Reciprocal Learning Between Military and Civilian Surgeons: Past and Future Paths for Medical Innovation.

Numerous surgical advances have resulted from exchanges between military and civilian surgeons. As part of the U.S. National Library of Medicine Michael E. DeBakey Fellowship in the History of Medicine, we conducted archival research to shed light on the lessons that civilian surgery has learned from the military system and vice-versa. Several historical case studies highlight the need for immersive programs where surgeons from the military and civilian sectors can gain exposure to the techniques, expertise, and institutional knowledge the other domain provides. Our findings demonstrate the benefits and promise of structured programs to promote reciprocal learning between military and civilian surgery.

History and Current Status of Cardiovascular Surgery at the University of Pennsylvania.

The cardiothoracic surgery program at the University of Pennsylvania has enjoyed a decades long tradition of leadership and contributions to the field. Consistent with its place as a robust contributor in a major academic medical center, its focus is on the tripartite mission of clinical care, research and education, including the provision of cutting edge care delivered to patients in a multidisciplinary fashion. Faculty members' pursuit of translational research facilitates the delivery of such exceptional treatment and provision of excellent care. This foundation is ideal for the training of the outstanding surgeons of tomorrow, as evidenced by a history of such contributions.

Improvement in ß-cell secretory capacity after human islet transplantation according to the CIT07 protocol.

The Clinical Islet Transplantation 07 (CIT07) protocol uses antithymocyte globulin and etanercept induction, islet culture, heparinization, and intensive insulin therapy with the same low-dose tacrolimus and sirolimus maintenance immunosuppression as in the Edmonton protocol. To determine whether CIT07 improves engrafted islet ß-cell mass, our center measured ß-cell secretory capacity from glucose-potentiated arginine tests at days 75 and 365 after transplantation and compared those results with the results previously achieved by our group using the Edmonton protocol and normal subjects. All subjects were insulin free, with CIT07 subjects receiving fewer islet equivalents from a median of one donor compared with two donors for Edmonton protocol subjects. The acute insulin response to glucose-potentiated arginine (AIRpot) was greater in the CIT07 protocol than in the Edmonton protocol and was less in both cohorts than in normal subjects, with similar findings for C-peptide. The CIT07 subjects who completed reassessment at day 365 exhibited increasing AIRpot by trend relative to that of day 75. These data indicate that engrafted islet ß-cell mass is markedly improved with the CIT07 protocol, especially given more frequent use of single islet donors. Although several peritransplant differences may have each contributed to this improvement, the lack of deterioration in ß-cell secretory capacity over time in the CIT07 protocol suggests that low-dose tacrolimus and sirolimus are not toxic to islets.

Historical overview of transplantation.

Except for legends and claims of miracles, most histories of transplantation cover only the last 60 years because there were no earlier successes. However, the story of even this era has been documented in such rich detail that a full account would fill several volumes. Thus, this brief summary must be limited to highly selected "landmarks." Some landmarks had an immediate impact, but the importance of others went unrecognized for decades. Some findings that deserved landmark status were overlooked or forgotten, whereas others of no biological significance had major impact. Placing these events in perspective is challenging. Several of transplantation's pioneers are still alive, and most of the others are within living memory. Virtually all of them have produced their own accounts. For the most part, they agree on what the "landmarks" are, but their differences in emphasis and perspective make an interesting story.

Islet alone versus islet after kidney transplantation: metabolic outcomes and islet graft survival.

BACKGROUND: Isolated islet transplantation with infusions from two to three donor pancreata and Edmonton immunosuppression consistently achieves insulin independence in patients with type 1 diabetes. The success of this protocol has been attributed to a novel combination of immunosuppressive agents and avoidance of steroids; however, the outcome of islet transplantation may differ in kidney transplant recipients who are already immunosuppressed. METHODS: We compared the metabolic outcomes and graft survival of islet transplantation in our program where nine patients underwent islet transplantation alone treated with Edmonton immunosuppression and eight patients received islet after kidney (IAK) transplants under standard kidney transplant immunosuppression often including steroids. RESULTS: Transplants in the IAK and islet transplantation alone setting demonstrated similar islet potency (islet equivalents/unit insulin reduction) and recipients from both groups routinely gained insulin independence, functional islet mass, and duration of graft survival, however, seemed superior in the IAK group. CONCLUSIONS: These results suggest that better islet graft function and survival may be attained using non-Edmonton rather than Edmonton immunosuppression and can include maintenance steroid therapy.

B lymphocyte-directed immunotherapy promotes long-term islet allograft survival in nonhuman primates.

We found that an induction immunotherapy regimen consisting of rabbit anti-thymocyte globulin (Thymoglobulin) and the monoclonal antibody to CD20 rituximab (Rituxan) promoted long-term islet allograft survival in cynomolgus macaques maintained on rapamycin monotherapy. B lymphocyte reconstitution after rituximab-mediated depletion was characterized by a preponderance of immature and transitional cells, whose persistence was associated with long-term islet allograft survival. Development of donor-specific alloantibodies was abrogated only in the setting of continued rapamycin monotherapy.

Availability of suitable islet donors in the United States.

BACKGROUND: We characterize donor utilization for islet transplantation and estimate the number of recipients who could achieve normoglycemia through islet transplantation if the current donor pool were used. METHODS: Potential islet donors from all United Network for Organ Sharing donors (1/00-5/04) were identified and categorized into "optimal" islet donors (16-40 yr, body mass index >27 kg/m, hemodynamically stable) or "standard" donors (as traditionally described). RESULTS: Of 27,552 potential donors during this period, 6,140 donor pancreata were used for whole organ transplant. Of the remaining 21,412 donors, 10,417 potential islet donors were identified (9260 [88.9%] standard and 1157 [11.1%] optimal donors). Islets from only 218 donors were used for transplant, representing 8.7% of optimal donors and 2.1% of all potential islet donors. CONCLUSION: The widespread use of isolated islets could provide insulin independence for approximately 1000 type I diabetics a year, but at current rates of islet transplant, all recipients could be transplanted with islets from ideal donors.

T-reg mediated suppression of the allograft response in the draining lymph node.

We previously demonstrated that T-regs inhibit proliferation of graft-reactive T cells in the draining lymph node (DLN), suggesting that this site may be important for regulation. TCR transgenic mice (TS1) specific for viral hemagglutinin (HA) provided antigen-specific T cells for adoptive transfer into syngeneic Balb/c hosts bearing HA+ skin grafts. T-regs were obtained from (TS1xHA28)F1 mice known to have an expanded population of HA-specific T-regs. To determine whether the lymph node is an independent site of suppression, we developed a model in which donor antigen that migrates from the allograft to the DLN drives T-cell activation after graft removal. T-regs that did not encounter the allograft itself remained able to inhibit graft antigen-specific T-cell proliferation in the DLN. Alloantigen-induced regulation can occur in the absence of the graft. This finding identifies the DLN as a potentially critical site of regulation in the early posttransplant period.

Islet cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes.

Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, whether intrahepatic islets respond appropriately to hypoglycemia after transplantation has not been fully studied. We evaluated six islet transplant recipients, six type 1 diabetic subjects, and seven nondiabetic control subjects using a stepped hyperinsulinemic-hypoglycemic clamp. Also, three islet transplant recipients and the seven control subjects underwent a paired hyperinsulinemic-euglycemic clamp. In response to hypoglycemia, C-peptide was similarly suppressed in islet transplant recipients and control subjects and was not detectable in type 1 diabetic subjects. Glucagon was significantly more suppressed in type 1 diabetic subjects than in islet transplant recipients (P < 0.01), although the glucagon in islet transplant recipients failed to activate as in the control subjects (P < 0.01). Pancreatic polypeptide failed to activate in both type 1 diabetic subjects and islet transplant recipients compared with control subjects (P < 0.01). In islet transplant recipients, glucagon was suppressed normally by hyperinsulinemia during the euglycemic clamp and was significantly greater during the paired hypoglycemic clamp (P < 0.01). These results suggest that after islet transplantation and in response to insulin-induced hypoglycemia, endogenous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored.

{beta}-Cell function following human islet transplantation for type 1 diabetes.

Islet transplantation can provide metabolic stability for patients with type 1 diabetes; however, more than one donor pancreas is usually required to achieve insulin independence. To evaluate possible mechanistic defects underlying impaired graft function, we studied five subjects at 3 months and four subjects at 12 months following intraportal islet transplantation who had received comparable islet equivalents per kilogram (12,601 +/- 1,732 vs. 14,384 +/- 2,379, respectively). C-peptide responses, as measures of beta-cell function, were significantly impaired in both transplant groups when compared with healthy control subjects (P < 0.05) after intravenous glucose (0.3 g/kg), an orally consumed meal (600 kcal), and intravenous arginine (5 g), with the greatest impairment to intravenous glucose and a greater impairment seen in the 12-month compared with the 3-month transplant group. A glucose-potentiated arginine test, performed only in insulin-independent transplant subjects (n = 5), demonstrated significant impairments in the glucose-potentiation slope (P < 0.05) and the maximal response to arginine (AR(max); P < 0.05), a measure of beta-cell secretory capacity. Because AR(max) provides an estimate of the functional beta-cell mass, these results suggest that a low engrafted beta-cell mass may account for the functional defects observed after islet transplantation.

Transplantation for type I diabetes: comparison of vascularized whole-organ pancreas with isolated pancreatic islets.

OBJECTIVE: We sought to compare the efficacy, risks, and costs of whole-organ pancreas transplantation (WOP) with the costs of isolated islet transplantation (IIT) in the treatment of patients with type I diabetes mellitus. SUMMARY BACKGROUND DATA: A striking improvement has taken place in the results of IIT with regard to attaining normoglycemia and insulin independence of type I diabetic recipients. Theoretically, this minimally invasive therapy should replace WOP because its risks and expense should be less. To date, however, no systematic comparisons of these 2 options have been reported. METHODS: We conducted a retrospective analysis of a consecutive series of WOP and IIT performed at the University of Pennsylvania between September 2001 and February 2004. We compared a variety of parameters, including patient and graft survival, degree and duration of glucose homeostasis, procedural and immunosuppressive complications, and resources utilization. RESULTS: Both WOP and IIT proved highly successful at establishing insulin independence in type I diabetic patients. Whole-organ pancreas recipients experienced longer lengths of stay, more readmissions, and more complications, but they exhibited a more durable state of normoglycemia with greater insulin reserves. Achieving insulin independence by IIT proved surprisingly more expensive, despite shorter initial hospital and readmission stays. CONCLUSION: Despite recent improvement in the success of IIT, WOP provides a more reliable and durable restoration of normoglycemia. Although IIT was associated with less procedure-related morbidity and shorter hospital stays, we unexpectedly found IIT to be more costly than WOP. This was largely due to IIT requiring islets from multiple donors to gain insulin independence. Because donor pancreata that are unsuitable for WOP can often be used successfully for IIT, we suggest that as IIT evolves, it should continue to be evaluated as a complementary alternative to rather than as a replacement for the better-established method of WOP.

Decreased use of iliac extensions and reduced graft junctions with software-assisted centerline measurements in selection of endograft components for endovascular aneurysm repair.

OBJECTIVE: The purpose of this study was to determine the impact of using computerized software-assisted centerline measurements for extensions and graft junctions during the selection of endograft components for modular aortic endografts in endovascular repair of abdominal aortic aneurysms. METHODS: From April 1998 to December 2002, 289 modular aortic endografts were implanted at our institution. These included 248 grafts (prior to 2002, group 1) with components selected on the basis of manual caliper measurements from combined contrast computed tomography (CT) and marker-catheter arteriography data, and 41 grafts (2002, group 2) with components selected with the use of computerized software that allowed for centerline measurements on 3-dimensional reconstructions based on CT data. These 2 groups were compared for the number and type of extensions required per case. Seventeen other relevant variables were analyzed for their potential influence on selection of endograft components. These variables included age, gender, maximum aneurysm size, level of distal fixation, length and diameter at the fixation points, endograft manufacturer (make), and configuration. The significance of the observed differences was analyzed with a multivariate regression model, adjusting for potentially confounding preoperative measures. RESULTS: Multivariate analysis demonstrated that the number of right iliac extensions, left iliac extensions, total extensions, and total graft junctions was significantly reduced by the use of computerized software-assisted centerline measurements (group 2) compared with caliper measurements (group 1), independent of all other 17 preoperative variables. Notably, the mean number of required right iliac extensions was double in group 1 versus group 2. CONCLUSIONS: Centerline software-assisted measurements can significantly reduce the need for iliac extensions and, concomitantly, the number of required endograft junctions. On average, twice as many extensions were required for right iliac fixation when the manual caliper measurements were used compared with software-assisted measurements. These findings are highly relevant to issues of total endograft cost and long-term endograft integrity and focus attention on the tools that may need to be considered standards of care rather than optional for selection of endograft components.

Promotion of allograft survival by CD4+CD25+ regulatory T cells: evidence for in vivo inhibition of effector cell proliferation.

Regulatory T cells preserve tolerance to peripheral self-Ags and may control the response to allogeneic tissues to promote transplantation tolerance. Although prior studies have demonstrated prolonged allograft survival in the presence of regulatory T cells (T-reg), data documenting the capacity of these cells to promote tolerance in immunocompetent transplant models are lacking, and the mechanism of suppression in vivo remains unclear. We used a TCR transgenic model of allograft rejection to characterize the in vivo activity of CD4(+)CD25(+) T-reg. We demonstrate that graft Ag-specific T-reg effectively intercede in the rejection response of naive T cells to established skin allografts. Furthermore, CFSE labeling demonstrates impaired proliferation of naive graft Ag-specific T cells in the draining lymph node in the presence of T-reg. These results confirm the efficacy of T-reg in promoting graft survival and suggest that their suppressive action is accomplished in part through inhibition of proliferation.

Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects.

Type 2 diabetic subjects manifest both disordered insulin action and abnormalities in their pancreatic islet cells. Whether the latter represents a primary defect or is a consequence of the former is unknown. To examine the beta-cell mass and function of islets from type 2 diabetic patients directly, we isolated islets from pancreata of type 2 diabetic cadaveric donors (n = 14) and compared them with islets from normal donors (n = 14) matched for age, BMI, and cold ischemia time. The total recovered islet mass from type 2 diabetic pancreata was significantly less than that from nondiabetic control subjects (256,260 islet equivalents [2,588 IEq/g pancreas] versus 597,569 islet equivalents [6,037 IEq/g pancreas]). Type 2 diabetic islets were also noted to be smaller on average, and histologically, islets from diabetic patients contained a higher proportion of glucagon-producing alpha-cells. In vitro study of islet function from diabetic patients revealed an abnormal glucose-stimulated insulin release response in perifusion assays. In addition, in comparison with normal islets, an equivalent number of type 2 diabetic islets failed to reverse hyperglycemia when transplanted to immunodeficient diabetic mice. These results provide direct evidence for abnormalities in the islets of type 2 diabetic patients that may contribute to the pathogenesis of the disease.

Geographic differences in access to transplantation in the United States.

BACKGROUND: The Etablissement français des Greffes reports regional variability in access to organ transplantation in France. Some variability seems to be inevitable for reasons discussed in the French article. We provide comparative data on a similar phenomenon in the United States, including some historical perspectives and recent attempts to minimize geographic variability especially for patients in urgent need of liver transplants. METHODS: To assess regional variability in access to heart, liver, and kidney transplants, a competing risks method was used. Outcomes were examined for primary transplant candidates added to the waiting list during 3-year periods. Results were stratified by region of listing. RESULTS: Four months after listing, the transplant rate for all U.S. kidney transplant candidates was 10.9%. Regionally the 4-month transplant rate ranged from 4.2% to 18.5% for highly sensitized patients and from 5.4% to 19.6% for nonsensitized patients. For liver candidates, the overall national transplant rate 4 months after listing was 22%, but the overall regional rate varied from 11.8% to 36.5%. The overall transplant rate for heart candidates 4 months after listing was 43.9%, whereas regional 30-day transplant rates for the most urgent heart candidates (status 1A) ranged from 25.1% to 47.1%. Four-month transplant rates for less urgent heart candidates ranged from 24.9% to 40.7%. CONCLUSION: Similar to the French experience, pretransplantation waiting times in the 11 U.S. regions vary considerably. Computer-simulated modeling shows that redrawing organ distribution boundaries could reduce but not eliminate geographic variability. It may be too early to tell whether the recently implemented Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease liver allocation system will decrease regional variability in access to transplant as compared with the previous system.