Proposed Thresholds for Pancreatic Tissue Volume for Safe Intraportal Islet Autotransplantation After Total Pancreatectomy

The simple question of how much tissue volume (TV) is really safe to infuse in total pancreatectomy–islet autotransplantation (TP–IAT) for chronic pancreatitis (CP) precipitated this analysis. We examined a large cohort of CP patients (n = 233) to determine major risk factors for elevated portal pressure (PP) during islet infusion, using bivariate and multivariate regression modeling. Rates of bleeding requiring operative intervention and portal venous thrombosis (PVT) were evaluated. The total TV per kilogram body weight infused intraportally was the best independent predictor of change in PP (ΔPP) (p < 0.0001; R² = 0.566). Rates of bleeding and PVT were 7.73% and 3.43%, respectively. Both TV/kg and ΔPP are associated with increased complication rates, although ΔPP appears to be more directly relevant. Receiver operating characteristic analysis identified an increased risk of PVT above a suggested cut‐point of 26 cmH₂O (area under the curve = 0.759), which was also dependent on age. This ΔPP threshold was more likely to be exceeded in cases where the total TV was >0.25 cm³/kg. Based on this analysis, we have recommended targeting a TV of <0.25 cm³/kg during islet manufacturing and to halt intraportal infusion, at least temporarily, if the ΔPP exceeds 25 cmH₂O. These models can be used to guide islet manufacturing and clinical decision making to minimize risks in TP–IAT recipients.     

Total Pancreatectomy: Indications,Operative Technique,and Postoperative Sequelae

Total pancreatectomy has been used to treat both benign and malignant disease of the pancreas, but its use has been limited by concerns about management of the apancreatic state with its attendant total endocrine and exocrine insufficiency. Here, we review the indications for total pancreatectomy, operative technique, and improvements in the postoperative management of patients. Total pancreatectomy remains a viable option in the treatment of intractable pain associated with chronic pancreatitis, multicentric or extensive neuroendocrine tumors, patients with familial pancreatic cancer with premalignant lesions, and in patients with intraductal papillary mucinous neoplasia with diffuse ductal involvement or invasive disease. Improvements in postoperative management include auto-islet cell transplantation, advances in insulin formulations, and the use of glucagon rescue therapy which allow much tighter control of blood glucose than previously possible. This markedly lessens the risk of life-threatening hypoglycemia and decreases the risk of long-term complications, resulting in improved quality of life for these patients.     

Intramuscular Autotransplantation of Pancreatic Islets in a 7-Year-Old Child: A 2-Year Follow-Up

A 7-year-old girl with severe hereditary pancreatitis underwent total pancreatectomy. A total of 160 000 islet equivalents (6400 islet/kg) were transplanted to the brachioradialis muscle of the right forearm. Her plasma C-peptide level was undetectable after pancreatectomy but increased to 1.37 ng/mL after 17 days; at this time point, her insulin requirement was 0.75 units of insulin/kg/day. At 5- and 27-months, her hemoglobin A1c (HbA1c) and insulin requirements were 4.5 and 5.3% and 0.3 and 0.18 units/kg/day, respectively. Basal and stimulated C-peptide levels were 0.67 ± 0.07 and 3.36 ± 1.37 ng/mL, respectively. Stimulated insulin levels were 30% higher in the islet-bearing arm compared to the contralateral arm after glucagon stimulation. After surgery and islet transplantation, the quality of life improved dramatically and she gained 8 kg of weight. In summary, a normal HbA1c, a low insulin requirement and the absence of recurrent hypoglycemia and the gradient of insulin between the arms indicate that the intramuscularly transplanted islets contribute to a long-term clinically significant metabolic control.     

慢性胰腺炎胰腺切除术后自体胰岛移植现状

目前,胰腺切除后自体胰岛移植（IAT）主要用于治疗伴有顽固性疼痛的慢性胰腺炎。IAT可以防止或者减少由胰腺切除引起的外科糖尿病的发生,最大程度地保留胰腺内分泌功能。随着胰岛制备技术的不断提高,IAT的效果逐渐得到改善,且具有手术安全、术后不需免疫抑制剂、可有效防止糖尿病发生、改善预后等优点,应于国内推广开展。     

Unmethylated Insulin DNA Is Elevated After Total Pancreatectomy With Islet Autotransplantation: Assessment of a Novel Beta Cell Marker

Beta cell death may occur both after islet isolation and during infusion back into recipients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis. We measured the novel beta cell death marker unmethylated insulin (INS) DNA in TPIAT recipients before and immediately after islet infusion (n = 21) and again 90 days after TPIAT, concurrent with metabolic functional assessments (n = 25). As expected, INS DNA decreased after pancreatectomy (p = 0.0002). All TPIAT recipients had an elevated unmethylated INS DNA ratio in the first hours following islet infusion. In four samples (three patients), INS DNA was also assessed immediately after islet isolation and again before islet infusion to assess the impact of the isolation process: Unmethylated and methylated INS DNA fractions both increased over this interval, suggesting death of beta cells and exocrine tissue before islet infusion. Higher glucose excursion with mixed‐meal tolerance testing was associated with persistently elevated INS DNA at day 90. In conclusion, we observed universal early elevations in the beta cell death marker INS DNA after TPIAT, with pronounced elevations in the islet supernatant before infusion, likely reflecting beta cell death induced by islet isolation. Persistent posttransplant elevation of INS DNA predicted greater hyperglycemia at 90 days.     

Survival and Metabolic Function of Syngeneic Rat Islet Grafts Transplanted in the Omental Pouch

Many sites have been tested in an effort to identify the most ideal site to support islet function and viability. The aim of this study was to evaluate an omental pouch site for islet transplantation and compare it with the renal subcapsular space. All streptozotocine-induced diabetic rats receiving 2000 syngeneic islets in the omental pouch (n = 13) or under the kidney capsule (n = 10) returned to normoglycemia. At 7 days post-transplant and throughout the follow-up period, the mean blood glucose value in both groups was < 9.0 mM. At 4 and 8 weeks post-transplant, both groups displayed normal and similar glucose tolerance curves. Gain in the recipient's body weight after transplantation was similar between the two groups. At the end of follow up prompt hyperglycemia was observed in all rats after removal of the islet graft. No significant differences were found in the insulin contents of the harvested grafts, irrespective of the transplantation site. Histological examination of the grafts showed numerous well-granulated insulin-containing cells in both sites. The results indicate that the omental pouch is a viable site which offers a safe, convenient and efficacious alternative to the renal subcapsular space to transplant islets in rodents.     

Cytomegalovirus Prevalence and Transmission After Islet Allograft Transplant in Patients with Type 1 Diabetes Mellitus

Cytomegalovirus (CMV) serological status of transplant donors and recipients has important implications on antiviral prophylaxis, morbidity/mortality, donor selection and hospital stay. We evaluated CMV prevalence in our islet transplant candidates (ITC) in comparison with organ donors. We correlated the CMV serological status of our ITC with serology for Epstein-Barr virus and Parvovirus B19, auto-antibodies, patient's age, age at DM onset, duration of DM, gender, race, ABO group, HLA haplotype and C-peptide levels. Cytomegalovirus transmission after islet transplant using the Edmonton regimen was also evaluated. Cytomegalovirus seropositivity varied according to patient group, age, gender and race. Type 1 DM patients had reduced odds of CMV seropositivity when compared with organ donors. In all groups studied, older patients, females, and non-Caucasians were more likely to be CMV seropositive. In addition, no CMV reactivation, infection or disease was observed among our transplanted patients using this steroid-free regimen even after donor/recipient CMV mismatch.     

Sitagliptin Treatment After Total Pancreatectomy With Islet Autotransplantation: A Randomized,Placebo‐Controlled Study

Insulin independence after total pancreatectomy and islet autotransplant (TPIAT) for chronic pancreatitis is limited by a high rate of postprocedure beta cell apoptosis. Endogenous glucagon‐like peptide‐1 and glucose‐dependent insulinotropic peptide, which are increased by dipeptidyl peptidase 4 inhibitor therapy (sitagliptin) may protect against beta cell apoptosis. To determine the effect of sitagliptin after TPIAT, 83 adult TPIAT recipients were randomized to receive sitagliptin (n = 54) or placebo (n = 29) for 12 months after TPIAT. At 12 and 18 months after TPIAT, participants were assessed for insulin independence; metabolic testing was performed with mixed meal tolerance testing and frequent sample intravenous glucose tolerance testing. Insulin independence did not differ between the sitagliptin and placebo groups at 12 months (42% vs. 45%, p = 0.82) or 18 months (36% vs. 44%, p = 0.48). At 12 months, insulin dose was 9.0 (standard error 1.7) units/day and 7.9 (2.2) units/day in the sitagliptin and placebo groups, respectively (p = 0.67) and at 18 months 10.3 (1.9) and 7.1 (2.6) units/day, respectively (p = 0.32). Hemoglobin A_1c levels and insulin secretory measures were similar in the two groups, as were adverse events. In conclusion, sitagliptin could be safely administered but did not improve metabolic outcomes after TPIAT.     

全胰切除术治疗胰腺良恶性疾病11例

目的 探讨全胰切除术（total pancreatectomy,TP）治疗胰腺良恶性疾病的指征、安全性、可行性,总结临床经验。方法 回顾性分析2018年1月至2020年12月在中国科学技术大学附属第一医院胆胰外科行全胰切除术的11例胰腺良恶性疾病患者的临床资料。结果 11例中慢性胰腺炎3例,胰腺导管腺癌4例,胰腺黏液癌2例,胰腺导管内乳头状黏液肿瘤（intraductal papillary mucinous neoplasms,IPMN)）1例,神经内分泌肿瘤1例。11例均成功施行全胰切除术,其中腹腔镜下全胰切除术2例。术后并发胃十二指肠动脉残端出血1例。8例获得随访,平均随访20个月,术后每日胰岛素总量（31.22±4.79）U,血糖控制基本稳定。结论 全胰切除术在治疗胰腺良恶性疾病中是安全、可行的,但应严格掌握适应证,对于胰腺癌患者,可以提高R0切除率。     

Vascular reconstruction technique of a perforated portal vein during a pediatric total pancreatectomy and islet autotransplant

Hereditary pancreatitis (HP) is a progressive disease that can manifest in childhood with debilitating, relapsing pain. A total pancreatectomy and islet autotransplant (TPIAT) is a surgical option to relieve chronic pain while preserving the available β‐cell mass. The clinical course of HP is fraught with pancreatitis‐related sequelae that can both necessitate and complicate a TPIAT. We describe a child with HP who developed a pancreatic pseudocyst–portal vein (PV) fistula. Active hemorrhage of the perforated PV into the pseudocyst and PV thrombosis complicated the planned TPIAT procedure and, preoperatively, required urgent image‐guided stenting. During the TPIAT procedure, the endovascular stent was found to be protruding through the PV into the pseudocyst. Using the autologous splenic vein from the TPIAT specimen, we performed a vascular reconstruction of the perforated PV. This case underscores the need for evaluation of children with HP by a multidisciplinary pancreatic TPIAT care team to best prepare for the potential ramifications of pancreatitis‐related complications. It also illustrates a useful vascular reconstruction technique for PV complications.     

Total pancreatectomy and autologous islet cell transplantation as a means to treat severe chronic pancreatitis

Autologous islet cell transplantation after near-total or total pancreatic resection can alleviate pain in patients with severe chronic pancreatitis and preserve endocrine function. From February 2000 to February 2003, a total of 22 patients, whose median age was 38 years, underwent pancreatectomy and autologous islet cell transplantation. Postoperative complications, metabolic studies, insulin usage, pain scores, and quality of life were recorded for all of these patients. The average number of islet cells harvested was 245,457 (range 20,850 to 607,466). Operative data revealed a mean estimated blood loss of 635 ml, an average operative time of 9 hours, and a mean length of hospital stay of 15 days. Sixty-eight percent of the patients had either a minor or major complication. Major complications included acute respiratory distress syndrome (n = 2), intra-abdominal abscess (n = 1), and pulmonary embolism (n = 1). There were no deaths in our series. All patients demonstrated C-peptide and insulin production indicating graft function. Forty-one percent are insulin independent, and 27% required minimal amount of insulin or a sliding scale. All patients had preoperative pain and had been taking opioid analgesics; 82% no longer required analgesics postoperatively. Pancreatectomy with autologous islet cell transplantation can alleviate pain for patients with chronic pancreatitis and preserve endocrine function. Presented at the Presidential Plenary Session, at the Forty-Fourth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Florida, May 18–21, 2003 (oral presentation).     

Assessment of simple indices based on a single fasting blood sample as a tool to estimate beta‐cell function after total pancreatectomy with islet autotransplantation – a prospective study

We investigated six indices based on a single fasting blood sample for evaluation of the beta‐cell function after total pancreatectomy with islet autotransplantation (TP‐IAT). The Secretory Unit of Islet Transplant Objects (SUITO), transplant estimated function (TEF), homeostasis model assessment (HOMA‐2B%), C‐peptide/glucose ratio (CP/G), C‐peptide/glucose creatinine ratio (CP/GCr) and BETA‐2 score were compared against a 90‐min serum glucose level, weighted mean C‐peptide in mixed meal tolerance test (MMTT), beta score and the Igls score adjusted for islet function in the setting of IAT. We analyzed values from 32 MMTTs in 15 patients after TP‐IAT with a follow‐up of up to 3 years. Four (27%) individuals had discontinued insulin completely prior to day 75, while 6 out of 12 patients (50%) did not require insulin support at 1‐year follow‐up with HbA1c 6.0% (5.5–6.8). BETA‐2 was the most consistent among indices strongly correlating with all reference measures of beta‐cell function (r = 0.62–0.68). In addition, it identified insulin independence (cut‐off = 16.2) and optimal/good versus marginal islet function in the Igls score well, with AUROC of 0.85 and 0.96, respectively. Based on a single fasting blood sample, BETA‐2 score has the most reliable discriminant value for the assessment of graft function in patients undergoing TP‐IAT.     

Alpha-Defensin Offers Limited Utility in Work-Up Prior to Reimplantation in Chronic Periprosthetic Joint Infection in Total Joint Arthroplasty Patients

BackgroundAlpha-defensin (AD) is a synovial biomarker included in the 2018 consensus criteria for diagnosing periprosthetic joint infection (PJI). Its value in assessing eradication of infection prior to second stage reimplantation is unclear. The purpose of this study was to evaluate the impact of AD on eligibility for reimplantation following resection for chronic PJI.MethodsThis study included patients who previously underwent resection arthroplasty for PJI. Synovial fluid aspirated from 87 patients was retrospectively reviewed. All patients completed a 6-week course of intravenous antibiotics and an appropriate drug holiday. Synovial white blood cell count, percentage neutrophils, and culture from the AD immunoassay laboratory were reviewed with serum erythrocyte sedimentation rate and C-reactive protein values from our institution. A modified version of the 2018 consensus criteria was used, including white blood cell count, percentage neutrophils, erythrocyte sedimentation rate, and C-reactive protein. AD was then added to determine if it changed diagnosis or clinical management.ResultsFour patients were categorized as “infected” (score >6), none exhibited a positive AD or positive culture. Sixty eight patients were diagnosed as “possibly infected” (score 2 to 5), none had a positive AD, and one had a positive culture (Cutibacterium acnes). AD did not change the diagnosis from “possibly infected” to “infected” in any case or alter treatment plans. Fifteen patients had a score of <2 (not infected) and none had a positive AD.ConclusionThe routine use of AD in the work-up prior to a second-stage arthroplasty procedure for PJI may not be warranted.