Marty T. Sellers

Mucosal IL-8 and TGF-β recruit blood monocytes: evidence for cross-talk between the lamina propria stroma and myeloid cells

The lamina propria of the gastrointestinal mucosa contains the largest population of mononuclear phagocytes in the body, yet little is known about the cellular mechanisms that regulate mononuclear cell recruitment to noninflamed and inflamed intestinal mucosa. Here, we show that intestinal macrophages do not proliferate. We also show that a substantial proportion of intestinal macrophages express chemokine receptors for interleukin (IL)‐8 and transforming growth factor‐β (TGF‐β), and a smaller proportion expresses receptors for N‐formylmethionyl‐leucyl‐phenylalanine and C5a, but, surprisingly, they do not migrate to the corresponding ligands. In contrast, autologous blood monocytes, which express the same receptors, do migrate to the ligands. Blood monocytes also migrate to conditioned medium (CM) derived from lamina propria extracellular matrix, which we show contains IL‐8 and TGF‐β that are produced by epithelial cells and lamina propria mast cells. This migration is specific to IL‐8 and TGF‐β, as preincubation of the stroma‐CM with antibodies to IL‐8 and TGF‐β significantly blocked monocyte chemotaxis to the stromal products. Together, these findings indicate that blood monocytes are the exclusive source of macrophages in the intestinal mucosa and underscore the central role of newly recruited blood monocytes in maintaining the macrophage population in noninflamed mucosa and in serving as the exclusive source of macrophages in inflamed mucosa.

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.

Molecular Biomarkers for Breast Cancer Prognosis: Coexpression of c-erbB-2 and p53

ObjectiveTo assess the prognostic significance of molecular biomarkers, particularly c-erbB-2 and p53, through study of prospective clinical data and archival breast cancer tissues for women accrued to the Alabama Breast Cancer Project. Summary Background DataDefining molecular abnormalities in breast cancer is an important strategy for early detection, assessment of prognosis, and treatment selection. Evidence is strong that selective biomarkers, including c-erbB-2 and p53, have prognostic significance in breast cancer. Few studies have analyzed the prognostic significance of coexpression of biomarkers. MethodsStudy patients were those accrued to the Alabama Breast Cancer Project (1975–1978) who had archival breast cancer tissues available for analysis. Criteria for entrance into the Alabama Breast Cancer Project were T1–3 breast cancer with M0 status. Age, nodal status, and histologic grade were also documented. Patients were randomized to radical versus modified radical mastectomy, and node-positive patients were also randomized to adjuvant chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]) versus melphalan. Archival breast cancer tissues were studied for c-erbB-2, TGF-&agr;, p53, cathepsin D, bcl-2, and estrogen and progesterone receptor expression using immunohistochemistry. Survival curves were developed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test, multivariate analysis using a rank regression model. ResultsThree hundred eleven patients were accrued to the Alabama Breast Cancer Project, and paraffin-embedded breast cancer tissues for 90 patients were available for immunohistochemical analysis of molecular biomarkers. Univariate analysis showed nodal status, c-erbB-2 expression, and p53 expression to have prognostic significance. Coexpression of c-erbB-2 and p53 was also found to have prognostic significance by the log-rank test. Multivariate analysis showed T stage, nodal status, c-erbB-2 expression, and p53 expression to have independent prognostic significance. ConclusionsThese data suggest that c-erbB-2 and p53 expression in breast cancer have prognostic significance. After median follow-up of 16 years, coexpression of c-erbB-2 and p53 may have more prognostic significance than traditional prognostic factors such as T stage and nodal status. Prospective study of large numbers of patients with breast cancer is encouraged to validate these findings.

Improved outcomes in cadaveric renal allografts with pulsatile preservation

Background: Early immunologic and non‐immunologic injury of renal allografts adversely affects long‐term graft survival. Some degree of preservation injury is inevitable in cadaveric renal transplantation, and, with the reduction in early acute rejection, this non‐immunologic injury has assumed a greater relative importance. Optimal graft preservation will maximize the chances of early graft function and long‐term graft survival, but the best method of preservation – pulsatile perfusion (PP) versus cold storage (CS) – is debated. 
Methods: Primary cadaveric kidney recipients from January 1990 through December 1995 were evaluated. The effects of implantation warm ischemic time (WIT) (≤20 min, 21–40 min, or >40 min) and total ischemic time (TIT) (< or ≥20 h) on death‐censored graft survival were compared between kidneys preserved by PP versus those preserved by CS. The effect of preservation method on delayed graft function (DGF) was also examined. 
Results: There were 568 PP kidneys and 268 CS kidneys. Overall death‐censored graft survival was not significantly different between groups, despite worse donor and recipient characteristics in the PP group. CS kidneys with an implantation WIT >40 min had worse graft survival than those with <40 min (p=0.0004). Survival of PP kidneys and those transplanted into 2 DR‐matched recipients was not affected by longer implantation WIT. Longer TIT did not impact survival. DGF was more likely after CS preservation (20.2% versus 8.8%, p=0.001). 
Conclusions: Preservation with PP improves early graft function and lessens the adverse effect of increased warm ischemia in cadaveric renal transplantation. This method is likely associated with less preservation injury and/or increases the threshold for injury from other sources and is superior to CS.

Tolerance In Renal Transplantation After Allogeneic Bone Marrow Transplantation—6-year Follow-up

Despite significant advancements in clinical transplantation, very few reports describe the long-term acceptance of transplanted solid organs without indefinite immunosuppression. The immunosuppressive agents used are nonspecific and have serious potential side effects. We present a patient who received a living-donor renal allograft from the same person who had donated bone marrow to her several years earlier. Tolerance was expected based on previous acceptance of full-thickness skin grafts from the donor. Indeed, there has been no evidence of rejection during a 6-year follow-up period, and no induction or maintenance immunosuppression has been given. All noninvasive parameters of graft function remain normal. This and similar reports prove that genetically disparate solid organs can coexist without pharmacological immunosuppression.

Use of Preserved Vascular Homografts in Liver Transplantation: Hepatic Artery Aneurysms and Other Complications

Hepatic artery aneurysms/pseudoaneurysms (HAAs) are rare but serious complications after orthotopic liver transplantation (OLT). Revascularization should accompany aneurysmectomy if possible and is more feasible if the aneurysm presents late after transplantation. The optimal conduits for revascularization in this situation are not known. Two patients with hepatic artery aneurysms/pseudoaneurysms who had aneurysmectomy and revascularization with third‐party cadaveric iliac arterial grafts 1 and 4 years after OLT are presented in detail, with an emphasis on the preservation method used for the grafts. Both livers were successfully revascularized with arterial grafts preserved for 21 and 26 days after procurement. Hepatic patency was documented in both 5 and 6 months after repair; graft function has remained normal 13 and 32 months after repair. Third‐party vessels preserved for shorter periods have been used successfully in four other situations, including living‐donor liver transplantation, and are briefly discussed. In conclusion, properly preserved vascular homografts are useful in LT for purposes other than initial vascular reconstruction. They also provide an excellent vascular conduit in recipients of livers from other (possibly living) donors.

The Great Recession and the Importance of Donation After Circulatory Determination of Death (DCDD)

Introduction Review of economic activity trends since 1988 indicates that fluctuations in the economy is associated with an impact on organ donation, specifically a decline in deceased brain dead (DBD) donors. Trending of the Gross Domestic Product (GDP) and changes in the DBD growth rate per million population (pmp) indicates the Great Recession of 2007-2009 with its associated slower recovery rate seems to have had an impact on donation. To ensure continued increases in organ donation, organ procurement organizations must pursue additional sources of deceased organs, e.g. from DCDD donors. Methods Review of changes in the United States GDP growth rate and the corresponding growth rate of national DBD and DCDD donors pmp (per OPTN data) was done to determine if concurrent and subsequent growth rates were correlated with GDP fluctuations during the three recessions since 1988: July 1990-March 1991, March 2001-November 2001, and December 2007-June 2009. Results During and following each of the recessions prior to the “Great Recession” there was a decrease in the growth rate of DBD donors pmp. In the 1990–91 recession there was a -1.0% change in 1991 and -1.5% in 1992 in DBD donors pmp. These deficits were recovered by 1993. In the 2001 recession there was a -0.2% change with deficits recovered in 2002 (Figure 1). Figure. No caption available. The “Great Recession” (Figures 2 and 3) noted by a much longer and slower recovery, resulted in a significant and sustained decrease in DBD donors pmp growth rates. For the years 2007-2009 the decreases were -2%, -3%, and -1.4%, respectively, with no immediate post-recession recovery. In fact, annual deficits continued until 2014, resulting in a cumulative loss between 2007-13 of -10% (Figure 2). Figure. No caption available. In contrast, DCDD pmp growth rates during and following the “Great Recession” remained positive. Overall deceased donors (including DBD and DCDD) pmp growth rates for the years 2007-2009 were -.1%, -2.1% and -.5%, respectively, while DCDD pmp growth rates were 22.1%, 6.3% and 7.4% (Figure 3). Figure. No caption available. Conclusion Economic downturns have a negative association with organ donation. During and following each recession since 1988, DBD donors pmp has decreased. DBD donors pmp decreased during and after the Great Recession of 2007-2009 while DCDD donors pmp increased. Our observations show that steady increases in organs from DCDD donors mitigated the impact of economic fluctuations and should be a strong organ recovery focus. Without the positive DCDD impact, overall deceased organ donation would have more significantly declined during/after the Great Recession, leading to an even worse impact on number of organs transplanted and lives saved. Organ procurement organizations should continuously evaluate new practices to counter unpredictable, inevitable lulls in donation especially in times of economic turndown, as the donation recovery phase could be prolonged.

Success of a “Multicultural Donation Education Program” to Increase African-American Organ Donation in a Donor Service area with a High African-American Population

Introduction Our donor service area (DSA) has a population over 10 million with a greater than two-fold proportion of African-Americans (AA) compared to the rest of the United States (31% vs. 13%). It was apparent in the 1990s that transplant programs in our DSA had an even higher disproportionate number of AA on organ waiting lists; in contrast, we had a disproportionately low number of AA donors. Efforts to decrease this disparity were desperately needed. We aimed to address this by the creation of a “Multicultural Donation Education Program” (MDEP) in 1994. We report the success of this ongoing program. Methods MDEP began in 1994; quality improvement was driven by frequent evaluations based on donation data and stakeholder feedback; it evolved and refocused accordingly. Various staffing and general public educational practices were implemented over 4 time periods – e.g., racial sensitivity training, “like-race” donation requestors, focused media campaigns and public service announcements on public transit and in predominately AA churches, businesses, schools/colleges, professional associations, and communities; increased emphasis during Black History Month; AA transplant recipient participation in outreach. A detailed timeline is shown in Figure 1. Donor demographics over these periods were recorded in a prospective database and compared to national (OPTN) data. Additionally, in the 4th time period (2013-16) a survey inside and in multiple states outside our DSA was performed to see if there was increased willingness to be an organ donor among AA in our DSA. Results The AA population in our DSA increased during the study period from 27% to 31%; the proportion of AA donors increased from 21% to 33% (15/70 vs. 102/306). Our proportion of AA donors has exceeded that in our general population for the past decade, during which we have had at least 19% more AA donors than any other DSA in the United States (Fig 2). By comparison, the proportion of AA in the general/donor populations nationally have remained stable (Fig 3). Additionally, our survey data (n=126) showed willingness to donate among AA in our DSA to be significantly higher than among AA outside our DSA (74.8% vs. 52.2%, p=0.025). One strategy we evolved away from was “like-race” donation requestors, as this was noted to not impact AA donation. We feel the improvement in AA donation rates and increased willingness to donate among AA in our DSA are directly attributable to the MDEP, its periodic evaluations and resultant changes in strategies and outreach efforts. Figure. No caption available. Figure. No caption available. Figure. No caption available. Conclusion The development, implementation, and ongoing refinement of a dedicated, racially sensitive program (MDEP) has led to a significant and sustained increase in AA donation in our DSA compared to the US. Our experience supports similar initiatives in other DSAs, particularly those with a greater than average minority population, to increase minority donation nationally.

Outcomes from Livers Transplanted from Deceased Donors with End-Stage Renal Disease

Introduction Decedents with end-stage renal disease (ESRD) have comorbidities that also impact the quality of extra-renal, especially thoracic, organs. Livers, however, are less susceptible to ESRD-associated damage, yet many organ procurement organizations (OPOs) in the United States have not pursued such donors because of financial and regulatory disincentives. Because of the high liver waitlist mortality, however, all usable livers should be transplanted. No data are published on the outcomes of livers transplanted from deceased donors with ESRD; if outcomes are acceptable, financial disincentives must be addressed. We describe the outcomes of livers retrieved from donors with ESRD in a single OPO. Methods Donors (n=47) with ESRD who donated livers from January 2010-May 2017 were identified in a prospective database; relevant variables were extracted into a separate database analyzed with Stata. Our primary aim was to determine graft and patient survival; these data were obtained from TEIDI and from the transplant centers. Results 47 livers were retrieved and transplanted from ESRD donors. Mean time on dialysis was 3.3 years (range 1 month to 13 years). Causes of death included CVA (n=24), anoxia (n=19), trauma (n=3), other (n=1). Two recipients died within 30 days (hemorrhage, day 19; multisystem organ failure, day 23); one patient was retransplanted on day 14 (unknown cause of graft loss). All other patients (95.8%) and grafts (93.6%) survived more than 30 days (Figure 1). Interestingly, livers exported out of our service area (n=14) had significantly better survival than those transplanted locally (Figure 2). No other variable analyzed impacted graft survival. Ischemic times ranged from 2.2 to 10. 6 (mean = 6.0) hours were similar between exported and locally transplanted livers – mean = 6.4 and 5.9 hours, respectively, p=0.813. Figure. No caption available. Figure. No caption available. Conclusions Livers from donors with ESRD can be transplanted with excellent outcomes, especially in circumstances where short ischemic times can be achieved. Given the high liver waitlist mortality worldwide, these donors should be aggressively pursued. Financial and regulatory disincentives must be eliminated in order to increase the number of livers retrieved and transplanted.

A Systems-Based Approach to Increasing Organs Transplanted: One Organ Procurement Organization’s experience

Introduction As everywhere, our donor service area does not have enough organ donors to supply the need of those on the waitlist. Moreover, our population is older on average than the rest of the United States, with an inherent increase in eligible donor co-morbidities and decrease in organ quality. Enhanced efforts to improve organ donation are necessary to offset these disadvantages. Therefore, we critically reviewed our processes and made several strategic, system-based changes in our response and philosophy to potential donor referrals. We report herein the improvements seen over the 5 years since implementation. Methods A critical review of our processes for referral response, donor management, staff development/education, and hospital outreach was performed in 2012. Responses to referrals were changed and driven by protocol-based algorithms. Hospital development included focused education on clinical triggers and increasing awareness of the potential for donation after circulatory determination of death (DCDD). Active cancer became our only reason for not sending staff for an onsite evaluation, regardless of patient neurologic status. A multitude of group communication pathways were developed to provide platforms for multidisciplinary discussions related to referral evaluation and triage including two Administrator on call evaluations prior to a DCDD rule out and a daily multidisciplinary staff call at 6:45 a.m. The system-based approach continues to evolve according to quality improvement evaluations based on donation data and hospital feedback. Our donation service area (DSA) organ donation and transplantation data were maintained in a prospective database and compared to US (OPTN) data. Results From 2012-2016 we experienced a 16% increase in total death referrals (18956 to 22002) and a 51% increase in potential organ donor referrals (2513 to 3796). This led to a 36% increase in organ donors (169 to 230; Figure 1) and a 32% increase in organs transplanted (499 to 661) in our OPO, greater than the 22% and 24.5% increase in US donors (8143 to 9971) organs transplanted (22187 to 27630), respectively. We are currently recovering at a rate of 41.81 donors per million population (230/5.5M). Additionally, expanded criteria donors (ECD) have increased from 23.7% of organ donors to 26.1%. We attribute this increase in growth to the review and changes initiated beginning in 2012. Our systems-based approach has been associated with significantly more donors and organs transplanted. Conclusion Key system improvements, which focus on staff engagement, defined protocols for referral evaluation and management and proactive attitudes and relationships with key stakeholders, have resulted in significant success in an OPO DSA with an increase in organ referrals, organ donors and organs transplanted, well above the national rates. Figure. No caption available.