Digestive System Diseases

Symptoms and General Pathology

All Conditions

Neoplasms

Liver Cirrhosis

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Hematinics

All Drugs and Chemicals

Liver Extracts

Preoperative flow and MRI + intraoperative measures of flow and pressures

partial hepatectomy by laparotomy on healthy or pathologic parenchyma.

Golse Nicolas, M.D

Vibert Eric, M.D

Despite the medical and surgical progress of the last two decades, the selection of candidates for liver surgery remains based on old principles and insufficiently sensitive to fine-tune the gesture to patient-specific characteristics and make almost zero risks of postoperative liver failure (PLF) and death. It is therefore necessary to develop new tools that will make possible to predict the evolution of the postoperative portocaval gradient (difference of pressure between portal vein and vena cava), a well-known major risk factor for PLF. Hemodynamic modeling of the human liver during surgery will represent the purpose of this work in order to help the clinicians in their patient's selection and anticipation of postoperative risk.

Introduction:

Surgical management of liver cancers is increasingly complex, with often extensive and iterative resections on pathological liver. This attitude is made possible by good selection and perioperative management of patients, as well as the regenerative capacity of the liver. However, even if extensive resections are routinely performed, the limit remains the risk of postoperative liver failure (PLF), especially in patients with chronic liver disease. Despite many known risk factors, some of which being preventable, PLF and / or postoperative decompensation (ascites) remain common complications (incidence \> 5%) and PLF is one of the leading causes of postoperative death.

The difficulty lies in the choice of a treatment adapted to the oncological needs, with the balance between what is technically feasible and what will be functionally and metabolically tolerated. This balance is based on a surgical evaluation, based on objective factors (liver volumetry and biological tests for example) and on the surgeon's experience. This estimate is imperfect, the proof being the mortality at 3 months after hepatectomy which remains high, 5 to 7%. Moreover, the current criteria lead to an often-inappropriate selection. It therefore remains very difficult for a given patient (particularly cirrhotic) to accurately predict the risk of postoperative decompensation and some patients may sometimes be undertreated for fear of decompensation. In these patients, it is therefore a loss of chance.

It would be obviously possible to further improve these results and numerical tools must find their place in the medico-surgical algorithm. The investigators think that hemodynamic simulation could be used as a decision-making tool.

After hepatectomy, the post-resection portocaval gradient is one of the most relevant reflections for understanding the hemodynamic conditions of a liver and the risk of PLF but it is only available intraoperatively, after completion of the surgical procedure, and is therefore not used as a tool for selecting candidates for surgery. Moreover, for a given patient, it is not currently possible to anticipate the variation of portocaval gradient and therefore the risk of occurrence of PLF.

The hypothesis based on experimental results in animals, consists in proposing a model of intrahepatic and systemic hemodynamics pre / postoperative scale 0D, that is to say in the form of simplified electrical circuit. The investigators can thus predict the evolution of the portocaval gradient in order to better select patients who are candidates for liver resection.

Description of Acts and Proceedings Added by Research To perform 0D modeling on human data to predict evolution of post-resection hepatic/systemic flows and pressures.

* Intraoperative flow measurement: installation of a certified CE marked (93/42EEC) and certified ISO9001 / EN46001 sensor around the portal vein and / or the hepatic artery during the procedure in order to estimate blood flow. Acquisition time: 5 min / patient / measurement (1 pre-resection measurement, 1 post-resection measurement). No injection or vascular puncture will be necessary for this acquisition. The risk of trauma is almost zero (no reported cases). The probe will be sterilized between two patients.
* MRI flow: addition of a specific acquisition sequence performed during a "standard" MRI indicated in the preoperative assessment. No intravascular injection required, no irradiation (magnetic field only). Acquisition time: about 5 minutes. MRI performed in routine (unless contraindicated) to all patients operated for a hepatectomy for positive assessment (tumor characterization) and tumor extension.

Potential Benefits There is no individual benefit because no clinical decision will be made during this study on the findings of the specific examinations carried out. In addition, 0D simulations will be performed after surgery, retrospectively.

On the other hand, there is a collective benefit expected from a positive study because the surgeons will then have additional tools to develop their decisional algorithm and adapt their technical gesture. Benefits = avoid cases of PLF, limit the risk of postoperative death.

The foreseeable risks for patients are considered minimal because:

* Flow measurement is a routine procedure for some teams, with no reported risk since a simple probe / vessel contact is required. No vascular puncture or possible trauma. Constraint: additional anesthesia duration = 5 min / measurement
* The flow MRI has no specific risk since it is simply an "extra" acquisition sequence, performed following the other sequences, without injection of contrast medium. Constraint = MRI duration extended by approximately 5 minutes.
* The extension of the anesthesia, due to the measurement of the flow measurement, is considered as risk-free by our team of anesthesiologists because it is about surgical operations lasting usually\> 6 hours, with a cardio-vascular monitoring and systematic neurological. No specific anesthetic drugs will be administered in addition to the usual operative / anesthetic practice.

Experimental plan Prognostic and prospective research (prediction of the occurrence of a potentially lethal risk for the patient).

This study will be non-comparative and uncontrolled because at the actual stage of development, The investigators only want to apply and transpose to the human digital tools of decision support (pilot study).

Description of the statistical methods planned.

Calculation of the number of subjects needed:

This study is comparable to a phase II study. In order to evaluate the predictive reliability of the portocaval gradient, it is necessary to proceed according to a Simon mini max design in two stages. The feasibility hypotheses are p0 = 70%, p1 = 90%, risk α = 5%, power = 90%. In the first stage, 18 patients will be included and analyzed. If the reliability (portocaval gradient predicted with a margin of error +/- 4 mmHg) is not objectified in at least 13 patients, the recruitment will be stopped and The investigators will rework the algorithm in depth, for example by modifying the input data (= clinical-biological parameters introduced in the model). The investigators will test the new version of the model on the same 18 first patients until validation in at least 13 patients.

If ≥13 patients have a reliable prediction, then 14 additional patients will be recruited. The total number will be 32 patients. To be considered potentially interesting, at least 26 patients will have to have a reliable prediction at +/- 4 mmHg ".

All statistical analyzes will be performed with STATA version 15.1 software (StataCorp LLC, TX, USA). A statistical analysis plan will be drafted and finalized before closure of the study that is to say the freezing of the base. The Statistical Analysis Plan will provide all detailed analyzes of the primary and secondary endpoints.

All statistical tests will be bilateral with a risk of the first species at 5%.

Raw analysis:

The raw analysis will be intent-to-treat analysis including recruited patients.

Methods planned for the analysis:

Main analysis:

Analysis of the primary endpoint will be made by intent to treat. The reliability analysis will be performed by a Chi 2 or Fisher exact test if the number is less than 5. No adjustment will be made.

Secondary analysis:

Secondary analyses will be performed in the intent-to-treat population. The binary criteria will be analyzed by a Chi 2 or Fisher exact test if the number is less than 5, the quantitative criteria by a paired t test.

Methods of analysis of missing data:

No analysis is planned for missing data Quantitative data will be expressed on average (+/- SD). A Mann-Whitney test will be used for continuous data and a Chi-2 (or Fisher if applicable) test for categorical data.

Liver Resection Modeling

Haemodynamic Modeling of Intrahepatic Blood Flow and Interaction With the Systemic Circulation

Institut National de Recherche en Informatique et en Automatique

Assistance Publique - Hôpitaux de Paris

Heart and Blood Diseases

Neoplasm Metastasis

Syndrome

Hypertension

Hypertension, Portal

preoperative flow MRI + intraoperative measures of flow and pressures + pre/intra/post-procedural ultrasonographic flowmetry

Partial hepatectomy (open approach)

liver transplantation

Portal vein embolization

GOLSE Nicolas, M.D

VIBERT Eric, M.D

Nicolas GOLSE, phD

" Despite the medical and surgical progress of the last two decades, the selection of candidates for liver surgery remains based on old principles and insufficiently sensitive to fine-tune the gesture to patient-specific characteristics and make almost zero risks of postoperative liver failure (PLF) and death. It is therefore necessary to develop new tools that will make possible to predict the evolution of the postoperative portocaval gradient (difference of pressure between portal vein and vena cava), a well-known major risk factor for PLF. Hemodynamic modeling of the human liver during surgery will represent the purpose of this work in order to help the clinicians in their patient's selection and anticipation of postoperative risk.

The aim is to develop and validate an hemodynamics mathematical model to predict the evolution of the portocaval gradient in three surgical situations of increasing complexity: portal modulation by embolization, hepatectomy, and small partial graft liver transplantation.

The endpoints will be the estimation of the intraoperative post-procedural portocaval gradient and comparison of the estimated portocaval gradient with that measured at the end of the procedure. This pressure differential is performed before parietal closure, after surgery. "

"The surgical management of liver cancer is becoming increasingly complex, with resections often extensive, iterative and on pathological liver (cirrhosis or multi-chemotherapies). This attitude is made possible by a better selection and perioperative management of patients, as well as by the regenerative capacity of the liver. However, even if extensive resections are routinely performed, the limitation remains the risk of postoperative liver failure (PLF), especially in patients with chronic liver disease. Despite numerous known risk factors, some of which are avoidable, PLF and/or postoperative liver decompensation (ascites) remain frequent complications (incidence \> 5%) and PLF remains one of the main causes of postoperative death.

The difficulty lies finally in the choice of a treatment adapted to the carcinological needs, with the balance between what is technically feasible and what will be tolerated on the functional and metabolic level. This balance is founded on a surgical evaluation based on objective elements (volumetry and biological tests in particular) and on the surgeon's experience. This estimate is imperfect, the proof being the mortality at 3 months after hepatectomies which is still high, 5 to 7% if considering all types of hepatectomies. It is obviously possible to further improve these results and the computer tool must find its place in the medical-surgical algorithm. It is already known that virtual (preoperative) 3D hepatic reconstructions are an important aid and lead to a decrease in postoperative morbidity and mortality but hemodynamic simulation could also be used as a decision-making tool.

After hepatectomy, the imperative to maintain a satisfactory liver function is to preserve a sufficient residual parenchymal volume associated with an intrahepatic blood supply (inflow) adapted to the volume of the liver and to the splanchnic flow, and a sufficient effluent (outflow) to avoid any intrahepatic congestion. The post-resection portocaval gradient is one of the most relevant reflections of the hemodynamic conditions of a liver and the risk of PLF but it is only available intraoperatively, after the surgical procedure has been performed, and therefore cannot be used as a tool for selecting candidates for surgery. Currently, there are several decision algorithms to guide the surgical management of a patient, based on preoperative clinical or biological data (platelets, bilirubin, indocyanine green clearance, ascites, esophageal varices...). The pre-resection portocaval gradient ≥10 mmHg, measured or estimated non-invasively, allows selection of high-risk patients, but remains not very sensitive and specific, and does not prevent the occurrence of any PLF.

It therefore remains very difficult for a given patient (especially cirrhotic) to accurately predict the risk of postoperative decompensation and some patients may sometimes be undertreated for fear of decompensation. In these patients, it is therefore a loss of chance.

In liver transplantation, the same need for adequacy between the vascular bed and the portal flow is necessary, especially in case of a small graft or partial liver. In case of mismatch, a small for size syndrome, i.e. portal hypertension (PHT) and organ failure (PLF equivalent) may occur, thus endangering the graft and the patient. As with partial hepatectomies, prediction of the post-transplant portocaval gradient would help avoid small-for-size syndrome by fine-tuning the maximum mass portal flow not to be exceeded. Thus, a better matching of the donor/recipient pair could be proposed, especially for living donor or auxiliary transplants.

Finally, portal embolization is a radiological procedure to prepare an organ for hepatectomy via atrophy on the embolized side and contralateral hypertrophy. Sometimes, especially in cirrhosis, portal embolization can be complicated by portal thrombosis, the main risk factor of which is the elevation of the portocaval gradient. Currently, there is no tool to anticipate this gradient and a 0D simulation would allow to avoid this risk by adjusting the embolized volume (seuential embolizations if needed).

In the end, and despite the medical-surgical progress of the last two decades, the selection of candidates for liver surgery remains based on old and insufficiently sensitive principles to finely adapt the procedure to the specific patient characteristics and minimize the postoperative risk. The aim of this study is to help surgeons in their decisions thanks to modern simulation tools that have never been tested in humains.

The proposed tool is a 0D model applied to liver surgery. It is based on ordinary differential equations: blood flows are represented by electric currents and blood pressures by electric voltages. It is called 0D because there is no space dimension in the equations.

Simulations and predictions will require:

* Collection of preoperative data (imaging, biology, clinical,...).
* Collection of intraoperative pre-procedural and post-procedural data: hemodynamic and biological measurements.
* Collection of postoperative data (immediate postoperative follow-up, current biology, anatomopathology).

These pre-procedure data are used to adjust the model for each patient. Once the model is ""calibrated"" to the real conditions, the simulation of the intervention can be performed to predict the post-procedural data, and compare them to the real measurements, as well as correlate them to the post-procedural events.

Scheme: in a first phase, use of preoperative and intraoperative data to improve the 0D model initially developed in animals and tested in a pilot study in humans. Depending on the final accuracy of the algorithm, a validation of the algorithm will then be performed in a second phase.

Expected benefits for the participants: no benefit because no modification of the medical-surgical management based on the measurements performed. All the simulations will be performed after the surgery, in a retrospective way.

Expected benefits for the society (future patients):

* Improved criteria for selecting organs or patients who are candidates for hepatectomy/transplantation/interventional radiology to minimize the risk of complications or death.
* Possible improvement of surgical techniques (vascular anastomoses and liver positioning).

Procedure:

All potentially eligible patients will be asked to participate in the study during a preoperative visit performed as part of the care. Eligible patients who have signed the consent form will have protocol procedures performed as part of their care, such as flow MRI and ultrasound-based hepatic and cardiac flowmetry.

Protocol procedures will also be performed intraoperatively at the beginning and end of the procedure (hepatectomy, TH or portal embolization). Patients with hepatectomy or TH will have the same follow-up as the care at D7 and D30 post-procedure with ultrasound, CT scan, biological work-up and consultation with the surgeon.

Patients with portal embolization will also have the protocol procedures at the time of hepatectomy which will take place 4 to 6 weeks after portal embolization. These patients will be followed up 1 month after hepatectomy, at D7 and D30 post hepatectomy.

Statistical analysis:

LSM is an exploratory predictive model development and feasibility study, with no a priori hypothesis to test; therefore, the number of subjects needed is based on feasible inclusions over 36 months at the participating center. The potential inclusion is 50 patients per year, or 150 patients over 3 years. The study has two phases: a development and improvement phase of the 0D algorithm and a validation phase. In the first phase, the algorithm is tested as it is developed on an increasingly large cohort. At each test of the algorithm, the concordance between the porto-cavity gradient (PCG) measured postoperatively and the simulated PCG is calculated using the intraclass correlation coefficient and the Bland \& Altman graph. The completion of the second phase depends on the results of the first phase.

These numbers are consistent with the recruitment center being a high-volume referral center.

Hepatic and Systemic Hemodynamic Modeling During Liver Surgery

The pressure differential is performed before the parietal closure, after resection. The simulation is accurate if the difference with the measurement is ≤ 3 mmHg.

Rare Diseases

Carcinoma

Cholangiocarcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Bile Duct Cancer

Amino Acids

Fluorides

Fluorodeoxyglucose F18

Radiopharmaceuticals

Protective Agents

Glutamic Acid

Patients undergo an 18F-FSPG PET scan within 4 weeks of surgery or OLT. Patients may also receive a second 18F-FSPG PET scan following standard-of-care treatment.

Patients may undergo either carbon-11 (11C)-Acetate PET or 18F-FDG PET scans within 4 weeks of surgery or OLT.

Fluorine F 18 L-glutamate Derivative 18F-FSPG

Carbon C 11 Acetate

Undergo 18F-FSPG, 11C-acetate, or 18F-FDG PET

Positron Emission Tomography

Laboratory Biomarker Analysis

Fluorine F 18 2-deoxy-2-(18F)fluoro-D-glucose

Lesley Flynt, MD

This clinical trial studies fluorine F 18 L-glutamate derivative BAY94-9392 (18F-FSPG) positron emission tomography (PET) in imaging patients with liver cancer before undergoing surgery or transplant. Diagnostic procedures, such as 18F-FSPG PET, may help find and diagnose liver cancer and find out how far the disease has spread.

PRIMARY OBJECTIVES:

I. To evaluate the relationship between 18F-FSPG PET/computed tomography (CT), pathology, and cancer metabolism in patients with suspected hepatocellular carcinoma (HCC) scheduled for liver resection surgery and orthotopic liver transplant (OLT).

II. To compare 18F-FSPG PET/CT with standard-of-care (SOC) diagnostic MRI imaging in patients with suspected HCC scheduled for liver resection surgery or OLT.

III. To compare the uptake of 18F-FSPG PET/CT with 11C-acetate PET/CT AND 18F-FDG PET/CT in suspected HCC and background liver in patients scheduled for liver resection surgery or OLT.

IV. To evaluate uptake of 18F-FSPG PET/CT in benign liver lesions compared to background.

V. To evaluate uptake of 18F-FSPG PET/CT in malignant non-HCC liver tumors.

OUTLINE:

Patients undergo 18F-FSPG PET and either carbon-11 (11C)-acetate PET or 18F-FDG PET scans within 4 weeks of surgery or OLT.

Cohorts A and B are Parallel. Cohorts C and D are Single Group. Cohorts E and F Single Group

18F-FSPG PET in Imaging Patients With Liver Cancer Before Undergoing Surgery or Transplant

PET Imaging of Hepatocellular Carcinoma With 18F-FSPG

The Standardized Uptake Value (SUV) for 18F-FSPG PET images will be determined in the hepatocellular carcinoma (HCC) tumor lesions, non-HCC liver tumors (benign), and background liver (normal tissue). These metrics include SUVmax, SUVpeak, or SUVmean and are common PET imaging measures.

The Standardized Uptake Value (SUV) for 11C-acetate PET images will be determined in the tumor lesions and background liver (normal tissue). These metrics include SUVmax, SUVpeak, or SUVmean and are common PET imaging measures.

The Standardized Uptake Value (SUV) for 18F-FDG PET images will be determined in the hepatocellular carcinoma (HCC) tumor lesions and background liver (normal tissue). These metrics include SUVmax, SUVpeak, or SUVmean and are common PET imaging measures.

The pharmacokinetics of 18F-FSPG, 11C-acetate and 18F-FDG uptake will be determined using compartmental modeling of PET imaging data. Venous samples will be collected over the course of 18F-FSPG, 11C-acetate and 18F-FDG scans to confirm blood pool radioactivity, evaluate metabolism, and to calibrate image-derived input functions. We will also utilize blood samples collected prior to scanning to assay plasma levels of carbon-12 acetate and glucose in each patient to explore normalizing pharmacokinetic parameters across patients.

The number of lesions detected by 18F-FSPG PET will be determined and compared to the number of lesions detected by standard-of-care MRI, 11C-acetate PET, or 18F-FDG PET on a per patient basis.

Sensitivity is defined as the true positive rate. It is defined as true positive/(true positive + false negative). The determination of HCC status will be based on diagnostic pathology.

Specificity is defined as the true negative rate. It is defined as true negative/(true negative + false positive). The determination of HCC status will be based on diagnostic pathology.

Tissue samples will be obtained for patients following either liver resection surgery or orthotopic liver transplant. Pathology will be performed on these tumor tissues as the gold-standard assessment to confirm the presence of HCC tumor. Histology will be correlated to PET imaging data.

Tissue samples will be obtained for patients following either liver resection surgery or orthotopic liver transplant. Tumor grade will be determined from pathology of tissue samples and correlated to PET imaging data for 18F-FSPG, 11C-acetate and 18F-FDG PET. The concordance of 18F-FSPG PET/CT and 11C-acetate PET/CT or 18F-FSPG PET/CT and 18F-FDG PET/CT will be evaluated. This will determine whether 18F-FSPG can be used singularly in place of combined use of 11C-acetate PET/CT (which typically detects low grade HCC) and 18F-FDG PET/CT (which typically detects high grade HCC).

Tissue samples will be obtained for patients following liver resection surgery. The expression of immunohistochemical markers (ie. xC- and CD44) will be evaluated in these tumor tissues on an ordinal scale of 0, 1, 2 or 3 and correlated to 18F-FSPG PET imaging data. In addition, markers of inflammation and immune cell recruitment (ie. CD86, CD163, CD3), proliferation (Ki67), and apoptosis (Caspase 3) will also be evaluated and correlated to 18F-FSPG PET imaging data.

HCC tumor and non-cancerous liver tissue samples will be obtained for patients following liver resection surgery. Overall, tumoral tissue, peritumoral tissue and grossly normal surrounding liver will be evaluated. Metabolic profiles will be analyzed by mass spectrometry. The unbiased metabolomic phenome will be determined and correlated to 18F-FSPG PET.

Milan criteria will be applied to standard-of-care (SOC) MRI images. The number and size of lesions will be determined. A patient will be deemed to meet Milan criteria if they exhibit A) A single lesion 2 to 5 cm in diameter or B) Three or fewer tumors, each measuring 1 to 3 cm in diameter, and C) No evidence of extrahepatic involvement or microvascular invasion. The proportion of patients whose Milan classification by novel imaging classification changed following validation by histological confirmation will be determined.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Liver Resection Modeling	NCT04023136	Benign Liver Tu... Malignant Tumor... Cirrhosis	partial hepatec...	18 Years -	Assistance Publique - Hôpitaux de Paris
Hepatic and Systemic Hemodynamic Modeling During Liver Surgery	NCT05339984	Liver Diseases Liver Transplan...	Partial hepatec... liver transplan... Portal vein emb...	18 Years -	Assistance Publique - Hôpitaux de Paris
18F-FSPG PET in Imaging Patients With Liver Cancer Before Undergoing Surgery or Transplant	NCT02379377	Adult Hepatocel... Resectable Hepa... Cholangiocarcin... Benign Liver Tu... Metastases to L...	Fluorine F 18 L... Carbon C 11 Ace... Positron Emissi... Laboratory Biom... Fluorine F 18 2...	18 Years -	M.D. Anderson Cancer Center
Liver Resection Modeling	NCT04023136	Benign Liver Tu... Malignant Tumor... Cirrhosis	partial hepatec...	18 Years -	Assistance Publique - Hôpitaux de Paris

Spots Global Cancer Trial Database for benign liver tumor