Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Neoplastic Processes

Liver Diseases

Hematinics

All Drugs and Chemicals

Liver Extracts

Liver transplantation for the treatment of unresectable colorectal cancer liver metastases

Liver transplantation

CRISTINA DOPAZO, MD/PhD

CRISTINA DOPAZO

Cristina Dopazo, PhD/MD

Ramón Charco

Elena Elez

Cristina Dopazo

Ernest Hidalgo

Itxarone Bilbao

Concepción Gómez-Gavara

Mireia Caralt

Javier Ros

Francesc Salva

Isabel Campos-Varela

Lluis Castells

The patients with non-resectable colorectal liver metastases (CRLM) have always being considered a particular subgroup of CRLM in which the therapeutic approach, is focused on strategies that allow a potential surgery like neoadjuvant systemic treatments. But, the underlying biology that causes this particular profile of spread in a proportion of patients that always recur and progress in the liver has not been properly characterized from a biological point of view. Unfortunately, these patients finally develop liver metastasis not amenable for local treatments and become refractory to systemic treatments even without developing extrahepatic liver metastases. As a result, liver transplantation (LT) is a potential for patients without extrahepatic involvement and nonresectable CRLM. There are several studies that aims to evaluate if LT increases overall survival compared to best alternative care. To our knowledge, none of these studies incorporate objectives focused on the underlying tumor biology of this particular population and the development of focused strategies including a dynamic disease monitoring and targeted treatments for this particular population.The METLIVER trial will permit to expand the genetic studies to the whole complexity of metastatic lesions and a more precise evaluation of their genetic heterogeneity. Moreover, it will help to precise the type of genetic analyses on liquid biopsies that can be designed for patients that will unfortunately relapse mostly with lung metastases after LT. Our proposal will maximize the opportunity to produce an unprecedented knowledge on CRLM evolution and will provide new opportunities for relapsed patients.

A prospective multicenter Spanish clinical phase II trial is proposed. The study population will consist of male and female with non-resectable CRLM, who are 18 to 70 years old, inclusive, at the time of providing informed consent. Patients will be identified, treated and followed by the clinical investigators within the different centers included in the present study. Those patients deemed unresectable CRLM by consensus in multidisciplinary meeting will be pre-screened for eligibility to be included in the study. After receiving the corresponding chemotherapy and if the patient meets the inclusion criteria and none of the exclusion criteria will sign the informed consent and will be evaluated for liver transplantation according to institutional protocols at the transplant unit. Patients eligible for liver transplantation will continue chemotherapy until the time of an organ is available. However, patients receiving treatment with bevacizumab or aflibercept will discontinue this treatment at time of inclusion in waiting list. If there are no further contraindications at the time of transplantation, laparotomy including tumor staging will be performed and if there is no sign of extrahepatic disease, liver transplantation will continue according to institutional protocols. Participants will be followed for 5 years and monitored for safety, survival and disease recurrence.

Regarding the translational research:

* The metastatic liver removed on day of transplant will be analysed using high-throughput single-cell RNA sequencing (scRNA-seq) which will allow deep phenotyping of cells for detection of rare and common cell populations and determination of developmental trajectories of distinct cell lineages.
* RAS allele fraction will be monitored by BEAMing and it will be performed before chemotherapy treatment, before LT, post-transplantation, and every 3 months until the patient relapses if relapses.

Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research

Clinical Impact of Molecular Biomarkers in Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research

High-throughput single-cell RNA sequencing (scRNA-seq) will allow deep phenotyping of cells, allowing detection of rare and common cell populations and determination of developmental trajectories of distinct cell lineages from the metastatic liver removed to the recurrence (hepatic or extrahepatic).

ctDNA monitorization will be performed pre-chemotherapy, pre-transplantation and every three months after transplantation

Percentage of subject who reach the endpoint of overall survival from the inclusion in waiting list until death or last follow-up

Percentage of subjects who reach the endpoint of overall survival from the inclusion in waiting list until death or last follow-up

Percentage or patients who did not progress from transplantation until death or last follow-up analysed using Kaplan-Meier and the log-rank test.

Percentage of patients that drop-out of the study prior to liver transplantation

Defined as porcentage of patients with hepatic recurrence, extrahepatic recurrence or both

These questions allowed categorizing patients into whether they exhibited a clinically important symptom/functional impairment for each scale from 1 (not at all) to 4 (very much). It would be assessed pretransplantation and every 6 months after transplantation.

Hospital Vall d'Hebron

Consultant surgeon, MD/PhD

Gland and Hormone Related Diseases

Rare Diseases

Pancreatic Neoplasms

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

The investigator will administer neoadjuvant chemotherapy After neoadjuvant chemotherapy, multidisciplinary team will decide to surgery or continuing chemotherapy based on following imaging studies and tumor markers.

The patients who undergo surgery after neoadjuvant chemotherapy will be included responders.

The patients who show cancer progression even after neoadjuvant chemotherapy will be classify with non-responder. And the investigator will change palliative chemotherapy.

the investigator will compare genetic mutation between responder and non-responder using next generation sequencing examination.

next generation sequencing

The patient will be examined next generation sequencing before changing palliative chemotherapy for non-responders.

following next generation sequencing

Song-Choel Kim, MD.PhD

Woohyung Lee, MD

Woohyung Lee

The purpose of this study is to identify and apply biomarkers that can provide better information than previous imaging and blood tests when evaluating the response after neoadjuvant chemotherapy in pancreatic cancer patients who require neoadjuvant therapy before surgery.

BACKGROUND

* Pancreatic cancer is a rare cancer of the digestive system, but it is known to have a poor prognosis with a very poor survival rate. Five-year survival rate of all patients with pancreatic cancer is less than 6%, and only 10-20% of patients are eligible for surgery at the time of diagnosis.
* Postoperative complications of pancreatic cancer are reported in 30-50% of cases, and only 50% of patients undergoing postoperative chemotherapy at the appropriate time after surgery are reported. As a result of these concerns, the study of neoadjuvant chemotherapy (NACT) was begun. Recently, several clinical studies of chemotherapy have been performed. Cancer (BRPC), locally advanced pancreatic cancer (LAPC) patients who have had difficult surgical resection, are turning to treatment by combining surgical treatment after NACT.
* Although standard treatments for advanced chemotherapy have yet to be established through many clinical studies, the most commonly used regimens are FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), gemcitabine and nab-paclitaxel. The response rate after prior chemotherapy is known as 30-50%, and the response of patients undergoing surgery after prior chemotherapy was compared with the serum markers before and after chemotherapy through CA19-9, PET-CT, and CT. The response could be estimated by the reduction, the size change in the imaging test, or the decrease in SUVmax. However, there are only a few studies on genetic and molecular studies of which patients will respond. Under these circumstances, this study on the discovery of biomarkers for the response of advanced chemotherapy in patients with pancreatic cancer may provide guidelines for the application of advanced chemotherapy and the selection of appropriate drugs, as well as clues for future research.

Primary endpoint:

-Discovery of genetic mutation in response to NACT

METHODOLOGY Recruitment and sample collection of patients undergoing NACT Identifying pancreatic cancer specific candidate genes in response to NACT

EXPECTED RESEARCH RESULTS

* Predictable genes and biomarkers of responsiveness for NACT can be identified.
* It is possible to understand the progress of pancreatic cancer widely
* The development of biomarkers that can predict the response of NACT
* In patients with BRPC or LAPC who need NACT, appropriate screening will be possible.

Development of Biomarker for the Evaluation of Response After Neoadjuvant Therapy in Patients With Pancreatic Cancer

Discovery of genetic mutation in response to neoadjuvant chemotherapy

overall survival and recurrence free survival

Asan Medical Center

Professor

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Patients with newly diagnosed glioma that receive tumor resection

Glioma groups based on molecular pathology or genetic variation

Zhenyu Zhang, Dr.

This study aims to collect clinical, radiological, pathological, molecular and genetic data including detailed clinical parameters, MR and histopathology images, molecular pathology and genetic data. This study seeks to find the prognostic and clinical significance based on molecular and genetic biomarkers/subgroups of gliomas.

Precise classification based on molecular and genetic biomarkers/subgroups for gliomas is challenging. This study aims to collect clinical, radiological, pathological, molecular and genetic data including detailed clinical parameters, MR and histopathology images, molecular pathology (1p/19q co-deletion, MGMT methylation, IDH and TERTp mutations, etc) and genetic data (Whole exome sequencing, RNA sequencing, proteomics, etc). This study seeks to find the prognostic and clinical significance based on molecular and genetic biomarkers/subgroups of gliomas.

All participants have signed the informed consent. Fresh frozen tissues of participants are collected immediately after tumor resection and preserved in liquid nitrogen. Whole exome sequencing, RNA sequencing and proteomics are planed to be conducted.

Survival Significance of Molecular Pathology and Genetic Variation in Brain Gliomas

Survival Significance and Clinical Characteristics of Molecular Pathology and Genetic Variation in Brain Gliomas

The length of time from enrollment until the time of death (OS, overall survival)

The First Affiliated Hospital of Zhengzhou University

Doctor

Antineoplastic Agents

Bevacizumab

Temozolomide

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Group A: gene evolution with relapsed. From the first day after the operation, the ctDNA was extracted from TISF before concurrent chemoradiotherapy as the baseline, and then the ctDNA was detected again after concurrent chemoradiotherapy. For the third time, ctDNA was detected in intensive chemotherapy with temozolomide. The image showed that the tumor progress was detected for the fourth time, and the ctDNA was detected for the fifth time when the tumor recurred. Patients with glioma were routinely treated with temozolomide chemotherapy from the 4th week after operation, for 5 days continuously, once every 4 weeks, with a single dose as follows: Single dose = BSA (body surface area) \* 150mg/m2/day BSA(Body Surface Area)=\[weight (kg)\* height (cm)/3600\]2,

After the recurrence, temozolomide combined with bevacizumab was used for chemotherapy, After bevacizumab was applied after six week , ctDNA is tested every six weeks. temozolomide combined with bevacizumab (600mg) in the course of tumor progression once a month.

Patients with glioma were routinely treated with temozolomide chemotherapy from the 4th week after operation, for 5 days continuously, once every 4 weeks, with a single dose as follows: Single dose = BSA (body surface area) \* 150mg/m2/day BSA(Body Surface Area)=\[weight (kg)\* height (cm)/3600\]2, According to the molecular pathological grade (WHO CNS5 grade), it is decided whether to combine radiotherapy (GBM combined with radiotherapy) and temozolomide combined with bevacizumab (600mg) in the course of tumor progression, Recording image changes

Gene evolution and molecular response under Bevacizumab treatment

Xingyao Bu, Ph.D

Huibin Ning, Ph.D

Xingyao Bu

Little is known about the evolution of genetic and epigenetic changes that occur in the progression of glioma. We inferred the evolution trajectories of matched pairs of primary tumors and progression tumor in situ fluid (TISF) based on deep whole-genome-sequencing data (ctDNA). A monocentric, Gene grouping controlled trial design was used to select patients. and to compare gene evolution of different subtypes of glioma under therapy. To predict the molecular reaction of bevacizumab treatment, clarify the mechanism of drug resistance of bevacizumab treatment.

Patient: Adult glioma, pathological diagnosis combined with molecular diagnosis (i.e. IDH- mutant glioma, IDH- mutant glioma with 1p/19q- co-deletion, glioblastoma). The patients were divided into three groups: group A (IDH mutant glioma), group B (IDH mutant with 1p/19q co-deletion oligodendroglioma ) and group C (IDH wild glioblastoma). From the first day after surgery, the ctDNA was extracted with TISF before concurrent chemoradiotherapy as the baseline, and the ctDNA was detected again after concurrent chemoradiotherapy. For the third time, ctDNA was detected in temozolomide intensive chemotherapy. ctDNA was detected for the fourth time when the image showed tumor progression. After the progress, temozolomide combined with bevacizumab was used for chemotherapy. ctDNA was detected 6 weeks after the application of bevacizumab, and ctDNA was re-measured every 6 weeks during the treatment of bevacizumab. At the same time, imaging examination was performed to determine the tumor progress. Check and record adverse events and drug use in detail, and evaluate the compliance of subjects; After TISF tissue extraction, the retained blood samples were sent to simcere Company and Beijing Genetron Health Technology Co. Ltd for ctDNA quantification and detection. To study the differences of gene evolution of different subtypes of glioma under pressure therapy, to clarify the differences of molecular responses of different subtypes of glioma to bevacizumab, and to evaluate the therapeutic effect and safety.

A small amount of TISF was harvested from the implanted reservoir(Intra-operative retention) during postoperative progression of 20 glioma patients under stress therapy. At the same time, blood samples (5ml) for germline DNA control were also acquired. Fresh tumor tissues were obtained for comparing evolution analysis with TISF ctDNA under bevacizumab treatment.

Study on Gene Evolution in Glioma Under Stress Therapy

Study on Gene Evolution and Anti-VEGF Treatment Response of Different Subtypes of Glioma Based on ctDNA

We evaluated the efficacy of bevacizumab on different subtypes of glioma at recurrence according to delta-VAF and Ratio combined with imaging.The mean change in VAF (delta-VAF) was calculated per patient as the sum of the ontreatmentVAF minus the pretreatment VAF for each detected SNV or indel divided by the number of detected SNVs or indels, we found that the "molecular responce" model could generally be represented in simpler terms through a ratio of ontreatment VAF to pretreatment VAF

We compared and analyzed the genes before and after bevacizumab treatment according to the gene evolution of ctDNA.To clarify the molecular mechanism of bevacizumab resistance.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research	NCT05398380	Colorectal Canc... Liver Metastase... Genetic Change	Liver transplan...	18 Years - 70 Years	Hospital Vall d'Hebron
Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research	NCT05398380	Colorectal Canc... Liver Metastase... Genetic Change	Liver transplan...	18 Years - 70 Years	Hospital Vall d'Hebron
Development of Biomarker for the Evaluation of Response After Neoadjuvant Therapy in Patients With Pancreatic Cancer	NCT04110769	Genetic Change Chemotherapy Ef... Pancreatic Canc...	next generation... following next ...	20 Years -	Asan Medical Center
Survival Significance of Molecular Pathology and Genetic Variation in Brain Gliomas	NCT04216537	Glioma Molecular Seque... Genetic Change	Glioma groups b...	1 Year - 95 Years	The First Affiliated Hospital of Zhengzhou University
Survival Significance of Molecular Pathology and Genetic Variation in Brain Gliomas	NCT04216537	Glioma Molecular Seque... Genetic Change	Glioma groups b...	1 Year - 95 Years	The First Affiliated Hospital of Zhengzhou University
Study on Gene Evolution in Glioma Under Stress Therapy	NCT05512325	Genetic Change	Gene evolution ...	18 Years - 75 Years	Henan Provincial People's Hospital
Development of Biomarker for the Evaluation of Response After Neoadjuvant Therapy in Patients With Pancreatic Cancer	NCT04110769	Genetic Change Chemotherapy Ef... Pancreatic Canc...	next generation... following next ...	20 Years -	Asan Medical Center
Study on Gene Evolution in Glioma Under Stress Therapy	NCT05512325	Genetic Change	Gene evolution ...	18 Years - 75 Years	Henan Provincial People's Hospital

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