). Plasma and biopsy samples of the target liver tumour were taken pre-LTLD, post-LTLD and post-LTLD+FUS.

All participants in Part II received:

ThermoDox® (LTLD) Focused Ultrasound of Target Liver Tumour Post-LTLD Biopsy of Target Liver Tumour

Following a minimum of 5 Part I cases, and subject to Trial Management Group approval, Part II of the study was opened to run in parallel to Part I. Part II did not require implantation of a thermometry device, and instead used predictions from Part I data to set the FUS parameters. Targeted drug delivery in Part II thus proceeded completely non-invasively, and this part of the study was designed to more closely reflect how the therapy might be implemented in routine clinical practice. Plasma samples were taken pre-LTLD, post-LTLD and post-LTLD+FUS. Biopsy samples of the target liver tumour were taken only post-LTLD+FUS.

ThermoDox® (LTLD) infusion at a dose of 50mg/m2 whilst under general anaesthetic during intervention (Day 1)

ThermoDox® (LTLD)

Whilst the ThermoDox® was circulating in the blood stream, the JC200 Therapeutic Ultrasound device was used to induce mild hyperthermia in a single (region of) a target liver tumour.

Focused Ultrasound of Target Liver Tumour

Pre-LTLD Biopsy of Target Liver Tumour

Post-LTLD Biopsy of Target Liver Tumour

Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver Tumour

A clinically approved thermistor or thermocouple was placed in the target liver tumour for real-time thermometry.

Thermometry of Target Tumour

Mark R Middleton, PhD, FRCP

This proof of concept study proposes targeted delivery of a broad-spectrum cytotoxic agent (doxorubicin), via a specially formulated LTSL (ThermoDox®) activated by mild hyperthermia, by using focused ultrasound (FUS), to achieve enhanced intra-tumoural doxorubicin concentrations for the same systemic dose.

Adult patients with incurable confirmed hepatic primary or secondary tumours received a single cycle of LTLD, followed by ultrasound-mediated hyperthermia to a single target liver tumour. The primary endpoint relates to evidencing enhanced delivery of doxorubicin from LTLD at the target tumour site, by comparing intratumoural concentrations of the drug before and after focused ultrasound (FUS) exposure.

To date, purely pharmacological approaches have failed to address what is essentially a threefold challenge: (i) to deliver therapeutically significant concentrations of active agents to the tumour vasculature while minimizing off target effects; (ii) to release the therapeutic agent 'on-demand' at the target site; and, (iii) to improve the distribution and spread of the therapeutic agent against the intra-tumoural pressure gradient in order to achieve a therapeutically relevant concentration throughout the tumour.

Recent pre-clinical studies performed at Oxford using ThermoDox® released using FUS has shown that increased uptake at the target site is achievable. Hence there is great promise in using this combination therapy to achieve increased tumour uptake and local dose for the equivalent dose of doxorubicin used in systemic chemotherapy for human subjects, which has a well established and safe toxicity profile. The first extracorporeal FUS device in Europe was used for a study performed at Oxford between 2002 and 2004.

This single centre trial was sponsored by the University of Oxford. The recruiting study site was Oxford University Hospitals NHS Trust, where there is extensive clinical FUS experience.

The study is split into two parts. Part I identified optimal FUS exposure parameters for a range of patient BMIs and tumour locations within the liver using real time thermometry data from an implanted thermistor. After at least 5 and no more than 14 participants have had the intervention using real-time thermometry, data was reviewed by the Trial Management Group (TMG) to confirm readiness to proceed without real-time thermometry. Part II, which did not require thermistor implantation, is designed to reflect how the therapy would be implemented in clinical practice.

Participants received treatment for 1 day and are followed up for 30 days. All evaluable participants from both Part I and Part II were included in the endpoint analysis. Doxorubicin concentrations were directly determined from tissue biopsies of the target tumour, using a Good Laboratory Practice-validated high performance liquid chromatography (HPLC) assay, based on previously published methods.

If this study demonstrates successful targeted drug delivery in human subjects using LTSLs released by mild-hyperthermia, this could potentially transform the future of chemotherapy in clinical practice; targeted therapy using LTSLs containing other chemotherapeutic agents triggered non-invasively by mild hyperthermia could be applied to any solid organ cancer.

Parts I and II of the study were not randomised, and both Parts of the study are detailed further in the published protocol summary, detailed in References section. After a minimum of 5 patients were treated in Part 1 (Arm 1), Part 2 (Arm 2) of the study could be opened.

Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours

A Proof of Concept Study to Investigate the Feasibility of Targeted Release of Doxorubicin From Lyso-thermosensitive Liposomal (LTSL) Doxorubicin (ThermoDox®) Using Focused Ultrasound in Patients With Primary or Secondary Liver Tumours

Key patient data with tumour characteristics is available in the Lancet Oncology clinical paper (https://doi.org/10.1016/S1470-2045(18)30332-2).

Analytical chemistry (High Performance Liquid Chromatography) for total doxorubicin (including both released and unreleased forms) was performed on section of intratumoral biopsy samples in Good Clinical Practice Laboratory, using a validated assay.

Doxorubicin concentration was evaluated in biopsy samples both post-LTLD and post-LTLD+FUS.

Tumour samples were not analysed same day and were frozen at -80\^oC for subsequent analysis. Required to evaluate the primary endpoint.

To satisfy the primary endpoint, a demonstrable two-fold increase in\*, or value exceeding 10μg/g of, the concentration of intra-tumoural doxorubicin at the treated tumour site following FUS-induced mild hyperthermia, was required in at least 50% of evaluable participants.

\* As per the a priori protocol design, in Part II the biopsy prior to FUS-induced mild hyperthermia is not performed and therefore the average value for all evaluable tumours receiving intervention in Part I is used as a comparison for the two-fold increase from pre-FUS to post-FUS biopsy.

Achievement of hyperthermia in the target liver tumour, as determined by real-time thermometry obtained by an indwelling thermometry device.

For success, sustained and controlled hyperthermia is required in the target tumour, consequent with drug release (in excess of 39.5\^oC). Real time thermometry plots for each Part I patient are available in the key Lancet Oncology publication, details available in the References section.

Post-LTLD+FUS tissue from the targeted liver tumours was obtained by biopsy at the time of the intervention, between 24/03/2015 and 29/03/2017. Cytokeratin-8 (CK-8) is a cell viability marker which if present, demonstrates lack of ablative cell death by any ablative modality, including FUS.

Not all histological cell types express CK8, thus if the Post-LTLD+FUS it may either indicate:

i) Non-CK8 expression ii) Thermal ablation and consequent cell death.

Note there was uncertainty about CK8 expression of individual patient tumours prior to recruitment. In this study if the Post-LTLD+FUS tissue shows specific cellular CK8 cellular staining, then it demonstrates that i) the tumour is CK8+, and, ii) the tumour was not instantaneously thermally ablated and any subsequent cell death is likely due to drug delivery/chemo-ablation.

For more information see key TARDOX Lancet Oncology publication and Cytokeratin 8 reference (both detailed in References section).

Adverse Events are listed separately in the subsequent results, but were also specified as a secondary endpoint in the a priori protocol and thus significant events are summarised here.

'Definitely' or 'Probably' related events are included.

Oxford University Hospitals NHS Trust

Imunon

University of Oxford

Part I (Patients Enrolled Between March 2015-April 2017)

Part II (Patients Enrolled Between June 2016-Feb 2017)

Part I

Part II

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

United Kingdom

Region of Enrollment

Body Mass Index

Key Lancet Oncology paper (detailed in References section) addresses these limitations:

1. Laboratory limitations not detailed e.g. under/over estimates
2. Tertiary endpoints not presented

Sarah Pearson, Trial Management Director

A paired t-test was used for Part I (Arm 1) only. Analysis only applies to Part I (Arm 1) because only this study arm has matched Post-LTLD (i.e. post-drug alone) and Post-LTLD+FUS biopsy samples obtained from the same liver tumours before and after targeted drug delivery. In Part II of the study design in which drug delivery occurred completely non-invasively, no Post-LTLD tissue sample is obtained and only a single tumour biopsy is obtained following drug delivery (Post-LTLD+FUS).

Pre-FUS Intratumoural Doxorubicin Concentration

Post-FUS Intratumoural Doxorubicin Concentration

Part I of the study was designed to identify optimal focused ultrasound (FUS) exposure parameters for a range of tumour locations within the liver, using real-time thermometry data from an implanted thermometry device (a thermistor or thermocouple). Patients in Part I receive a single cycle of Lyso-Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) intravenously, at a dose of of 50 mg/m2. After a minimum of five patients have received the Part I intervention with real-time thermometry, data was reviewed by the Trial Management Group (TMG) to confirm readiness to proceed without real-time thermometry in Part II of the study. Plasma and biopsy samples of the target liver tumour were taken pre-LTLD, post-LTLD and post-LTLD+FUS.

Parts I and II of the study were not randomised, and both Parts of the study are detailed further in the published protocol summary (https://doi.org/10.1186/s40349-017-0104-0).

Following a minimum of 5 Part I cases, and subject to Trial Management Group approval, Part II of the study was opened to run in parallel to Part I. Part II did not require implantation of a thermometry device, and instead used predictions from Part I data to set the FUS parameters. Targeted drug delivery in Part II thus proceeded completely non-invasively, and this part of the study was designed to more closely reflect how the therapy might be implemented in routine clinical practice.

Plasma samples were taken pre-LTLD, post-LTLD and post-LTLD+FUS. Biopsy samples of the target liver tumour were taken only post-LTLD+FUS. Parts I and II of the study are not randomised, and both Parts of the study are detailed further in the published protocol summary (https://doi.org/10.1186/s40349-017-0104-0).

Concentration of Total Intratumoral Doxorubicin in Liver Tumour (Biopsies) Following Targeted Release of Doxorubicin From ThermoDox® ('Drug') Using Mild Hyperthermia Generated Non-invasively by Focused Ultrasound (FUS)

Patients Demonstrating >Two-fold Increase in the Amount of Intratumoural Doxorubicin Before and After Focused Ultrasound

Part I (July 2014-July 2017)

Part II (May 2016-July 2017)

In Part II there was no real-time thermometry and this endpoint only applies to Part I patients.

(Part I Only) Achievement of Satisfactory Hyperthermia Within the Target Liver Tumour for a Range of Participant Body Mass Indices (BMIs) and Tumour Locations Within the Liver (Optimal FUS Exposure Parameters)

5/6 Part I patients and 4/4 Part II patients had tissue which was analysable for CK-8. The Outcome Measure Data Table demonstrates the number of patients from each arm having CK-8 positive tumour biopsy samples post-LTLD+FUS, indicating lack of thermal ablation (which is consistent with desired hyperthermia rather than undesirable FUS ablation).

Persistence of Cell Viability Stain Post-LTLD+FUS

Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to ThermoDox (LTLD)

Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to FUS Procedure

Part I of the study was designed to identify optimal focused ultrasound (FUS) exposure parameters for a range of tumour locations within the liver, using real-time thermometry data from an implanted thermometry device (a thermistor or thermocouple). Patients in Part I receive a single cycle of Lyso- Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) intravenously, at a dose of of 50 mg/m2. After a minimum of five patients have received the Part I intervention with real-time thermometry, data was reviewed by the Trial Management Group (TMG) to confirm readiness to proceed without real-time thermometry in Part II of the study. Plasma and biopsy samples of the target liver tumour were taken pre-LTLD, post-LTLD and post- LTLD+FUS.

Parts I and II of the study were not randomised, and both Parts of the study are detailed further in the published protocol summary (https://doi.org/10.1186/s40349-017-0104-0).

Following a minimum of 5 Part I cases, and subject to Trial Management Group approval, Part II of the study was opened to run in parallel to Part I. Part II did not require implantation of a thermometry device, and instead used predictions from Part I data to set the FUS parameters. Targeted drug delivery in Part II thus proceeded completely non-invasively, and this part of the study was designed to more closely reflect how the therapy might be implemented in routine clinical practice.

Plasma samples were taken pre-LTLD, post-LTLD and post-LTLD+FUS. Biopsy samples of the target liver tumour were taken only post-LTLD+FUS.

Parts I and II of the study are not randomised, and both Parts of the study are detailed further in the published protocol summary (https://doi.org/10.1186/s40349-017-0104-0).

Overall Study

Biopsy system that enables real-time bioimpedance measurement from the tip of the biopsy needle.

BIP Biopsy system is essentially similar as traditional biopsy systems but it enables real-time bioimpedance measurement from the tip of the biopsy needle.

BIP Biopsy System

Kirsti Numminen, PhD MD

This clinical device investigation is conducted by performing liver biopsies using the BIP - Biopsy Tool. The aim is to assess the feasibility of bioimpedance spectroscopy based biopsy tool guidance method and test how well BIP biopsy system is able to distinguish liver tumours from surrounding tissue. In addition, user feedback is obtained to improve the usability of the investigational device. The study does not affect the traditional treatment procedure and only the patients in clinical need for diagnosis by liver biopsy are included on voluntary basis. The invasive products used in actual biopsy operation are designed so that their performance is essentially equal to the currently used biopsy devices, the only difference is the measurement capability of biopsy needle and connection to measurement device.

Identification of Liver Tumours Using BIP - Biopsy System

INJ-LIVERB-01 Identification of Liver Tumours Using BIP - Biopsy System

Liver biopsy is performed in traditional way but with biopsy needle that enables bioimpedance measurement from multiple frequencies (spectrum). Tumorous and nontumorous tissue is measured during ultrasound guided biopsy procedure and the tumorous tissue type is verified by histological biopsy sample analysis. The bioimpedance spectra (impedance and phase angle) are compared with each other and differences in means of the spectra calculated. The data analysis is performed offline.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Thermal Ablation in Larger Liver and Kidney Tumours	NCT01720706	Liver and Kidne...	RFA Loosely wou...	18 Years -	University Health Network, Toronto
Waterjet Versus Ultrasound Dissection During Hepatic Transection	NCT02041065	Liver Tumour	Waterjet induce... CUSA induced di...	18 Years -	Karolinska University Hospital
Methylprednisolone N Acetylcysteine in Hepatic Resections	NCT01726465	Ischemic Reperf... Insufficiency; ... Liver Tumour	Methylprednisol... N-acetylcystein...	18 Years - 70 Years	Istituto Clinico Humanitas
Thermal Ablation in Larger Liver and Kidney Tumours	NCT01720706	Liver and Kidne...	RFA Loosely wou...	18 Years -	University Health Network, Toronto
Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours	NCT02181075	Liver Tumour	ThermoDox® (LTL... Focused Ultraso... Pre-LTLD Biopsy... Post-LTLD Biops... Post-LTLD+FUS (... Thermometry of ...	18 Years -	University of Oxford
Identification of Liver Tumours Using BIP - Biopsy System	NCT02620228	Liver Biopsy	BIP Biopsy Syst...	18 Years -	Injeq Ltd

Spots Global Cancer Trial Database for liver tumour

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