Tumor: Stroma Interaction and Cancer.

The understanding of how normal cells transform into tumor cells and progress to invasive cancer and metastases continues to evolve. The tumor mass is comprised of a heterogeneous population of cells that include recruited host immune cells, stromal cells, matrix components, and endothelial cells. This tumor microenvironment plays a fundamental role in the acquisition of hallmark traits, and has been the intense focus of current research. A key regulatory mechanism triggered by these tumor-stroma interactions includes processes that resemble epithelial-mesenchymal transition, a physiologic program that allows a polarized epithelial cell to undergo biochemical and cellular changes and adopt mesenchymal cell characteristics. These cellular adaptations facilitate enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components. Indeed, it has been postulated that cancer cells undergo epithelial-mesenchymal transition to invade and metastasize.In the following discussion, the physiology of chronic inflammation, wound healing, fibrosis, and tumor invasion will be explored. The key regulatory cytokines, transforming growth factor ß and osteopontin, and their roles in cancer metastasis will be highlighted.

Should donors who have used marijuana be considered candidates for living kidney donation?

BACKGROUND: The use of marijuana in the USA has been steadily increasing over the last 10 years. This study is the first to investigate the effect of marijuana use by live kidney donors upon outcomes in both donors and recipients. METHODS: Living kidney donor transplants performed between January 2000 and May 2016 in a single academic institution were retrospectively reviewed. Donor and recipient groups were each divided into two groups by donor marijuana usage. Outcomes in donor and recipient groups were compared using t-test, Chi-square and mixed linear analysis (P < 0.05 considered significant). RESULTS: This was 294 living renal donor medical records were reviewed including 31 marijuana-using donors (MUD) and 263 non-MUDs (NMUD). It was 230 living kidney recipient records were reviewed including 27 marijuana kidney recipients (MKRs) and 203 non-MKRs (NMKR). There was no difference in donor or recipient perioperative characteristics or postoperative outcomes based upon donor marijuana use (P > 0.05 for all comparisons). There was no difference in renal function between NMUD and MUD groups and no long-term difference in kidney allograft function between NMKR and MKR groups. CONCLUSIONS: Considering individuals with a history of marijuana use for living kidney donation could increase the donor pool and yield acceptable outcomes.

Transplantation of hepatitis C virus (HCV) antibody positive, nucleic acid test negative donor kidneys to HCV negative patients frequently results in seroconversion but not HCV viremia.

Anecdotal reports have suggested that transplantation of hepatitis C virus (HCV) antibody positive (Ab+)/nucleic acid test negative (NAT-) donor kidneys into HCV negative recipients is not associated with HCV transmission. We reviewed our center's outcomes of 32 HCV negative patients who received kidney allografts from 25 donors who were HCV Ab+/NAT-. The mean recipient age was 56.9 ± 12.1 years and the mean donor age was 41.5 ± 14 years, with a median Kidney Donor Profile Index (KDPI) of 68%. Twelve donors (48%) met Public Health Service (PHS) increased risk status. All patients received antithymocyte globulin induction followed by tacrolimus, mycophenolate mofetil, and steroid maintenance immunosuppression. With a mean follow-up posttransplant of 10 ± 2.7 months, 1- and 3- month serum creatinine levels were 1.7 ± 0.8 and 1.3 ± 0.4, respectively, and patient and graft survival rates were 100% and 97%, respectively. Fourteen patients (44%) seroconverted and became HCV Ab+ posttransplant. However, all 32 patients were HCV RNA negative at 1- and 3- months posttransplant, and 27 and 8 patients tested at 6- and 12-months posttransplant, respectively, remain HCV RNA negative. In conclusion, transplantation of HCV Ab+/NAT- kidneys to HCV negative recipients frequently causes HCV Ab seroconversion but not HCV viremia.

Improving the efficiency of breast radiotherapy treatment planning using a semi-automated approach.

OBJECTIVES: To reduce treatment planning times while maintaining plan quality through the introduction of semi-automated planning techniques for breast radiotherapy. METHODS: Automatic critical structure delineation was examined using the Smart Probabilistic Image Contouring Engine (SPICE) commercial autosegmentation software (Philips Radiation Oncology Systems, Fitchburg, WI) for a cohort of ten patients. Semiautomated planning was investigated by employing scripting in the treatment planning system to automate segment creation for breast step-and-shoot planning and create objectives for segment weight optimization; considerations were made for three different multileaf collimator (MLC) configurations. Forty patients were retrospectively planned using the script and a planning time comparison performed. RESULTS: The SPICE heart and lung outlines agreed closely with clinician-defined outlines (median Dice Similarity Coefficient > 0.9); median difference in mean heart dose was 0.0 cGy (range -10.8 to 5.4 cGy). Scripted treatment plans demonstrated equivalence with their clinical counterparts. No statistically significant differences were found for target parameters. Minimal ipsilateral lung dose increases were also observed. Statistically significant (P < 0.01) time reductions were achievable for MLCi and Agility MLC (Elekta Ltd, Crawley, UK) plans (median 4.9 and 5.9 min, respectively). CONCLUSIONS: The use of commercial autosegmentation software enables breast plan adjustment based on doses to organs at risk. Semi-automated techniques for breast radiotherapy planning offer modest reductions in planning times. However, in the context of a typical department's breast radiotherapy workload, minor savings per plan translate into greater efficiencies overall.

Alcohol inhibits osteopontin-dependent transforming growth factor-ß1 expression in human mesenchymal stem cells.

Alcohol (EtOH) intoxication is a risk factor for increased morbidity and mortality with traumatic injuries, in part through inhibition of bone fracture healing. Animal models have shown that EtOH decreases fracture callus volume, diameter, and biomechanical strength. Transforming growth factor ß1 (TGF-ß1) and osteopontin (OPN) play important roles in bone remodeling and fracture healing. Mesenchymal stem cells (MSC) reside in bone and are recruited to fracture sites for the healing process. Resident MSC are critical for fracture healing and function as a source of TGF-ß1 induced by local OPN, which acts through the transcription factor myeloid zinc finger 1 (MZF1). The molecular mechanisms responsible for the effect of EtOH on fracture healing are still incompletely understood, and this study investigated the role of EtOH in affecting OPN-dependent TGF-ß1 expression in MSC. We have demonstrated that EtOH inhibits OPN-induced TGF-ß1 protein expression, decreases MZF1-dependent TGF-ß1 transcription and MZF1 transcription, and blocks OPN-induced MZF1 phosphorylation. We also found that PKA signaling enhances OPN-induced TGF-ß1 expression. Last, we showed that EtOH exposure reduces the TGF-ß1 protein levels in mouse fracture callus. We conclude that EtOH acts in a novel mechanism by interfering directly with the OPN-MZF1-TGF-ß1 signaling pathway in MSC.

Doing well by doing good: linking access with quality.

BACKGROUND: We hypothesize that medical centers that prioritize altruism can also deliver superior quality care. METHODS: Data were obtained from California's Office of Statewide Health Planning and Development, Medicare Hospital Compare, and the Joint Commission US Census Bureau's American Community Survey. Outcomes were measured using summary statistics, regression analysis, and quality indices. Total discounted revenue/total revenue (TDR/TR) served as a proxy for altruistic care. RESULTS: In nonprofit hospitals, TDR/TR positively correlated with 5 quality indices including pneumonia (P < .001), heart failure (P = .05), and overall surgical process of care (P = .009). Hospital size predicted higher quality surgical process (P = .06, 201 to 300 beds; P = .01, >301 beds), hospital teaching status demonstrated positive correlation (ß = .048, P = .69), and poverty was negatively correlated (ß = -.00072, P = .89). Positive TDR/TR did not adversely affect mortality or readmission rates (P = .52). CONCLUSIONS: TDR/TR predicts quality in nonprofit hospitals without increasing mortality and readmission. Altruistic motivation may be associated with the delivery of higher quality surgical care.

Engagement, workplace satisfaction, and retention of surgical specialists in academic medicine in the United States.

BACKGROUND: Academic medical centers strive for clinical excellence with operational efficiency and financial solvency, which requires institutions to retain productive and skillful surgical specialists. Faculty workplace perceptions, overall satisfaction, and intent to leave are relationships that have not been examined previously among US surgeons in academic medicine. We hypothesize that critical factors related to workplace satisfaction and engagement could be identified as important for enhancing institutional retention of academic surgeons. STUDY DESIGN: The 2011-2012 Association of American Medical Colleges Faculty Forward Engagement Survey evaluated demographic variables, physician workplace satisfaction, and overall engagement among faculty subgroups, including comparison of surgical and nonsurgical clinicians. Multiple regression analysis (ß = standard regression coefficient) was performed to identify critical factors most closely related to surgeon satisfaction and intent to leave their institutions. RESULTS: A total of 1,356 of 1,949 (70%) surgeons from 14 medical schools responded across different faculty subgroups, and comparisons were made with 1,105 nonsurgical clinicians. Multiple regression indicated that the strongest predictors of surgeons' overall satisfaction with their department included department governance (ß = 0.36; p < 0.001), collegiality and collaboration (ß = 0.23; p < 0.001), and relationship with supervisor (ß = 0.17; p < 0.001). Although compensation and benefits were important (ß = 0.08; p < 0.001), these did not rank as the most important factors. Promotion equality (odds ratio = 0.62; p < 0.05), collegiality and collaboration (odds ratio = 0 .51; p < 0.05), and nature of their work (odds ratio = 0.52; p < 0.05) were most closely related to intent to leave the medical school within 1 to 2 years. CONCLUSIONS: In the largest survey focusing on workplace factors affecting surgical faculty satisfaction and intent to leave, we conclude that institutional understanding of, and improvement in, specific work environment factors can enhance recruitment and retention of academic surgeons.

Correction of Diabetic Hyperglycemia and Amelioration of Metabolic Anomalies by Minicircle DNA Mediated Glucose-Dependent Hepatic Insulin Production.

Type 1 diabetes mellitus (T1DM) is caused by immune destruction of insulin-producing pancreatic ß-cells. Commonly used insulin injection therapy does not provide a dynamic blood glucose control to prevent long-term systemic T1DM-associated damages. Donor shortage and the limited long-term success of islet transplants have stimulated the development of novel therapies for T1DM. Gene therapy-based glucose-regulated hepatic insulin production is a promising strategy to treat T1DM. We have developed gene constructs which cause glucose-concentration-dependent human insulin production in liver cells. A novel set of human insulin expression constructs containing a combination of elements to improve gene transcription, mRNA processing, and translation efficiency were generated as minicircle DNA preparations that lack bacterial and viral DNA. Hepatocytes transduced with the new constructs, ex vivo, produced large amounts of glucose-inducible human insulin. In vivo, insulin minicircle DNA (TA1m) treated streptozotocin (STZ)-diabetic rats demonstrated euglycemia when fasted or fed, ad libitum. Weight loss due to uncontrolled hyperglycemia was reversed in insulin gene treated diabetic rats to normal rate of weight gain, lasting ∼1 month. Intraperitoneal glucose tolerance test (IPGT) demonstrated in vivo glucose-responsive changes in insulin levels to correct hyperglycemia within 45 minutes. A single TA1m treatment raised serum albumin levels in diabetic rats to normal and significantly reduced hypertriglyceridemia and hypercholesterolemia. Elevated serum levels of aspartate transaminase, alanine aminotransferase, and alkaline phosphatase were restored to normal or greatly reduced in treated rats, indicating normalization of liver function. Non-viral insulin minicircle DNA-based TA1m mediated glucose-dependent insulin production in liver may represent a safe and promising approach to treat T1DM.

An MAPK-dependent pathway induces epithelial-mesenchymal transition via Twist activation in human breast cancer cell lines.

BACKGROUND: Twist is an epithelial-mesenchymal transition (EMT) transcription factor that instigates cell invasion. Our research has shown that osteopontin (OPN) regulates the EMT factor Twist. The underlying signaling pathway is unknown. We hypothesized that OPN activates Twist to induce EMT in human breast cancer. METHODS: Potential kinases for Twist were identified using NetPhosK. Inhibitors of MEK1/2, JNK, p38 MAPK, and PI3K were applied to human breast cancer cells MDA-MB231 (OPN high). After 24 h, Twist was immunoprecipitated and incubated with phosphoserine. Expression of the Twist target protein, Bmi-1, was determined following 24-h osteopontin aptamer (APT) treatment; mutant aptamer (MuAPT) was used as the control. Scratch-wound assay was imaged 12, 24, and 48 h after APT and MuAPT treatment. RESULTS: MEK1/2 inhibition caused ≈ twofold decrease in Twist serine phosphorylation (P < .05). APT blockade of OPN in MB231 decreased Bmi1 protein twofold (P < .05). Aptamer-treated cells were significantly decreased in cell migration and wound closure in the scratch wound-assay (P < .001). CONCLUSION: We demonstrate that OPN extracellular binding to MB231 activates an autocrine MAPK intracellular signaling pathway resulting in Twist activation and promoting Bmi1 expression to further EMT initiation and cellular migration. Our results elucidate a previously undescribed role for OPN as a prime regulator of EMT in human breast cancer cells.

Obesity and trends in malpractice claims for physicians and surgeons.

BACKGROUND: The increasing prevalence of obesity has altered the practice of medicine and surgery, with the emergence of new operations and medications. We hypothesized that the landscape of medical malpractice claims has also changed. METHODS: We queried the Physician Insurers Association of American database for 1990 through 1999 and 2000 through 2009 for cases corresponding to International Classification of Diseases, 9th edition, codes for obesity. We extracted adjudicatory outcome, closed and paid claims data, indemnity payments, primary alleged error codes, National Association of Insurance Commissioners severity of injury class, procedural codes, and medical specialty data. RESULTS: A total of 411 obesity claims were filed from 1990 to 1999 and 1,591 obesity claims were filed from 2000 to 2009. General surgery was the specialty with the greatest number of obesity claims from 1990 to 1999 and was second to family practice for 2000 to 2009. Although the percentage of paid general surgery obesity claims has decreased significantly from 69% in 1990-1999 to 36% in 2000-2009, the mean indemnity payments have increased substantially ($94,000 to $368,000). CONCLUSION: Recently, the percentage of paid general surgery obesity claims has significantly decreased; however, individual and total indemnity payments have increased. Obesity continues to impact general surgery malpractice substantially. Efforts to manage this component of physician and hospital practices must continue.

Osteopontin up-regulates critical epithelial-mesenchymal transition transcription factors to induce an aggressive breast cancer phenotype.

BACKGROUND: Tumor cells undergoing epithelial-mesenchymal transition (EMT) develop cellular properties leading to stroma invasion and intravasation. We have previously shown in a xenograft breast cancer model that blocking osteopontin (OPN), a secreted phosphoprotein, decreases EMT. This study examines OPN's role in EMT initiation through its regulation of EMT transcription factors (TFs) Snail, Slug, and Twist. OPN's role in Twist activation is examined through immunoprecipitation and Western blot. STUDY DESIGN: MDA-MB-231 breast cancer cells secreting high levels of OPN were treated with OPN aptamer (APT) or mutant APT. Osteopontin APT binds to and inhibits extracellular OPN. Low-OPN-secreting breast cancer cells, MCF-7, were treated with OPN, OPN+APT, or OPN+mutant APT. Twist was isolated in MDA-MB-231 with immunoprecipitation. Phospho-serine antibody detected activated Twist in Western blot. Activation of Twist was confirmed by chromatin immunoprecipitation. RESULTS: Analysis through quantitative polymerase chain reaction demonstrated APT inhibition of OPN in MDA-MB-231 cells caused a decrease in EMT-TF expression (MDA-MB-231 vs MDA-MB-231+APT: *Twist ΔΔCT: 1.0 vs 0.07; *Snail ΔΔCT: 1.0 vs 0.11; *Slug ΔΔCT: 1.0 vs 0.11; *p < 0.001). Mutant APT did not change EMT-TF expression (NS). Treatment of MCF-7 cells with OPN caused an increase in EMT-TF expression (MCF-7 vs MCF-7+OPN: Twist ΔΔCT: 1.0 vs 9.1; *Snail ΔΔCT: 1.0 vs 11.2; *Slug ΔΔCT: 1.0 vs 10.9; *p < 0.001). The EMT-TF expression in MCF-7 treated with OPN+APT did not differ significantly from MCF-7 alone. Phosphorylated Twist protein was reduced 2-fold with APT in MDA-MB-231 compared with MDA-MB-231 and MDA-MB-231+mutant APT. Twist phorphorylation induced binding to the promoter regions of Twist-regulated gene, B lymphoma Mo-MLV insertion region 1 homolog, a critical protein for EMT progression. CONCLUSIONS: This study shows that OPN is critical in EMT initiation through activation of Twist via serine phosphorylation. These unique observations indicate that OPN APT can serve a clinical role as a novel therapeutic agent by diminishing breast cancer oncogenesis.

Comparing 20 years of national general surgery malpractice claims data: obesity versus morbid obesity.

BACKGROUND: We hypothesized that the increasing body mass index of the population has affected general surgery malpractice claims. METHODS: We queried the Physician Insurers Association of America database from 1990 to 1999 (ie, period 1) and 2000 to 2009 (ie, period 2) for claims associated with obesity and morbid obesity. We analyzed the error involved, injury severity, procedure, and outcome. RESULTS: Five hundred seventy-five claims were identified. The percentage of paid claims did not differ by body mass index. Improper performance was the most common alleged error, gastric bypass was the most common procedure, and death was the most common injury. For obesity claims, the case was more likely to be settled in period 1 and withdrawn/dismissed in period 2 (P < .001). The number of morbid obesity claims rose from 9 in period 1 to 249 in period 2. CONCLUSIONS: The significant rise in morbid obesity claims between periods is likely caused by the substantial increase in the number of bariatric procedures performed.

Impact of business infrastructure on financial metrics in departments of surgery.

BACKGROUND: In the current environment, pressure is ever increasing to maximize financial performance in surgery departments. Factors such as physician extenders, billing and collection, payor mix, contracting, incentives from the Centers for Medicare and Medicaid Services, and administrative incentives may greatly influence financial performance. However, despite a plethora of information from the University HealthSystem Consortium and the Association of American Medical Colleges, best-practice information for business infrastructure is lacking. To obtain a sampling of current practices, we conducted a survey of departments of surgery. METHODS: An anonymous 30-question survey addressing demographics, productivity, revenue and expense profile, payor mix, physician extender and staff personnel, billing and collections methodology, and financial performance was distributed among members of the Society of Surgical Chairs via SurveyMonkey. This was approved by the Loyola Institutional Research Board. Multivariate linear regression analyses and t tests/rank-sum tests were performed, as appropriate. Data are presented as mean ± SEM. RESULTS: A total of 25 (19%) departments responded; 14 were integrated with the hospital/health system, and 11 were integrated with the medical school. In 60% (n = 15), the main hospital had 500 to 1,000 beds; 48% (n = 12) had >4 hospitals in their system. For FY10, MD clinical full-time equivalents (FTEs) were 49 ± 10; total work relative value units (wRVUs) were 320 ± 8 k; and total billed cases were 43 ± 16 k. A total of 23 of 25 used physician-extenders with an average of 18 ± 5 per department and in 22 of 23, the physician extenders billed. On average, there were 18 ± 6 clinical-support staff, 25 ± 11 front-office staff, and 13 ± 3 back-office support staff FTEs. Among these FTEs, there were 16 ± 5 devoted to business operations (billing, coding, denial/claims management, financial oversight). Collections/wRVUs were $60 ± 3 (range, 39-80). Regression modeling demonstrated that total wRVUs were determined by the number of MD FTEs (P = .01), number of physician extenders (P = .01), number of front-office staff (P = .01), number of back-office staff (P = .02), and number of total business staff (P = .01). Collections/wRVUs were predicted by number of hospitals (P = .04), number of MD FTEs (P = .03), number of physician extenders (P = .01), and number of cases/total business staff (P = .02). Interestingly, wRVUs/MD was predicted by number of MD FTEs (P = .01) but were not greatly impacted by numbers of clinical or business support staff. In 4 of 25, the billing and coding staff were incentivized and had a Collections/wRVU = 64 ± 5 whereas nonincentivized staff had collections/wRVU = 59 ± 3. (P = NS) Also, %Accounts receivable >90 days (15% vs 25%) were not substantially different. Only 48% (12/25) have departments have recouped Centers for Medicare and Medicaid dollars for Physician Quality Reporting Initiative, Meaningful Use, Patient-Centered Medical Homes, or other Accountable Care-like programs. One-half (13) of the departments had both an inpatient and outpatient electronic medical record. Finally, on a scale of 1-10 (10 = highest), the average level of satisfaction with billing and collections processes was 6. CONCLUSION: Our results indicate that the physician extender, clinical support staff, and business staff environment can impact surgeon productivity, and there is opportunity for improvement. Determining best practices for ratios of support staff/MD and optimizing the role of electronic medical record in workflow and billing/collections are critical in the current environment. Our pilot study requires extension across more institutions for validation.

Epithelial-mesenchymal transition, TGF-ß, and osteopontin in wound healing and tissue remodeling after injury.

Epithelial-mesenchymal transition (EMT) is a process essential to wound healing and tissue remodeling after a thermal burn or other injury. EMT is characterized by phenotypic changes in epithelial cells that render them apolar, with decreased cell-cell adhesions, increased motility, and changes in cytoskeletal architecture similar to mesenchymal stem cells. With regard to healing a thermal burn wound, many facets of wound healing necessitate cells to undergo these phenotypic changes; two will be described in the following review. The first is the differentiation of epithelial cells into myofibroblasts that rebuild the extracellular matrix and facilitate wound contraction. The second is reepithelialization by keratinocytes. The primary cytokine signal identified in the literature that triggers EMT is transforming growth factor (TGF)-ß. In addition to its vital role in the induction of EMT, TGF-ß has many other roles in the wound healing process. The following review will provide evidence that EMT is a central event in wound healing. It will also show the importance of a regulated amount of TGF-ß for proper wound healing. Finally, osteopontin will be briefly discussed with its relation to wound healing and its connections to EMT and TGF-ß.

Intersecting pathways in inflammation and cancer: Hepatocellular carcinoma as a paradigm.

Viral infection and chemical carcinogens trigger somatic changes resulting in activation of oncogenes during tumor initiation in the development of cancer. However, a critical interaction resides in the synergism between these somatic changes and an inflamed tumor microenvironment where myeloid and hematopoietic cells are subverted to enhance tumor progression. The causative molecular mechanisms leading to the development of hepatocellular cancer remain incompletely understood but appear to result from multiple factors related to direct hepatocyte injury and the ensuing inflammatory changes mediated by the host response to tissue injury, DNA damage, repair of cellular damage, and chronic, repetitive injury. In this review, the molecular and cellular changes that regulate inflammation and tissue repair will be compared to the activated local tumor microenvironment. Cell-cell signaling within this microenvironment that enhances tumor progression and inhibits anti-tumor immunity will be discussed.

Donation after cardiac death: a 29-year experience.

OBJECTIVE: To report the long-term outcomes of 1218 organs transplanted from donation after cardiac death (DCD) donors from January 1980 through December 2008. METHODS: One-thousand two-hundred-eighteen organs were transplanted into 1137 recipients from 577 DCD donors. This includes 1038 kidneys (RTX), 87 livers (LTX), 72 pancreas (PTX), and 21 DCD lungs. The outcomes were compared with 3470 RTX, 1157 LTX, 903 PTX, and 409 lung transplants from donors after brain death (DBD). RESULTS: Both patient and graft survival is comparable between DBD and DCD transplant recipients for kidney, pancreas, and lung after 1, 3, and 10 years. Our findings reveal a significant difference for patient and graft survival of DCD livers at each of these time points. In contrast to the overall kidney transplant experience, the most recent 16-year period (n = 396 DCD and 1,937 DBD) revealed no difference in patient and graft survival, rejection rates, or surgical complications but delayed graft function was higher (44.7% vs 22.0%; P < .001). In DCD LTX, biliary complications (51% vs 33.4%; P < .01) and retransplantation for ischemic cholangiopathy (13.9% vs 0.2%; P < .01) were increased. PTX recipients had no difference in surgical complications, rejection, and hemoglobin A1c levels. Surgical complications were equivalent between DCD and DBD lung recipients. CONCLUSION: This series represents the largest single center experience with more than 1000 DCD transplants and given the critical demand for organs, demonstrates successful kidney, pancreas, liver, and lung allografts from DCD donors.

Luminex-based desensitization protocols: the University of Wisconsin initial experience.

BACKGROUND: We have demonstrated that immunodominant donor-specific antibody (DSA) more than 100 mean fluorescence intensity (MFI) at the time of transplant is associated with a significantly higher risk of rejection. We now present short-term outcomes of DSA-based desensitization (DSZ) strategies in patients with a negative complement-dependent cytotoxicity crossmatch. METHODS: Between January 1, 2009, and January 1, 2010, live-donor kidney transplant recipients were divided into three protocols based on their immunodominant DSA MFI pretransplant (D1: 100-500, D2: 501-1000, and D3: 1001-3000). Deceased donor kidney transplant recipients were stratified into two protocols (D4: 501-1000 and D5: 1001-3000). The intensity of the conditioning treatment increased with DSA levels and included thymoglobulin induction, plasmapheresis, and intravenous immunoglobulin in the highest risk groups. We compared outcomes between desensitized patients (DSZ) and those undergoing no DSZ (or D0) during the same interval. RESULTS: Forty-eight of 249 (23%) kidney transplants underwent DSZ (n=20, 4, 3, 4, and 17 in D1-D5 protocols, respectively). There was more retransplantation (50% vs. 18%, P<0.001) and live donor transplantation (56% vs. 30%, P<0.001) in the DSZ group. In this group, mean peak panel reactive antibody and MFI at transplant were 51% ± 7% and 960 ± 136, respectively. The incidence of antibody-mediated rejection (25% vs. 12.5%, P=0.008) and acute cellular rejection (23% vs. 14%, P=0.02) was greater in the DSZ group. However, mixed rejection (8%), graft loss (0 vs. 6), patient death (0 vs. 3), cytomegalovirus infection (15% vs. 12%), and 1-year serum creatinine (1.4 ± 0.5 and 1.4 ± 0.4 mg/dL) were similar between DSZ and no-DSZ groups. CONCLUSION.: Long-term follow-up is needed to determine the role of Luminex-based strategies in current preconditioning regimens.

Long-term outcomes after simultaneous pancreas-kidney transplant.

PURPOSE OF REVIEW: Simultaneous pancreas-kidney (SPK) transplantation represents the only proven long-term therapeutic approach for type 1 diabetic, dialysis-dependent patients. This procedure potentially liberates these patients from dialysis and the need for exogenous insulin replacement. For the first time, data on the long-term natural history of patients receiving SPK have recently been analyzed. In this review, we discuss the outcomes and complications for patients receiving SPK in the context of the current literature. RECENT FINDINGS: In our analysis of 1000 SPKs performed at our center, we demonstrated that SPK increases patient survival compared with live-donor kidney alone or deceased donor kidney alone transplantation. The 5-year, 10-year, and 20-year patient survival for SPK recipients was 89, 80, and 58%, respectively. Enteric drainage improves quality of life, but not allograft survival, when compared with bladder drainage. After transplantation, approximately 50% of bladder-drained transplants undergo enteric conversion and late conversion after transplantation is associated with a higher complication rate. Surgical complications are higher in enteric-drained compared with bladder-drained pancreas transplants. SUMMARY: Selecting the appropriate therapy for a type 1 diabetic recipient with renal failure continues to be a critical decision for programs offering pancreas transplantation. The principles and guidelines at our center are driven by the potential benefit of the SPK transplant needing to outweigh the increased morbidity of the surgical procedure and the use of lifelong immunosuppression. Results from long-term studies demonstrating improved patient survival suggest that the treatment of choice for an appropriate type 1 diabetic recipient is an SPK transplant.