Expanding Indications for Islet Cell Autotransplantation

Vol. 27, Issue 3 (September 2022)

	Steven M. Hadley, Jr., AB Clinical Research Coordinator Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire, United States
	Timothy B. Gardner, MD, MS Director, Gastroenterology & Hepatology Fellowship Program Director, Pancreatic Disorders Medical Director, Islet Cell Transplant Program Professor of Medicine, Geisel School of Medicine, Dartmouth Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire, United States

Introduction:

Islet cell autotransplantation (IAT) was first utilized in 1977 as a way to mitigate the risk of developing diabetes in patients who underwent pancreatectomy.¹ Since then, gradual improvements in isolation techniques have enabled IAT to serve as an effective treatment for chronic pancreatitis (CP) and recurrent acute pancreatitis (RAP).^2-4 As IAT continues to be refined and become more accessible, evidence suggests that IAT can be expanded to include indications other than CP and RAP. By not discarding benign pancreas and by harvesting viable islets for transplantation, physicians will generate enhanced clinical outcomes for patients requiring pancreatectomy.

 

IAT Procedure:

After surgical excision of the pancreas, the main arteries in the head (gastroduodenal artery) and tail (splenic artery) of the pancreas are cannulated and flushed with lactated ringer’s solution. Any non-pancreatic tissue is removed. Then, an angiocath is inserted into the pancreatic duct(s) and flushed with a solution containing proteases and collagenases. After the pancreas is saturated with the enzyme solution, the organ is mechanically fractionated with scissors. These pieces are then put into a Ricordi chamber, which is shaken and warmed to augment enzymatic digestion. Every few minutes, samples are collected and stained for inspection under a microscope to examine islet cell form and number. During the isolation, the islets progress from being “embedded” in the exocrine tissue, to becoming “free” from the acinar tissue, to becoming “fragmented” with ongoing digestion. Although the stopping point of the isolation is subjective, some evidence suggests that erring on the side of a longer digestion towards the development of more “fragments” results in enhanced clinical glycemic outcomes.⁵ Once the digestion is deemed finished, the cells are gathered, centrifuged, and then washed. They are then suspended with human serum albumin and heparin and infused into the portal venous system.⁶

 

Expanding Access to IAT:

Although local isolation with a dedicated islet isolation facility remains the gold standard for IAT, islet isolation labs are expensive and require specialized training and equipment. Consequently, some hospitals coordinate with centers that have such facilities to expand the accessibility of IAT. In this remote isolation, the explanted pancreas is transported to a remote site for isolation and then transported back for infusion of the islets. Though local isolation leads to improved islet function following transfusion, remote isolation results in similar rates of insulin independence as local isolation.

 

Moreover, local islet isolation without a dedicated islet isolation lab, first reported by Fan et al., presents another solution for the scarcity of dedicated islet isolation facilities.⁷ The isolation occurs in the operating room after pancreatic resection. Navas et al. demonstrated that intraoperative isolation is comparable to remote isolation regarding IEQ/kg, insulin requirements, mean c-peptide levels, and hemoglobin A1c (HbA1c).⁸ Given these results, both remote and intraoperative isolation present effective options for when local isolation with a dedicated islet cell lab is not feasible.

 

Pancreatic Inflammatory Disease:

When partial pancreatectomy is indicated for pancreatic inflammatory disease, IAT should be considered to reduce the patient’s risk of diabetes. In a retrospective study of 22 patients who had pancreatectomy for benign pancreatic inflammatory disease, Siegel et al. found that compared to those who did not have IAT, the nine who underwent IAT experienced statistically significant smaller increases in HbA1c levels. At 22 months post-operation, IAT patients had an average HbA1c increase of 0.42 mmol/mol versus the average increase of 2.83 mmol/mol in patients who did not have IAT. Of the 22 patients evaluated in the study, one IAT patient developed diabetes compared to three control patients, though this value did not reach statistical significance.⁹

 

Ris et al. conducted a study comparing islet isolation results in 15 patients who underwent IAT after partial pancreatectomy with those results in 10 patients who had CP or were donors with brain death (DBD). Those who underwent IAT after a partial pancreatectomy experienced statistically significantly higher mean islet yields (5,455 IEQ/gram) than the CP and DBD patients (1,457 IEQ/gram in CP patients and 3,738 in DBD patients). At ten years following the operation, the investigators observed insulin independence in 94 percent of the IAT partial pancreatectomy patients combined with a 100 percent survival rate.¹⁰

 

In another study, Balzano et al. examined patients who underwent partial pancreatectomy for benign or borderline malignant pancreatic disease and either received IAT or no IAT. Those who received IAT experienced statistically significant longer diabetes-free survival rates over a ten-year period than those who did not receive IAT. Balzano also observed a trend towards insulin independence in patients who underwent IAT, though this value did not reach statistical significance. 76 percent of patients who had IAT remained insulin independent compared to 55.9 percent of patients who did not have IAT.¹¹

 

Despite the absence of randomized controlled trials, the evidence indicates the efficacy and safety of IAT for enhancing clinical glycemic outcomes in patients who have partial pancreatectomy for benign pancreatic disease. Jin et al. determined that at two years post-operation, only 27 percent of patients with an islet yield greater than 5,154 IEQ/Kg experienced impaired glycemic control compared to 86 percent of patients with a yield under 5,154 IEQ/Kg.¹² Thus, a high islet cell yield combined with the right patient (each case should still be considered and evaluated individually) has the potential to enhance both clinical outcomes and the patient’s quality of life.

 

Trauma:

Despite the rarity of pancreatic trauma, IAT should be considered in cases of damage resulting in surgical removal in order to mitigate the risks of diabetes. Three cases have been reported—each underscoring the value of IAT when benign pancreas is resected. In one case, an 18-year-old female victim of a motor vehicle collision required a partial pancreatectomy due to trauma. IAT was administered because of a family history of diabetes. Although she initially required a small amount of insulin upon discharge, at 20 months post-operation, she was insulin independent with a healthy HbA1c of 5.6 percent.¹³ In the next case, an 18-year-old male was stabbed, which resulted in pancreatic ductal injury requiring a total pancreatectomy. After IAT, the patient was insulin independent the day of his transplantation. He remained insulin independent at his six-year follow-up.¹³ The third case involved a 21-year old male who was shot in the abdomen three times. After extensive abdominal surgery, IAT was performed, which resulted in normal islet function 114 days post-transplant. Despite requiring a small amount of insulin immediately following the procedure, the patient successfully discontinued insulin 24 days post-transplant.¹⁴

 

Islet Cell Tumors:

Islet cell tumors are contraindications for IAT. In one patient who had a planned IAT for CP, the physicians incidentally discovered a neuroendocrine tumor. Although they ultimately decided to proceed with the patient’s IAT, islet cell malignancy remains a contraindication for IAT.¹⁵

 

Pancreatic Adenocarcinoma:

Though typically IAT is limited in cases of cancer because of the risk of spreading cancerous cells, some evidence suggests that IAT should not be completely excluded in patients with pancreatic cancer. One case report of a 63-year-old male who underwent pancreatectomy for pancreatic adenocarcinoma received IAT. After an R0 resection of the pancreatic mass, the physicians discovered a life-threatening leakage of the pancreaticojejunostomy. Consequently, a total pancreatectomy with IAT was performed. A K-ras mutation was present in the adenocarcinoma but was not detected in the islets before transplantation. At his one-year follow-up, although he required exogenous insulin, his engrafted islets functioned, no signs of local or liver metastases existed, and no evidence of K-ras appeared in the peripheral blood. However, the patient passed 2.5 years post-operation from tumor recurrence.¹⁶ In any potential case involving IAT after pancreatectomy for malignancy, the patient should be informed of the risk of infusing malignant cells into the liver and should be monitored closely for liver metastases. Further investigation is needed to reveal to what extent and in which cases pancreatic cancer is multicentric and to determine whether IAT can be performed safely without contamination.

 

Ampullary Adenocarcinoma:

One case has been reported in which a 72-year-old woman with acute necrotizing pancreatitis secondary to an ampullary adenocarcinoma underwent total pancreatectomy because the normal treatment of pancreaticoduodenectomy to excise the ampullary lesion was contraindicated due to the necrotizing pancreatitis. To diminish the risk of diabetes, IAT accompanied the pancreatectomy. At her three-month post-operative follow-up, she only required a small amount of exogenous insulin.¹⁷ Her case demonstrates the efficacy of pancreatectomy with IAT for treating ampullary adenocarcinoma when the preferred method of pancreaticoduodenectomy cannot be performed.

 

Conclusion:

As the IAT procedure continues to be refined, expanding indications for IAT enables this effective treatment option to be utilized in a greater number of patients who must undergo total or partial pancreatectomy and who would significantly benefit from the enhanced clinical glycemic outcomes associated with IAT. While each case should be evaluated on an individual basis, as a general rule, benign pancreas should not be discarded. Given the success of IAT, islet transplantation should be considered to reduce the risk of diabetes and its associated morbidity.

 

References:

[1]        Najarian JS, Sutherland DE, Matas AJ, Steffes MW, Simmons RL, Goetz FC. Human islet transplantation: a preliminary report. Transplant Proc. 1977;9(1):233-236.

[2]        Sutherland DE, Radosevich DM, Bellin MD, et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg. 2012;214(4):409-426.   doi:10.1016/j.jamcollsurg.2011.12.040.

[3]        Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb DC. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020;115(3):322-339. doi:10.14309/ajg.0000000000000535.

[4]        Chinnakotla S, Beilman GJ, Dunn TB, et al. Factors Predicting Outcomes After a Total Pancreatectomy and Islet Autotransplantation Lessons Learned From Over 500 Cases. Ann Surg. 2015;262(4):610-622. doi:10.1097/SLA.0000000000001453.

[5]        Hadley Jr. SM, Smith KD, Chaidarun SS, Fischer DA, Gardner TB. Progression to Fragmentation during Cellular Isolation Improves Clinical Glycemic Outcomes in Patients Undergoing Islet Cell Transplantation. JOP. 2021; S7:01-08.

[6]        Kesseli SJ, Smith KA, Gardner TB. Total pancreatectomy with islet autologous transplantation: the cure for chronic pancreatitis?. Clin Transl Gastroenterol. 2015;6(1):e73. Published 2015 Jan 29. doi:10.1038/ctg.2015.2.

[7]        Fan CJ, Hirose K, Walsh CM, et al. Laparoscopic Total Pancreatectomy With Islet Autotransplantation and Intraoperative Islet Separation as a Treatment for Patients With Chronic Pancreatitis. JAMA Surg. 2017;152(6):550-556. doi:10.1001/jamasurg.2016.5707.

[8]        Navas CM, Smith KD, Chaidarun SS, Fischer DA, Gardner TB. Effectiveness of Intraoperative Versus Dedicated Islet Cell Laboratory Isolation for Total Pancreatectomy With Islet Autotransplant. Transplant Direct. 2022;8(5):e1314. Published 2022 Apr 7. doi:10.1097/TXD.0000000000001314.

[9]        Siegel M, Barlowe T, Smith KD, et al. Islet autotransplantation improves glycemic control in patients undergoing elective distal pancreatectomy for benign inflammatory disease. Clin Transplant. 2020;34(7):e13891. doi:10.1111/ctr.13891.

[10]      Ris F, Niclauss N, Morel P, et al. Islet autotransplantation after extended pancreatectomy for focal benign disease of the pancreas. Transplantation. 2011;91(8):895-901. doi:10.1097/TP.0b013e31820f0892.

[11]      Balzano G, Maffi P, Nano R, et al. Diabetes-free survival after extended distal pancreatectomy and islet auto transplantation for benign or borderline/malignant lesions of the pancreas. Am J Transplant. 2019;19(3):920-928. doi:10.1111/ajt.15219.

[12]      Jin SM, Oh SH, Kim SK, et al. Diabetes-free survival in patients who underwent islet autotransplantation after 50% to 60% distal partial pancreatectomy for benign pancreatic tumors. Transplantation. 2013;95(11):1396-1403. doi:10.1097/TP.0b013e31828c0c29.

[13]      Garraway NR, Dean S, Buczkowski A, et al. Islet autotransplantation after distal pancreatectomy for pancreatic trauma. J Trauma. 2009;67(6):E187-E189. doi:10.1097/TA.0b013e31815ede90.

[14]      Jindal RM, Ricordi C, Shriver CD. Autologous pancreatic islet transplantation for severe trauma. N Engl J Med. 2010;362(16):1550. doi:10.1056/NEJMc0912392.

[15]      Serrano OK, Peterson KJ, Mettler T, et al. Incidental Neuroendocrine Tumor Discovered After Total Pancreatectomy Intended for Islet Autotransplantation: Important Considerations for Surgical Decision-Making. Pancreas. 2018;47(6):778-782. doi:10.1097/MPA.0000000000001069.

[16]      Forster S, Liu X, Adam U, et al. Islet autotransplantation combined with pancreatectomy for treatment of pancreatic adenocarcinoma: a case report. Transplant Proc. 2004; 36(4):1125-1126.

[17]      Iyegha UP, Asghar JA, Beilman GJ. Total pancreatectomy and islet autotransplantation as treatment for ampullary adenocarcinoma in the setting of pancreatic ductal disruption secondary to acute necrotizing pancreatitis. A case report. JOP. 2012; 13(2):239-242.