Quality of life and metabolic outcomes after total pancreatectomy and simultaneous islet autotransplantation.

Background: Pancreas surgery remains technically challenging and is associated with considerable morbidity and mortality. Identification of predictive risk factors for complications have led to a stratified surgical approach and postoperative management. The option of simultaneous islet autotransplantation (sIAT) allows for significant attenuation of long-term metabolic and overall complications and improvement of quality of life (QoL). The potential of sIAT to stratify a priori the indication for total pancreatectomy is yet not adequately evaluated.
Methods: The aim of this analysis was to evaluate the potential of sIAT in patients undergoing total pancreatectomy to improve QoL, functional and overall outcome and therefore modify the surgical strategy towards earlier and extended indications. A center cohort of 24 patients undergoing pancreatectomy were simultaneously treated with IAT. Patients were retrospectively analyzed regarding in-hospital and overall mortality, postoperative complications, ICU stay, hospital stay, metabolic outcome, and QoL.
Results: Here we present that all patients undergoing primary total pancreatectomy or surviving complicated two-stage pancreas resection and receiving sIAT show excellent metabolic outcome (33% insulin independence, 66% partial graft function; HbA1c 6,1 ± 1,0%) and significant benefit regarding QoL. Primary total pancreatectomy leads to significantly improved overall outcome and a significant reduction in ICU- and hospital stay compared to a two-stage completion pancreatectomy approach. Conclusions: The findings emphasize the importance of risk-stratified pancreas surgery. Feasibility of sIAT should govern the indication for primary total pancreatectomy particularly in high-risk patients. In rescue completion pancreatectomy sIAT should be performed whenever possible due to tremendous metabolic benefit and associated QoL.

Introduction

Traditionally, islet autotransplantation (IAT) has been performed in patients undergoing pancreatectomy for chronic pancreatitis[1-3]. Increasing evidence emerges that IAT simultaneously performed with total or subtotal pancreatic surgery is a beneficial strategy for extended indications beyond chronic pancreatitis that may lead to reduced complications, improved metabolic outcome, and quality of life (QoL)[4-6]. Indeed, the option of islet isolation and autologous re-transplantation may shift the indication towards primary total pancreatectomy and avoid relaparatomies/rescue pancreatectomies and complications in borderline or high-risk patients.

Pancreas surgery remains technically challenging and is associated with considerable morbidity and mortality for all indications[7,8]. Particularly, postoperative pancreatic fistula (POPF) is the single most common complication after major partial pancreatic resections[9-11] and the concomitant complications (e.g. postoperative pancreatic hemorrhage, PPH) significantly increases the perioperative mortality[12]. Even if acute complications were prevented or overcome, the loss of pancreatic endocrine and exocrine parenchyma leads to the development of pancreatogenic diabetes. This diabetes type ranks among the worst forms of diabetes due to the concurrent glucagon deficiency and is further complicated by exocrine deficiency. Metabolic lability and severe hypoglycemia are typical complications in this patient group. Moreover, suboptimal metabolic control causes long-term complications and there is increasing evidence, that metabolic control is significantly associated with the oncological outcome[13]. IAT is a viable option to prevent pancreatogenic diabetes or reduce the severity of diabetes after total pancreatectomy[4]. Pancreatic islets are isolated from resected pancreas tissue by enzymatic digestion, optionally purified from exocrine tissue and intraportally grafted. In this analysis, we report on our experience with IAT established in a high-volume pancreas center in patients undergoing pancreas surgery for various indications from non-malignant, borderline, and malignant diseases to salvage pancreatectomy due to complications following pancreaticoduodenectomy and pancreas involving abdominal trauma. Our data demonstrate the feasibility, efficacy, and safety of IAT in this patient cohort and may stimulate further evaluation of this strategy to improve overall outcome, metabolic control, and QoL after pancreatic surgery.

Methods

Patients

From 05/2012 to 08/2018 patients scheduled for pancreatic surgery at the Department of Visceral,- Thorax- and Vascular Surgery at the TU Dresden were evaluated for eligibility for IAT (Table 1). The following conditions (n = 29) were included: (1) chronic pancreatitis and exhausted conservative treatment, (2) traumatic pancreas rupture, (3) severe complications after pancreatic surgery requiring completion pancreatectomy, (4) primary or completion pancreatectomy following duodenal ulcers/adenoma, (5) duodenal or papillary tumor, (6) localized IPMN, and (7) highly differentiated neuroendocrine tumor and sarcoma in the pancreas head (Table 2). Prior to surgery, all patients were assessed by contrast-enhanced computer tomography scan and transabdominal/endoscopic ultrasound, partially with fine needle aspiration. According to individual indications, additional studies including Magnetic Resonance Imaging and Positron Emission Tomography were performed.

Table 1

Patient characteristics.

Number of cases evaluated	n = 52
Number of realized islet isolations	n = 35
Number of transplantations	n = 24
Median follow-up (months)	46 ± 5.7
Age (years)	57 ± 23
Sex (m/f)	14/10
BMI (kg/m²)	24.9 ± 4.7
Weight (kg)	72.3 ± 21.6
Fasting plasma glucose (mmol/l)	4.6 ± 0.8
Impaired fasting glucose	2/24 (8%)
HbA1c (%)	5.2 ± 0.3

Table 2

Diagnosis and transplant characteristics.

	sIAT after primary total pancreatectomy	sIAT after completion pancreatectomy
Patients (n)	14	10
Diagnosis
Chronic pancreatitis	4	3
Abdominal trauma	1	1
Pancreatic cystic neoplasm	2	–
NET (Grade 2)	1	–
Dendritic cell sarkoma	1	–
Mesenchymal mediastinal sarkoma	1	–
Non pancreas related
Duodenal adenoma/ulcer	2	3
Mesenteric ischemia	1	–
Duodenal carcinoma	1	1
Papillary tumor	–	2
Trimmed pancreas weight (g)	85 ± 39*	51 ± 24*
Purification (y/n)	14/0	7/3
Islet yield [IEQ (x10³)]	256 ± 93	214 ± 190
Islet yield (IEQ/g)	3590 ± 2680	4798 ± 5252
Purity (%)	67 ± 15	57 ± 26
Pre-transplant culture (y/n)	0/14	1/9
Endotoxin/microbiology positive (y/n)	0/14	0/10
Islets infused (IEQ/kg BW)	3351 ± 676	2618 ± 2516

Significant difference between the groups.

*p < 0.05.

Indication for islet transplantation

According to the center licence for pancreas retrieval and utilization for islet processing and transplantation, the indication for IAT was chronic pancreatitis when subtotal or total pancreatectomy was indicated (failed medical therapy), patients undergoing pancreaticoduodenectomy where pancreatic anastomosis was assessed as high risk for leakage (combination of narrow duct and soft and/or frail pancreatic parenchyma), severe complications after pancreatic surgery; grade C pancreatic fistula (according to the definition of the International Study Group on Pancreatic Fistula) requiring relaparotomy with completion pancreatectomy. General exclusion criteria were portal vein thrombosis, liver disease with reduction of liver function, multifocal pancreatic neoplasm at preoperative imaging or intraoperative evaluation, malignant disease where the pancreatic transection margin is involved (no confirmed margin negativity by immediate intraoperative pathology) including any degree of dysplasia or ductal dysepithelialization, diagnosis of multiple endocrine neoplasm, diabetes mellitus of any type with insulin deficiency that requires insulin treatment.

All patients were treated following center standards according to the respective underlying disease.

Islet processing and transplantation

Islets were isolated and optionally purified from resected pancreas tissue according to a modified Ricordi method[14]. Briefly, Collagenase, neutral protease (Serva Electrophoresis, Heidelberg, Germany), and Pulmozyme (Roche, Grenzach, Germany,) were infused into the main pancreatic duct. Islets were optionally separated from exocrine tissue by centrifugation on a continuous Biocoll gradient (Biochrom AG, Berlin, Germany) in a COBE 2991 cell processor (Lakewood, CO, USA). Isolation characteristics are summarized in Table 2. Negative gram stain and endotoxin measurement were defined as mandatory release criteria immediately before transplantation. Additionally, bacterial culture was performed for 14 days in every preparation. Strict release criteria as established for allogeneic islet transplantation regarding islet viability, yield, and purity were not generally defined. However, an islet yield <100 IEQ/kg BW was considered as failed isolation procedure and as not transplantable.

Islets were transplanted at the same day according to the surgical, clinical, and logistic situation either intraoperatively or after a short time interval at the ICU unit. Islet transplantation was performed by direct puncture of the portal vein, introduction of a triple-lumen catheter, and under continuous monitoring of portal vein pressure. Heparin (5000 IU) was added to the islet preparation, immediately postoperatively patients were started on a continuous intravenous heparin drip, monitored and adjusted according to activated partial thromboplastin time (PTT; range of 40–50 s) for at least 48 h and thereafter switched to subcutaneous low molecular weight heparin until discharge. Target PTT was discussed with the surgeons and adjusted where appropriate[15].

Perioperative management and follow-up

Intraoperatively patients were started with i.v. insulin infusion with target blood glucose levels between 4 and 8 mmol/l and continued during at least 3 postoperative days. According to clinical conditions (no pressors, oral feeding), therapy was switched to a subcutaneous insulin treatment regimen adapted to metabolic requirements. Islet function was assessed by measurement of fasting C-peptide, blood glucose measurements, and daily insulin requirement. In case of malignant diseases, adjuvant chemotherapy or radiotherapy was administered when indicated, imaging and serum marker testing were performed as per center standard.

Hospital and ICU stay

For all patients included in this analysis, total hospital stay and duration of ICU treatment were comparatively calculated for sIAT after primary total pancreatectomy after completion pancreatectomy.

Diabetes therapy

Patients were evaluated at least every three months regarding glycemic control and insulin therapy was adjusted or discontinued. Insulin independence was defined as adequate glycemic control (HbA1c <7%, fasting blood glucose levels <6.9mmol/l, and 2‐h postprandial blood glucose levels <10 mmol/l) without insulin therapy[4,16,17]. Partial graft function was defined as fasting c-peptide level >0.26 nmol/l and need for supportive exogenous insulin to achieve adequate glycemic control. Primary graft non-function or graft loss was defined as fasting C-peptide levels <0.26 nmol/l after islet infusion or during follow-up respectively.

Quality of life assessment

All patients were assessed using the validated Diabetes Distress (DD) Score[18] that includes a total number of 28 questions regarding seven sources of DD among adults that are critically related to a variety of patient demographic and disease-related characteristics: Feel of powerlessness, difficulties in handling the diabetes, problems with hypoglycemia, social burden, eating-related burden, physician-related burden, family/friends related burden. The assessment was performed according to Fisher et al[18]. by calculation of a mean item-score that is then grouped into three categories: 1,0: no or minimal diabetes-associated distress; 1,0–1,9: moderate diabetes-associated distress; ≥2,0: increased diabetes-associated distress. As control group, an equal number of patients that underwent standard surgical treatment without islet auto-transplantation resulting in total pancreatectomy and insulin deficiency were identified and matched with regard to age, gender, malignant/non-malignant underlying disease.

Ethics approval

The retrospective study was approved by the TU Dresden Institutional Review Board (EK 310062019) with written informed consent obtained from each participant. Additionally, all patients included in this study have provided written informed consent as required within our center licence for islet transplantation and consented to scientific data analysis. Approval for QoL assessment was obtained from the Ethics committee of the University of Dresden, Germany on June 12 2017 (EK 255062017), University of Zurich, Switzerland on April 20th 2015 (KEK-ZHNo: 2014–0631).

Statistical analysis

Data processing was performed using GraphPad Prism 4 (Graph-Pad Software, La Jolla, CA, USA). Student’s t test was used to establish comparisons between groups. Results are shown as mean ± SD. Survival was estimated according to Kaplan-Meier analysis. Significance levels were established at a p-value of <0.05.

Table 3

Quality of life assessed by Diabetes Distress Score (DDS).

	Number of questions (total of 28)	Patients after total pancreatectomy and IAT (n = 24)	Matched patients with total pancreatectomy (without IAT) (n = 24)
Feel of powerlessness	5	2,18	3,49
Difficulties in handling the diabetes	4	1,42	2,08
Problems with hypoglycemia	4	1,79	3,28
Social burden	4	1,17	1,75
Eating related burden	3	1,61	2,88
Physician related burden	4	1,71	1,88
Family/friends related burden	4	1,42	2,7

Bold numbers indicate “increased diabetes-associated distress”.

A total of 28 questions covering 7 sub-categories were tested and analyzed using a validated score system (Fisher et al.). 1,0: no or minimal diabetes-associated distress; 1,0–1,9: moderate diabetes-associated distress; ≥2,0: increased diabetes-associated distress. Patients receiving sIAT were compared to matched patients undergoing standard surgical treatment without IAT.