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Patients benefited from total pancreatectomy for resectable adenocarcinoma of the cephalic region at high risk of postoperative pancreatic fistula, with intaportal/intramuscular islet autotransplantation

The total pancreatectomy will be performed in two steps: The pancreatectomy will begin by a standard pancreaticoduodenectomy procedure.

The section margin will be sent for intraoperative histological analysis to confirm the absence of invasion of the left remnant pancreas.

When absence of tumor invasion is confirmed and the high-risk of postoperative pancreatic fistula is validated intraoperatively, the extended left distal pancreatectomy will be performed, with splenic preservation when possible.

Then, the left side of the pancreas will be resected and cooled (4-6°) in the preservation solution and shipped to Lille Biotherapy platform to perform islet isolation and purification. The reconstruction after total pancreatectomy will be done as usually performed by center expert surgeon.

total pancreatectomy

The final islet preparation will be cultured and shipped 48 hours after total pancreatectomy from the Lille laboratory to the surgical center, and finally transplanted into the patient through a venous catheter placed in the portal trunk (91% of the total islet mass) and at the same time, a small fraction of the isolated islet (5% of the total islet mass) will be transplanted into the forearm muscle.

intraportal islet autotransplantation

François PATTOU, MD,PhD

Curative management of locally resectable invasive adenocarcinomas located in the cephalic region of the pancreas (pancreas, duodenum and ampulla of Vater) requires a pancreaticoduodenectomy followed by adjuvant chemotherapy. Pancreaticoduodenectomy is a major surgery that often leads to major complications including approximately 20% of relevant clinical postoperative pancreatic fistula.

Postoperative complications following pancreaticoduodenectomy can lead to early discontinuation of the complete oncologic strategy, i.e., chemotherapy for malignancy is performed in only about a third of patients who experienced a grade C fistula.

A total pancreatectomy rather than a pancreaticoduodenectomy is an alternative procedure that involves the complete and definitive resection of all pancreatic tissue, eliminating any risk of postoperative pancreatic fistula but is associated with unavoidable endocrine insufficiency and potentially severe metabolic complications, such as "brittle diabetes".

Total Pancreatectomy following by intraportal Islet AutoTransplantation (TPIAT) can prevent "brittle diabetes" and improve the quality of life. The endocrine islets can be isolated from the pancreatic surgical specimen with standardized procedures and transplanted in the liver through intraportal infusion, in absence of immunosuppression and allow adequate control of glucose metabolism with a reduced need for exogenous insulin and an effective graft function in 70% of cases at 3 years Thereby, the investigators hypothesize that total pancreatectomy with intraportal Islet autotransplantation rather than classical pancreaticuduodenectomy, in patients with high-risk of postoperative fistula will increase the rate of complete access to adjuvant chemotherapy, while maintaining an adequate metabolic control.

Curative management of locally resectable invasive adenocarcinomas located in the cephalic region of the pancreas (pancreas, duodenum and ampulla of Vater) requires a pancreaticoduodenectomy followed by adjuvant chemotherapy. Pancreaticoduodenectomy is a major surgery that often leads to major complications including approximately 20% of relevant clinical postoperative pancreatic fistula. Severe postoperative pancreatic fistulas (grade C) require reoperation or lead to organ failure and/or mortality. In an extensive international registry study of pancreaticoduodenectomy procedures, chemotherapy for malignancy was performed in only about 33% (on time in 7% and delayed in 25.6 % of patients) and never delivered in about 67,4 % of patients who experienced a grade C fistula. Therefore, postoperative complications following pancreaticoduodenectomy can lead to early discontinuation of the complete oncologic strategy.

A total pancreatectomy rather than a pancreaticoduodenectomy is an alternative procedure that involves the complete and definitive resection of all pancreatic tissue, eliminating any risk of postoperative pancreatic fistula.

Total pancreatectomy could represent a major shift in the surgical management of patients with a high-risk of postoperative fistula by eliminating the life-threatening risk associated with fistula and by increasing the opportunity to initiate and to complete adjuvant chemotherapy without delay.

However, total pancreatectomy is associated with unavoidable endocrine insufficiency and potentially severe metabolic complications, such as "brittle diabetes".

Total Pancreatectomy with intraportal Islet AutoTransplantation (TPIAT) is currently performed in patients with chronic pancreatitis under chronic pain failing endoscopic treatment and dependent on long-term opioid treatment.

Therefore, islet autotransplantation following total pancreatectomy can prevent "brittle diabetes" and improve the quality of life.

The endocrine islets can be isolated from the pancreatic surgical specimen with standardized procedures and transplanted in the liver through intraportal infusion, in absence of immunosuppression and allow adequate control of glucose metabolism with a reduced need for exogenous insulin and an effective graft function in 70% of cases at 3 years

Thereby, the investigators hypothesize that total pancreatectomy with intraportal Islet autotransplantation rather than classical pancreaticuduodenectomy, in patients with high-risk of postoperative fistula will increase the rate of complete access to adjuvant chemotherapy, while maintaining an adequate metabolic control.

Efficacy and Safety of TPIAT for Resectable Adenocarcinoma of the Pancreas Region at High Risk of Postoperative Fistula

Efficacy and Safety of Total Pancreatectomy With Intraportal Islet Autotransplantation for Resectable Adenocarcinoma of the Cephalic Region of the Pancreas at High-risk of Postoperative Fistula and Requiring Systemic Adjuvant Chemotherapy

success is defined when patients treated with TPIAT will have completed the adjuvant systemic chemotherapy initially approved and planned by the local multidisciplinary expert team according to current international guidelines

postoperative complication will be evaluated with Dindo Clavien classification

complications related to islet transplantation will be reported according to CTCAE v5.0.

the time in weeks between TPIAT procedure and the adjuvant systemic chemotherapy will be reported

The cancer recurrence will be assessed according standard of care imaging (Thorax multi-detection Computed Tomography, Abdomino-pelvis imaging : Mutli-detection Computed Tomography OR Magnetic Resonance Imaging) through the follow up using the Recist 1.1 criteria

Postopeartive diabetes and exocrine insufficiency will be evaluated with clinical examination (symptoms, Pancreatic enzyme replacement therapy dosage, Diabetes medication : non insulin medication, insulin (daily insuline dosage UI/kg); blood samples (Fasting C-peptide and glycemia, Post-prandial C-peptide and glycemia, HbA1C (%))

EORTC QLQ-C30 and QLQ -PAN26 are self-completion questionnaires specific to cancer patients quality of life and pancreatic cancer patients quality of life

adverse events will be reported according to CTCAE v5.0 and classified according to their suspected or confirmed reason (i.e. chemotherapy, intraportal islet transplantation, pancreatic surgery)

Islet transplantation succes status is defined by HbA1C \< 7% AND no severe hypoglycemic event

Islet transplantation succes status is defined by HbA1C \< 7% AND no severe hypoglycemic event AND C-peptide ≥ 0.2 ng/mL

Defined by the Beta 2 score calculated at 1 month post TPIAT using blood sample with fasting C peptide and glycemic, HbA1c and exogenous insuline requirement

Serious Hypoglycemic Event is defined as one requiring third-party assistance or resulting in hospitalization in an intensive care unit

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Efficacy and Safety of TPIAT for Resectable Adenocarcinoma of the Pancreas Region at High Risk of Postoperative Fistula	NCT05116072	Adenocarcinoma ... Adenocarcinoma ... Ampullary Adeno...	total pancreate... intraportal isl...	18 Years -	University Hospital, Lille
Efficacy and Safety of TPIAT for Resectable Adenocarcinoma of the Pancreas Region at High Risk of Postoperative Fistula	NCT05116072	Adenocarcinoma ... Adenocarcinoma ... Ampullary Adeno...	total pancreate... intraportal isl...	18 Years -	University Hospital, Lille

Spots Global Cancer Trial Database for adenocarcinoma of the duodenum